Fysikkens rolle i medisinen og biologien

Bergen, 15. mai, 2009Johan Moan

Nearly all progress in biology and medicine made after Hippocrates is based on application

og physical instruments and methods!!

• Morphology on cell- and tissue level• Understanding of mechanisms• Investigational manipulations

• Diagnosis of diseases• Therapy of diseases

Physics in medicine and biologyThe Italian anatomist and physician LuigiGalvani was one of the first to investigateexperimentally the phenomenon of whatcame to be named "bioelectrogenesis".

Luigi Galvani In a series ofexperiments around1780 he found that theelectric current causedcontractions of themuscles in the leg of a frog.

Microscopy• Transmission, res. 200 nm,Ibn al-Haytam,

(1029); Galilei, (1609); Chr. Huygen, (1680), biology.

• Fluorescence, res. 200 nm.• Confocal laser scanning, spatial modulation

gives res. 10 nm.• Electron microscopy, res. 0.05 nm;trans.,

scanning, freeze fracture.• Scanning tunnelling, res. 0.1 nm or less (1981).

X-ray chrystallography

• Gave us the structure of DNA!!!!• Can someone beat that???

Aakus & Poppe. Medisinsk radiologi i Norge 1995

W. C. Røntgen

X-ray diagnostics

L

K

Elektron hνK

Ionization Elektron transfer Emission of characteristicphoton

X-ray spectrum

hν

T0

T0-hν

Z Z

Bremsstralung

Characteristic radiation

X-ray diagnostics

X-ray diagnosticsX ray tube

patient

detector

X-ray immage

Computer-tomography-CT

COMPUTED MEDICAL IMAGING

”Computed tomography measuresthe attenuation of X-ray beams passing through sections of thebody from hundreds of differentangles, and then a computer is ableto reconstruct pictures of thebody’s interior.”

GODFREY N. HOUNSFIELD,Nobel Lecture, 8 December, 1979

Sir Godfrey N. Hounsfield

Allan M. Cormack

Computer tomography (CT)

Positron emission

tomography

PET

TIME No. 48, 2000

PETPositron emisjons tomografi

• Decay: p+ → n + e+ + ν• Annihilation: e+ + e- → ‘positronium’→2*γ• Simultaneous detection of photons (511 keV)• No collimator needed• Enhanced sensitivity and resolutions compared to

other radio-isotope imaging modalities PET

Positron emission tomography (PET)

Boellaard (2007) Heart Metab. 34

Positron emission tomography (PET)

http://upload.wikimedia.org/wikipedia/commons/c/c1/PET-schema.png

Nuclear imaging

Nuclear imaging

Gamma camera

• Apply radioactive material, photon emitter, iv, oraly, injection

• Collimated detection

Magnetic resonnance-

MR

B0

Siemens AG. Magnets, spins and resonances 1992

Magnetic resonance imaging

fLarmour~B

• T1 relaxation – how fast do the spins line up with the applied field B0

Magnetic resonanceimaging

• T2 relaxation – how fast do the spins randomize in the XV plane after a pulse coordinating them in one plane

• T1 relaxation• T2 relaxation• T2* relaxation• magnetisation transfer

contrast (MTC)• diffusion• perfusion• blood flow• oxygenation• temperature• spectroscopy of different

atomic species (carbon, hydrogen, phosphor)

• ….

Effective alveolar sizehistogram

3He Diffusion mapping of a 69-year old COPD patient

Courtesy of MD Anderson Cancer Center

Magnetic resonance imaging

Magnetic resonance imaging

vs

MR-spektroskopi - MRSSpektra of tissue in an exact position of the body (tumor, tissue) give a lot of information about composition and reactions taking place

– Energy metabolism:– Lipid metabolism:– pH

Magnetic resonance imaging

Ultrasound

BushbergBushberg, et al. The Essential Physics of , et al. The Essential Physics of Medical Imaging, 2Medical Imaging, 2ndnd ed., p. 509.ed., p. 509.

A-mode “amplitude”mode: displays echo amplitude vs. time (depth) One “A-line” of data per pulse repetition

Christian Andreas Doppler 1803-1853

The Doppler effect

Ultrsound-Doppler can be usded to measure speed of for instance red cells and heart beats .

( )2 cosi r id

t

vf f f f

cθ

= − =

BushbergBushberg, et al. The Essential Physics of , et al. The Essential Physics of Medical Imaging, 2Medical Imaging, 2ndnd ed., p. 532.ed., p. 532.

Ultrasound

“Finally, in the biological sciences the rays of radium and its emanation produce interesting effects which are being studied at present. Radium rays have been used in the treatment of certain diseases like lupus, cancer, nervous diseases.”

P I E R R E C U R I ERadioactive substances, especially radiumNobel Lecture, June 6, 1905

Radiation therapy

• Photoelectric effect• Compton scattering• Pair production

Shung et al. Principles of medical imaging 1992

Medical radiation physics

Radiation therapy of cancer

Depth

Dos

e

Proton radiation

Radiation therapy of cancer

The Bragg peak

One single energy Several energies Many energies, added

Dose distribution for protons and photons

Depth (cm)

Dos

e de

posi

tion

photons

protons

tumor

Radiation therapy

Proton therapy

Ordinary radiation therapy

Radiation therapyTumor behind the eye. Proton therapy saves normal tissue

Lasers in Therapy of Human diseases

A new and promising option.Many modes of action.

Many possibilities of optimalization

Excimer - Ar:F 193 nm, Kr:F 248 nm nm (microscopic surgery)Ar - 488, 514 nm (retinal and ear surgery, birthmarks, facial veins)Ruby - 694 nm (freckles, naevus, hair removal)Alexandrite - 755 nm (hair and tattoo removal)Dye - 577-585 nm(vascular lesions, PWS)Diode - 800-900 nm (hair removal, dental surgery, treatment of veins)Nd:YAG - 1064 (tissue cut, hair, tattoo removal), 532 nm (vascular lesions)Ho:YAG - 2070 nm (bone and cartilage ablation, urology, dental fields)Er:YAG - 2940 nm (cosmetic skin resurfacing, dental drill)CO2 - 10600 nm (first laser used by surgeons)

- (moles, warts, keratoses; tumours; wrinkles)

Photothermal damage

R.R.Anderson and J.A.Parish (1983) Science 220, 524-527.

Selective photothermolysis (SP))confine damage to specific tissue structuresby regulating pulse duration and repetition

rate

target 0.1 1-10 100 1000 µmpulse 10-9 10-6 10-3 10-1 s

P.Rol et al. (2000) Graefe’s Arch. Clin. Exp. Ophthalmol. 238, 249-272.A.Pirracchio et al. (2001) J. Bombay Ophthalmol. Assoc. 11, 135-144.

Photothermal therapy in Ophthalmology

Pupillary and retinal melanomasRetinal detachment

C.Gorman (1999) Time 154(18), 60-65

LASIK- laser assisted

in situ keratomileusis

Correction of nearsightedness and

farsightedness

Excimer lasers

Photothermal therapy in Ophthalmology

T.S.Alster et al. (1998) South. Med. J. 91, 806-814.

Vascular diseases

Photocoagulation or PHD ofhemorrhage and bleeding

Photothermal destruction or PDTof atherosclerotic plaques

E.B.Diethrich (2002)

Hair RemovalSelective Absorption in the folliclesDestruction of the follicle structure

K.G.Klavuhn and D.Green (2002) Lasers Surg. Med. 31, 97-105.

Skin rejuvenation

Wrinkle removal

Lasers emittingin µm region(CO2, Er:YAG)

K.Karpowicz (2002)

Action spectroskopyAction spectroskopyis our best tool in is our best tool in

evaluating evaluating

HEALTH EFFECTS OF HEALTH EFFECTS OF SUN AND SUN BED SUN AND SUN BED

EXPOSUREEXPOSURE

Action spectra

Tid på dagen

4 6 8 10 12 14 16 18 20 22

Føflekk-kreftD vitamin

1.0

0,5

0,0

In vivo Raman Spectroscopy

• Can be used for:

• Diagnosis, for instance of skin cancer• Real time investigations of chemical

reactions in vivo

Fluorescence diagnostics

• The use of fluorescing and localizing dyes for diagnosis amd delineation of malignant or abnormal tissue (Skin, brain, bladder, lung).

• The tissue must be reached by light.

PDT articles published in 1950-2006

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed

Peng Q. et al. Cancer (1997) 79:2282-308.

• Topically applied ALA acts deeper and goes systemically in mice.

• Ester derivatives of ALA induce PpIX only in the site of cream application.

• ALA goes to the blood and high contents of ALA in the blood may be neuro- and livertoxic.

Juzeniene A. et al. Photochem. Photobiol. (2002) 76:329-334.

ALA and ALA methylester (MAL) induced PpIX: Penetration depth

PHOTOREJUVENATION

Optical coherence tomography (OCT)

http://en.wikipedia.org/wiki/File:HautFingerspitzeOCT.gif

OCT tomogram of a fingertip

Steiner and Rapp (2007)DOI: 10.1117/2.1200702.0685

Photoacoustic spectroscopy

http://www.ehponline.org/realfiles/docs/1999/107-10/innovations.html

Haisch and Niessner (2002)Spectr. Europe 14

Evanescent wave microscopy(within ≤ 100 nm)

Axelrod (2001) Traffic 2

Evanescent wave microscopy

Optical tweezers

Kimura and Bianco (2006) Analyst 131

Laser microsurgeryof a chromosome

Before After

Liang et al. (1993) Exp. cell res. 204.

Electric Cell-Substrate Impedance Sensing (ECIS)

Ivar Giæver and Cahrles R. Keese (1984)

http://www.nature.com/nnano/journal/v2/n8/full/nnano.2007.223.html

Nanoparticles

Electroporation

Electroporation

Electroporation applies brief electrical pulses, inducing pores to open in the cell membrane and dramatically increasing uptake of useful drugs, genes & DNA vaccines

Therapeutic Platform Based on ElectroporationTherapeutic Platform Based on ElectroporationTherapeutic Platform Based on Electroporation

Cell MembraneBefore Pulse

Cell MembraneDuring Pulse

Cell MembraneAfter Pulse

(Cell returns to original state)

A simple and effective system of delivering drugs or genes into cells

ElectroporationDC

Cancer Therapy Procedure Utilizing EPTCancer Therapy Procedure Utilizing EPTCancer Therapy Procedure Utilizing EPT

Very effective treatment requiring low level of technical skills

DC

Electroporation

Cell Poration, drug enters cells

Injection ofBleomycin

Pulsing theTumor withapplicator

Cells ResealAnd Die

Drug SurroundsTumor Cells

Electroporation Therapy (EPT)

Patient 002: EPT

Electroporation Therapy (EPT) is applied with the applicator.

Electroporation Therapy in Head and Neck Cancer

Electroporation Therapy in Head and Neck Electroporation Therapy in Head and Neck CancerCancer