CMOS Nanowire Biosensor Systems - IEEE Boise 22April11 public.pdf · CMOS Nanowire Biosensor...

CMOSCMOS NanowireNanowireCMOSCMOS NanowireNanowireCMOS CMOS NanowireNanowireBiosensor SystemsBiosensor SystemsCMOS CMOS NanowireNanowire

Biosensor SystemsBiosensor SystemsMark Mark ReedReed

Yale UniversityYale UniversityMark Mark ReedReed

Yale UniversityYale University

Departments of Applied Physics and Electrical Engineering Departments of Applied Physics and Electrical Engineering Yale Institute for Yale Institute for NanoscienceNanoscience and Quantum Engineeringand Quantum EngineeringDepartments of Applied Physics and Electrical Engineering Departments of Applied Physics and Electrical Engineering Yale Institute for Yale Institute for NanoscienceNanoscience and Quantum Engineeringand Quantum Engineering

with: Eric Stern, Alek Vacic, Nitin Rajan, David Routenberg, Erin Steenblock, Jason Criscione, Jason Park, P f T k F h

with: Eric Stern, Alek Vacic, Nitin Rajan, David Routenberg, Erin Steenblock, Jason Criscione, Jason Park, P f T k F hProf. Tarek Fahmy

Thanks to: Jin Chen, James Klemic, Daniel Turner-Evans, Pauline Wyrembak Cathy Jan

Prof. Tarek Fahmy

Thanks to: Jin Chen, James Klemic, Daniel Turner-Evans, Pauline Wyrembak Cathy JanWyrembak , Cathy JanLabs of Profs. Ronald Breaker, Andrew Hamilton, Tarek Fahmy

Wyrembak , Cathy JanLabs of Profs. Ronald Breaker, Andrew Hamilton, Tarek Fahmy

WMED Boise, ID April 22, 2011 M. Reed (Yale) WMED Boise, ID April 22, 2011 M. Reed (Yale)

Current Macromolecular SensingCurrent Macromolecular SensingLabeled sensingLabeled sensingLabeled sensingLabeled sensing

DNA i diDNA i di DNA flDNA fl ELISA I di flELISA I di flDNA sequencing, radiotagDNA sequencing, radiotag DNA array, fluorDNA array, fluor ELISA: Indirect fluorELISA: Indirect fluor

Unlabeled sensingUnlabeled sensing


Suspended cantileverSuspended cantileverSurface plasmon resonanceSurface plasmon resonance Electrical : ISFETElectrical : ISFET

NanowireNanowire biosensorsbiosensors(unlabeled detection)(unlabeled detection)(unlabeled detection)(unlabeled detection)

ISFETs detection limits ISFETs detection limits typically ~typically ~ μμMM

10nm diameter

dI 1~1typically ~ typically ~ μμMM

GaN NW

rdQIWMED Boise, ID April 22, 2011 M. Reed (Yale) WMED Boise, ID April 22, 2011 M. Reed (Yale)

Vapor-Liquid-Solid (VLS) nanowire FETsVapor-Liquid-Solid (VLS) nanowire FETs

VVDD

SourceSourceGateGate DrainDrainNW NW mobilitiesmobilities vsvs theoretical limits, theoretical limits, epiepi

GateGate

SiSi

SiOSiO22

100

1000

s)

max theory

VVGG

1

10

bilit

y (c

m2 / V

s

CVD GaN NWs

0.1

1

As-grown GaN NWsOptimized GaN NWs

Theoretical ITheoretical II

GaN Epitaxial

Mo

significant spread in characteristics

0.011017 1018 1019 1020 1021 1022

Theoretical II

Carrier Concentration (cm-3)

characteristics

B J PhB J Ph 3636 824 (2006)824 (2006)


J. Vac. Sci. Technol. J. Vac. Sci. Technol. B24B24, , 231 (2006). 231 (2006). Appl. Phys. Appl. Phys. LettLett. . 8888, 053106 (2006) ., 053106 (2006) .

Braz. Jour. Phys. Braz. Jour. Phys. 3636, 824 (2006). , 824 (2006).

Silicon-on-insulator (SOI) CMOS NanowiresSilicon-on-insulator (SOI) CMOS Nanowires

1 µm

30 nm 30 nm channel channel

idthidth2µm

2 µm

widthwidth

multiplexed


anisotropic etchinganisotropic etching(100)/(111) etch rates ~ 1000:1 dx /dt ~ 3Å/sec

SS

(100)/(111) etch rates ~ 1000:1, dx(111)/dt ~ 3Å/sec

DDGGGG

++200nm

p++

x


p-type accumulation mode (backgate) – 1st genp-type accumulation mode (backgate) – 1st gen

-3µ 1n

100n

A)|

ΔVG=1V300K, dry

VG=-40V VSD=-1V

-2µ

D (A

)

1f

100f

10p

|I SD (Aw=50nm, t=25nm

-1µ

I SD 0 -10 -20 -30 -401f

VGD (V)

400

0 -5 -10 -15

0

VSD (V)

0V

400

cm2 /V

s)

HallDrift

SD ( )

30 10040

100

Mob

ility

(c

w = 300 nmt = 25 nm

max max = 139 cm= 139 cm22/V/V--ss

Fully depleted; n0 ~ 1x1015 cm-3

= 54 cm= 54 cm22/V/V--ss30 100

Temperature (K)


Complimentary devices – 2nd genComplimentary devices – 2nd gen

1E-8

1E-6

A)

-0.1 V -0.2 V -0.3 V -0.4 V

0 5 V 1E-8

1E-6 n channel45nmV =6 5V

1E-12

1E-10

1E 8

Dra

in C

urre

nt (A -0.5 V

1E-12

1E-10

1E 8

Dra

in C

urre

nt

0.1 V 0.2 V 0.3 V 0.4 V 0.5 V

p channel45nmVt=-2.8V~ 200 cm2/V-sSS= 400mV/dec

Vt=6.5V~ 500 cm2/V-sSS=525mV/dec

-20 -10 0 10 201E-14

Back Gate Voltage-5 0 5 10

1E-14

Back Gate Voltage

1.0x10-6

1.5x10-6

urre

nt

-5V -4 V -3 V -2V -1 V 0 V 1 V2 V

2.0x10-7

urre

nt

10 V 9 V 8 V 7 V 6 V 5 V

2 0 1 5 1 0 0 5 0 00.0

5.0x10-7

Dra

in C

u 2 V 3 V

0 0 0 5 1 0 1 5 2 00.0

1.0x10-7D

rain

Cu

-2.0 -1.5 -1.0 -0.5 0.0Drain-Source Voltage

0.0 0.5 1.0 1.5 2.0Drain-Source Voltage


1/f noise of nanowires1/f noise of nanowires

SnO2

InAs

αS HIITRSSi SOI NW (best)αH = 1.6 x 10-4

Nf=

IHI

2


HoogeHooge parameterparameter SubthresholdSubthreshold slopeslope


N. K. Rajan et al, Elect. Dev. Lett. 31, 615 (2010).

Operating PointOperating Point

Linear Region:Linear Region:

dsdsds

ds

initialD

D

VVVVV

VI

dVdI

211

21

02

0,

0

ox

VVV

LWC

S bth h ldS bth h ld

22

kTqV

IkTq

dVdIgs

D 1exp0

0

s

tgs

d

VVV

Subthreshold Subthreshold Region:Region: SkT

q

kTqV

I

kTkTI

dVdI

gsD

initialD

gD 1

exp0,

)(11

gs

CC

dV

)(1 oxd CC

G = 8 2 x 10-6In Subthreshold Region In Linear Region

exampleexample

Subthreshold Swing = 190 mV/decS = 1/SS = 5.3pH Response = 0.3 Dec/pH

Gm 8.2 x 10ID = 8.0 x 10-6 x Overdrive VoltageS= Gm / ID = 1.03/ VOpH Response = 0.062/VO Dec/pH


At 1 volt overdrive, sensitivity is decreased by 5X

Selective FunctionalizationSelective FunctionalizationFunctionalizationFunctionalization

DecDec--99--enylenyl--carbamic acid carbamic acid terttert--butyl esterbutyl ester

APTESAPTES

Ratio of Si sensor area Ratio of Si sensor area to parasitic importantto parasitic important

NH

H

p pp p

3-aminopropyl-

SiOOO

triethoxysilane


Fluid ConsiderationsFluid Considerations Nano LettNano Lett 55, 803 (2005) , 803 (2005)

1E8

1E10

1E12

1E8

1E10

1E12

100

10000

1000000

1E8

cule

s/M

in

xx

Silicon-specificfunctionalization

100

10000

1000000

1E8

cule

s/M

in

xx

Silicon-specificfunctionalization

2 0

1E-4

0.01

1

100

# M

olec

xxNonspecificfunctionalization1E-4

0.01

1

100

# M

olec

xxNonspecificfunctionalization

020

2

Cudz

CdDJ zz 0

10-15 10-14 10-13 10-12 10-11 10-10 10-91E-6

C0 (M)10-15 10-14 10-13 10-12 10-11 10-10 10-9

1E-6

C0 (M)

xx = microfluidics= microfluidicsScienceScience 293, 293, 12891289 (2001)(2001)


xx = mixer (resorvoir)= mixer (resorvoir)NatureNature 445, 445, 519 (2007)519 (2007)

Biotin-Avidin & Streptavidin SensingBiotin-Avidin & Streptavidin SensingStreptavidin SensingStreptavidin Sensing

300

receptorreceptor(biotin)(biotin)

pp--type accumulation mode, type accumulation mode,

300n

StreptavidinQuenched S-AvPEGylated

analyteanalyte

pp ypypbiotinylatedbiotinylated NW deviceNW device

avidinavidin positive charge positive charge

200n

I SD (A

)|

yAvidin

pos t ve c a gepos t ve c a ge current decreasecurrent decrease

streptavidinstreptavidin negative chargenegative charge

100n|I

negative chargenegative charge current increasecurrent increase

poly(ethylene glycol) poly(ethylene glycol) (PEG)(PEG) latedlated de icede ice

-20 0 20 400

Time (sec)1 nM protein in0.1X PBS (D ~ 2.2 nm)(PEG)(PEG)--ylatedylated device, device,

quenched quenched avidinavidin controlscontrols0.1X PBS (D 2.2 nm)

NatureNature, , 445445, 519 (2007), 519 (2007)WMED Boise, ID April 22, 2011 M. Reed (Yale) WMED Boise, ID April 22, 2011 M. Reed (Yale)

Proving Protein Presence: Cleavage ResponseProving Protein Presence: Cleavage Response

S-S

pp--type accumulationtype accumulation

300.0n1 nM streptavidin TCEP

pp ypyp Red: functionalization with Red: functionalization with

LCLC--biotin (inert PEG linker)biotin (inert PEG linker) Green: functionalization withGreen: functionalization with

200.0n

|I SD (A

)| Green: functionalization with Green: functionalization with

SSSS--biotin (dithiol linker) biotin (dithiol linker) Arrow: Addition of Arrow: Addition of

reducing agent TCEPreducing agent TCEP

100.0n SS-Biotin LC-Biotin

TCEP

reducing agent TCEP reducing agent TCEP (tris(2(tris(2--carboxyethyl)phosphine)carboxyethyl)phosphine)

SSSS--biotin functionalized biotin functionalized sensor exhibits cleavagesensor exhibits cleavage

-20 0 20 40 60 80 100 120 140

Time (sec)

sensor exhibits cleavagesensor exhibits cleavage


Sensitivity: Concentration DependenceSensitivity: Concentration Dependence

initial S/Ninitial S/N2 0

2.2 initial S/N initial S/N

~ 140 (@10fM)~ 140 (@10fM)

100100 MM li itli it1.6

1.8

2.0

SD (A

)|

<100 <100 aMaM limitlimit(< 3 (< 3 fgfg/ml)/ml)

1.0

1.2

1.4

mal

ized

|IS

1 nM 10 pM

((1 1 aMaM = 30 = 30 molecule per mmmolecule per mm33))

20 0 20 40 60 80

0.6

0.8Nor

m

100 fM 10 fM

-20 0 20 40 60 80

Time (sec)DC, ambient


Complementary SensingComplementary Sensing 400nAvidinStreptavidin

Critical for error detectionCritical for error detection

200n

300n

I SD (A

)

n-type

Critical for error detectionCritical for error detection nn--type inversion (on same wafer)type inversion (on same wafer)

nn--typetype

-20 0 20 40

100nnoisenoise

nn typetypepp--typetype

positivepositive

6µ

8µΔVG=1V300K, dry

w=50nm, t=40nm

VG=40V Time (sec)

Streptavidin

2µ

4µ

µ

I SD (A

)

200n

300n

(A)|

pAvidin

p-type

0 5 10 15

0

2µ

V =0V 0

100n

|I SD p type

VSD (V) VG=0Vn-type inversion mode

-20 0 20 40

Time (sec)


DNA sensing: DNA sensing: •• Capture1 is the Capture1 is the complementary strand of Probe1;complementary strand of Probe1;g

criss-crossg

criss-cross •• Capture2 is the Capture2 is the complementary strand of Probe2complementary strand of Probe2SS DD

3.0µ

3.2µ 3.5µ

2.2µ

2.8µ

|I SD (A

)|

Probe 11.0µ

3.0µ

|I SD (A

)|

P b 1

-50 0 50 100 150 200

2.0µ

Time (sec)

Probe 1 Probe 2

-50 0 50 100 150 200500.0n

Time (sec)

Probe 1 Probe 2

Surface: Capture2Surface: Capture2

( ) Time (sec)

Surface: Capture1Surface: Capture1S D


Crisscross Protein Assay: Antibody-Antigen Specificity Crisscross Protein Assay: Antibody-Antigen Specificity mousemouse--IgAIgA YesYesouseouse gg

mousemouse--IgGIgGYesYes

NoNo

YesYes

NoNo

Surface:Surface: mousemouse IgAIgA Surface:Surface: mousemouse IgGIgG

PEG controlNoNo

PEG controlNoNo

Surface: Surface: --mousemouse--IgAIgA Surface: Surface: --mousemouse--IgGIgG100 fM mouse100 fM mouse--IgG/IgA in 1.5 mM bicarbonate (IgG/IgA in 1.5 mM bicarbonate (DD ~ 6.8 nm)~ 6.8 nm)

275nmouse-IgA 220n

175

200n

225n

250n

(A)|

gmouse-IgGPEGylated

140

160n

180n

200n

(A)|100 fM

( k li i )

100n

125n

150n

175n

|I SD

20 0 20 4060n

80n

120n

140n|I SD

mouse-IgGmouse-IgAPEGylated

(approx kD limit)

-20 0 20 40 60

Time (sec)

-20 0 20 40

Time (sec)


Unlabeled Cellular DetectionUnlabeled Cellular Detection Most cells (including Most cells (including

pathogenic) release Hpathogenic) release H++

in response to specific in response to specific H+ H+

H+H+

H+

H+p pp p

stimulationstimulation H+


Nat Rev ImmunolNat Rev Immunol 33 (2003) 973(2003) 973

T-lymphocyte activationT-lymphocyte activation

1µC57BL/6 (B6) mouse splenocytes

800n

A)| anti-CD3 to:

normal

600n|I SD (A

normalinhibited

(Genistein)ISD

H+ H+H+

H+

H+-20 -10 0 10 20 30 40 50

400n

Time (s)

time

H+H+H

H+

Time (s)

RealReal--time measurement of celltime measurement of cellRealReal time measurement of cell time measurement of cell immune response dynamicsimmune response dynamics


Transgenic peptide-specific MHC T-cell response

Transgenic peptide-specific MHC T-cell response

OTOT--11 2C2C

KKbb --

SIY

SIY

XMHC T cell responseMHC T cell responseOTOT--1/2C transgenic 1/2C transgenic murinemurine CD8CD8++ TT--cells cells

OTOT 1 reacts to H1 reacts to H 2K2Kbb SIIN not HSIIN not H 2K2Kbb SIYSIY

HH--2

K2KSI

INSI

IN

XX OTOT--1 reacts to H1 reacts to H--2K2Kbb--SIIN, not HSIIN, not H--2K2Kbb--SIYSIY

2C reacts to H2C reacts to H--2K2Kbb--SIY, not HSIY, not H--2K2Kbb--SIINSIIN HH--2

K2Kbb --

SS X

1 0µ

1.2µ

1.4µ

1 0µ

1.2µ

1.4µ

4 0

5.0µ

6.0µ

7.0µH-2Kb-SIINH-2Kb-SIY

4 0

5.0µ

6.0µ

7.0µH-2Kb-SIINH-2Kb-SIY

2C

600.0n

800.0n

1.0µ

|I SD (A

)|H-2Kb-SIIN

600.0n

800.0n

1.0µ

|I SD (A

)|H-2Kb-SIIN1.0µ

2.0µ

3.0µ

4.0µ

|I SD (A

)|

1.0µ

2.0µ

3.0µ

4.0µ

|I SD (A

)|

OT-1

-25 0 25 50 75400.0n

Time (sec)

H 2K SIINH-2Kb-SIY

-25 0 25 50 75400.0n

Time (sec)

H 2K SIINH-2Kb-SIY

-25 0 25 50 750.0

µ

Time (sec)-25 0 25 50 75

0.0

µ

Time (sec)

Model system for detecting autoimmune diseases and cancerModel system for detecting autoimmune diseases and cancerNanoNano LettLett. . 88, 3310 (2008), 3310 (2008)


Nanowire electronic ELISA : ne-ELISANanowire electronic ELISA : ne-ELISAELISA: proven method for quantitative & sensitive protein assaysELISA: proven method for quantitative & sensitive protein assaysELISA: proven method for quantitative & sensitive protein assaysELISA: proven method for quantitative & sensitive protein assaysnene--ELISA: for short ELISA: for short λλDEBYEDEBYE conditions, smaller samplesconditions, smaller samples

ELISAne-ELISA

ILIL--2 detection limit2 detection limit~ 2 pg/ml ~ 2 pg/ml ––

~10~1044 less molecules less molecules of proteinof protein

SmallSmall

1.6pg/mlSmallSmallDOI: DOI: 0.1002/smll.2009015510.1002/smll.200901551


Debye ScreeningThe limitation of NW sensingDebye ScreeningThe limitation of NW sensingThe limitation of NW sensingThe limitation of NW sensing

2/1241

i iiB

Dzl

b t = 0:t = 0:b t = 0:t = 0:

i ii

for 0.1 mM PBS, for 0.1 mM PBS, DD ~ 2.2nm~ 2.2nm

b1.0µ

t 0:.01X AloneS-Av (.01X)

1.0µt 0:

.01X AloneS-Av (.01X)

b1.0µ

t 0:.01X AloneS-Av (.01X)

1.0µt 0:

.01X AloneS-Av (.01X)

.01X

DD

800.0n

|I SD (A

)|

.1X 1X .01X TCEP.01X

800.0n

|I SD (A

)|


800.0n

|I SD (A

)|


800.0n

|I SD (A

)|

.1X 1X .01X TCEP.01X(cleave)

.1X0 100 200 300600.0n

0 100 200 300600.0n

0 100 200 300600.0n

0 100 200 300600.0n

(cleave)

1XTime (s)Time (s)Time (s)Time (s)

Stern Stern et al, et al, NanoNano LettLett. . 77, 3405 (2007), 3405 (2007)


The outstanding challenge:whole blood sensingThe outstanding challenge:whole blood sensingwhole blood sensing whole blood sensing High salt, very short High salt, very short DebyeDebye (~0.8nm)(~0.8nm) NonNon--specific bindingspecific bindingNonNon specific bindingspecific binding NW detection in blood until now has NW detection in blood until now has

not been donenot been done

New approach: New approach: capturecapture--releaserelease

Functionalize CFunctionalize C--R region R region with 1with 1stst antibodiesantibodies

Blood introduction, Blood introduction, protein absorptionprotein absorption

Wash, release, capture on Wash, release, capture on NWs with 2NWs with 2ndnd antibodiesantibodies


Simultaneous quantitative measurement of Simultaneous quantitative measurement of bi k i h l bl dbi k i h l bl d

Simultaneous quantitative measurement of Simultaneous quantitative measurement of bi k i h l bl dbi k i h l bl dcancer biomarkers using whole bloodcancer biomarkers using whole bloodcancer biomarkers using whole bloodcancer biomarkers using whole blood

1.03

1.04

1.05

I DS

CA15.3(30 U/mL)1 010

1.015

1.020

I DS

PSA

(2.5 ng/mL)

1 00

1.01

1.02

Nor

mal

ized

I ( )

1.000

1.005

1.010

Nor

mal

ized

I

-25 0 25 50 75 100 1250.99

1.00

control (unspiked blood)

Time (sec)-50 0 50 100 150 200

0.995control (unspiked blood)

Time (sec)

Clinically relevant range , accuracy & reproducibility < 10%Clinically relevant range , accuracy & reproducibility < 10%Minimum demonstrated: PSA, .2 Minimum demonstrated: PSA, .2 ngng//mLmL; CA 15.3, 3 U/; CA 15.3, 3 U/mLmL

Stern et al., Stern et al., Nature Nanotech.Nature Nanotech. 55, 138 (2010). , 138 (2010).


QuantificationQuantificationI iti l t ti l tI iti l t ti l t l tl t t tit ti

QuantificationQuantificationI iti l t ti l tI iti l t ti l t l tl t t tit tiInitial rates proportional to Initial rates proportional to analyteanalyte concentrationconcentrationInitial rates proportional to Initial rates proportional to analyteanalyte concentrationconcentration

1.020

1.010

1.015

ed I D

S

2.5 ng/mL PSA2.0 ng/mL PSA

1.03

1.04

ed I D

S

30 U/mL CA15.315 U/mL CA15.3

1.000

1.005

Nor

mal

ize

Slope ratio = 1.38

1 00

1.01

1.02

Nor

mal

ize

Slope ratio = 1.94

-50 0 50 100 150 2000.995

Time (sec)-25 0 25 50 75 100 125

1.00

Time (sec)

End point detectionEnd point detectionvsvs

HomolaHomola J., J., Anal Anal BioanalBioanalChemChem (2003) 377:528 (2003) 377:528

Initial kinetic ratesInitial kinetic ratesWMED Boise, ID April 22, 2011 M. Reed (Yale) WMED Boise, ID April 22, 2011 M. Reed (Yale)

Top gated Si NWTop gated Si NWTop gated Si NWTop gated Si NW1E-6

0.1 V 0.2 V0 3 V

μp,max ~ 400 cm2/V-s

1E-10

1E-8

Dra

in C

urre

nt

0.3 V 0.4 V 0.5 V 0.6 V 0.7 V 0.8 V 0.9 V 1.0 V

SS=77mV/dec

Ion/Ioff=2x106

4 um4 um-4 -2 0 2 4

1E-14

1E-12

Top-gate Voltage

VT = 0.0V

pp--channel (accumulation)channel (accumulation)

μn,max ~ 1300 cm2/V-s

1E-10

1E-8

1E-6

ain

Cur

rent 0.1 V

0.2 V 0.3 V 0.4 V0 V

SS=128mV/dec

Ion/Ioff=2x105

V = 3 5V

200 nm200 nm-2 0 2 4 6

1E-14

1E-12

Dra

Top Gate Voltage

0.5 V 0.6 V 0.7 V 0.8 V 0.9 V 1.0 V

VT = 3.5V

Top Gate Voltage

nn--channel (inversion)channel (inversion)WMED Boise, ID April 22, 2011 M. Reed (Yale) WMED Boise, ID April 22, 2011 M. Reed (Yale)

SummarySummarySummarySummary CMOSCMOS--integrableintegrable “NWs” “NWs”

LabelLabel--free sensing to free sensing to aMaM resolutionresolutionEnables systemEnables system level integrationlevel integration-- Enables systemEnables system--level integrationlevel integration

-- Multiplexed Multiplexed Macromolecular assaysMacromolecular assays Interesting device variantsInteresting device variants

RealReal time cellular immune responsetime cellular immune response RealReal--time cellular immune response time cellular immune response Applicable to simple diagnosticsApplicable to simple diagnostics Immune response dynamicsImmune response dynamics

PointPoint--ofof--care diagnosticscare diagnostics multiple biomarker assays disease discoverymultiple biomarker assays disease discovery multiple biomarker assays, disease discoverymultiple biomarker assays, disease discovery whole blood sensingwhole blood sensing


CMOS Nanowire Biosensor Systems - IEEE Boise 22April11 public.pdf · CMOS Nanowire Biosensor...

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