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© A.G. Andreou 1ISR, University of Maryland College Park, 12/04/2007
Andreas G. Andreou
Electrical and Computer Engineering andWhitaker Biomedical Engineering InstituteJohns Hopkins University
Microsystems engineering at the interface of physics biology and chemistry
© A.G. Andreou 2ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 3ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 4ISR, University of Maryland College Park, 12/04/2007
Hybrid MicrosystemsComplex structures at the interface of physics, chemistry and biology
How: Multidomain and multiscale integration from nano to micro and macro using both top down and bottom up fabrication methods.
solid, liquid and gas or vapor stateelectromagnetic and electromechanical
organic and in-organicCMOS and other material systems
electronic and ionicliving and non-living
Why: Increased structural complexity to attain improved performance / higher system functionality and or lower cost.
© A.G. Andreou 5ISR, University of Maryland College Park, 12/04/2007
biotechnology applications
• Stem cell research• Viral transfection• Gene therapy• Nanoparticle drug delivery• Monitoring intra/intercellular
signaling pathways• Biosensors for hazardous
substance monitoring
© A.G. Andreou 6ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 7ISR, University of Maryland College Park, 12/04/2007
Quantum ComputingDNA Computing
Quantum Cellular Automata
Self AssemblySoft Lithography
uFluidics
Single Quantum FluxElectron Interference
Spintronics
Carbon NanotubesMolecular Devices
Coulomb BlockadeInterband Tunneling
Resonance TunnelingGiant Magnetoresistance
Plastic ElectronicsPhotonic Crystals
Emerging
Technologies
nano-CMOS SOI-CMOS3D-CMOS
Microsystems
© A.G. Andreou 8ISR, University of Maryland College Park, 12/04/2007
silicon CMOS
Human Hair
100μm
100000000 X1 nm
L
P-substrate(Bulk)
Gate
Gate Oxide
B
SourceDrainG
D
S
10 nm
MOS transistor500 nm
Blue
Human Cell
10 mμ
© A.G. Andreou 9ISR, University of Maryland College Park, 12/04/2007
• Optically transparent
• Electrically insulating
• Stable to chemicals
• Bio-compatible
• 50 times cheaper than silicon
silicone: PDMS poly-(dimethylsiloxane)
CH3CH3
SiO
SiO
CH3CH3
n
© A.G. Andreou 10ISR, University of Maryland College Park, 12/04/2007
PDMS Fabrication Replica Molding
Y. Xia and G. Whitesides, “Soft lithography,” Angewandte Chem. Inte. Ed., vol. 37, no. 5, pp. 550–575, Dec. 1998.S. Quake and A. Scherer, “From micro to nanofabrication with soft materials,” Science, vol. 290, no. 5496, pp. 1536–1539, Nov. 2000.
© A.G. Andreou 11ISR, University of Maryland College Park, 12/04/2007
soft-lithography and replica molding
© A.G. Andreou 12ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 13ISR, University of Maryland College Park, 12/04/2007
micro-electronics scaling: Moore’s law
Electronics, Volume 38, Number 8, April 19, 1965
1. More transistors per unit silicon area2. Lower energy costs for computation
Intel Core 2 Duo “Extreme” CPU
200,000,000 components
© A.G. Andreou 14ISR, University of Maryland College Park, 12/04/2007
micro-fluidics scaling: Moore’s law no more
© A.G. Andreou 15ISR, University of Maryland College Park, 12/04/2007
MICROFLUIDICS
a new paradigm for integration
“Fabrication of a single 2 gram silicon DRAM microchip requires 32kg of water and 41MJ of energy and produces 1.7kg of waste”
E. Williams and R. Ayres and M. Heller, Environmental Science and Technology, 2002
© A.G. Andreou 16ISR, University of Maryland College Park, 12/04/2007
system architecture
Highly FunctionalReusable Components
Reconfigurable
Low Cost
Environmentally Friendly
Simple, Low-CostDisposable Components
Actuation
Sensing
Feedback
© A.G. Andreou 17ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 18ISR, University of Maryland College Park, 12/04/2007
cell culture today
Incubator FlaskPhotography by Andreas Andreou
© A.G. Andreou 19ISR, University of Maryland College Park, 12/04/2007
1882 – beating heart in salt solution, Sydney Ringer
1885 - embryonic chick cells maintained in vitro, Wilhelm Roux
1907 - in vitro tissue culture (nerve growth), Ross G. Harrison, Johns Hopkins University
history of cell-tissue culture and incubation
the growth of cells derived from
living tissue in an artificial medium
WasteIncubatorCulture Flask
Computer DAQ Chip-Scale Incubators
our goal
© A.G. Andreou 21ISR, University of Maryland College Park, 12/04/2007
Kovac and DeBusschere, Proceedings of the IEEE, June 2003
2 hours in ambient environment
the state of the art
© A.G. Andreou 22ISR, University of Maryland College Park, 12/04/2007
History Cell/Tissue Culture
© A.G. Andreou 23ISR, University of Maryland College Park, 12/04/2007
• Microfluidic Geometry
• Diffusion
• Fluid Flow and Volume
• Thermal Characterization
• On-Chip Electronics Design
• Electrical Interface
Conditions for Cell Growth
Asepsis
Oxygen Supply
Culture Medium
Temperature
© A.G. Andreou 24ISR, University of Maryland College Park, 12/04/2007
Hybrid Microsystem: Micro-Incubator (I)
© A.G. Andreou 25ISR, University of Maryland College Park, 12/04/20071. DPDMS= Diffusivity of Oxygen through PDMS
PDMS
Cellular Oxygen Supply: A Balancing Act
PDMS
culture well
atmosphere
Maximum Oxygen Consumption1.00 x 10 -16 mol
cell x sec
Atmospheric Oxygen
Rate of Oxygen Diffusion through PDMS
Flux = DPDMS
1 x Δ Cthickness
© A.G. Andreou 26ISR, University of Maryland College Park, 12/04/2007
heating and temperature measurement (I)
© A.G. Andreou 27ISR, University of Maryland College Park, 12/04/2007
heating and temperature measurement (II)
Thermistor
Heater
PTAT
© A.G. Andreou 28ISR, University of Maryland College Park, 12/04/2007
Front Back
Finite Element Analysis
Empirical DataEmpirical Data
Finite Element Analysis
© A.G. Andreou 29ISR, University of Maryland College Park, 12/04/2007
Empirical Thermal Testing Setup
1. USB-TEMP with cold junction compensation
2. Small (40) gauge thermocouple
3. Micro-Incubator
4. XYZ stage micromanipulator
© A.G. Andreou 30ISR, University of Maryland College Park, 12/04/2007
packaging: what works! (I)
2.9x10-9 W/m2
© A.G. Andreou 31ISR, University of Maryland College Park, 12/04/2007
why the obvious does not work!
1.8x10-5 W/m2
© A.G. Andreou 32ISR, University of Maryland College Park, 12/04/2007
hybrid microsystem: micro-incubator (III)
J. Blain Christen and A.G. Andreou, “Design, fabrication and testing of a hybrid CMOS/PDMS microsystem for cell culture and incubation,” IEEE Transactions on Biomedical Circuits and Systems, Vol.1, No. 1, pp. 2-14, April 2007
© A.G. Andreou 33ISR, University of Maryland College Park, 12/04/2007
hybrid microsystem: micro-incubator (II)
© A.G. Andreou 34ISR, University of Maryland College Park, 12/04/2007
micro-incubator architecture
© A.G. Andreou 35ISR, University of Maryland College Park, 12/04/2007
BHK: fibroblast morphologywhat healthy cells look like!
© A.G. Andreou 36ISR, University of Maryland College Park, 12/04/2007
cell growth in micro-incubatorchip version 1
42 hours 60 hours
© A.G. Andreou 37ISR, University of Maryland College Park, 12/04/2007
72 hours (3 days)
cell growth in micro-incubatorchip version 2
© A.G. Andreou 38ISR, University of Maryland College Park, 12/04/2007
• Introduction– hybrid microsystems (I): why?– emerging technologies– hybrid microsystems (II): how?
• Integrating Nano, Micro and Macro – u-incubator– and beyond
• Concluding Remarks
outline
© A.G. Andreou 39ISR, University of Maryland College Park, 12/04/2007
Devices ArchitectureNetworks
molecules macromoleculescells
nano-CMOS nanowiresribbons
Self-assembly
Energy
Information (human insight)
Adaptation and Learning
beyond the u-incubator (I)
© A.G. Andreou 40ISR, University of Maryland College Park, 12/04/2007
beyond the u-incubator (II)
• Temperature Dependent Assay– Heater array chip1 for
addressable temperature control
• Optical Assay– Imager array– Optical filtering needed for
many applications
1 “CMOS Heater Array for Incubation Environment Cellular Study”, J. Blain Christen and A. Andreou, Proceedings of the 48th Midwest Symposium on Circuits and Systems. 2005
© A.G. Andreou 41ISR, University of Maryland College Park, 12/04/2007
wireless communication (I)
Signaling Platform – Control and Gather Data
USBRFID Tagged Array
© A.G. Andreou 42ISR, University of Maryland College Park, 12/04/2007
wireless communication (II)
Signaling Platform – Control and Gather Data
USB
Microfluidic Device Array
© A.G. Andreou 43ISR, University of Maryland College Park, 12/04/2007
3D CMOS
MIT Lincoln 3D 180 nm SOI CMOS technology
50nm
JHU multiproject site
Imager Integrated Interferometer
© A.G. Andreou 44ISR, University of Maryland College Park, 12/04/2007
3D CMOS activestructures design
(top down)Self Assembly (bottom up)
complex 3D matter: bottom up and top down
© A.G. Andreou 45ISR, University of Maryland College Park, 12/04/2007
Thermal Control Mechanical Stimulation
OpticalInput
Electrical Stimulation& Recording
Cell Culture
OpticalDetection
3D hybrid integration
© A.G. Andreou 46ISR, University of Maryland College Park, 12/04/2007
self-assembly (II)
© A.G. Andreou 47ISR, University of Maryland College Park, 12/04/2007
cell to cell (micro and nano)chip to chip (micro and nano)MOSFET to
MOSFET(nano)
hybrid matter
energy supply optical and radio frequency photons (macro and meso) chip to virus to cell to
chip (micro and nano)
macromolecule to macromolecule(nano)
© A.G. Andreou 48ISR, University of Maryland College Park, 12/04/2007
2007
2027
© A.G. Andreou 49ISR, University of Maryland College Park, 12/04/2007
year 2027Johns Hopkins Medicine, Hospital and associated Medical Institutions have been turned into a historical museum for visitors in Baltimore.
Visitors can get a glimpse of how top tier medical care and research was carried out in the premier research hospital of the Nation back in the 20th century.
• Health care is done at home using patient monitor services and chip level implantable instrumentation, uTAS, and uMRI. Electronically programmed chips control delivery of drugs in a timely and precise fashion.
© A.G. Andreou 50ISR, University of Maryland College Park, 12/04/2007
Acknowledgements
Jennifer Blain Christen, Assistant Professor, ASU
MIT/LL and DARPA, 3D CMOS technologyProf. Sachs and Prof. Elisseeff, cell-culture share facilityNSF grant ECS-0225489, “Cell Clinics On a Chip”NSF graduate student fellowship to JBCIEEE EDS and CAS DLP program
© A.G. Andreou 51ISR, University of Maryland College Park, 12/04/2007
questions?