CMOS Emerging Technologies Research Symposium, 2014

Magnetoresistive Biosensors for

Quantitative Proteomics

Prof. Drew Hall

(drewhall@ucsd.edu)

Biosensors and Bioelectronics Group

Web: http://BioEE.ucsd.edu

University of California, San Diego

Applications of Biosensors

Slide 1

Biomedical Research• Drug discovery

• Kinetics of protein

interactions

Clinical Diagnostics• Disease detection

— HIV/AIDS

— Cancer

— Cardiovascular

(heart) disease

• Therapy progression

Environmental Testing• Water pollution

• Food contamination

• Toxins

Concept

Slide 2

Disposable

Test StickTest Stick

Reader

Outline

• Motivation and Applications

• Magnetic Biosensing

– Background

– High throughput readout

– Temperature correction technique

• CMOS Biosensor Microarray

– Circuit and system design

– Measurement results

• Conclusion

Slide 3

Capture Ab

immobilized

Sample

added

Detection

Ab addedMagnetic nano-

tags added

Sensor

readout

Slide 4

The Magnetic ImmunoassayR.S. Gaster, D.A. Hall, et al.

Nature Medicine 2009

Giant Magnetoresistive Spin-Valves (GMR SV)

Bias Point (90˚)

𝑴𝑹 =𝑹𝑨𝑷 − 𝑹𝑷

𝑹𝑷Parallel (0˚)

Antiparallel (180˚)

Slide 5

The GMR SV as a Biosensor

2

Magnetic biochip

Sensor resistance

changes from 1 2

Resi

stance

Time

1

2

net

signal

1

1 µm

20 µm

Slide 6

Sensor Noise Spectrum

Slide 7

D.A. Hall, R.S. Gaster, et al. - Biosensors and Bioelectronics 2010

B. de Boer, et al. Biosens. and Bioelec. 2007

Signal Modulation Scheme

Aytur, et al. Actuator and Microsystems 2002

S. Han, et al. ISSCC 2007

𝑰𝟎 𝒄𝒐𝒔 𝝎𝒄𝒕𝑽𝑮𝑴𝑹

𝒄𝒐𝒔 𝝎𝒇𝒕

Magnetic

Tickling

Field

Excitation

Slide 8

• Modulate the signal from magnetic nanotags away

from 1/f noise of sensor and interface electronics

• Electrical excitation and magnetic field modulated

𝑽𝑮𝑴𝑹 𝒕= 𝑰𝟎𝑹𝟎 𝐜𝐨𝐬 𝝎𝒄𝒕

+𝑰𝟎∆𝑹𝟎𝟐

𝐜𝐨𝐬 𝝎𝒄 ±𝝎𝒇 𝒕

High Throughput Readout

Slide 9

• Techniques used to reduce readout time

– Parallelized “column” readout

– Frequency division multiplexing (FDM)

– Time division multiplexing (TDM)

400 µm

4x8x8 GMR SV Array

64 sensors/scan

0 500 1000 1500 2000 2500 3000 3500 4000 4500-180

-160

-140

-120

-100

-80

-60

-40

-20

0

Two Tone Example

Spectral

Analysis

Spectrogram

Time

Frequency

Time

Slide 10

Temperature Induced Signals

ΔT > 20°CTime

Ca

rrie

r To

ne

Slide 11

TimeUn

co

rre

cte

d

Sid

e T

on

e

Temperature Correction

• Use the carrier tone to

measure relative

temperature change

• Corrected side tone

• κ is a predetermined

ratio of the TCMR/TCR

Slide 12

Time

Co

rre

cte

d

Sid

e T

on

e

Time

Ca

rrie

r To

ne

TimeUn

co

rre

cte

d

Sid

e T

on

e

𝜟𝑺𝑻 − κ ∙ 𝑪𝑻

Outline

• Motivation and Applications

• Magnetic Biosensing

– Background

– High throughput readout

– Temperature correction technique

• CMOS Biosensor Microarray

– Circuit and system design

– Measurement results

• Conclusion

Slide 13

System Architecture

Slide 14

Pseudo-differential analog front-end

Second order ΣΔ modulator

D.A. Hall, et al. – VLSI 2011, JSSC 2013

Carrier Suppression

• Resistive DAC (RDAC)

– Injects current 180° out of

phase to suppress carrier

– 6+1 bit R-2R ladder

Slide 15

30 dB

Analog Front-End

• Sensor interface

requirements

– Single ended input

– Fixed input potential

– High linearity

– Isolation from ADC

kickback

Slide 16

D.A. Hall, et al. – JSSC 2013

Enti

re C

hip

Technology: 0.18 μm (2P / 6M)

VddA / Vdd / VddD: 2.0 V / 2.1 V / 1.8 V

Readout Columns: 16

Area: 2.7 mm x 2.7 mm

Power Consumption: 55.8 mW

Fro

nt-

End Gain: 17.5 kΩ (84.9 dBΩ)

Input Referred Spot Noise: 120 pA/√Hz (58 nT/√Hz )

w\ sensors: 160 pA/√Hz (78 nT/√Hz )

Power Consumption: 19.8 mW (36 %)

AD

C

Sampling Frequency: 10 MHz

Oversampling Ratio: 500

Dynamic Range: 84 dB

Senso

rs # Sensors: 256

Readout Time: 4 s

Resistance / MR ratio: 1.5 kΩ / 11 %

Performance Summary

Slide 17

Sensor Die

Readout IC

Temperature Correction

Slide 18

-45°C-25°C

+25°C

-45°C-25°C

Temperature Correction

Slide 19

Proteomic Measurement Results

Slide 20

Secretory leukocyte peptidase inhibitor (SLPI)

Clinical Ovarian Cancer Data

Slide 21

p > 0.1

p > 0.1

p < 0.1

p < 0.1 p < 0.0005

p < 0.0001

p < 0.0001

Summary

• Demonstrated a scalable CMOS integrated

biosensing platform based on GMR SV sensors and

magnetic nanotags

– Fully quantitative and highly sensitive

– Large sensor array with multiplex detection

– Rapid real-time readout

– Carrier referenced temperature correction scheme

Slide 22

Acknowledgements

Slide 23

Richard S. Gaster

Harvard Med.

Sebastian J. Osterfeld

MagArray, Inc.

Kofi Makinwa

TU Delft

Shan X. Wang

Stanford

Boris Murmann

Stanford