26 february 2014 - polytechnique montréal · 2014-02-25 · ez smart monitoring laboratory-on-chip...

26 February 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.


• Low sample consumption;

• Fast biochemical reactions & Miniaturization;

• Point-of-care.

Laboratory-on-Chip : Advantage


Laboratory-on-Chip : CMOS technology

•  Low voltage, and low power;

•  Addressable sensing or manipulating sites;

•  Standard technology.


I.  Introduction

II.  Biochemistry

III.  Microfluidic Packaging

IV.  Capacitive Sensors

V.  On-Chip Cells Detection and Manipulation.

Laboratory-on-Chip : Outline


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!


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


Affymetrix Inc.!

Requires scanner for reading out!

EZ Smart Monitoring

Laboratory-on-Chip : Technologies

Glucose Detection DNA µarray Rapid Bacterial Diagnosis

STMicro-electronics


Laboratory-on-Chip : Future Technologies

Display

Disposable needle

Sensor

Syringe Microchannel

Past Room

Laboratory

Today Desktop

Laboratory

Future Pencil-Size Laboratory


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


• 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.


,...,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!


!  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!


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!


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.


I.  Introduction

II.  Biochemistry






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!


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.



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.


Polymerase Chain Reaction (PCR)

Centrifuge system Fragmentation

PCR

Cells

DNA

Molecules



•  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.


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).


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..


•  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


Antibody

Antigen


I.  Introduction

II.  Biochemistry






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


•  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!


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 --


•  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!


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


•  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



Removal of fugitive ink

Ink deposition

Before degassing

After degassing

During infiltration

Optical microscope images during resin infiltration process


•  Resin infiltration between patterned features •  Solidification (Resin cures at room temperature) •  Removal of fugitive ink under vacuum.

Femlab


(a)

(b)

•  Sensing electrodes

•  Fugitive Ink and fluidic Connection

•  Fugitive dam, epoxy resin, ink removel, and analyte injection.

(c)

Microfluidic Packaging : Direct-write assembly


•  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


I.  Introduction

II.  Biochemistry

III. Microfluidic Packaging

IV. Capacitive Sensors

V.  Cells Manipulation and Detection.



Laboratory-on-Chip : Capacitive sensors


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


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


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


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


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



Gnd!

Gnd!


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!



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



•  Microscopic images of chip.

•  Interdigitated electrodes

•  Passivation layer removal

•  Reference and sensing electrodes.

Ghafar-Zadeh et al, Sensors and Actuators A: Physical, 2008


•  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)


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 WiV

out (

mV

)

20% change of 1200

Mismatch only affects an offset voltage

LoC : CBCM : Linearity & mismatch error


•  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



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

)


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



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)


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


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



•  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


Laboratory-on-Chip : Measurement set-up



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)


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


Laboratory-on-Chip : Bacteria growth monitoring



•  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.


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 : Magnetic manipulation

• Carbon array of electrodes used to push the bacteria toward the sensing electrode for measurement.


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


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


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.

26 february 2014 - polytechnique montréal · 2014-02-25 · ez smart monitoring laboratory-on-chip...

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