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Simultaneous Measurement of Simultaneous Measurement of Nonlinearity and Electrochemical Nonlinearity and Electrochemical Impedance for Protein Sensing Using Impedance for Protein Sensing Using Two Two-Tone Excitation Tone Excitation Jon

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SLIDE 1

Simultaneous Measurement of Simultaneous Measurement of Nonlinearity and Electrochemical Nonlinearity and Electrochemical Impedance for Protein Sensing Using Impedance for Protein Sensing Using Two Two-Tone Excitation Tone Excitation

Jon Daniels, Ph.D. Candidate jon.daniels@stanford.edu IEEE EMBC08 24-Aug-08 SuBT2.5 Stanford Department of Electrical Engineering Stanford Genome Technology Center (SGTC) Co-authors: Erik P. Anderson – Stanford EE, SGTC

  • Prof. Thomas H. Lee – Stanford EE
  • Prof. Nader Pourmand – SGTC, UC Santa Cruz
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SLIDE 2

Affinity Affinity Biosensors Biosensors

  • Immobilized

probe selectively captures target

  • Target capture

changes surface properties

Incubation, probe target

Jon.Daniels@stanford.edu 2 IEEE EMBC08 24-Aug-08 SuBT2.5

properties

  • Detecting

change in surface properties = detecting target

Incubation, washing

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SLIDE 3

Probe Layer Solution

Impedance for Affinity Impedance for Affinity Biosensors Biosensors

Jon.Daniels@stanford.edu 3 IEEE EMBC08 24-Aug-08 SuBT2.5

  • Binding changes electrical properties of surface
  • Selectivity determined by probe layer => platform

amenable to various applications by changing probe

Electrode Probe Layer (Insulator)

( )

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SLIDE 4

Measuring Impedance Measuring Impedance

I

− + Vout Vin

Zf ZDUT

V = -V (Z /Z )

Jon.Daniels@stanford.edu 4 IEEE EMBC08 24-Aug-08 SuBT2.5

V

Vout = -Vin (Zf /ZDUT)

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SLIDE 5

Electrode “ Electrode “Impedance Impedance” is Nonlinear ” is Nonlinear

  • Electrode-electrolyte impedance depends

(quite strongly) on DC bias => nonlinear

  • ionic double layer capacitance:

Cdl(φ) =

  • 228 µF/cm2
  • C0

mol/L

  • 1 + 1

8 φ VT 2

Jon.Daniels@stanford.edu 5 IEEE EMBC08 24-Aug-08 SuBT2.5

  • mol/L
  • 8
  • VT

I V

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SLIDE 6

Question #1 Question #1

Can changes in nonlinearity be used to discriminate target binding?

Jon.Daniels@stanford.edu 6 IEEE EMBC08 24-Aug-08 SuBT2.5

vs. ?

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SLIDE 7

Question #2 Question #2

Can nonlinearity be quantified without extra measurement time?

I

Jon.Daniels@stanford.edu 7 IEEE EMBC08 24-Aug-08 SuBT2.5

I V

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SLIDE 8

Measuring Nonlinearity w/ 2 tones Measuring Nonlinearity w/ 2 tones

Vin = A cos(ωAt) + B cos(ωBt) ZDUT(ω) = Z0(ω)

  • 1 + α1Vin + α2V 2

in

  • Vout = −Vin

Zf(ω) Z0(ω) 1 1 + α1Vin + α2V 2

in Z (ω )

− + Vout Vin

Zf ZDUT

Vout = -Vin (Zf /ZDUT)

Conventional Low frequency

Jon.Daniels@stanford.edu 8 IEEE EMBC08 24-Aug-08 SuBT2.5

Vout =

−Zf(ωA) Z0(ωA) A cos(ωAt)

+

1 2α1AB Zf(ωA−ωB) Z0(ωA−ωB) cos((ωA − ωB)t)

+

1 2α1AB Zf(ωA+ωB) Z0(ωA+ωB) cos((ωA + ωB)t)

+

1 4α2AB2 Zf (ωA−2ωB) Z0(ωA−2ωB) cos((ωA − 2ωB)t)

+

1 4α2AB2 Zf (ωA+2ωB) Z0(ωA+2ωB) cos((ωA + 2ωB)t)

+

  • ther terms far removed from ωA

Small-signal impedance IM2 IM3

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SLIDE 9

ADC FFT Select DUT Tone Outputs 0.1-100 kHz PC with LabView and ADC/DAC card chip with 36 electrodes ωΑ

System Diagram System Diagram

Jon.Daniels@stanford.edu 9 IEEE EMBC08 24-Aug-08 SuBT2.5

− + ZDUT,1 16:1 ZDUT,16

Σ

17 Hz Zf PCB electrodes Vout Vin ωΒ

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SLIDE 10

PCB Implementation PCB Implementation

Jon.Daniels@stanford.edu 10 IEEE EMBC08 24-Aug-08 SuBT2.5

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SLIDE 11

12.35 12.4 12.45 12.5 Capacitance [nF]

10 nF 1 kΩ

Validating Measurement Approach Validating Measurement Approach

Jon.Daniels@stanford.edu 11 IEEE EMBC08 24-Aug-08 SuBT2.5

−100 −75 −50 −25 25 50 75 100 12.2 12.25 12.3 12.35 Bias [mV] Capacitance [nF]

  • = measured manually with custom setup
  • = measured manually with commercial LCR meter

– = extrapolated from nonlinearity tones at 0 mV

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SLIDE 12

Making “Biology” Happen is Hard Making “Biology” Happen is Hard

fluorescently-labeled streptavidin BSA BSA-biotin polymer multilayer

Jon.Daniels@stanford.edu 12 IEEE EMBC08 24-Aug-08 SuBT2.5

300µm electrodes Contact pads O-ring (holds solution)

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SLIDE 13

10 11 12 13 14 15 CPE Magnitude ["nF"] 0.9 0.905 0.91 0.915 0.92 0.925 CPE phase parameter 24 25 26 27 28 29 30 |Zdut| @ 1 kHz [kΩ]

Measured Biological Data Measured Biological Data

before

Jon.Daniels@stanford.edu 13 IEEE EMBC08 24-Aug-08 SuBT2.5

50 100 150 Electrode Bias [mV] 50 100 150 Electrode Bias [mV] 50 100 150 Electrode Bias [mV] 50 100 150 10 11 12 13 14 15 Electrode Bias [mV] CPE Magnitude ["nF"] 50 100 150 0.9 0.905 0.91 0.915 0.92 0.925 Electrode Bias [mV] CPE phase parameter 50 100 150 24 25 26 27 28 29 30 Electrode Bias [mV] |Zdut| @ 1 kHz [kΩ]

after addition of 1 µg/mL avidin

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SLIDE 14

0.02 0.04 0.06 α1 [V−1]

Nonlinearity Nonlinearity Indicates Binding Indicates Binding

change after addition of 250 ng/mL avidin

Jon.Daniels@stanford.edu 14 IEEE EMBC08 24-Aug-08 SuBT2.5

BSA−biotin (positive) BSA (negative) −0.08 −0.06 −0.04 −0.02 ∆ α

n=4 n=8

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SLIDE 15

Conclusions Conclusions

  • Two-tone approach allows simultaneous

measurement of small-signal impedance and nonlinearity

– No extra measurement time – Cost is redesigning measurement apparatus

  • Nonlinearity can indicate target binding

Jon.Daniels@stanford.edu 15 IEEE EMBC08 24-Aug-08 SuBT2.5

  • Nonlinearity can indicate target binding
  • Nonlinearity appears to be influenced by

surface charge

– Surrogate for field-effect sensor?

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SLIDE 16

Questions? Questions?

Suggestions? Suggestions?

Jon.Daniels@stanford.edu 16 IEEE EMBC08 24-Aug-08 SuBT2.5

Suggestions? Suggestions?

Jon.Daniels@stanford.edu Jon.Daniels@stanford.edu

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SLIDE 17

Backup Slides Backup Slides

Jon.Daniels@stanford.edu 17 IEEE EMBC08 24-Aug-08 SuBT2.5

Backup Slides Backup Slides

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SLIDE 18

What is Impedance? What is Impedance?

  • impedance = measure of opposition to a

sinusoidal alternating electric current, generalizing Ohm's law to AC circuit analysis

  • impedance = ∆voltage / ∆current

Z = 1000 + 15915 j

Jon.Daniels@stanford.edu 18 IEEE EMBC08 24-Aug-08 SuBT2.5

15915 j 1000 10 nF |Z| = 15947 θZ = -86.4°

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SLIDE 19

Impedance Spectroscopy Impedance Spectroscopy

Jon.Daniels@stanford.edu 19 IEEE EMBC08 24-Aug-08 SuBT2.5 Source: http://www.gamry.com/App_Notes/EIS_Primer/EIS_Primer.htm

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SLIDE 20

Affinity Detection Affinity Detection

Kd = koff

kon , probe coverage

Readout/transducer type

Transducer Selective Probe Electrical Chemical Target concentration Target surface coverage Surface property change

affinity readout

Jon.Daniels@stanford.edu 20 IEEE EMBC08 24-Aug-08 SuBT2.5

Post-processing Amplifier Data Acquisition Transducer Acquired Electrical (a) (b) (c) Measured change

Instrumentation

Surface property change

readout Daniels/Pourmand, Electroanalysis 19:1239-1257 (2007)

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SLIDE 21

Typical Measurement Approach Typical Measurement Approach

$10-30k

Jon.Daniels@stanford.edu 21 IEEE EMBC08 24-Aug-08 SuBT2.5

  • Single electrode measurement
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Custom Measurement Apparatus Custom Measurement Apparatus

300µm electrodes Contact pads O-ring (holds solution) Rknown Vin

DUT

Computer with LabView

Jon.Daniels@stanford.edu 22 IEEE EMBC08 24-Aug-08 SuBT2.5

Socket PCB with circuitry Chip Vout

DUT

ZDUT = -(Vin/Vout)*Rknown

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SLIDE 23

Double Layer Capacitance Double Layer Capacitance

  • α2 ~ 188 V-2 for double layer capacitance

according to Gouy-Chapman model

  • Predict α ~ 14 V-2 in our measurement based

Cdl(φ) =

  • 228 µF/cm2
  • C0

mol/L

  • 1 + 1

8 φ VT 2

Jon.Daniels@stanford.edu 23 IEEE EMBC08 24-Aug-08 SuBT2.5

  • Predict α2 ~ 14 V-2 in our measurement based
  • n voltage across ionic layer (vs. interface)

– expect less due to Stern modification

  • We observe |α1| ~ 0.1-1 V-1 and |α2| ~ 1-10 V-2

in all our measurements

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SLIDE 24

Next Steps Next Steps

  • Custom measurement IC design (in progress)

and testing

  • Explore nonlinear effects with constant phase

element?

  • Try “real biology”?

Jon.Daniels@stanford.edu 24 IEEE EMBC08 24-Aug-08 SuBT2.5

  • Graduate and get a “real job”!
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SLIDE 25

Acknowledgements Acknowledgements

  • Nader Pourmand, Prof. Ron Davis (Biochem)
  • Erik Anderson, Prof. Tom Lee (ElecEng)
  • Heng Yu (surface chemistry)
  • Other SGTC personel
  • NIH and NSF for direct and indirect funding

Jon.Daniels@stanford.edu 25 IEEE EMBC08 24-Aug-08 SuBT2.5

  • NIH and NSF for direct and indirect funding