Bringing the Benefits of Moore’s Law to Medicine Prof. Dim‐Lee Kwong Institute of Microelectronics Agency for Science, Technology, and Research Singapore
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
hC
, SER
I/S
eering snical an
Part
nK
E, S
BIC
solutionnd m
arkic
al P
NU
S-D
UK ns w
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