I. Introduction II. Biochemistry III. Microfluidic Packaging IV. Capacitive Sensors V. On-Chip Cells Detection and Manipulation.

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1 25 février 2010 Laboratory-on-Chip : Outline I. Introduction II. Biochemistry III. Microfluidic Packaging IV. Capacitive Sensors V. On-Chip Cells Detection and Manipulation. GBM Dispositifs Médicaux Intelligents 2 1

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 d Fast biological assays 1 hr to 1ms

2 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 d Fast biological assays 1 hr to 1ms Miniaturized devices + E - Home healthcare, Point-of-care monitoring, Home diagnostic, V Portable devices Miniaturization is only solution for single cell detection : Sensitivity = DVolume/Volume GBM Dispositifs Médicaux Intelligents 3 Laboratory-on-Chip : CMOS-Based µsystems Application Method Microfluidic CMOS Year Authors Cells monitoring Organic solvent Sensor Bioluminane detection DNA detection Magnetic manipulation Virus detection Cell localization Capacitive Sensor Core CBCM capacitive Sensor Optical Method Capacitive Sensor Array of µcoils Capacitive Sensor Capacitive Sensor Adhesive technique 0.5um 2007 Prakash et al DWFP 0.18um 2007 Ghafar-Zadeh et al Rapid Prototyping 0.18um 2007 Eltoukhy et al Rapid Prototyping 0.5um 2006 Stagni et al MEMS based Procedures 0.18um 2006 Lee et al Rapid Prototyping 0.35um 2005 Balasubramanian et al Adhesive technique 0.35um 2004 Romani et al Dielectrophoresis Array of Rapid 0.35um 2003 Medoro et al manipulation µelectrodes prototyping GBM Dispositifs Médicaux Intelligents 4 2

3 Laboratory-on-Chip : Technologies Glucose Detection Rapid Bacterial Diagnosis DNA µarray EZ Smart Monitoring STMicroelectronics Affymetrix Inc. Requires scanner for reading out GBM Dispositifs Médicaux Intelligents 5 Laboratory-on-Chip : Multidisciplinarity Selected bioparticle Electric Signal Diagnostic information Patient Blood sample preparation Laboratoron-Chip Lab-on- Information technology Physician BIO Micro / Nano BioInfo Material flow Information flow GBM Dispositifs Médicaux Intelligents 6 3

Laboratory-on-Chip : CMOS-based devices Microchannel

On-chip nonuniform electric field; Cell manipulation.

Laboratory-on-Chip : Capacitor sensing applications DNA

Antibody-antigen recognition Cell monitoring (charges

Organic solvent detection (Chemical gas change

Our reported new applications : 1) Organic Solvent

4 Laboratory-on-Chip : CMOS-based devices Microchannel Sensing Layer Vdd Cell Interface Circuit Electrode ΔC On-chip nonuniform electric field; Cell manipulation. Microfluidic structure ; Sensing layer ; Interface circuit : Sensor or Manipulator. GBM Dispositifs Médicaux Intelligents 7 Laboratory-on-Chip : Capacitor sensing applications DNA detection (hybridisation generates extra charges) Antibody-antigen recognition Cell monitoring (charges generate dipoles). Organic solvent detection (Chemical gas change dielectric capacitance). Our reported new applications : 1) Organic Solvent Detection, 2) Bacteria Growth Monitoring, 3) Polyelectrolyte layer detection. Hagleither et al, IEEE SSCJ, Dec Ghafar-Zadeh et al, CJECE, GBM Dispositifs Médicaux Intelligents 8 4

Laboratory-on-Chip : Fundamental of Biochemistry Fundamental of biological particles Blood ; Cells ; Chromosomes

chromosome consists of long supercoiled strands of molecules.

biological test through desktop, or room size systems Sampling Concentration Purification Microfluidic needle

levitation, rotation, etc. Electrophoresis for molecule level preparation. P.Grodzinski & al. Motorola labs.

5 Laboratory-on-Chip : Fundamental of Biochemistry Fundamental of biological particles Blood ; Cells ; Chromosomes ; Genes ; DNA ; Fractioning Blood Chromosomes DNA Strands 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. GBM Dispositifs Médicaux Intelligents 9 Laboratory-on-Chip : Fundamental of Biochemistry A typical biological test through desktop, or room size systems Sampling Concentration Purification Microfluidic needle Dielectrophoresis (no charge) Electrophoresis (charge) Signal Analysis Digital and Software DEP for Separation, levitation, rotation, etc. Electrophoresis for molecule level preparation. P.Grodzinski & al. Motorola labs. Anal. chem. 76, P.1824, 2004 Centrifuge system Detection Analog DNA PCR Amplification Microfluidic and Molecules Temperature control system PCB Microfluidic Sensor Fragmentation Uniform electric field Cells Polymerase Chain Reaction (PCR) GBM Dispositifs Médicaux Intelligents 10 5

Laboratory-on-Chip : Fundamental of Biochemistry An antigen is defined as a substance that can be bound

Specific Recognition Signal Anti-body No Signal Antigen Antibody Non-specific Recognition GBM8320 -

fluidics (Silicon) Various applications: microvalves, microjets, lab-on-chip, Gas Chromatography,

6 Laboratory-on-Chip : Fundamental of Biochemistry An antigen is defined as a substance that can be bound by an antibody molecule through its antigen-binding sites, also called epitopes. Specific Recognition Signal Anti-body No Signal Antigen Antibody Non-specific Recognition GBM Dispositifs Médicaux Intelligents 11 Laboratory-on-Chip : Microfluidic Packaging 3D microstructures for fluidics (Silicon) Various applications: microvalves, microjets, lab-on-chip, Gas Chromatography, microfluidics. Micronozzle on silicon for sampling purposes. MINOS, Ljubljana, D. Resnik et al GBM Dispositifs Médicaux Intelligents 12 6

Sacrificial layer Robotically controlled

7 Microfluidic Packaging : Rapid prototyping On-Chip magnetic manipulation Microfluidic PCB Flow -- Rapid prototyping methods -- Glass Gasket CMOS Chip Lee, H. et al, IEEE, Journal of Solid State Circuits, Manaresi, N. et al, IEEE, Journal of Solid State Circuits, GBM Dispositifs Médicaux Intelligents 13 Microfluidic Packaging : Direct-write assembly Robotic based method for ink dispensing Ink : Sacrificial layer Robotically controlled deposition (RCD) machine* Cesarano, J., Freeforming objects with low-binder slurry, US patent. Therriault et al., Nature Materials, GBM Dispositifs Médicaux Intelligents 14 7

Microfluidic Packaging : Direct-write assembly Resin infiltration Solidification

controlled apparatus for deposition in a predefined pattern; Micronozzle

is binary organic ink composed of petroleum jelly and microcrystalline wax.

Direct-write assembly Sensing electrodes Fugitive Ink and fluidic Connection

8 Microfluidic Packaging : Direct-write assembly Resin infiltration Solidification of structural material Removal of fugitive ink Ink deposition Robotically controlled apparatus for deposition in a predefined pattern; Micronozzle Air-operated dispensing system for ink extrusion through micronozzle Fugitive ink is binary organic ink composed of petroleum jelly and microcrystalline wax. GBM Dispositifs Médicaux Intelligents 15 Microfluidic Packaging : Direct-write assembly Sensing electrodes Fugitive Ink and fluidic Connection Fugitive dam, epoxy resin, ink removel, and analyte injection. (a) (b) (c) GBM Dispositifs Médicaux Intelligents 16 8

9 LoC : Charge-Based Capacitive Measurement Interconnect or sensing capacitance C can be retrieved/measured from the following equation: (I S I R ) = f V dd ΔC Vdd CBCM Is where C = Cs - C0, and C0 = CR Originated Year 1997 External tools Main application Resolution Frequency UC Berkeley DC Ammeter Capacitance characterization Sub femtofarad <15 MHz CR M3 B M4 M1 A M2 CS GBM Dispositifs Médicaux Intelligents 17 LoC : CBCM-based capacitive sensor Current mirror and integrating capacitor instead of dc Ammeter. ( Vdd VTP ) CS VS = ( Vdd VTP ) dv K ( V V ) t + C S 2 CS = K x ( Vgs VTP ) Vdd-Vs=Vgs 2 dt [( Vdd VTP ) CS ] K x AI 1 I( CS, t) 2, Low K ( V V ) t + C V d d A I S M 1 C A M 2 x dd TP S [ ] x dd TP S V d d M 3 M 4 Is I(Cs,t) Is M 1 Vs Vout Cin Cin Cs M 2 Ghafar-zadeh, Sawan, IEEE TBioCAS, 2007 GBM Dispositifs Médicaux Intelligents 18 9

LoC : CBCM-based capacitive sensor dvout = IS dt Cin Vout CS dvs I s = dt AI Vdd ΔC + C0 = AI (Vdd VTP ) + V0 Cin Cancellation of C0 (C0 >>!C ) Accurate reference current is needed.

limit the dynamic range, then Voff should be minimized. Is Vout!C << Cp, the effect of Cp is almost cancelled by measuring CS-CR before converting to voltage.

10 LoC : CBCM-based capacitive sensor dvout = IS dt Cin Vout CS dvs I s = dt AI Vdd ΔC + C0 = AI (Vdd VTP ) + V0 Cin Cancellation of C0 (C0 >>!C ) Accurate reference current is needed. Vout = AI IS M1 C Is/AI A M2 Charging mode Reset mode Vout Sampling Cs (V VTP ) + Voff Cin dd 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. Is Vout!C << Cp, the effect of Cp is almost cancelled by measuring CS-CR before converting to voltage. GBM Dispositifs Médicaux Intelligents 19 LoC : CBCM-based capacitive sensor In agreement with the calculation and simulation; Higher dielectric constant of organic solvent, higher output voltage. M5 M3 CBCM* ID1 M Is M1 13 Vb1 M7 CS Vout Vout Methanol Injection Is- Dichloromethane Injection Vout Cint M10 GBM Dispositifs Médicaux Intelligents 20 10

LoC : CBCM-based capacitive sensor Microscopic images of chip. Interdigitated electrodes Passivation layer removal Reference and sensing electrodes.

11 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 GBM Dispositifs Médicaux Intelligents 21 LoC : CBCM : Linearity & mismatch error Mismatch only affects an offset voltage M7 M4 M2 M % change of 1100 W1 W2 W3 W4 Vb1 M3 M1 IS Vout Vb1 Vout (mv) W5 W6 W7 W8 CR M6 M8 CS Cint % change in Wi Reset mode Vout Sampled voltage Cs (ff) GBM Dispositifs Médicaux Intelligents 22 11

12 LoC : CBCM-based capacitive sensor Cancellation of Vos Vdd Rp through Rp; A replica of sensing circuit is employed to generate reference current. M8 M7 M5 M1 ID2 M2 ID1 CR M4 Cs M3 SR IS - Cin M10 M6 IS M9 FPGA Vo GBM Dispositifs Médicaux Intelligents 23 Laboratory-on-Chip : Outline Adjustable current mirror gain (D1-Dm) Three stages unity current mirror. M13 CBCM Q2 Q1 M 1 3 CBCM V d d B V a V b A C M 10 M 9 M 8 I s S 1 A V c M 14 I M 5 V o u t B M c m M c 1 M 15 S W 1 M 6 D m D 1 M 7 C GBM Dispositifs Médicaux Intelligents 24 12

13 Laboratory-on-Chip : Outline Adjustable current mirror gain (D1-Dm) 1-bit DAC Calibration circuit Vdd MDAC MCM MC1 M6 M4 M3 M5 SDAC SCM SC1 qn Dm D1 IDAC Vb1 M8 Vb2 M10 CR CBCM M2 M1 Ck1 M13 M14 Ck2 ID1 Is M7 Vb1 CS Vb2 M9 Cint M11 Vout Is- Ck3 M12 I R = I R0 (1 + 2 m-1 D C m-k D Ck + + D CM ). M10 GBM Dispositifs Médicaux Intelligents 25 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. x n + LPF q n I Vout x 1-bit DAC I s q n = x Xn I x I x F 1 I(Cs, t) F 2 - V o Sw1 + C i n Sw2 V R V R n Q 1 Q 2 Ghafar-zadeh & Sawan, J. of IEEE Sensors, no.4, 2008 GBM Dispositifs Médicaux Intelligents 26 13

Laboratory-on-Chip : Sigma-Delta ADC Xn Post-layout simulation results Unique sequence. Sw1 I x - + V R I(Cs, t) V o C i n Sw2 Vout (output pulse) Q 1 Q 2 1. 8 C = 0.3 ff (V) 1. 8 0 C = 0.

14 Laboratory-on-Chip : Sigma-Delta ADC Xn Post-layout simulation results Unique sequence. Sw1 I x - + V R I(Cs, t) V o C i n Sw2 Vout (output pulse) Q 1 Q C = 0.3 ff (V) C = 0.22 ff Time (msec) GBM Dispositifs Médicaux Intelligents 27 Laboratory-on-Chip : Outline An array of capacitive sensors. O f f - c h i p F P G A S y s t e m CS1 CS2 CS3 Adjustable reference current. dc A/D converter Offset cancellation procedure ( FPGA). Stop calibration & recording D1-m N o F 1 F 2 U < V t h D 1 - m = D 1 - m + 1 Y e s ADC S1 S2 S3 Reset UIC1 S 1 V o u t B u f f e r UIC2 S 2 I s Cin CR UIC3 S 3 I R Ajustable Current Mirror D 1-8 f s VR On-chip circuit GBM Dispositifs Médicaux Intelligents 28 14

Laboratory-on-Chip : Outline ( I I ) = f V ΔC S R dd log( I I ) = log f + log( V ΔC) 2 1 dd ΔC where Cs=ΔC+C0 Extraction of sensing capacitance variation 10 Log (I2-I1) -50-60 -70-80 -90-100 Acetone

15 Laboratory-on-Chip : Outline ( I I ) = f V ΔC S R dd log( I I ) = log f + log( V ΔC) 2 1 dd ΔC where Cs=ΔC+C0 Extraction of sensing capacitance variation 10 Log (I2-I1) Acetone Methanol DI water ( C0: Parasitic capacitance) -110 D C -120 B -130 A 1 1E1 1E2 1E3 f(hz) 1E4 1E5 1E6 GBM Dispositifs Médicaux Intelligents 29 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 GBM Dispositifs Médicaux Intelligents 30 15

Laboratory-on-chip based sensors Part 2: Capacitive measurements

GBM8320 Dispositifs Médicaux Intelligents Laboratory-on-chip based sensors Part 2: Capacitive measurements Mohamad Sawan et al. Laboratoire de neurotechnologies Polystim!!! http://www.cours.polymtl.ca/gbm8320/!