FET Based Sensors Lecture 8 U-Tokyo Special Lectures Biosensors - - PowerPoint PPT Presentation

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

FET Based Sensors

Lecture 8

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Summary

• Ion Sensitive Field Effect Transistors
• Theory of operation, pH sensitivity
• Instrumentation and CMOS integration
• The REFET and differential measurement
• Weak inversion and charge trapping
• Example of ISFET Sensor IC
• Silicon nanowire biosensors

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Ion Sensitive Electrodes

• Potentiometric devices characterised by the

Nernst equation:

• Common form is the glass electrode for

measurement of pH

• Difficult to miniaturise so look for a solid

state equivalent?

3 E = E0 + RT nF ln ✓ai1 ai2 ◆

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Solution Source Encapsulation Vref Reference Electrode p−Si Drain SiO2 n−Si n−Si

Ion Sensitive Field Effect Transistor

• First developed in early 1970’s by Bergveld

at the Univ. of Twente

• MOSFET without 


a gate electrode

• Gate dielectric 


(SiO2) becomes 
 ion sensitive 
 membrane

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

MOSFET/ISFET

• Drain current of both MOSFET and ISFET:
• Threshold voltage (VSB = 0):
• Flatband voltage (MOSFET):

5 IDS = β ✓ (VGS − VT )VDS − V 2

DS

2 ◆ β = µCox W L VT = VF B + QB Cox + 2φF VF B = ΦMS − Qf + Qox Cox

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

VFB in an ISFET

• ISFET gate voltage is set by RE but the

solution will contribute to the VT

• Expression for ISFET flatband voltage:
• χsol - Solution dipole potential, Ψ0 - oxide

surface potential (solution side)

• All terms are constant except for Ψ0

6 VF B = Eref + Ψ0 + χsol − ΦSi − Qf + Qox Cox

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Oxide Surface Reactions

• Hydroxyl groups

formed at SiO2 surface

• Equilibrium reactions

• Protons from bulk

solution bind to sites

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Si Si Si O O Oxide Surface Solution O− proton
 donor OH2+ OH proton
 acceptor neutral site

SiOH ⇔ SiO− + H+

B

SiOH+

2 ⇔ SiOH + H+ B

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Surface Potential

• Full derivation is beyond this course, but

surface potential Ψ0 depends on pHB

• α is a dimensionless sensitivity parameter

and as it approaches unity the ISFET pH sensitivity becomes more Nernstian

• If α=1 then ∆Ψ0 = –59.2 mV/pH at 298K

8 δΨ0 δpHB = −2.3kT q α

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Sensitivity α

• Formula for ISFET sensitivity factor:
• We know k, T & q, so the important factors

are Cdl and βint

• Cdl - Electrical double layer capacitance
• βint - Buffer capacity of the oxide surface

9 α = 1

2.3kT Cdl q2βint

+ 1

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Double Layer Capacitance

• Cdl made up of two parts,

compact “Helmholtz layer” and the diffuse layer

• Diffuse layer width

decreases with solution concentration, increasing Cd

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+ − − − − − + + + + − − − − + + + + − − − − + + + + Electrode Surface Helmholtz Layer Diffuse Layer

CH Cd

1 Cdl = 1 CH + 1 Cd

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Buffer Capacity

• Ability of the dielectric surface to accept or

donate protons from solution

• The higher this is the closer α is to unity
• SiO2 hasn’t got a very high βint and

sensitivity is around –30 mV/pH

• Si3N4, Al2O3 and Ta2O5 are all better. Why?

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Effects of Gate Dielectric

• As βint increases the

response becomes more Nernstian

• Ta2O5 has high βint

and a sensitivity of 
 –58 mV pH–1

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Effects of Gate Dielectric

• Cdif varies with ionic

concentration

• This can seriously

affect an ISFET

• Ta2O5 βint is so high

that Cdif doesn’t matter

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Response

• Surface potential Ψ0 ∝ pHB and:
• So the ISFET VT will change with Ψ0 and:
• Assuming other terms stay constant

14 VF B = Eref + Ψ0 + χsol − ΦSi − Qf + Qox Cox δVT δpHB = −2.3kT q α

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Measuring ISFETs

• ISFETs are often biased in the linear region.
• Constant IDS and VDS with
• VT controlled by pH of measured solution
• Needs some electronic feedback

15 IDS = β ✓ (VGS − VT )VDS − V 2

DS

2 ◆ β = µCox W L

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Source and Drain Follower Circuit

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− + D S ISFET + − R

• Ref. electrode

V V

1 in 2

• ut

R R

3

V+ VDS = V− = V+ VR3 = VR1 = VinR1 R1 + R2 V+ = VR2 = VinR2 R1 + R2 IDS = VR3R3

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Source and Drain Follower Circuit

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− + D S ISFET + − R

• Ref. electrode

V V

1 in 2

• ut

R R

3

V+ IDS = VR3R3 VDS = VR2

CONSTANTS

δVT δpHB = −2.3kT q α δVout δpHB = 2.3kT q α

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Source and Drain Follower Circuit

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− + D S ISFET + − R

• Ref. electrode

V V

1 in 2

• ut

R R

3

V+ δVout δpHB = 2.3kT q α −1.3V < Vout < 3V

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Amplifier

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D S ISFET

• Ref. electrode

− + − + − + R R R R

2 2 3 3

Vout R1

Vdd

R1 RDS − +

ref

V Rout RS Iin I f

VDS = IinRDS δVS = IfRS IDS controlled by feedback Vout = IfRout = δVs Rout RS Vout = −δVT Rout RS

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Amplifier

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D S ISFET

• Ref. electrode

− + − + − + R R R R

2 2 3 3

Vout R1

Vdd

R1 RDS − +

ref

V Rout RS Iin I f

At pH=7 set Vref to give Vout=0V Vout ∝ δpH Set Rout for desired
 pH sensitivity

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Fabrication

• CMOS uses a “self

aligned” process

• Source/Drain implant

requires the polysilicon or metal gate as a mask

• Problem for

integrated ISFET production 21

e e te - self-aligned. e - self-aligned.

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

CMOS Compatible ISFET Structures

• Use metallisation layers

available in CMOS

• Connect ISFET gates to

the surface of IC

• Top passivation on ICs

is typically silicon nitride

• Ideal as a pH sensing

layer 22

S S D D G G G

p-type silicon substrate n-well Inter-Layer Dielectric Metallisation Silicon Nitride Membrane pH Sensing Region Oxide

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

CMOS Integration

• Previous instrumentation example doesn’t

work with n-ISFETs in CMOS

• N-MOS/ISFET has common, grounded p-

type substrate in most technologies

• Body effect - Offset voltage between bulk

and source.

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VT = VF B + 2φF + p 2εsqNa(2φF + VBS) Cox

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

The REFET

• One of the biggest problems in microscale

electrochemical sensors is the lack of a solid-state reference electrode

• These can be miniaturised (Ag/AgCl) but at

the cost of performance.

• The REFET isn’t a solid state reference

electrode but a way to do without one!

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

REFET Concept

• REFET - ISFET with pH sensing blocked
• Allows the use of a pseudo-reference
• This could be a simple platinum electrode

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ISFET

Pseudo

REFET +

• Diff.

Amp. Reference Electrode

V=f(pH,VPRE) V=f(VPRE) V=f(pH)

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

REFET Problems

• Ideally a REFET would be identical to the

ISFET but with no pH sensitivity

• In practice this is very difficult as the

blocking layers can affect VT mismatch

• This is a significant barrier to developing

practical ISFET based sensors

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Problems

• ISFETs are temperature dependent so an

integrated temperature sensor is useful

• Drift is a huge issue, with a Si3N4 sensing

layer it can gradually change to SiO2 or a silicon oxynitride in aqueous solutions

• Good encapsulation of metal connections is

essential for long-term stability

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Weak Inversion ISFET

• When VGS < VT the drain current is:
• If VDS > 4kT/q ignore the last part
• VT dependent on pH so:
• Where γ is a constant including the

reference electrode potential

28 ID = ID0 exp ✓q(VGS − VT ) nkT ◆ h 1 − exp ⇣ −VDS q kT ⌘i ID = ID0 exp  q nkT (VGS − γ − 2.3αkT q pH)

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Weak Inversion ISFET Sensitivity

• Sensitivity is affected by the slope factor n
• In an ISFET the slope factor includes effects
• f passivation layer and double layer:

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S D B Vref Cd CH CH Cpass solution device floating gate

n = 1 + Cdep Ceff 1 Ceff = 1 Cd + 1 CH + 1 Cpass + 1 Cox

S S D D G G G

p-type silicon substrate Inter-Layer Dielectric Metallisation Oxy-Nitride Passivation Oxide n+ source-drain regions

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Weak Inversion ISFET Output

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Georgiou, P ., & Toumazou, C. (2009). Sensors & Actuators: B. Chemical, 143(1), 211–217. doi:10.1016/j.snb.2009.09.018

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ChemFETs

• The ISFET is really a subspecies of

ChemFET

• Changing the oxide material can make it

sensitive to other ions (K+, Ca2+, F–, etc.)

• Alternatively coat with another material

that is sensitive to a non-ionic chemical

• This sensing layer should change local pH or

produce a change in charge for FET sensing

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ENFETs

• Similar to enzymatic conductivity sensors

discussed in previous courses

• Using an ISFET as transducer requires an

enzymatic reaction that produces protons

• Can easily be combined with a bare ISFET

for differential measurement as with REFET

• Sensitivity can be extremely non-linear

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Bio-FET Sensors

• Other possibilities include
• Immuno-FETs with immobilised anti-bodies
• “Gene-FETs” with immobilised DNA
• Cell-FETs, measuring cellular processes
• Useful review paper:
• M.J. Schöning and A. Poghossian, The Analyst, 

• vol. 127, pp.1137–1151, 2002.

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

METOXIA Chip

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Structure

• AMS standard 0.35µm CMOS process

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S D B D CPass CP Cov1 Si3N4 SiO2 M1 M2 M4 . . . Cov2 CP

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Circuit

• Differential ISFET

interface.

• Two “complementary

ISFET

• MOSFET pairs”
• Should have linear

response 36 ∆Vout = ∆VTn ✓ 1 √a1 − 1 √a2 ◆

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Oxygen Sensor

• Noble metal working electrode held at

cathodic potential in aqueous solution

• Multiple reactions can occur:
• O2 + 2H2O + 2e– → H2O2 + 2OH–
• H2O2 + 2e– → 2OH–
• O2 + 2H2O + 4e– → 4OH–
• O2 + 4H+ + 4e– → 2H2O

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Oxygen Sensor

• All of these reactions will increase the pH

close to the electrode.

• O2 + 2H2O + 2e– → H2O2 + 2OH–
• H2O2 + 2e– → 2OH–
• O2 + 2H2O + 4e– → 4OH–
• O2 + 4H+ + 4e– → 2H2O

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

The O2-FET

39

436

B.-IC Sohn, C,-S. gim / Sensors and Actuators B34 (1996)435--440

A

I"' U

141Ol

ion sensing get

A'

Vrs

. . . . . . ] !ocal pH

Vrs-O.65V ~ / change

LJ--~LIT--~ i °-- i ~

• .--1-E.4.~---4-~

Fig, 1, Cross-~ction and layout of a sensor (1, source; 2, substrate; 3, Pt working electrode; 4, drain; not to real scale).

such as cathode material, electrolyte pH, pretreatment and aging of the cathode surface. An electrochemical current flows between the two electrodes, giving current output related to the dissolved

• xygen concentration. The conventional Clark type oxy-

gen sensor determines dissolved oxygen concentration by measuring this electrochemical current. A pH change by the generation of hydroxyl ions (OH-) as well as a current flow occurs simultaneously and this pH change is of im- portance in the proposed sensor. A working electrode surrounding a pH-sensing gate of a pH-ISFET electro- lyzes dissolved oxygen, resulting in a pH variation due to

• xygen reduction in close proximity to the pH-sensing

gate as shown in Fig. 1. The pH-ISFET, a well-known pH sensor, then detects this pH variation that is logarithmi- cally proportional to the oxygen content. This can be used as either a pH sensor or a dissolved oxygen sensor. Such a device structure including a noble metal electrode has also been used for application to a ISFET-based titration system [10-12] although the subject treated in these pa- pers is different from oxygen sensing. The accumulation of hydroxyl ions near the cathode has been treated by many researchers [ 13-15]. Their work focused on the effect of accumulation of the reaction products on the iinearity, sensitivity and transient charac- teristics of the amperometric signal. The transport of the neutral oxygen molecules to the cathode is a well known diffusion-limited process, which results in a zero oxygen concentration at the cathode surface and a limiting diffu- sion current determined by the concentration gradient. Hale et al. [ 13] treated the transport of hydroxyl ions from the cathode as diffusion from a continuous point source

• n an infinite plane surface by making proper assump-

tions for a membrane-covered probe. His simple calcula- tion showed that the concentration of hydroxyl ions at the

• uter edge of cathode was about 26 mM, which corre-

sponds to pH 12.4 in an initially neutral and unbuffered solution, after the establishment of a steady-state current in an air-saturated sample. Without the permeable mem- brane, this pH change is expected to diminish since the hydroxyl ions can diffuse away from the cathode surface to the bulk solution more easily.

• 3. Experiments and results

The ISFET was fabricated by a conventional CMOS process and the gate material consisted of 50 nm thick SiO2 and 50 nm thick Si3N4. A 15 nm thick titanium glue layer and a 150 nm thick platinum layer were sputtered

• n the wafer and patterned by a lift-off process. The size
• f the pH-sensing gate was 20 × 400#m and the

exposed working electrode area after encapsulation was 0.056 mm 2.

• Fig. 2 shows a bias configuration for the sensor opera-
• tion. The pH-ISFET was operated in a constant drain cur-

rent (/ds = 150MA) and constant drain voltage (Vds = 3 V)

• mode. A three electrode system was used to eliminate any
• hmic potential drop through the solution. The Ag/AgCI

reference electrode used was not an integrated one but a sleeve type single junction electrode (ORION model 900100) and the counter electrode was placed on the backside of the sensor probe. The measurement technique is based on the chroaoamperometric method [16] in which a stepwise potential pulse is imposed on the work- ing electrode. The working electrode potential (Vw) is changed from a rest value (ground potential) where the reduction of oxygen can hardly occur to a predetermined reduction potential chosen in a voltammogram. In the chronoamperometric method, there is an initial current

Vw

+v

• V
• Fig. 2. Bias configuration for the sensor operation.

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

The O2-FET

• Apply –0.65 to –0.85 V to NME vs. Ref
• Bias ISFET with fixed VDS, IDS
• Two separate reference


electrodes used

• Measure Vs vs. RE to 


get the local pH

• Modulate VNME to 


measure pO2 and pH

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

ISFET Based pO2 Sensing

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Pad opening for FIB deposited platinum

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Silicon Nanowire Biosensors

• Summary
• Sensing - why use nanowires
• Fabrication - top down vs. bottom up
• Novel top down fabrication techniques
• Biosensor applications

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Nanowire Sensing

• Similar concept to a

FET based sensor

• Sensing changes

conduction in NW

• Increased surface to

volume ratio

• Label free detection

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

SiNW Fabrication

• Bottom up

fabrication

• Pre-doped silicon

substrate

• Gold nanoparticle

catalyst

• Vapour-liquid-solid

CVD process to grow wires

• Process controls NW

length and diameter

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

SiNW Fabrication

• Bottom up fabrication
• SiNW removed

from growth substrate

• Deposit and

fabricate 
 S/D electrodes

• Other techniques

can be used to align NWs 45

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Si-NW Fabrication

• Top down fabrication
• Silicon on insulator

substrate

• Pre-doped device

layer

• Pattern and etch to

produce nanowires

• Requires expensive 


nano-scale lithography

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Cheaper Top-Down Processes?

• Typical top down process requires

expensive nano-lithography

• Alternative processes leverage standard

microfabrication techniques

• Plane dependent wet etching of Si
• “Spacer” process for PolySi-NW

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Anisotropic Silicon Etch

48

• Developed at the
• Univ. of Twente
• Standard micro-

lithography

• Lattice dependent

etch with TMAH

• Custom process

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Polysilicon Nanowires

• Similar technique to

spacers in advanced CMOS technologies

• LPCVD - conformal

polysilicon deposition

• Anisotropic RIE to

leave nanowires

• Southampton work
• n rectangular NW

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

SiNW Biosensors

• What do we need from a biosensing

element for it to work with a SiNW?

• Enzyme?
• Antibody/Antigen interaction?
• DNA/RNA recognition?

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Si Nanoribbon Biosensor

• Measure the H+ ions released during

enzymatic reaction

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Mu, L. et al., (2014), Nano Letters, 14(9), 5315–5322. doi:10.1021/nl502366e

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Polysilicon NW Sensor

• Sub-threshold swing 2-3

V/decade (back gate)

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Polysilicon NW Sensor

• 1-7 increased TNF-α conc. 10 fM to 100 nM

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Charge Screening in SiNW Sensors

• TNF-α has an overall positive charge
• In theory this should reduce conductivity in

a p-type polySiNW

• Debye length of the solution determines

the effective sensing depth

• In this case it screens the positive change of

the antigen giving a negative potential effect

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Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Si-NW DNA Sensors

• Univ. of Twente nano-

wire process

• Peptide nucleic acid

(PNA) probe

• Boron doped (p-type)

silicon nano-wires

• –ve charged DNA

binding causes change in conductance 55

images of fabricated Si-NWs. (a) 2-wire Si-NW device. (b) 16-wire Si-NW devic

De, A.,et al., (2013) The Analyst, 138(11), 3221–3229. doi:10.1039/C3AN36586G

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Si-NW DNA Sensors

• Differential mode

reduces common mode effects

• AC measurement

with lock-in-amplifier to reduce noise

• Problem of making

the reference sensor may remain 56

De, A.,et al., (2013) The Analyst, 138(11), 3221–3229. doi:10.1039/C3AN36586G

Stewart Smith Biosensors and Instrumentation U-Tokyo Special Lectures

Summary

• Ion Sensitive Field Effect Transistors
• Theory of operation, pH sensitivity
• Instrumentation and CMOS integration
• The REFET and differential measurement
• Weak inversion and charge trapping
• Example of ISFET Sensor IC
• Silicon nanowire biosensors

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