Bringing the Benefits of Moore’s Law to Medicine

Prof. Dim‐Lee KwongInstitute of Microelectronics

Agency for Science, Technology, and ResearchSingapore

M th M Di ifi ti & I t ti

More on Moore and More Than Moore

130

More than Moore: Diversification & Integration

Analog/RF MedicalDevicesPassives Si Photonics Sensors

ActuatorsBiochips

urization 

ory, Logic

130nm

90nm

Interfacing with People  and EnvironmentWireless Integrated Microsystems Integrated

Functionalities

oore: M

iniatu

PU, M

emo 65nm

45nm

InformationProcessing

Digital content

More Mo

CMOS: C 32nm

22nm

.

System‐‐on‐chip(SOC)

.

U i CMOS l tf f d l i i ti i t i l d i i it d• Using CMOS platform for deploying innovations in material, device, circuit and packaging to improve power and cost as well as to acquire integrated functionalities

• CMOS will continue to supply the world with electronic devices for a long time—and grow to be a much larger industry

Bringing the Benefits of Moore’s Law to Medicine

100mm

10mm Tissue

Incr Bionic Eye Heart

1mm

100µm

ants

reasing Pace maker Neuroprobe

Moo

10µm

1µm

cells

Bacteria

g Com

C ll Cli i Neural 

ore’s µ

100nm

10

Bacteria

Viruses

mplexit

Cell Clinicsmonitoring

Law10nm

1nm Proteins DNA

ty

SiNW virus detection Nanosensor array

3 nm Si NW0.1nm

SiNW array for multiplexed detection

3 nm Si‐NW

Si micro‐ring Resonator array

• Dimensional matching of electronics device and biomaterials allows manipulation and sensing / monitoring of bio-species or their activity

• Advances in MM and MtM increases synergy between electronics and biology

page 4

Medical Device Technology Trend:Miniturization and PortabilityMiniturization and Portability

• Medical manufacturers will move the entire system into a portable unit size of a cell phone or smallerunit size of a cell phone or smaller– For home-based testing, monitoring and diagnostics

• Semiconductor technologies enabling the acceleration of medical device technology innovations indevice technology innovations in

– Sensors with extreme sensitivity and repeatability– Wireless integrated microsystems– Ultra low power electronicsp– Packaging and assembly (3-D TSV)

IME Confidential & Proprietary

Benefits from Moore’s Law: Large‐Scale IntegrationIon Torrent’s sequencing chip

• Large‐Scale High‐Density Bio Interface Array Multiplexed Detection

• Towards Single‐Chip Human Genome Sequencing

NanoretinaPhotodiode 

array

R d t &Electrodearray

Readout & stimulation circuit array

Second Sight

Scaling from >100m pitch to <10m pitch 

CMOS Silicon PhotonicsIntegrated CMOS LDElectrical

C tCMOS IC Platform

DC Electron Supply

gPhotonics Platform

DC Electron Supply

DC Photon Supply

Fiber

Connects

Transmitter‐IC

Receiver‐IC

MOD/MUX

DEMUX/PD

Electrical I/OElectronic IC

Manipulates Opto-Electronic ICManipulates both photons Optical I/O [Optical Fiber]

[Copper Lines]electrons

using transistors Electrical I/O [Copper Lines]and electrons

using transistors

A L C t Pl tf T h l ith Wid R f Hi h V lA Low-Cost Platform Technology with Wide Range of High-Volume Applications Leveraging on Existing Semiconductor Infrastructure

Low Power High Speed Small Form Factor & Low Cost Data Highly Sensitive MechanicalLow‐Power, High‐Speed, Small‐Form Factor & Low‐Cost Data‐Communication (e.g., Data Center, Home‐Entertainment)

Highly Sensitive Mechanical& Biological Sensors

Silicon Photonics Technology Platform

Ph t d t tVDD

CMOS CircuitElectrical

Signal

Electronic-Photonics Integrated Chip

• Passive ComponentsPhotodetector

Vin Vout

D Signal p• Precision Alignment

& Packaging

GND Modulated Optical Signal

1

Photonic Waveguide

Data BusI/O

ModulatorWDM Optical Filter

Laser Diode

1…n

Light Source

Photonic Waveguide Power Bus

Confidential

With Sidewall Directional

IME’s 8” Silicon Photonics: Passive and Active Devicess

140-200 nm

R=1-6 m

Gap as-Etched

With SidewallSmoothing

Assembly

DirectionalCoupler

oton

ics p

Down to ~0.1mAssembly

Slots

~5o Mode evolution rotator

Nan

oPh

~15o

Mode coupling splitterAWGRing Filter/Coupler

Low Loss Crossing

ME’

s N Ge Photo-

DetectorsOptical

Ge Photo-DetectorsOptical

Ge MSMGe MSM Ge APDGe APD WaveguidedWaveguidedGe PiN PDGe PiN PD

WGWG--GeGe--PDPD

IM ModulatorsModulators MSMMSM--based based Grating ElectrodeGrating Electrode

& Low Dark Current& Low Dark Current

Integrated MOD/PD

Si-Modulator (MOS, P/N)

IME’s Miniaturized Medical Devices ProgramIME’s Miniaturized Medical Devices ProgramN

I Innovation in microelectronics technology to enable solutions to the most challenging problems in medical and health care

hip

SNEC

, NN Engine

clinthe most challenging problems in medical and health care

ners

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Part

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BIC

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arkic

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NU

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ith ket rele

Ultrasound platformMEMS sensors and probesC

lini

NU

HS,

N impact

evanceAnalog Front End

Sensor I f

ADC RadioC

DSP MEMS sensors and probesAdvanced packaging

Si PhotonicsUWB

NU

H, tful Power Management, Battery, Harvester

Interface DSP

Silicon-Photo-Multiplier (SiPM) for Compact Positron Emission Tomography (PET) Imagers

PET l M t b li i f tiMRI only High-quality Imaging PET only Metabolic informationThere is a tumor… But where is it exactly?

Excellent tissue imaging…But is there a tumor?

PET-MRI Simultaneous 3-D tomography + Metabolic information

There is a tumor, and we know its exact location!

20µm

SEM image of a 20µm×20µm silicon APD

SiPM array

20µm

Sample-to-answer integrated microsystemsfor Point-of-Care (POC) diagnostics( ) g

ASICSample preparation Amplification Detection

Sample in (bl d

Results(blood, saliva, etc…)

available for clinical decision

1. Molecular diagnosticsEarly diagnosis of diseasesNucleic acid and protein Biomarker detection

2. Cell‐based diagnosticsBiomarker detection

Therapy monitoringE.g., Rare circulating cells detectiong , g

Holy grails of biomolecular analysis: Single‐molecule, label‐free, real‐time, high bandwidth

page 12

Technology for Point-of-Care (POC) Diagnosticsfor early detection of diseases and disease y

treatment and managementFeatures Technical RequirementsFeatures Technical Requirements

Affordable Low-cost manufacturability

Integrated WirelessCMOS

Sensitive

Molecule Specific CMOS-based Micro

High-performanceMolecule Specific

RepeatableSystemRapid

User-friendly

IME Confidential & Proprietary

Integrated SystemPortable

Si-Based Integrated Microsystems for POC Diagnostic

Complex sample composition low analyte concentration and fastComplex sample composition, low analyte concentration, and fast sample-to-answer response have posed the major technical challenges

Utilizing microelectronics technologies toUtilizing microelectronics technologies to overcome these challenges

Microfluidic sample purification

Highly sensitive biosensors

Integrated ICfor fast detection

SiNW: nucleic acid and proteins

Mi l t d

DNA/RNA extraction chip

Micro PCR for PCRr PCRr

PCR thermal cycling controller

ASIC IC chip forMicroelectrode array for cellular

biomarkers

Silicon

Micro-PCR for DNA/RNA

amplification

Pillar micro-

ASIC IC chip for rapid multiplex

sensor read-out

Multi-channelSilicon photonic ring

resonator

structure for plasma

separation

Multi channelsimultaneousEIS system

IME’s silicon nanowire molecular diagnostic platformprobe Probe‐target Silicon nanowire arrayprobe Probe target y

alized

 ctance

malized

 ctance

Norma

cond

uc

Norm

cond

uTime (s) Time (s)

Application Detection limit

DNA‐DNA hybridization (DNA diagnostics) 10 fM

Protein‐DNA (hormone –receptor biology for breast cancer) 10 fM

Troponin‐T (cardiac biomarker) 1 fM

page 15Integrated system for multiplexing molecular diagnostics

40Dengue 1 PNA Dengue 2 PNA

Multiplexing Specificityblood

15

20

25

30

35

R-R

o)/R

o [%

]

Dengue 1 PNA Dengue 2 PNADengue 3 PNA Dengue 4 PNA

Sample PreparationIntegrated Microbiofluidic device

0

5

10

15(R

Dengue 1(1pM)

Dengue 2(1pM)

Dengue 3(1pM)

Dengue 4(1pM)

gViral RNA Extraction

Amplification by RT-PCRDenaturation by super-cooling

denaturated ssDNA (1pM) (1pM) (1pM) (1pM)

Integrated System Testing (Probe station vs ASIC)Detection

Nanowire Biosensor

PCR product ssDNA

ASIC Readout &Data Processing

electricalcharge

multiplexeddetection

g

resultsASIC read out speed: <1min/ 255 NW wires

Probe station: >1hr /255 wires

IME Confidential & Proprietary

Demonstrated the capability of multiplexing detection of 4 serotypes dengue virus within 4 hrs in few drops of blood. The virus concentration equivalents to at least 2 days before of fever symptoms occur.

Micro-ring resonator based biosensor

- SOI micro-ring Resonators- Refractive index-based (RI) sensor

g

reseff

nn

neff : the change of the effective index caused by the analyte bindingres : the initial resonance wavelengthng :the group index

Key Advantages• Precise quantitative output (linear response to mass change)

• Current detection limit of IME’s device ~5 pg/mm2

p g )• Low sample volume (due to the small footprint of sensor rings)

• Multiplexed panelsLabel free detection

P16Confidential and Property of Institute of Microelectronics. Copyright ® 2007

• Label-free detection• Low-cost (mass manufacturing)

IME’s Biophotonics DeviceArrays of micro-ring resonators

Silicon micro-ring resonators-Biosensor- small foot-print-Individually addressableaddressable

Sensor ring

Sensor window

Reference ring

Grating for vertical coupling

Detection-128 pixel IR array - Real-time

Multiplexing

P17Confidential and Property of Institute of Microelectronics. Copyright ® 2007

coupling-High alignment tolerance (disposable chip)

- Multiplexing

Moore’s Law Benefits to Medical Devices

2011 2015 2030

Tiny implants that can test, diagnose, and alert doctors to problems with their patients will replace costly routine visits.

Conclusions

• Advances in semiconductor/electronic technology together with bio/medicine willAdvances in semiconductor/electronic technology together with bio/medicine will transform healthcare, enabling patient‐targeted solutions in preventive, diagnostic, and therapeutic environments. 

Si ifi t d t b d i d t di th i t ti t th• Significant progress needs to be made in understanding the interactions at the intersection of biology and Silicon or engineered Silicon.

• The field of bioelectronics and miniaturized medical devices are poised for exponential p pgrowth. CMOS, combined with other novel devices, will enable autonomous micro‐scale systems with many potential applications, creating huge markets and benefiting to the individuals and society