Upload
trannhi
View
215
Download
0
Embed Size (px)
Citation preview
1
3 November 2014
GBM8320 - Dispositifs Médicaux Intelligents 2
Laboratory-on-Chip : Purpose • A multidisciplinary approach
to miniaturize biological assays or procedures in analytical chemistry.
• To embed the required equipments for performing the biological assays in a single chip for single purpose.
2
GBM8320 - Dispositifs Médicaux Intelligents 3
• Low sample consumption;
• Fast biochemical reactions & Miniaturization;
• Point-of-care.
Laboratory-on-Chip : Advantage
GBM8320 - Dispositifs Médicaux Intelligents 4
Laboratory-on-Chip : CMOS technology
• Low voltage, and low power;
• Addressable sensing or manipulating sites;
• Standard technology.
3
GBM8320 - Dispositifs Médicaux Intelligents 5
I. Introduction
II. Biochemistry
III. Microfluidic Packaging
IV. Capacitive Sensors
V. On-Chip Cells Detection and Manipulation.
Laboratory-on-Chip : Outline
GBM8320 - Dispositifs Médicaux Intelligents 6
Laboratory-on-Chip : Miniaturization
• Low voltage E=V/d (d: 1cm to 1um, V:10kV to 1V) • Low-sample low-cost experiment with expensive
biomaterials 1ml to 1nl • Fast biological assays 1 hr to 1ms • Miniaturized devices • Home healthcare, Point-of-care monitoring, Home
diagnostic,… -------- • Portable devices • Miniaturization is only solution for single cell
detection : Sensitivity = DVolume/Volume
d!+! -!
V!
E!
4
GBM8320 - Dispositifs Médicaux Intelligents 7
Application Method Microfluidic CMOS Year Authors Cells
monitoring Capacitive
Sensor Adhesive technique 0.5um 2007 Prakash et al
Organic solvent Sensor
Core CBCM capacitive Sensor
DWFP 0.18um 2007
Ghafar-Zadeh et al
Bioluminane detection
Optical Method
Rapid Prototyping 0.18um 2007 Eltoukhy et al
DNA detection Capacitive
Sensor Rapid
Prototyping 0.5um 2006 Stagni et al
Magnetic manipulation
Array of µcoils
MEMS based Procedures 0.18um 2006 Lee et al
Virus detection
Capacitive Sensor
Rapid Prototyping 0.35um 2005
Balasubramanian et al
Cell localization
Capacitive Sensor
Adhesive technique 0.35um 2004 Romani et al
Dielectrophoresis Array of Rapid 0.35um 2003 Medoro et al manipulation µelectrodes prototyping
Laboratory-on-Chip : CMOS-Based µsystems
GBM8320 - Dispositifs Médicaux Intelligents 8
Affymetrix Inc.!
Requires scanner for reading out!
EZ Smart Monitoring
Laboratory-on-Chip : Technologies
Glucose Detection DNA µarray Rapid Bacterial Diagnosis
STMicro-electronics
5
GBM8320 - Dispositifs Médicaux Intelligents 9
Laboratory-on-Chip : Future Technologies
Display
Disposable needle
Sensor
Syringe Microchannel
Past Room
Laboratory
Today Desktop
Laboratory
Future Pencil-Size Laboratory
GBM8320 - Dispositifs Médicaux Intelligents 10
Lab-on-Chip Information
technology
Selected bioparticle
Electric Signal
Diagnostic information
BIO
Material flow
Information flow
Micro / Nano
BioInfo
Patient Physician
Blood sample
preparation
Laboratory-on-Chip : Multidisciplinarity !
Lab-on-
Chip
6
GBM8320 - Dispositifs Médicaux Intelligents 11
• Microfluidic structure ; • Sensing layer ; • Interface circuit : Sensor
or Manipulator.
Interface Circuit
Vdd ΔC
Electrode
Cell
Microchannel
Sensing Layer
Laboratory-on-Chip : CMOS-based devices!• On-chip non-
uniform electric field;
• Cell manipulation.
GBM8320 - Dispositifs Médicaux Intelligents 12
,...,C mΔ Δ QΔ
• Low complexity capacitive sensor • High precision optical sensor
Antigen labeled by fluorescence materials
Beads
Note: Impedometric and cantilever require removing the passivation layers
Antibody
Antigen
Laboratory-on-Chip : Optical/Capacitor sensing!
7
GBM8320 - Dispositifs Médicaux Intelligents 13
! Optical biosensors are becoming popular due to inherent advantages. ! The basis is enzymatic reactions, which alter the optical properties of
substances allowing to emit light upon illumination ; ! Means of detection include fluorescence, phosphorescence, chemi /
bioluminescence. -------------
! Photometric fiber sensors - changes in reflectivity & spectrum ; ! Temperature based fiber microprobes - The luminescence of a crystal at
the probes tip is temperature dependent (-50 to 200oC) ; ! Fiber based Pressure sensors - The fiber is in a catheter and operates
by the displacement of a membrane ; ! Chemical Sensors - Use of permeable membrane on the fiber probe,
which contains a reversible indicator that responds to a chemical stimulus by absorption or luminescence.
Laboratory-on-Chip : Optical/Capacitor sensing!
GBM8320 - Dispositifs Médicaux Intelligents 14
SHS
SHR
SIG
RST
COL BUS
RS
RST
VDD
CS
HOR BUS
VLN
VLP
VLP
PIXEL
GLOBAL
Integration starts
Signal sampled
Pixel reset level sampled Photodiode Voltage
0V
1V
2V
3V
33 ms 66 ms
Net signal
0V
1V
2V
3V
33 ms 66 ms
Laboratory-on-Chip : CMOS Imaging!
8
GBM8320 - Dispositifs Médicaux Intelligents 15
Our reported new applications : 1) Organic Solvent Detection, 2) Bacteria Growth Monitoring, 3) Polyelectrolyte layer detection.
Cell monitoring
(charges generate dipoles).
Organic solvent detection (Chemical gas change dielectric capacitance).
DNA detection
(hybridisation generates extra
charges)
Antibody-antigen recognition
Laboratory-on-Chip : Capacitor sensing applications!
Hagleither et al, IEEE SSCJ, Dec 2002. Ghafar-Zadeh et al, CJECE, 2008.
GBM8320 - Dispositifs Médicaux Intelligents 16
I. Introduction
II. Biochemistry
III. Microfluidic Packaging
IV. Capacitive Sensors
V. On-Chip Cells Detection and Manipulation.
Laboratory-on-Chip : Outline
9
GBM8320 - Dispositifs Médicaux Intelligents 17
Cell Separation DNA Extraction DNA Hybridization
For performing the biological assays, several equipments are required.
Manipulation protocols (Temperature, volume, others..).
DNA (Deoxyribonucleic) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known
living organisms.
Laboratory-on-Chip : Fundamental of Biochemistry!
GBM8320 - Dispositifs Médicaux Intelligents 18
Blood Chromosomes!
DNA Strands!
Fundamental of biological particles Blood ; Cells ; Chromosomes ; Molecules ; Genes ; DNA ; Fractioning…
• Genetic info is stored in the cell chromosomes • A chromosome consists of long supercoiled strands of molecules. • Each strand is a string of DNA fragments grouped as genes, each
expressing an identifiable function of the organism.
Laboratory-on-Chip : Fundamental of Biochemistry!
10
GBM8320 - Dispositifs Médicaux Intelligents 19
Sampling Concentration Purification
Amplification Detection Signal Analysis
A typical biological test through desktop, or room size systems
PCB
Microfluidic
Sensor
Analog Digital and Software Microfluidic and Temperature control system
Microfluidic needle Dielectrophoresis (no charge) Electrophoresis (charge)
P.Grodzinski & al. Motorola labs. Anal. chem. 76, P.1824, 2004
Uniform electric field
• Dielectrophoresis (DEP) for Separation, levitation, rotation, etc.
• Electrophoresis for molecule level preparation.
Laboratory-on-Chip : Fundamental of Biochemistry!
Polymerase Chain Reaction (PCR)
Centrifuge system Fragmentation
PCR
Cells
DNA
Molecules
GBM8320 - Dispositifs Médicaux Intelligents 20
Laboratory-on-Chip : Fundamental of Biochemistry!
• Gold electrode on CMOS • Solution is spread on electrodes for 18 h. • Single stranded DNA molecules immobi-
lized on the electrodes. • Unknown molecule detected through a
CMOS capacitive sensor.
Affymetrix Inc. -- On-chip DNA Detection --
LoC innovation : Gene chip. It requires: • Optical Scanner for readout / data mining ⇒ On-Chip Reader is needed, capacitive
sensor is a good candidate.
11
GBM8320 - Dispositifs Médicaux Intelligents 21
Fundamental of Biochemistry : DNA!• There are four types of nucleotides corresponding to four different
bases: adenine, guanine, cytosine, and thymine (A, G, C and T). • DNA Individual bases are hydrophobic, but strands of DNA are
quite soluble in water due to the polar backbone. • Single-stranded DNA tends to attach (or hybridize) through weak
hydrogen bonds to another strand of complementary base pairs (G–C and A–T), forming a double strand.
• In humans, for example, each of the 46 chromosomes is 5x400 exp (6) units long, while the single chromosome in the E. coli bacteria is 4x10 exp (6) units long.
• Each nucleotide consists of a base (B), a sugar linkage (S) and a phosphate bridge (P).
GBM8320 - Dispositifs Médicaux Intelligents 22
Fundamental of Biochemistry : Microarrays!
Ink jet
Pin Quill Pen
Pin Ring
• Robotic DNA Arrays : dispensing artificial DNA molecules (or probes) for diagnosis purposes.
• Photolithography method to create artificial DNA probes for diagnosis purposes (very large scale immobilized polymer array synthesis).
Light Mask
Gene-Chip
• Modify the surface by various chemical reactions to create the required T, C, G, A..
12
GBM8320 - Dispositifs Médicaux Intelligents 23
• An antigen is defined as a substance that can be bound by an antibody molecule through its antigen-binding sites, also called epitopes.
Signal
No Signal Anti-body
Specific Recognition
Non-specific Recognition
Laboratory-on-Chip : Fundamental of Biochemistry!
Antibody
Antigen
GBM8320 - Dispositifs Médicaux Intelligents 24
I. Introduction
II. Biochemistry
III. Microfluidic Packaging
IV. Capacitive Sensors
V. On-Chip Cells Detection and Manipulation.
Laboratory-on-Chip : Outline
13
GBM8320 - Dispositifs Médicaux Intelligents 25
Laboratory-on-Chip : Microfluidic Packaging!Ink jet printer
http://en.wikipedia.org/wiki/Inkjet_printer http://www.imaging.org/ist/resources/tutorials/inkjet_printer.cfm
GBM8320 - Dispositifs Médicaux Intelligents 26
• 3D microstructures for fluidics (Silicon)
• Various applications: microvalves, microjets, lab-on-chip, Gas Chromatography, microfluidics.
MINOS, Ljubljana, D. Resnik et al
• Micronozzle on silicon for sampling purposes.
Laboratory-on-Chip : Microfluidic Packaging!
14
GBM8320 - Dispositifs Médicaux Intelligents 27
Microfluidic Packaging : MEMS-based techniques!
Mold casting
Mold release
Casting against mold
Bonding
Clean
Photo-resist
UV exposure
Patterning
Deep etching
Clean
-- Adhesively bonding (polymeric) methods --
GBM8320 - Dispositifs Médicaux Intelligents 28
• On-Chip magnetic manipulation
Flow
PCB
Microfluidic
Lee, H. et al, IEEE, Journal of Solid State Circuits, 2006.
CMOS Chip
Gasket
Glass
Manaresi, N. et al, IEEE, Journal of Solid State Circuits, 2003.
-- Rapid prototyping methods --
Microfluidic Packaging : Rapid prototyping!
15
GBM8320 - Dispositifs Médicaux Intelligents 29
Microfluidic Packaging : Direct-write assembly!
Robotically controlled
deposition (RCD) machine*
Cesarano, J., “Freeforming objects with low-binder slurry,” US patent. Therriault et al., Nature Materials, 2003.
• Robotic based method for ink dispensing • Ink : Sacrificial layer
GBM8320 - Dispositifs Médicaux Intelligents 30
• Ink deposition – Robotically controlled apparatus for
deposition in a predefined pattern;
– Air-operated dispensing system for ink extrusion through micronozzle
– Fugitive ink is binary organic ink composed of petroleum jelly and microcrystalline wax.
Micronozzle
Resin infiltration
Solidification of structural material
Removal of fugitive ink
Microfluidic Packaging : Direct-write assembly!
16
GBM8320 - Dispositifs Médicaux Intelligents 31
Removal of fugitive ink
Ink deposition
Before degassing
After degassing
During infiltration
Optical microscope images during resin infiltration process
Microfluidic Packaging : Direct-write assembly!
• Resin infiltration between patterned features • Solidification (Resin cures at room temperature) • Removal of fugitive ink under vacuum.
Femlab
GBM8320 - Dispositifs Médicaux Intelligents 32
(a)
(b)
• Sensing electrodes
• Fugitive Ink and fluidic Connection
• Fugitive dam, epoxy resin, ink removel, and analyte injection.
(c)
Microfluidic Packaging : Direct-write assembly
17
GBM8320 - Dispositifs Médicaux Intelligents 33
• Fluidic connections – Between millimeter-scale fittings to micro-scale channel
• Fixed tubing, tapered opening for syringe tip insertion
Common techniques employed for connecting / fittings to microchannels
Microfluidic Packaging : Direct-write assembly
GBM8320 - Dispositifs Médicaux Intelligents 34
I. Introduction
II. Biochemistry
III. Microfluidic Packaging
IV. Capacitive Sensors
V. Cells Manipulation and Detection.
Laboratory-on-Chip : Outline
18
GBM8320 - Dispositifs Médicaux Intelligents 35
Laboratory-on-Chip : Capacitive sensors
GBM8320 - Dispositifs Médicaux Intelligents 36
Laboratory-on-Chip : Capacitor sensors
• Capacitive sensors for LoC applications do not require determining a single value of the sensing capacitance, but to distinguish between the device behavior in the presence rather than in the absence of analyte in microfluidic channel.
Capacitive sensor LOC
Array of capacitive sensors
Low complexity
Offset cancellation
Sandia National Laboratories, SUMMiTTM
Technologyies E.coli Bacteria
Ghafar-Zadeh & Sawan, IEEE-IMST3W 2008
3D Accelerometer
19
GBM8320 - Dispositifs Médicaux Intelligents 37
LoC : Charge-Based Capacitive Measurement
IR
M3 M4
M1 M2
Is
CR CS
CBCM
Gnd
Vdd
Originated UC Berkeley Year 1997 External tools DC Ammeter Main application Capacitance
characterization Resolution Sub femtoFarad Frequency <15 MHz
• Interconnect or sensing capacitance can be retrieved/measured from the following equation:
where = Cs - C0, and C0 = CR
F1
F2
F1
F2
A B (IS − IR ) = f ⋅Vdd ⋅ ΔC
ΔC
ΔC
GBM8320 - Dispositifs Médicaux Intelligents 38
LoC : CBCM-based capacitive sensor • Current mirror and integrating capacitor instead of dc Ammeter.
[ ][ ]
212
( )( , )
( )dd TP S x I
S
x dd TP S
V V C K AI C t
K V V t C
−≈
− +
2( )SS x gs TPdV
C K V Vdt
= ⋅ −
( )( )( )dd TP S
S dd TPx dd TP S
V V CV V V
K V V t C−= − −− +
Vdd-Vs=Vgs
V d d
F2
F1
Cin Cs
Is Vout
M 2
M 1
M 3 M 4
Cin
I(Cs,t)
F2
F1
M 2
M 1
V d d
I S
C A
A
Vs
F1 , F2 ≡ Low
Ghafar-zadeh, Sawan, IEEE TBioCAS, 2007
Is
20
GBM8320 - Dispositifs Médicaux Intelligents 39
00( )out I dd TP
in
C CV A V V V
CΔ += ⋅ − +
• Cancellation of C0 (C0 >> ) • Accurate reference current IR is needed.
IR Vout Is • Voff = f(mismatch in process, remnant in channel), Voff
does not affect the accuracy, but large Voff may limit the dynamic range, then Voff should be minimized.
• << Cp, the effect of Cp is almost cancelled by measuring CS-CR before converting to voltage.
Vout = AI ⋅
CsCin
(Vdd −VTP ) +Voff
S sS
I
dV ICdt A
=outin SdV
C Idt
=
Vout
Is/AI
Charging mode
Sampling
Reset mode
F1
F2
LoC : CBCM-based capacitive sensor
F2
F1
M 2
M 1
V d d
I S
C A
ΔC
ΔC
GBM8320 - Dispositifs Médicaux Intelligents 40
M1!M13!
M5!M3!
ID1!
CS!
CBCM*!
Ck5!
Vout!
Cint! M10!
Is!
Vdd!
Gnd!
Gnd!
F1!
F2!300m
500m
700m
900m
1.1
1.3
1.5
0.0 100µ 200µ 300µ 400µTime (s)
Vout
(V)
ΔC=0
ΔC=1fF
ΔC=2fF
ΔC=3fF
LoC : CBCM-based capacitive sensor
21
GBM8320 - Dispositifs Médicaux Intelligents 41
Gnd!
Gnd!
LoC : CBCM-based capacitive sensor
M1!M13!
M5!M3!
ID1!
CS!
CBCM*! Is!M7!
Vb1!
Cint!M10!
Is-IR!Gnd! IR!
F1!
F2! Vout!
• In agreement with the calculation and simulation;
• Higher dielectric constant of organic solvent, higher output voltage.
F2!Methanol Injection!
∆Vout!
F1!Dichloromethane Injection!
∆Vout!
GBM8320 - Dispositifs Médicaux Intelligents 42
Laboratory-on-Chip : Outline
M1 M2
F1
F2
Vdd
Gnd
Outlet
M1M2
VddAΦ1
Φ2
Inlet
MicrochannelSensingelectrodes
Φ1Φ2
Process 0.18 µm CMOS
Sensing electrode 100×750 µm²
Vdd 1.8 Volt
Frequency (f) 100Hz-1MHz
• Large interdigitated electrode • CBCM structure.
CM-s
Cs/2
CBCM
Cp1E1E2 E2
Cs/2
Cp1Cp1Cp1
Cp2Cp2
AnalytePassivation
layers
Interdigitated electrode CBCM
Ghafar-Zadeh, E., Sawan, M., IEEE TBioCAS, 2007
CM-S
Cp1 Cs CBCM E1 E2
Cp2
22
GBM8320 - Dispositifs Médicaux Intelligents 43
LoC : CBCM-based capacitive sensor
• Microscopic images of chip.
• Interdigitated electrodes
• Passivation layer removal
• Reference and sensing electrodes.
Ghafar-Zadeh et al, Sensors and Actuators A: Physical, 2008
GBM8320 - Dispositifs Médicaux Intelligents 44
• Sensing capacitances values for different analytes; • Parasitic capacitances of different chip samples; • Average of recorded samples from 3 electrodes.
LoC : CBCM-based capacitive sensor Dichloromethane (D) 10.8 Acetone (A) 20.0 Methanol (M) 32.0 Deionised water (W) 80.8 Saline water (S) conductive
The recorded data for a particular organic solvent
shows a decoded output of a 6-bit resolution.
1 2 3 4 5 8.6
9.0
9.4
Measured chips 0 40 80 Dielectric constant
∆C (p
F)
0.4
0.5
0.6
0.7
0.8
C0
(pF)
23
GBM8320 - Dispositifs Médicaux Intelligents 45
M7 M4
IR Vb1
IR M3 M8
M1 M6
M5 M2
IS
CR CS
Vout Vb1
Cint F1
F2
Vout Sampled voltage
Reset mode
W1 W2 W3 W4
W5 W6
Cs (fF)70.2 70.4 70.6 70.8 71.0 71.2
100
300
500
700
900
1100
W7 W8
0% change in Wi
Vou
t (m
V)
20% change of 1200
Mismatch only affects an offset voltage
LoC : CBCM : Linearity & mismatch error
GBM8320 - Dispositifs Médicaux Intelligents 46
• Cancellation of Vos through Rp;
• A replica of sensing circuit is employed to generate reference current.
Vo
Cin
Gnd
Vdd
Cs CR
M1
M5
M2
M7 M6 M8
M9 M10
M3 M4
SR IS - IR
IS ID1 ID2
Gnd
Rp
IR F1
F2
F2
FPGA
LoC : CBCM-based capacitive sensor
24
GBM8320 - Dispositifs Médicaux Intelligents 47
Laboratory-on-Chip : Outline Non-linearity of output voltage versus Rp1 and Rp2 .
Vdd
CR
M2
M7 M8
M9 M10
M4
IR
Rp1
B
Rp2
Rp2
Rp1/2 (kOhms) 0 200 400 600
0.8
0.9 0.9
1.0
1.1
1.2
Vo (V
)
GBM8320 - Dispositifs Médicaux Intelligents 48
Laboratory-on-Chip : Outline • Adjustable current mirror gain (D1-Dm) • Three stages unity current mirror.
V a
V b
I s V d d
D 1 D m
A
B
C
M 5
M 6
M 7 M 8
M 9
M 1 0
A B
C M 1 3 S 1
M c 1 M c m
V c V o u t
M 1 4
M 1 5 S W 1
I
M13
Q2 Q1
IR
CBCM CBCM
25
GBM8320 - Dispositifs Médicaux Intelligents 49
Laboratory-on-Chip : Outline
1-bit DAC
MDAC MCM MC1
IDAC SDAC SCM
qn Dm D1 SC1
Calibration circuit
M8
M6 M4
IR
M10 M12
Vb2 Vb1 IR M2
M14 M1
M13
M5 M3
ID1
CR CS Ck1
Ck2
CBCM Is M7
M9
Vb1
Vb2 M11 Ck3
Vout
Cint M10
Is-IR
Vdd
Gnd
Gnd
IR= IR0 (1 + 2m-1DC1 + … + 2m-kDCk + …+ DCM).
• Adjustable current mirror gain (D1-Dm)
GBM8320 - Dispositifs Médicaux Intelligents 50
Laboratory-on-Chip : Outline • By adding a voltage comparator and a switch in series with a current
source, a DC input sigma delta can be realized.
LPF + x n q n
1-bit DAC I x
Ghafar-zadeh & Sawan, J. of IEEE Sensors, no.4, 2008
C i n
I(Cs, t)
V R
- +
Q 2 Q 1
I x
Sw2
V o
Xn
Sw1
F 1 F 2
q n = I s
n
x I x
Vout V R
1 2 3 4 5 6 7 8
26
GBM8320 - Dispositifs Médicaux Intelligents 51
Laboratory-on-Chip : Sigma-Delta ADC
Time (msec) 5 0 7 5 2 5 0
Vout (output pulse)
0
0
1 . 8
1 . 8
(V)
• Post-layout simulation results • Unique sequence.
∆C = 0.22 fF
∆C = 0.3 fF
C i n
I(Cs, t)
V R
- +
Q 2 Q 1
I x
Sw2
V o
Xn
Sw1
GBM8320 - Dispositifs Médicaux Intelligents 52
Laboratory-on-Chip : Outline
• An array of capacitive sensors.
• Adjustable reference current.
• Sigma-Delta DC A/D converter
• Offset cancellation procedure ( FPGA).
S1
O f f - c h i p F P G A S y s t e m
N o
Y e s
f s
F 2
U < V t h
ADC
F 1 Stop calibration & recording D1-m
Reset D 1 - m = D 1 - m + 1
CS1
CR V o u t
On-chip circuit
Cin I R
B u f f e r
I s
Ajustable Current Mirror
D 1-8
UIC1
S 3 S 2 S 1
VR
S2 S3
CS2 CS3 UIC2 UIC3
27
GBM8320 - Dispositifs Médicaux Intelligents 53
Laboratory-on-Chip : Measurement set-up
GBM8320 - Dispositifs Médicaux Intelligents 54
Laboratory-on-Chip : Outline
ΔC where Cs=ΔC+C0
Extraction of sensing
capacitance variation
2 1log( ) log log( )ddI I f V C− = + ⋅Δ
( C0: Parasitic capacitance)
( )S R ddI I f V C− = ⋅ ⋅Δ
1E2 1E3
-50
1E1 1 A B
C D
10 L
og (I
2-I1
)
Dichloromethane Acetone Methanol DI water
-60 -70
-80
-90
-100
-110
-120
-130 1E4 1E5 1E6
f(Hz)
28
GBM8320 - Dispositifs Médicaux Intelligents 55
Laboratory-on-Chip : Outline • Microscopic image of fabricated chip
(a) Die including the electrodes and sigma delta sensor, (b) Interdigitated electrode.
Ghafar-Zadeh et al, Sensors and Actuators A: Physical, 2008
GBM8320 - Dispositifs Médicaux Intelligents 56
Laboratory-on-Chip : Bacteria growth monitoring
29
GBM8320 - Dispositifs Médicaux Intelligents 57
Laboratory-on-Chip : Outline
• Illustration of the proposed system for Bacteria-on-Chip monitoring:
• LB : medium for bacteria
• Bacteria settles on the surface of chip which results in a capacitive element.
GBM8320 - Dispositifs Médicaux Intelligents 58
OS
0T
T
0 L
Rt
B
CRt
Iin
TPddC V)dt
Re
Re(A
CVV
T1V
L1B
+−⋅⋅−=
>>
−−
∫)2/C(C
21B
OSin
1B1ITPdd V
C/2)CC(C
A)V(V +−
⋅⋅−=2/
Instead of Impedance measurement with R, we measure here only Cs.
Output of sensor versus parameters
Laboratory-on-Chip : Bacteria growth monitoring
30
GBM8320 - Dispositifs Médicaux Intelligents 59
Laboratory-on-Chip : Bacteria growth monitoring
GBM8320 - Dispositifs Médicaux Intelligents 60
Laboratory-on-Chip : Magnetic manipulation
• Carbon array of electrodes used to push the bacteria toward the sensing electrode for measurement.
31
GBM8320 - Dispositifs Médicaux Intelligents 61
Laboratory-on-Chip : Cells Detection/manipulation
Implantable devices • Neurotransmitter detection &
separation • High sensitivity / selectivity
Target diseases: • Epilepsy • Alzheimer • Parkinson
Intracortical neural
Control Data
acquisition
LoC
GBM8320 - Dispositifs Médicaux Intelligents 62
Quadrature signals
Output signal referring to liquid concentration
Acquisition module: CBCM technique
Actuation module: Frequency / Magnitude control
DEP force
Sensing electrodes: capacitive sensor*
Actuation electrode matrix
CMOS chip** (0.18µm)
*Technology: Mixed CMOS-Microfluidic
**The same CMOS chip include both the acquisition and actuation module.
CMOS chip** (0.18µm)
Laboratory-on-Chip : Cells Detection/manipulation
32
GBM8320 - Dispositifs Médicaux Intelligents 63
Laboratory-on-Chip : References 1. A. Romani et al “Capacitive sensor array for localization of bioparticles in CMOS lab-on-a-
chip,” Digest of Technical Papers, IEEE ISSCC Conf., 2004, pp. 224 – 225.
2. D. Sylvester et al, “Investigation of interconnect capacitance characterization using CBCM technique and three-dimensional simulation,” IEEE JSSC, Vol. 33, no. 3, 1998.
3. C. Guiducci, C. Stagni, G. Zuccheri, "DNA detection by integrable electronics," J.. Biosensors and Bioelectronics, vol. 19, no. 9, 2004.
4. A. Hierlemann, Integrated Chemical Microsensor Systems in CMOS Technology, New York: Springer-Verlag, 2006.
5. E. Ghafar-Zadeh, M. Sawan and D. Therriault, “Novel direct-write CMOS-based laboratory-on-chip: Design, assembly and experimental results”, Sensors and Actuators A: Physical, Volume 134, Issue 1, 28 February 2007, Pages 27-36.
6. E. Ghafar-Zadeh, M. Sawan, “A Core-CBCM Sigma Delta Capacitive Sensor Array Dedicated to Lab-on-Chip Applications”, In press in Sensors & Actuators: A. Physical
7. E. Ghafar-Zadeh, M. Sawan and D. Therriault,“A Microfluidic Packaging Technique for Lab-on-Chip Applications”, In press IEEE Trans. on Advanced Packaging.
8. E. Ghafar-Zadeh, M. Sawan, “Charge-Based Capacitive Sensor Array for CMOS-Based Laboratory-On-Chip Applications”, IEEE Sensors, Vol. 8, No. 4, April 2008, pp. 325-232.
9. E. Ghafar-Zadeh, M. Sawan, “A Hybrid Microfluidic/CMOS Capacitive Sensor Dedicated to Lab-on-Chip Applications”, IEEE TBioCAS, Vol. 1, No. 4, December 2007, pp. 270-277.