M Sentis

LP3 J Herman S Noel L Mercadier A Kabashin

P Blandin

CiNAM W Marine

LHuC T Itina

INRS (Canada) JC Kieffer and co-authors

INFLPR (Roumanie) I Mihalescu M Dinescu

Et beaucoup drsquoautres

Aix-Marseille University CNRS LP3 UMR 7341 13288 Marseille

France

Plasmas-Laser et applications

vers le biomeacutedical

Summary

Few words on pulsed laser matter interaction

Laser Plasma produced at moderate intensity

bull Bio thin films produced by PLD

bull Nanoclusters for imaging and therapy

bull LIBS for biomedical applications

Laser Plasma X-ray source

bull Phase contrast imaging

Laser Plasma Proton source

bullProton therapy

bullIsotopes for TEP

~1010

Wcm2

~1022

Wcm2

NGC 2009

Parameters of laser matter interaction

laser beam

wavelength

intensity pulse duration τL

beam quality time and spatial fluctuations

Important issues

dynamic processes

non-equilibrium phase

transformations liquid phase surface tension viscosity vapor phase vapor density electron density temperature gradient plasma absorption scattering

LT

LT ~ (D τL)12 thermal diffusion length (τLgt 1ps)

material parameters absorption coefficient α heat conductivity D heat capacity heat of melting heat of evaporation roughness

ambient environment

Air inert or reactive gas

liquid

Lα = α-1 optical penetration depth

Laser

Lα

Les reacutegimes drsquointeraction laser-matiegravere

Production de

proton

1022 Wcm2 103 Wcm2

Diffusion

X-ray

emission

laser

Production X

I = E(S x t)

E = energie

t= dureacutee de lrsquoimpulsion

S = tache focale

Ablation

S

1 fs = 10-15s - 1 ps = 10-12s

Focalisation sur des tregraves petites dimensions (surface min ~ sup2)

rarr Conseacutequence de cette concentration dans lrsquoespace

Densiteacutes de Puissance eacutenormes

Ordre de grandeur laser 10 W agrave λ = 500 nm (vert)

densiteacute de puissance max au waist (=Puissancesurface) =

10(0510-6)sup2 = 4 GWcm2

Lentille focale f

Diamegravetre D

Diamegravetre au waist (=col

en franccedilais)

Φasymp λ f πD Ordre de grandeur si f ~ D rarr Φ ~ λ

Proprieacuteteacute de focalisation de lrsquoeacutemission LASER

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Summary

Few words on pulsed laser matter interaction

Laser Plasma produced at moderate intensity

bull Bio thin films produced by PLD

bull Nanoclusters for imaging and therapy

bull LIBS for biomedical applications

Laser Plasma X-ray source

bull Phase contrast imaging

Laser Plasma Proton source

bullProton therapy

bullIsotopes for TEP

~1010

Wcm2

~1022

Wcm2

NGC 2009

Parameters of laser matter interaction

laser beam

wavelength

intensity pulse duration τL

beam quality time and spatial fluctuations

Important issues

dynamic processes

non-equilibrium phase

transformations liquid phase surface tension viscosity vapor phase vapor density electron density temperature gradient plasma absorption scattering

LT

LT ~ (D τL)12 thermal diffusion length (τLgt 1ps)

material parameters absorption coefficient α heat conductivity D heat capacity heat of melting heat of evaporation roughness

ambient environment

Air inert or reactive gas

liquid

Lα = α-1 optical penetration depth

Laser

Lα

Les reacutegimes drsquointeraction laser-matiegravere

Production de

proton

1022 Wcm2 103 Wcm2

Diffusion

X-ray

emission

laser

Production X

I = E(S x t)

E = energie

t= dureacutee de lrsquoimpulsion

S = tache focale

Ablation

S

1 fs = 10-15s - 1 ps = 10-12s

Focalisation sur des tregraves petites dimensions (surface min ~ sup2)

rarr Conseacutequence de cette concentration dans lrsquoespace

Densiteacutes de Puissance eacutenormes

Ordre de grandeur laser 10 W agrave λ = 500 nm (vert)

densiteacute de puissance max au waist (=Puissancesurface) =

10(0510-6)sup2 = 4 GWcm2

Lentille focale f

Diamegravetre D

Diamegravetre au waist (=col

en franccedilais)

Φasymp λ f πD Ordre de grandeur si f ~ D rarr Φ ~ λ

Proprieacuteteacute de focalisation de lrsquoeacutemission LASER

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

NGC 2009

Parameters of laser matter interaction

laser beam

wavelength

intensity pulse duration τL

beam quality time and spatial fluctuations

Important issues

dynamic processes

non-equilibrium phase

transformations liquid phase surface tension viscosity vapor phase vapor density electron density temperature gradient plasma absorption scattering

LT

LT ~ (D τL)12 thermal diffusion length (τLgt 1ps)

material parameters absorption coefficient α heat conductivity D heat capacity heat of melting heat of evaporation roughness

ambient environment

Air inert or reactive gas

liquid

Lα = α-1 optical penetration depth

Laser

Lα

Les reacutegimes drsquointeraction laser-matiegravere

Production de

proton

1022 Wcm2 103 Wcm2

Diffusion

X-ray

emission

laser

Production X

I = E(S x t)

E = energie

t= dureacutee de lrsquoimpulsion

S = tache focale

Ablation

S

1 fs = 10-15s - 1 ps = 10-12s

Focalisation sur des tregraves petites dimensions (surface min ~ sup2)

rarr Conseacutequence de cette concentration dans lrsquoespace

Densiteacutes de Puissance eacutenormes

Ordre de grandeur laser 10 W agrave λ = 500 nm (vert)

densiteacute de puissance max au waist (=Puissancesurface) =

10(0510-6)sup2 = 4 GWcm2

Lentille focale f

Diamegravetre D

Diamegravetre au waist (=col

en franccedilais)

Φasymp λ f πD Ordre de grandeur si f ~ D rarr Φ ~ λ

Proprieacuteteacute de focalisation de lrsquoeacutemission LASER

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Les reacutegimes drsquointeraction laser-matiegravere

Production de

proton

1022 Wcm2 103 Wcm2

Diffusion

X-ray

emission

laser

Production X

I = E(S x t)

E = energie

t= dureacutee de lrsquoimpulsion

S = tache focale

Ablation

S

1 fs = 10-15s - 1 ps = 10-12s

Focalisation sur des tregraves petites dimensions (surface min ~ sup2)

rarr Conseacutequence de cette concentration dans lrsquoespace

Densiteacutes de Puissance eacutenormes

Ordre de grandeur laser 10 W agrave λ = 500 nm (vert)

densiteacute de puissance max au waist (=Puissancesurface) =

10(0510-6)sup2 = 4 GWcm2

Lentille focale f

Diamegravetre D

Diamegravetre au waist (=col

en franccedilais)

Φasymp λ f πD Ordre de grandeur si f ~ D rarr Φ ~ λ

Proprieacuteteacute de focalisation de lrsquoeacutemission LASER

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Focalisation sur des tregraves petites dimensions (surface min ~ sup2)

rarr Conseacutequence de cette concentration dans lrsquoespace

Densiteacutes de Puissance eacutenormes

Ordre de grandeur laser 10 W agrave λ = 500 nm (vert)

densiteacute de puissance max au waist (=Puissancesurface) =

10(0510-6)sup2 = 4 GWcm2

Lentille focale f

Diamegravetre D

Diamegravetre au waist (=col

en franccedilais)

Φasymp λ f πD Ordre de grandeur si f ~ D rarr Φ ~ λ

Proprieacuteteacute de focalisation de lrsquoeacutemission LASER

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Les Lasers une course vers les tregraves hautes intensiteacutes

Zetta 1021

Exa 1018

Peta 1015

Tera1012

Giga 109

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Strickland amp Mourou Opt Comm 56 219 (1985)

t fs oscillateur

t

compresseur

t amplificateur

t eacutetireur

1985 Le concept

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Quelques grandeurs caracteacuteristiques

10 - 14

10 - 11

10 - 12

10 - 13

10 - 10

Thermalisation eacutelectronique

Relaxation eacutelectron - phonon

Diffusion Thermique

fusion

Ablation

non thermique

Thermique

temps (s)

Zepto 10-21

Atto 10-18

Femto 10-15

Pico 10-12

Nano 10-9

Sources laser cw impulsionnels (ms micros) courts (ns)ultra-courts (psfs as)

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

NGC 2009

Surface absorption Thermal conduction

Surface melting Vaporization

Plasma ignition Explosive phase change

Plasma absorption Self-regulating heat transfer

Collisional acceleration Plume splitting Ambient interpenetration

Rapid cooling Condensation Plume deceleration

0

ns

Plume detachment Stagnation and collapse

m s

Absorption reflection

Heat transfer

Thermodynamics (phase change)

Plasma breakdown

Shock waves (gas)

Stress waves (solid)

Laser-plasma interactions

Gas dynamic expansion

Atomic amp molecular processes

A wide range of physics is involved in

laser-matter interactions

wP =(4pe2neme)12

nc (cm-3) = 11 x 1021 (1 mmLaser)2

How is a laser plasma formed

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Laser Induced Plasma in gas and

liquids at moderate intensities

I = 10 11 to 10 14 Wcm2

bull Biomedical thin films by P LD in gaseous media

bull Nanoclusters produced by laser ablation for medical imaging and therapy

bull LIBS for biomedical applications

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

ns to fs laser pulse

duration

Laser Induced Plasma in Gas PLD

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

CCD PMT

spectrometer

Target

Substrates

or Faraday

cup

laser beam

Pulsed Laser Deposition

Target Just about anything (metals semiconductorshellip)

Laser Typically excimer (UV 10 nanosecond pulses)

Vacuum Atmospheres to ultrahigh vacuum

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

Laser pulse

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Electronic excitation

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

e- e-

e-

e- e-

e-

e-

e-

e-

e- e-

e-

e-

e-

Energy relaxation to lattice (~1 ps)

lattice

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

Heat diffusion (over microseconds)

lattice

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

Melting (tens of ns) Evaporation Plasma

Formation (microseconds) Resolidification

lattice

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in PLD

lattice

If laser pulse is long (ns) or

repetition rate is high laser may

continue interactions

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Processes in Pulsed Laser Deposition

1 Absorption of laser pulse in material

Qab=(1-R)Ioe-aL

(metals absorption depths ~ 10 nm depends on )

2 Relaxation of energy (~ 1 ps) (electron-phonon interaction)

3 Heat transfer Melting and Evaporation

when electrons and lattice at thermal equilibrium (long pulses)

use heat conduction equation

(or heat diffusion model)

abp QTKt

TC

)(

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

At peak of laser pulse temperatures on target can reach

gt105 K (gt 40 eV)

Electric Fields gt 105 Vcm also high magnetic fields

Plasma Temperatures 3000-5000 K

Ablated Species with energies 1 ndash100 eV

Initially Incredibly Non-Equilibrium

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Why biomaterials

- repair and reconstruction of parts of the musculo-skeletal system of vertebrates

- minimal biological requirement biocompatibility associated with the absence of

any adverse effect (non-toxic and non-allergic)

Other requests

- resistance to physiological fluids

- should not interfere with the bodyrsquos natural immunity system

- withstand mechanical stress during whole lifetime

- manufacturability in any appropriate shape

Possible classification

-a) biologically inactive (inert) alumina zirconia stainless steel CoCrNi

CoCrMo titanium titanium alloys carbon latex PE PMMA hellip

-b) porous Calcium Phosphates (CaPs) CaP-coated metal

-c) bioactive dense calcium phosphate ceramics bioactive glasses bioactive

glass-ceramics bioactive composites hellip

-d) Resorbable tricalcium phosphate calciumaliminate polylactic acid poly-L-

acetate

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Our option biocompatible porous and bioactive CaP

Acronym

Chemical formula Compound name CaP

ratio

HA Ca10(PO4)6(OH)2 Hydroxylapatite 167

FA Ca10(PO4)6F2 Fluorapatite 167

CDHA Ca10x(HPO4)x(PO4)6x(OH)2x (0x2) Calcium-deficient Hydroxylapatite 133-167

BA Ca83(PO4)43 (CO3-HPO4)17(OH)03

BA=carbonated CDHA (x=17)

Biological apatite 138-193

Mn-CHA HA with (04-2) Mn2+ and (2-6) CO32- Mn2+ doped carbonated hydroxylapatite 151- 165

OHA Ca10(PO4)6(OH)22xOxٱx (0x1) Oxyhydroxylapatite 167

OA Ca10O(PO4)6 Oxyapatite 167

MCPM Ca(H2PO4)2middotH2O Monocalcium phosphate monohydrate 05

MCPA Ca(H2PO4)2 Monocalcium phosphate anhydrate 05

DCPD CaHPO4middot2H2O Dicalcium phosphate dihydrate (Brushite) 1

DCPA CaHPO4 Dicalcium phosphate anhydrate 1

OCP Ca8(HPO4)2(PO4)4middot5H2O Octacalcium phosphate 133

a-TCP Ca3(PO4)2 (monoclinic) Tricalcium phosphate (phase a) 15

-TCP Ca3(PO4)2 (rhombohedral) Tricalcium phosphate (phase Whitlockite) 15

TTCP Ca4O(PO4)2 Tetracalcium phosphate 2

a-DCP Ca2P2O7 (orthorhombic) Dicalcium phosphate (phase a) 1

-DCP Ca2P2O7 (tetragonal) Dicalcium phosphate (phase ) 1

ACP Cax(PO4)y nH2O (Amorphous Calcium pyrophosphate) 12-22

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Bone

Resorbable CaP

CaP coating

Ti

Implant

Alternative solution Biomimetic coatings for metallic implants

Main deficiency of CaPs brittle in bulk

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

HA molecule Ca10(PO4)6OH2

Projection in the

(001) base plan of

the hydroxyapatite

unit cell (hexagonal

structure)

How difficult is to deposit CaPs (1)

- very complex molecules

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

How difficult is to deposit CaPs (2)

Crystal structure of OCP projected down the c-axis

Alternating apatite- and

hydrated- layers (100)

planes

The region with shaded

atoms the ldquoapatitic layerrdquo

is very similar to HA

The zone containing 10

water molecules is the

ldquohydrated layerrdquo

H atoms are omitted for

clarity

Octacalcium phosphate

(Ca8(HPO4)2(PO4)4middot5H2O)

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Mesures par spectroscopie optique

drsquoemission sur le plasma issu de lrsquoirradiation

laser 248 nm drsquoune cible drsquoHA pure

Croissance impulsion par impulsion

Preacutesence des ions de

bull calcium (Ca I et Ca II)

bull oxygegravene (O I et O II) et

bull phosphore (P II)

Eacutemissions dues agrave des espegraveces moleacuteculaires preacutesentes dans le plasma

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Couche mince drsquohydroxyapatite obtenue par

ablation laser

Goutelettes

CaP = 18 CaP = 21

CaP = 17 Trois reacutegions

typiques

i Reacutegion majoritaire lisse

ii Agglomeacuteration de gouttelettes sub-micromeacutetriques

iii Gouttelettes micromeacutetriques

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Human primary osteoblasts (hOB) were cultured on OCP coated-Ti

Mn-CHA coatedndashTi HA coated-Ti Ti control (polystyrene)

hOB response SEM micrographs

- on bare Ti (a) after 7 days (b) after 21 days

Elongated rod-like morphology

Bioactivity tests

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

- OCP coatings (c) after 7 days (d) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Numerous cytoplasmatic extensions

hOB response SEM micrographs

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

- Mn-CHA coatings (e) after 7 days (f) after 21 days

- In time cells spread and expand with flattened polyhedral-morphology

- Less cytoplasmatic extensions

hOB response SEM micrographs

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Biocompatible metallic thin films by PLD

Alloys NiTinol NiTi

NiTi characteristics ndash Super-Elastic Property

ndash Radiopaque

ndash Shape-Memory Effect

NiTi biomedical applications ndash Tweezers for removing foreign objects via small incisions

ndash Anchors for tendon fixation

ndash Stents for cardiovascular applications

ndash Dentistry - Orthodontic wires which no not need to be retightened and adjusted

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Deposition chamber Multitarget system

PULSED LASER DEPOSITION (PLD)

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

SEM

Nitinol 30 sequences Nitinol 20 sequences

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Cytotoxicity evaluation on microorganism culture

(a) E coli reference cell culture

(b) E coli cell culture on Ti surface

(c) E coli cell culture on NiTi surface

(d) S cerevisiae references cell culture

(e) S cerevisiae cell culture Ti surface

(f) S cerevisiae cell culture on NiTi surface

(g) SEM on E coli cell

culture on NiTi surface

(h) SEM on S cerevisiae cell culture on

NiTi surface E coli and S cerevisiae cell

cultures on the nitinol thin films

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

o Biocompatible

o Low adherence of microorganism on NiTi surface NiTi alloy does not stimulate the development at genetic level for specific genes which are involved in adhesion processes for microorganism cells

o Low release of Ni ions in solutions

CONCLUSIONS

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

MAPLE Matrix Assisted Pulsed Laser Evaporation

bull No need for UHV

bull Matrix prepared outside the

chamber

bull High flexibility

You can use everything

you can dissolve in a

solvent

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

MAPLE of polymers blends with Ag

nanoparticles

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Controlled release of antibacterial agents

MAPLE deposition of PEGPLGA films with incorporated silver nanoparticles (AgNPs)

0 5 10 15 20 25 30000

005

010

015

020

025

Nu

mb

er o

f E

C

oli

X109

Time (hours)

Killing activity

0 5 10 15 20 25 30 3500

05

10

15

20

25

Bact

eria

l ce

ll n

um

ber

X109

Time (hours)

Delay of bacterial growth

Antibacterial efficiency against E Coli

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Direct writing by femtosecond laser

pulses

Ormosil scaffolds for tissue engineering

50 lines ormosil sample

Distance between lines =

100 μm

30x30 lines ormosil

sample Distance between

lines = 50 μm

3 layers 30x30 lines ormosil

sample Distance between

lines = 100 μm

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Scaffold functionalization

Protein deposition on the scaffolds by MAPLE

- Lysozyme antibacterial antitumor uses

- Fibrinogen biocompatible protein

Fibroblast cells grown on a polymeric grid with 100 microm distance between lines

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Spectroscopie drsquoun panache plasma

laser femtoseconde

Laser

t =400 ns Spot 35x35 micromsup2 Cu

Z mm

Expeacuteriences reacutealiseacutees par (Grojo et al LP3Marseille)

nanoparticules

atoms

031 Jcm-2

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Formation de nano agreacutegats

AFM

(Pereira et al )

TEM

(Kabashin et al)

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Eacutetude des meacutecanismes de la formation drsquoagreacutegats

Couplage

- Direct Simulation Monte Carlo

- Dynamique Moleacuteculaire

Information deacutetailleacutee

-Continu du panache

-Distribution en taille des agreacutegats

K Gouriet thegravese (2008)

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Simulation par Dynamique Moleacuteculaire (MD)

=gtdistribution drsquoagreacutegats

Cluster size N

No

rmaliz

ed

Yie

ld

100

101

102

103

104

105

10-9

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

N-426

N-122

t=1 ns

τ = 15 ps F ~ 2 Fth 4010 nm t =1 ns

Zhigilei et al (Virginia University)

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Target applications of mobile nanomaterials

Bioimaging

Optical imaging deals with

visualization of biological objects

or tissues in order to detect

pathogens or follow the delivery

of drugs etc nanoparticles are

uses as contrast agents

In vitro

Cellular

imaging

In vivo Cancer

detection drug delivery

etc

Light-induced

therapies

Cancer therapy nanoparticles are used

as photosensitizers to produce local

targeted destruction of cancer cells

Photodynamic

therapy

Light-induced

hyperthermia

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Diagnosis and Sensing A Diseases can be diagnosed through the (simultaneous) detection of a (set of) biomolecule(s) characteristic to a specific disease type and stage (biomarkers)

Huffman Nanomedicine and Nanobiotechnology Vol 1 1 2009

D

molecular signature of sick cell of infecting agent

(eg an antibody)

Cell membrane

Nanoparticle

Coating molecule specifically attracted to the molecular signature

C A nanoparticle can be functionalized in such a way that specifically targets a biomarker Thus the detection of the nanoparticle is linked to the detection of the biomarker and to the diagnosis of a disease

B Each cell type has unique molecular signatures that differentiate healthy and sick tissues Similarly an infection can be diagnosed by detecting the distinctive molecular signature of the infecting agent

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Laser ablation of material from a solid target and production of

nanoparticlesnanostructures

Production of nanoclusters by laser

ablation and their subsequent cooling in

ambient medium Gaseous ambience

Nanoclusters can be

deposited on a

substrate forming a

nanostructured film

Aqueous ambience

Nanoclusters

crystallize and form

colloidal solution

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

NPs produced in gaseous ambience

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

0 20 40 60 80 100 120 140

0

2

4

6

8

Heig

ht

[nm

]

[nm]

01 1 102

3

4

5

6

7

Mean

part

icle

heig

ht

(nm

)

Helium pressure (Torr)

Silicon nanocrystal size AFM

Gas pressure decreases Nanocrystal size decreases

AFM of isolated laser-

ablated Si particles on

HOPG

Minimal particle size is 2-3 nm (from height measurements)

001Torr

1Torr

01Torr

10Torr

100Torr

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

NGC 2009

Photoluminescence of size selected nanoclusters

0 1 2 3 4 5 6

39 Jcm2

Num

ber

of

clust

ers

Size (nm)

30 Jcm2

14 Jcm2

0 1 2 3 4 5 6

He 4 Torr

10 Jcm2

15 20 25 30 35 40

0

500

1000

He 4 Torr

39 Jcmsup2

30 Jcmsup2

14 Jcmsup2

10 Jcmsup2

Inte

nsi

ty o

f P

L (

ua

)Photon energy (eV)

Silicon nanoclusters

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Medical Imaging A Optical properties of nanoparticles depend greatly on its structure Particularly the color (wavelength) emitted by a quantum dot (a semiconductor nanoparticle) depends on its diameter

C The quantum dots (QD) can be injected to a

subject and then be detected by exciting them to emit light

Source Department of immunology University of Toronto

Solutions of CdSe QDrsquos of different diameter

CdSe nanoparticle (QD) structure

Source Laurence Livermore Laboratories

Imaging of QDrsquos targeted on cellular structures

Nano Letters 2008 Vol 8 pp3887-3892

B

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

In vivo cancer targeting and imaging with

semiconductor quantum dots

Gao et al Nat Biotech 22 969 - 976 (2004)

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

NPs produced in aqueous ambience

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Advantages of laser ablation-based nanofabrication

compared to chemical methods

Disadvantage of chemical synthesis contaminationhelliphelliphellip

In particular chemical method for the fabrication of gold nanoparticles

Reduction of chloroauric acid (HAuCl4) with citrate in water

Control size by adding a stabilizing agent (thiol- (-SH) containing molecules)

Contamination impurities Cl- on surface non-biocompatible surfactantshellip

Problems in imaging

applications (especially

in vivo)

Problems in field-

enhanced applications (eg contaminants can

provide false Raman signals)

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Focalized laser beam

Liquid medium

Target

Plasma

Laser ablation in liquids a way to avoid residual

contamination

- Laser energy can be transmitted through a liquid to ablate a solid

target the nanomaterial is released to the solution

- The process can be performed without any dirty chemical products in

clean liquid environment (deionized water PBS solution) no

contamination

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Experiment

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Ablation of gold final colloidal solutions

-Solution are ranging from deep wine red to pink and purple

- Color related to the size dependant surface plasmon resonance

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Size distribution of Au nanoparticles prepared in

distilled water

0 50 100 150 200 250 300

0

200

400

600

800

1000

Rela

tive a

bundance (

arb

units)

Particle size (nm)

0 10 20 30 40 50 60 70 80 90 100

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm) 0 2 4 6 8 10

0

200

400

600

800

1000

Re

lative

Ab

un

da

nce

(a

rb u

nits)

Particle Size (nm)

F = 20F0 Jcm2 F = 5F0 Jcm2 F = F0 Jcm2

-Size and dispersion of nanoparticles can be controlled by laser fluence

- Shape of craters on target at high F suggests the presence of cavitation phenomena

4 plusmn 15 nm

A V Kabashin M Meunier J Appl Phys 94 7941 (2003)

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

In water Very dispersed population of nanoparticles

Dextran (MW=6000gmol) Quenches the growth of the nanoparticles 2-4nm nanoparticles are produced (230-1850 atoms) Very fast dextran-gold interaction

Influence of the concentration

Dextran 6k

In pure water

300mJ

Ablation in biopolymers (dextran PEG)

Au OH

O

-

Dextran (C6H10O5)n

Nanoparticles react with OH

groups of biopolymers

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Gold Nanoparticles vs Alzheimer

A Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein

D Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source wwwinternetchemistrycom

Chemical structure of Aβ-protein

Source wwwthefutureofthingscom

C

B

Alzheimerrsquos brain Healthy brain

Source Berkeley Lab

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Gold Nanoparticles vs Alzheimer A The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein The microwaves of certain frequency are irradiated on the sample Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006 Vol 6 pp110-115

Before irradiation After irradiation

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

LIBS for biomedical applications in vivo analysis of tissue for real-time

analysis

real-time diagnosis of pathogen

presence in human fluids (bloodurine

CSF sputum)

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

71 35

ICCD

spectromegravetre

Time and space

Emission spectroscopie

LIBS (Laser Induced Breakdown Spectroscopy)

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Principle of sample identification screening applications based on discriminant analysis here for warning when healthy tooth material is targeted during laser drilling

BMC Oral Health 2001 1 1 Ota Samek1 Helmut H Telle2 and David CS Beddows

Laser-induced breakdown spectroscopy a tool for real-time in vitro and in vivo identification of carious teeth

Sensitive Detection of Epithelial Ovarian Cancer Biomarkers

Using Tag-Laser Induced Breakdown Spectroscopy

Yuri Markushin and Noureddine Melikechi

Optical Science Center for Applied Research Delaware State University USA

X rays produced by laser plasmas

I = ~1016 agrave 1018 Wcm2

nc cm-3

1111021 mm 2

Thot Ilas2

1 3

Ilas2

3 4

Hot electrons

(characteristic lines)

X-ray

emission

laser

X-rays

Line emission Fast electrons knock

free core electrons

from the inner shell

Bremsstrahlung electrons deflected by nucleus

Laser-generated hot electrons produce x-rays by two dominant mechanisms

ne

critical surface (cf cathode)

conventional X-ray tube

Kmetec ldquoMeV X-ray generation with a femtosecond laserrdquo Phys Rev Lett 68 1527 (1992)

Rousse ldquoEfficient Ka X-ray source from fs-laser-produced plasmasrdquo Phys Rev E 50 2200 (1994)

(typical recombination lifetimes several fs)

Hou et al Appl Phys Lett 84 2259 (2004)

Tightly focused fs lasers create the worldrsquos smallest

hard x-ray source (~4 microm) for precision imaging

x-ray source size is ~ 4 larger than laser focus

because of lateral heat transport Bowes Opt Lett 31 116 (2006)

2004 premiegravere deacutemonstration drsquoimagerie avec contraste de phase avec une source X creacutee par laser

Source

Rayon non diffracteacute

Rayon diffracteacute

Lcoh 2R1

eacutechantillon

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

X rays produced by laser plasmas

I = ~1016 agrave 1018 Wcm2

nc cm-3

1111021 mm 2

Thot Ilas2

1 3

Ilas2

3 4

Hot electrons

(characteristic lines)

X-ray

emission

laser

X-rays

Line emission Fast electrons knock

free core electrons

from the inner shell

Bremsstrahlung electrons deflected by nucleus

Laser-generated hot electrons produce x-rays by two dominant mechanisms

ne

critical surface (cf cathode)

conventional X-ray tube

Kmetec ldquoMeV X-ray generation with a femtosecond laserrdquo Phys Rev Lett 68 1527 (1992)

Rousse ldquoEfficient Ka X-ray source from fs-laser-produced plasmasrdquo Phys Rev E 50 2200 (1994)

(typical recombination lifetimes several fs)

Hou et al Appl Phys Lett 84 2259 (2004)

Tightly focused fs lasers create the worldrsquos smallest

hard x-ray source (~4 microm) for precision imaging

x-ray source size is ~ 4 larger than laser focus

because of lateral heat transport Bowes Opt Lett 31 116 (2006)

2004 premiegravere deacutemonstration drsquoimagerie avec contraste de phase avec une source X creacutee par laser

Source

Rayon non diffracteacute

Rayon diffracteacute

Lcoh 2R1

eacutechantillon

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

X-rays

Line emission Fast electrons knock

free core electrons

from the inner shell

Bremsstrahlung electrons deflected by nucleus

Laser-generated hot electrons produce x-rays by two dominant mechanisms

ne

critical surface (cf cathode)

conventional X-ray tube

Kmetec ldquoMeV X-ray generation with a femtosecond laserrdquo Phys Rev Lett 68 1527 (1992)

Rousse ldquoEfficient Ka X-ray source from fs-laser-produced plasmasrdquo Phys Rev E 50 2200 (1994)

(typical recombination lifetimes several fs)

Hou et al Appl Phys Lett 84 2259 (2004)

Tightly focused fs lasers create the worldrsquos smallest

hard x-ray source (~4 microm) for precision imaging

x-ray source size is ~ 4 larger than laser focus

because of lateral heat transport Bowes Opt Lett 31 116 (2006)

2004 premiegravere deacutemonstration drsquoimagerie avec contraste de phase avec une source X creacutee par laser

Source

Rayon non diffracteacute

Rayon diffracteacute

Lcoh 2R1

eacutechantillon

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

Hou et al Appl Phys Lett 84 2259 (2004)

Tightly focused fs lasers create the worldrsquos smallest

hard x-ray source (~4 microm) for precision imaging

x-ray source size is ~ 4 larger than laser focus

because of lateral heat transport Bowes Opt Lett 31 116 (2006)

2004 premiegravere deacutemonstration drsquoimagerie avec contraste de phase avec une source X creacutee par laser

Source

Rayon non diffracteacute

Rayon diffracteacute

Lcoh 2R1

eacutechantillon

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

2004 premiegravere deacutemonstration drsquoimagerie avec contraste de phase avec une source X creacutee par laser

Source

Rayon non diffracteacute

Rayon diffracteacute

Lcoh 2R1

eacutechantillon

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

Absorption vs contraste de phase

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Dsource

Intensity

interface

dsource-object dobject-detector

X-ray

Source

Object

Detector

position

Fresnel Diffraction

Dsource

Intensity

interface

enhancement interface

R Toth et al

Rev Sci Instrum 76

083701 (2005)

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

Imagerie par contraste de phase

R Toth et al Rev Sci Instrum

76 083701 (2005)

copy INRS

bull Meilleure reacutesolution (5microm)

bull dose plus faible

bull meilleur contraste (phase)

bull lrsquoeacutenergie X peut ecirctre ajusteacutee

aux besoins de lrsquoimagerie

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

La reacutefeacuterence mondiale ALLS

(INRS- Montreacuteal) 200TW + Puissance moyenne 50W

47J 23fs 10Hz

in a 8microm spot

Sans miroir deacuteformable

microCT

Scan duration avec

50W10Hz (360 images)

2 min (mouse scan)

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

courtesy Prof Dr Oswald Willi U Duumlselldorf

MeV Protons produced by laser CR39 or RCF 1010 to 1013 H+

courtesy Prof Don Umstadter U Nebraska-Lincoln

Target Normal Sheath Acceleration hot electrons traversing

target electrostatically accelerate impurity hydrogen ions on the rear surface

virtual

cathode

I ge 1019 Wcm2

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

Protons de 10MeV (INRS )

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

~1022 Wcm2

Avantages des particules chargeacutees ou hadrons (protons ions) Rayons X de la Radio-Theacuterapie

Le pic de Bragg

La profondeur de peacuteneacutetration deacutepend de l rsquoeacutenergie incidente des protons

la tumeur la plus superficielle = l rsquoœil 70 MeV

la plus profonde = la prostate 200 - 250 MeV

Protontheacuterapie par laser (projet SAPHIR)

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

CPO

Exemple de dosimeacutetrie preacutevisionnelle

(photons vs protons)

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

Comparaison de lrsquoeacutepargne de dose dans les tissus sains en protons (image de droite)

par rapport aux photons (IMRT Intensity Modulated Radio-Therapy image de gauche)

Les irradiations colateacuterales en radiotheacuterapie et en protontheacuterapie

Avantage consideacuterable pour le traitement de tumeurs localiseacutees pregraves d rsquoorganes sensibles (œil cerveau)

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

currently treating patients 5

5 next 2 years

others awaiting approval

10000 m2 $125 M facility opened in 2006

12 m diameter 250 MeV synchrotron

ldquoThere are too few physicists in the world

and they are an incredibly important part of

doing this We have one of the largest

physics departments in the world with more than 50 medical physicistsrdquo

--- Dr James D Cox head of Radiation Oncology at MD Anderson Cancer Center Houston Texas

Proton Therapy enables precise exposure of small tumors

with minimal damage to surrounding healthy tissue

250 MeV

PROTON beam

10 20

Depth in Tissue [cm]

0 0

50

100

DO

SE

(

)

6 MV

PHOTON

beam

tunable

Bragg

peak

but requires large expensive facilities

eye tumors 65 MeV protons

deep tumors gt200 MeV

Laser proton therapy could be much smaller amp cheaper Fourkal Med Phys 29 2788 (2002)

Malka Med Phys 31 1587 (2004)

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

On-site production of short-lived isotopes for medical imaging

Laser-generated quasi-mono-energetic electrons efficiently photo-activate materials of interest

bull High Rep rate bull Low cost bull Compact

Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to

produce the short-lived radionucleotides for PET scanning Few hospitals and universities

are capable of maintaining such systems - Wikipedia -

radiotracer activation reaction half-life medical use

15O 16O (n)15O 2 minutes neuro-imaging

11C 12C(n)11C 20 minutes neuro-receptor-specific brain imaging

18F 19F(n)18F 110 minutes clinical oncology

Positron Emission Tomography

on-site

production

essential

18F PET scan of tumor 15O PET scan of human brain

Reed ldquoEfficient initiation of photonuclear reactions using quasi-monoenergetic electron beams from LWFArdquo J Appl Phys 102 073103 (2007)

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV

TEP in situ

+ in vivo

Modegravele animal

microCT +

contraste de phase

+ in vivo

modegraveles de cancer

Comprendre

le cancer

Preacuteparer le traitement

protons 50MeV