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Nanowire FET Nanowire FET Nanowire FET Biomolecular Biomolecular Biomolecular Sensors Sensors Sensors Mark Reed Mark Reed Mark Reed Yale University Yale University Yale University Departments of Applied Physics and Electrical

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SLIDE 1

1 1 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Nanowire FET Biomolecular Sensors

Mark Reed Yale University

Nanowire FET Nanowire FET Biomolecular Biomolecular Sensors Sensors

Mark Reed Mark Reed Yale University Yale 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 Jan Labs 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 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 Jan Labs of Profs. Ronald Breaker, Andrew Hamilton, Tarek Fahmy

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SLIDE 2

2 2 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

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

plasmonics plasmonics mesoscopics mesoscopics nanowire materials nanowire materials & devices & devices DNA DNA sequencing sequencing devices devices physics of physics of scaled scaled devices devices molecular molecular electronic electronic transport, transport, IETS IETS

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SLIDE 3

3 3 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Current Macromolecular Sensing Current Macromolecular Sensing

Labeled sensing Labeled sensing

DNA sequencing, radiotag DNA sequencing, radiotag DNA array, fluor DNA array, fluor ELISA: Indirect fluor ELISA: Indirect fluor Suspended cantilever Suspended cantilever Surface plasmon resonance Surface plasmon resonance Electrical : ISFET Electrical : ISFET

Unlabeled sensing Unlabeled sensing

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SLIDE 4

4 4 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Buffer BSA PSA

390 385 380

I (nA)

500 400 300 200 100

Time (s)

PSA In2O3 NW

r dQ dI I 1 ~ 1

Si Au/Ti SiO2 PSA

PSA antibody Linker

PSA NW/SWNT

ISFETs ISFETs detection limits detection limits typically ~ typically ~ µ µM M

(C. Zhou, USC)

10nm diameter GaN NW

Nanowire biosensors Nanowire biosensors (unlabeled detection) (unlabeled detection)

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SLIDE 5

5 5 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

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

  • 5
  • 10
  • 15
  • 1
  • 2
  • 3

ISD (A) VSD (V)

VG=-40V VG=0V

300K, dry 25nm SOI

Nature Nature 445, 445, 519 (2007) 519 (2007)

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SLIDE 6

6 6 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

  • 5
  • 10
  • 15
  • 1
  • 2
  • 3

ISD (A) VSD (V)

  • 10
  • 20
  • 30
  • 40

1f 100f 10p 1n 100n |ISD (A)| VGD (V)

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

∆VG=1V 300K, dry w=50nm, t=25nm

VG=-40V 0V VSD=-1V

30 100 40 100 400

Mobility (cm

2/Vs)

Temperature (K) Hall Drift

w = 300 nm t = 25 nm µ µmax

max = 139 cm

= 139 cm2

2/V

/V-

  • s

s Fully depleted; n0 ~ 1x1015 cm-3 µ µ = 54 cm = 54 cm2

2/V

/V-

  • s

s

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SLIDE 7

7 7 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

1/f noise of nanowires 1/f noise of nanowires

InAs SnO2

N f α = I S

H I 2

ITRS

Si SOI NW αH = 1.3 x 10-4

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SLIDE 8

8 8 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

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

large: large: w w = 1000 nm; = 1000 nm; t t = 80 nm = 80 nm small: small: w w = 100 nm; = 100 nm; t t = 25 nm = 25 nm

100 200 300 400 500 600 10n 100n 1

|ISD (A)| Time (s) large small

8.0 7.5 7.0 6.5 6.0 6.5 7.0 7.5 8.0

100 200 300 400 500 600 10n 100n 1

|ISD (A)| Time (s) large small

8.0 7.5 7.0 6.5 6.0 6.5 7.0 7.5 8.0

5 10 15 20 25 20 40

Sensitivity Inverse Radius (µm

  • 1)

NB device RIE device

,

2 n N R I I

s V SD SD

SD

α ⋅ = ∆

pH decade 1 is response max. decade mV 60 slope ld Subthresho pH mV 60 potential Nernst ∴ = =

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9 9 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Fluid Considerations Fluid Considerations

10

  • 15

10

  • 14

10

  • 13

10

  • 12

10

  • 11

10

  • 10

10

  • 9

1E-6 1E-4 0.01 1 100 10000 1000000 1E8 1E10 1E12

# Molecules/Min C0 (M)

x x x x

Silicon-specific functionalization Nonspecific functionalization

10

  • 15

10

  • 14

10

  • 13

10

  • 12

10

  • 11

10

  • 10

10

  • 9

1E-6 1E-4 0.01 1 100 10000 1000000 1E8 1E10 1E12

# Molecules/Min C0 (M)

x x x x

Silicon-specific functionalization Nonspecific functionalization

Nano Lett Nano Lett 5 5, 803 (2005) , 803 (2005) x x = microfluidics = microfluidics Science Science 293, 293, 1289 1289 (2001) (2001) x x = mixer (resorvoir) = mixer (resorvoir) Nature Nature 445, 445, 519 (2007) 519 (2007)

2 2

C u dz C d D J

z z

+ − =

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SLIDE 10

10 10 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Biotin-Avidin & Streptavidin Sensing Biotin-Avidin & Streptavidin Sensing

n n

p p-

  • type accumulation mode,

type accumulation mode, biotinylated NW device biotinylated NW device

n n

avidin avidin

u u

positive charge positive charge

u u

⇒ ⇒ current decrease current decrease

n n

streptavidin streptavidin

u u

negative charge negative charge

u u

⇒ ⇒ current increase current increase

n n

poly(ethylene glycol) poly(ethylene glycol) (PEG) (PEG)-

  • ylated device,

ylated device, quenched avidin controls quenched avidin controls

  • 20

20 40 100n 200n 300n

|ISD (A)| Time (sec)

Streptavidin Quenched S-Av PEGylated Avidin

1 nM protein in 0.1X PBS (λD ~ 2.2 nm)

analyte analyte receptor receptor (biotin) (biotin)

Nature Nature, , 445 445, 519 (2007) , 519 (2007)

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

Sensitivity: Concentration Dependence Sensitivity: Concentration Dependence

n n 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 mm molecule per mm3

3)

)

  • 20

20 40 60 80 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

Normalized |ISD (A)| Time (sec) 1 nM 10 pM 100 fM 10 fM

DC, ambient

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12 12 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

DNA sensing: criss-cross DNA 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 Probe2 complementary strand of Probe2 Surface: Capture2 Surface: Capture2

  • 50

50 100 150 200 2.0 2.2 2.8 3.0 3.2

|ISD (A)| Time (sec) Probe 1 Probe 2

  • 50

50 100 150 200 500.0n 1.0 3.0 3.5

|ISD (A)| Time (sec) Probe 1 Probe 2

S S D D S D

Surface: Capture1 Surface: Capture1

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13 13 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Debye Screening Considerations Debye Screening Considerations

( )

2 / 1 2

4 1

∑

=

i i i B D

z l ρ π λ

.01X .1X 1X

for 0.1 mM PBS, for 0.1 mM PBS, λ λD

D ~ 2.2nm

~ 2.2nm b

100 200 300 600.0n 800.0n 1.0

|ISD (A)| Time (s)

t = 0: .01X Alone S-Av (.01X)

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

100 200 300 600.0n 800.0n 1.0

|ISD (A)| Time (s)

t = 0: .01X Alone S-Av (.01X)

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

b

100 200 300 600.0n 800.0n 1.0

|ISD (A)| Time (s)

t = 0: .01X Alone S-Av (.01X)

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

100 200 300 600.0n 800.0n 1.0

|ISD (A)| Time (s)

t = 0: .01X Alone S-Av (.01X)

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

Stern Stern et al, Nano Lett. et al, Nano Lett. 7 7, 3405 (2007) , 3405 (2007)

(cleave)

add S-Av .01X

Control no S-Av

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14 14 NanoForum09 Las Vegas, NV A NanoForum09 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: α α-

  • mouse

mouse-

  • IgA

IgA

100 fM mouse 100 fM mouse-

  • IgG/IgA in 1.5 mM bicarbonate (

IgG/IgA in 1.5 mM bicarbonate (λ λD

D ~ 6.8 nm)

~ 6.8 nm)

  • 20

20 40 60 100n 125n 150n 175n 200n 225n 250n 275n

|ISD (A)| Time (sec) mouse-IgA mouse-IgG PEGylated

100 fM 100 fM

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15 15 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Unlabeled Cellular Detection Unlabeled Cellular Detection

n n Most cells (including

Most cells (including pathogenic) release H pathogenic) release H+

+

in response to specific in response to specific stimulation stimulation

H + H + H + H + H + H + H +

Nat Rev Immunol Nat Rev Immunol 3 3 (2003) 973 (2003) 973

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16 16 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

H + H + H + H + H + H + H +

  • 20
  • 10

10 20 30 40 50 400n 600n 800n 1

|ISD (A)| Time (s) anti-CD3 to: normal inhibited (Genistein)

C57BL/6 (B6) mouse splenocytes

Real Real-

  • time measurement of cell

time measurement of cell immune response dynamics immune response dynamics

ISD time

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

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17 17 NanoForum09 Las Vegas, NV A NanoForum09 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

25 50 75 400.0n 600.0n 800.0n 1.0 1.2 1.4

|ISD (A)| Time (sec)

H-2K

b-SIIN

H-2K

b-SIY

  • 25

25 50 75 400.0n 600.0n 800.0n 1.0 1.2 1.4

|ISD (A)| Time (sec)

H-2K

b-SIIN

H-2K

b-SIY

  • 25

25 50 75 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

|ISD (A)| Time (sec)

H-2K

b-SIIN

H-2K

b-SIY

  • 25

25 50 75 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

|ISD (A)| Time (sec)

H-2K

b-SIIN

H-2K

b-SIY

OT OT-

  • 1/2C transgenic murine CD8

1/2C transgenic murine CD8+

+ T

T-

  • cells

cells

  • OT

OT-

  • 1 reacts to H

1 reacts to H-

  • 2K

2Kb

b-

  • SIIN, not H

SIIN, not H-

  • 2K

2Kb

b-

  • SIY

SIY

  • 2C reacts to H

2C reacts to H-

  • 2K

2Kb

b-

  • SIY, not H

SIY, not H-

  • 2K

2Kb

b-

  • SIIN

SIIN

OT-1 2C

Model system for detecting autoimmune diseases and cancer Model system for detecting autoimmune diseases and cancer

Stern Stern et al et al, , Nano Lett. Nano Lett. 8 8, 3310 (2008). , 3310 (2008).

OT OT-

  • 1

1 2C 2C

H H-

  • 2K

2Kb

b-

  • SIY

SIY H H-

  • 2K

2Kb

b-

  • SIIN

SIIN

X X

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18 18 NanoForum09 Las Vegas, NV A NanoForum09 Las Vegas, NV April 29, 2009 M. Reed (Yale) pril 29, 2009 M. Reed (Yale)

Summary Summary Summary

n n CMOS

CMOS-

  • integrable

integrable “ “NWs NWs” ”

u u Label

Label-

  • free sensing to aM resolution

free sensing to aM resolution

  • Enables system

Enables system-

  • level integration

level integration

u u Macromolecular assays

Macromolecular assays

n n Real

Real-

  • time cellular immune response

time cellular immune response

u u Applicable to simple, point

Applicable to simple, point-

  • of
  • f-
  • care diagnostics

care diagnostics (all simple DC, ambient) (all simple DC, ambient)

u u Immune response dynamics

Immune response dynamics

n n Rich area for novel device designs, applications

Rich area for novel device designs, applications

n n The challenge:

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

Diagnostics Diagnostics