11NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Nanowire FET Biomolecular

Sensors

Mark ReedYale University

Nanowire FET Nanowire FET Biomolecular Biomolecular

Sensors Sensors

Mark ReedMark ReedYale UniversityYale University

Departments of Applied Physics and Electrical Engineering Yale Institute for Nanoscience and Quantum Engineering

with: Eric Stern, David Routenberg, Erin Steenblock, Alek Vacic, Nitin Rajan, Prof. Tarek Fahmy

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

Departments of Applied Physics and Electrical Engineering Departments of Applied Physics and Electrical Engineering Yale Institute for Nanoscience and Quantum EngineeringYale Institute for Nanoscience and Quantum Engineering

with: Eric Stern, David Routenberg, Erin Steenblock, Alek Vacic, Nitin Rajan, Prof. Tarek Fahmy

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

22NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

What I won’t talk about todayWhat I won’t talk about today

plasmonicsplasmonics

mesoscopicsmesoscopics

nanowire materials nanowire materials & devices& devices

DNA DNA sequencing sequencing

devicesdevices

physics of physics of scaledscaleddevicesdevices

molecularmolecularelectronicelectronictransport, transport,

IETS IETS

33NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Current Macromolecular SensingCurrent Macromolecular SensingLabeled sensingLabeled sensing

DNA sequencing, radiotagDNA sequencing, radiotag DNA array, fluorDNA array, fluor ELISA: Indirect fluorELISA: Indirect fluor

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

Unlabeled sensingUnlabeled sensing

44NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Buffer BSA PSA

390

385

380

I (n

A)

5004003002001000Time (s)

PSA

In2O3 NW

rdQdI

I1~1

Si

Au/Ti

SiO2

PSA

PSAantibody

Linker

PSA

NW/SWNTISFETs ISFETs detection limits detection limits typically ~ typically ~ µµMM

(C. Zhou, USC)

10nm diameter GaN NW

Nanowire biosensorsNanowire biosensors(unlabeled detection)(unlabeled detection)

55NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

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

0 -5 -10 -15

0

-1

-2

-3

I SD (A

)

VSD (V)

VG=-40V

VG=0V

300K, dry25nm SOI

NatureNature 445, 445, 519 (2007)519 (2007)

66NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

0 -5 -10 -15

0

-1

-2

-3

I SD (A

)

VSD (V)

0 -10 -20 -30 -401f

100f

10p

1n

100n

|I SD (A

)|

VGD (V)

p-type accumulation mode (backgate)p-type accumulation mode (backgate)

∆VG=1V300K, dry

w=50nm, t=25nm

VG=-40V

0V

VSD=-1V

30 10040

100

400

Mob

ility

(cm

2 /Vs)

Temperature (K)

HallDrift

w = 300 nmt = 25 nm

µµmax max = 139 cm= 139 cm22/V/V--ss

Fully depleted; n0 ~ 1x1015 cm-3

µ µ = 54 cm= 54 cm22/V/V--ss

77NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

1/f noise of nanowires1/f noise of nanowires

InAs

SnO2

Nfα=

IS HI

2

ITRS Si SOI NWαH = 1.3 x 10-4

88NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

NW Sensitivity Scaling with Size : pH SensingNW Sensitivity Scaling with Size : pH Sensing

large: large: ww = 1000 nm; = 1000 nm; tt = 80 nm= 80 nmsmall: small: ww = 100 nm; = 100 nm; tt = 25 nm= 25 nm

0 100 200 300 400 500 600

10n

100n

1

|I SD (A

)|

Time (s)

largesmall

8.0

7.5

7.0

6.5

6.0

6.5

7.0

7.5

8.0

0 100 200 300 400 500 600

10n

100n

1

|I SD (A

)|

Time (s)

largesmall

8.0

7.5

7.0

6.5

6.0

6.5

7.0

7.5

8.0

0 5 10 15 20 250

20

40

Sens

itivi

ty

Inverse Radius (µm-1)

NB device RIE device

00,

2nN

RII s

VSD

SD

SD

α⋅=

∆

pHdecade1 is response max. decademV60slope ldSubthresho

pHmV60potentialNernst

∴=

=

99NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Fluid ConsiderationsFluid Considerations

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

1E-4

0.01

1

100

10000

1000000

1E8

1E10

1E12

# M

olec

ules

/Min

C0 (M)

xx

xx

Silicon-specificfunctionalization

Nonspecificfunctionalization

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

1E-4

0.01

1

100

10000

1000000

1E8

1E10

1E12

# M

olec

ules

/Min

C0 (M)

xx

xx

Silicon-specificfunctionalization

Nonspecificfunctionalization

Nano LettNano Lett 55, 803 (2005) , 803 (2005)

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

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

020

2

Cudz

CdDJ zz +−=0

1010NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Biotin-Avidin & Streptavidin SensingBiotin-Avidin & Streptavidin Sensing

nn pp--type accumulation mode, type accumulation mode, biotinylated NW devicebiotinylated NW device

nn avidin avidin uu positive charge positive charge uu ⇒⇒ current decreasecurrent decrease

nn streptavidin streptavidin uu negative chargenegative chargeuu ⇒⇒ current increasecurrent increase

nn poly(ethylene glycol) poly(ethylene glycol) (PEG)(PEG)--ylated device, ylated device, quenched avidin controlsquenched avidin controls

-20 0 20 400

100n

200n

300n

|I SD (A

)|

Time (sec)

StreptavidinQuenched S-AvPEGylatedAvidin

1 nM protein in0.1X PBS (λD ~ 2.2 nm)

analyteanalyte

receptorreceptor(biotin)(biotin)

NatureNature, , 445445, 519 (2007), 519 (2007)

1111NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Sensitivity: Concentration DependenceSensitivity: Concentration Dependence

nn initial S/N initial S/N ~ 140 (@10fM)~ 140 (@10fM)

⇒⇒ <100 aM limit<100 aM limit(< 3 fg/ml)(< 3 fg/ml)

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

-20 0 20 40 60 80

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

Nor

mal

ized

|ISD

(A)|

Time (sec)

1 nM 10 pM 100 fM 10 fM

DC, ambient

1212NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

DNA sensing: criss-crossDNA sensing: criss-cross

•• Capture1 is the Capture1 is the complementary strand of Probe1;complementary strand of Probe1;•• Capture2 is the Capture2 is the complementary strand of Probe2complementary strand of Probe2

Surface: Capture2Surface: Capture2

-50 0 50 100 150 200

2.0

2.2

2.8

3.0

3.2

|I SD (A

)|

Time (sec)

Probe 1 Probe 2

-50 0 50 100 150 200500.0n

1.0

3.0

3.5

|I SD (A

)|

Time (sec)

Probe 1 Probe 2

SS DD

S D

Surface: Capture1Surface: Capture1

1313NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Debye Screening ConsiderationsDebye Screening Considerations

( ) 2/1241

∑=

i iiB

Dzl ρπ

λ

.01X

.1X

1X

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

b

0 100 200 300600.0n

800.0n

1.0

|I SD (A

)|

Time (s)

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

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

0 100 200 300600.0n

800.0n

1.0

|I SD (A

)|

Time (s)

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

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

b

0 100 200 300600.0n

800.0n

1.0

|I SD (A

)|

Time (s)

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

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

0 100 200 300600.0n

800.0n

1.0

|I SD (A

)|

Time (s)

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

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

Stern Stern et al, Nano Lett. et al, Nano Lett. 77, 3405 (2007), 3405 (2007)

(cleave)

add S-Av .01X

Controlno S-Av

1414NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Protein Assay: Antibody-Antigen Specificity Protein Assay: Antibody-Antigen Specificity Surface: Surface: αα--mousemouse--IgAIgA

100 fM mouse100 fM mouse--IgG/IgA in 1.5 mM bicarbonate (IgG/IgA in 1.5 mM bicarbonate (λλDD ~ 6.8 nm)~ 6.8 nm)

-20 0 20 40 60100n

125n

150n

175n

200n

225n

250n

275n

|I SD (A

)|

Time (sec)

mouse-IgAmouse-IgGPEGylated

100 fM100 fM

1515NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Unlabeled Cellular DetectionUnlabeled Cellular Detectionnn Most cells (including Most cells (including

pathogenic) release Hpathogenic) release H++

in response to specific in response to specific stimulationstimulation

H+ H+

H+H+

H+

H+

H+

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

1616NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

H+ H+

H+H+

H+

H+

H+

-20 -10 0 10 20 30 40 50400n

600n

800n

1

|I SD (A

)|

Time (s)

anti-CD3 to:normalinhibited

(Genistein)

C57BL/6 (B6) mouse splenocytes

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

ISD

time

Real-time live cellular response – T-lymphocyte activationReal-time live cellular response – T-lymphocyte activation

1717NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Transgenic peptide-specific MHC T-cell response

Transgenic peptide-specific MHC T-cell response

-25 0 25 50 75400.0n

600.0n

800.0n

1.0

1.2

1.4

|I SD (A

)|

Time (sec)

H-2Kb-SIINH-2Kb-SIY

-25 0 25 50 75400.0n

600.0n

800.0n

1.0

1.2

1.4

|I SD (A

)|

Time (sec)

H-2Kb-SIINH-2Kb-SIY

-25 0 25 50 750.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

|I SD (A

)|

Time (sec)

H-2Kb-SIINH-2Kb-SIY

-25 0 25 50 750.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

|I SD (A

)|

Time (sec)

H-2Kb-SIINH-2Kb-SIY

OTOT--1/2C transgenic murine CD81/2C transgenic murine CD8++ TT--cells cells

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

OT-1

2C

Model system for detecting autoimmune diseases and cancerModel system for detecting autoimmune diseases and cancerStern Stern et alet al, , Nano Lett. Nano Lett. 88, 3310 (2008)., 3310 (2008).

OTOT--11 2C2C

HH-- 2

K2Kbb --

SIY

SIY

HH-- 2

K2Kbb --

SIIN

SIIN

XX

1818NanoForum09 Las Vegas, NV ANanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

SummarySummarySummary

nn CMOSCMOS--integrable integrable ““NWsNWs””uu LabelLabel--free sensing to aM resolutionfree sensing to aM resolution

Enables systemEnables system--level integration level integration uu Macromolecular assaysMacromolecular assays

nn RealReal--time cellular immune response time cellular immune response uu Applicable to simple, pointApplicable to simple, point--ofof--care diagnosticscare diagnostics

(all simple DC, ambient)(all simple DC, ambient)uu Immune response dynamicsImmune response dynamics

nn Rich area for novel device designs, applicationsRich area for novel device designs, applications

nn The challenge:The challenge: sensing with physiologic solutions (blood)sensing with physiologic solutions (blood)

AlturaAlturaDiagnosticsDiagnostics