Lab-On-A-Chip: The Revolution in Portable Instrumentation - 4th Edition

10 Jan 2002

1. Executive Summary
2. Introduction
3. Markets
4. Barriers to Commercialization
5. LOC Technologies
6. Enabling Technologies
7. Appendices

Executive Summary xi

Lab-On-A-Chip xi
Introduction xi
Overview xi
Government Support .xiii
Scope and Methodology xiii
Market Outlook for LOCs xiv
Overview xiv
Diagnostic Testing xiv
Analytical Instrumentation .xiv
Microfluidics xv
Microarrays and Biochips .xv
Barriers to Development and Commercialization .xvi
Trends in LOC development xviii
General Trends xviii
Microfluidics vs Microarrays xviii
Conclusion xix

1. Introduction .1

Labs on a Chip . 1
Description 1
History . 2
Micro-Total Analytical Systems vs Limited Function LOCs .3
Advantages of LOCs 3
Trends in LOC Development 4
The Challenge of LOCs 6
Where Do LOCs Fit into Analytical Markets? . 7
Enabling Technologies 7
Microfluidics 7
Microarrays . 8
Introduction . 8
Description 9
DNA Microarrays . 10
Protein Microarrays 11
MEMS: Microelectromechanical Systems .11
Description 12
Applications of MEMS to LOCs 12
vi
Silicon Micromachining and MEMS 13
Specific Micromachining Techniques 13
Big problems for little MEMS: Stiction 15
Sensors 15
Surface Plasmon Resonance 16
Applications . 18
Combinatorial Synthesis for Drug Screening and
Materials Discovery .18
Description 18
Peptides . 18
Pharmaceutical chemistry and drug discovery 18
Materials Discovery 19
Combinatorial Products Already Headed to Market .20
DNA Analysis . 21
DNA Sequencing: Capillary Electrophoresis 21
Microfabricated Chip-Based Sequencers . 22
PCR . 24
SNPs 25
Impact . 26
Chemical Genomics. 26
Proteomics and Protein Analysis .27
Protein chips 27

2. Markets 29

Introduction 29
Trends in LOC Development 29
How to Exploit LOCs 31
SpecificMarket Sectors .31
Medical Diagnostics 31
Chemical Analysis Instrumentation .33
Microfluidics and Capillary Electrophoresis 35
Microfluidics . 35
Capillary electrophoresis .35
Biochips: DNA and Protein Microarrays 35
General Market. 35
DNA Microchips 37
Protein chips . 37
Proteomics 37
Sensors . 38
General Market. 38
Biosensors 41
Other Markets . 42
Environmental Testing 42
Water analysis 42
Gas detection, monitoring and analysis . 43
LOC Technology Redefines Itself 44
Microfluidics 44
Microarray LOCs and Instrumentation .44
List of LOC; Microarray; Microsystem Developers 44
Microarray Companies .46
European Microsystems Technology groups 47

3. Barriers to Commercialization 57

Introduction . 57
Mechanical and Process Issues for LOCs . 57
Performance Requirements 59
Limitations of LOCs 60
Throughput and Costs .61
Standardization 61
Marketing . 61
Patent Litigation 61
Sensors . 62

4. LOC Technologies 65

ƒÊTAS: Complete Chemistry Labs-On-A-Chip 65
MESA Research Institute: Fluid Handling; Mixing;
Reacting; and Detection 65
University of Pennsylvania: Total Integrated Microchip Platform . 69
Aviva Biosciences: Multiple-Force Biochips .70
Nanogen: Dielectrophoresis ƒÊTAS Chip Finds Germs; SNPs . 71
University of Michigan: DNA Analysis With Nanoliter LOC .73
Imperial College: Micromachined Chemical Amplifier
Speeds PCR Analysis; Tweaking ƒÊTAS for All
Manner of Things .74
Sandia National Laboratories: A Fully Integrated
Chemical Analysis LOC .76
Microfluids and Capillary Electrophoresis .77
Caliper Technologies Corp.: Microfluidics; Microfabrication; and
Molecular Separations for Drug Discovery 77
With Structural Genomix High Throughput Proteomics
Lab Chip . 79
Chemical library storage: ?gLibraryChip 79
Caliper?fs history 80
Patent battle with Aclara 81
Micralyne: Microfluidic Toolkit 82
With MDS Sciex: Mass Spec And Frontal
Affinity Chromatography on A Chi 83
Oak Ridge National Labs 83
The University of Alberta LOC 87
Aclara Biosciences Inc.: LabCard 88
Micronics; Inc.: Laminar Flow Prevents Mixing . 91
Curagen; Inc.: DNA Seperation by Weight 92
Nanogen; Inc : Electronic Control of DNA Analysis93
UC Berkely: Radial Capillary Array Electrophoresis System .98
Molecular Dynamics: Fluorescence-Based
Capillary Gel Electrophoresis Sequencing 99
viii
Applera Corporation: Applied Biosystems Incorporated (ABI) and
Celera Genomics: Human Genome Payoff 100
Gene Logic: READS (Restricition Enzyme Analysis of
Differentially-Expressed Sequences) .101
University of California; Davis: Surfactant Redox to
Move Fluids .101
Princeton University: Continuos Flow Mixer Gives You
Fast Mixing Without Turbulence 102
Los Alamos and IBM: Simulate Fluid Flows . 103
Tecan Group Turns CD Player Into a Bioanalysis Device .104
Detection and Analysis: Spectrometry; Chromatography;
Surface Plasmon Resonance .105
Advion and Intellisense: Electrospray Chip for Mass
Spectrometry 105
University of Washington: Annular Column Chromatography
With Built-in Optical Analysis 106
Texas Instruments; Inc : A matchbook-Sized Surface-
Plasmon-Resonance Analyzer .107
Genetrace Systems: Automated DNA Sequencing With
Time-of-Flight Mass Spectrometry 107
HTS Biosystems: Surface Plasmon Resonance .109
Phylos: Protein-Expression Chip .110
University of lllinois/Urbana-Champaign: NMR Analysis
On A Chip 110
Optical Addressing of LOCs 111
NIST: Embossed Gratings for Coupling Light into And
Out Of Waveguides: .113
University of Alberta: Z-Type Cell for Fluorescence And
Absorbence Detection .114
Clinical Instruments .115
i-Stat Corp.: Handheld Blood Analyzer Offers Bedside
Blood Panel.115
University of Neuchatel: Blood Gas Analyzers On A Chip .117
Given Imaging Inc.: Dreadful Endoscopy Made
Easy?Just Swallow 118
Georgia Tech: Microneedle Arrays Deliver Drugs 119
Sandia National Labs: Blood-Cell Laser to Detect
Blood Disorders .120
MIT: Implantable Microchip Releases On Demand .122
Microreactors; Combinatorial Chemistry; and Syntheis LOCs .123
Microreactors; Combinatorial Chemistry; and Synthesis LOCs 123
Irori Quantum Microchemistry: Microchip-Based
Combinatorial Chemistry Kit 123
University of Hull: Microreactors and Microwaves 124
University of South Australia: Microbioreactor. 125
Battelle Pacific Northwest Laboratory: Microscale Combuster 125
Symyx: Combinatorial Materials Synthesis . 126
Early work 126
Cepheid; Inc.: Microscale PCR Reactors . 130
Hebrew University: PCR Primers Immobilized On A Chip 131
Fraunhofer Institute: Meandering Flow Channels With
Access Ports 131
Microarrays and Biochips: DNA and Protein Analysis On A Chip 131
Microarrays and Biochips: DNA and Protein Analysis
On A Chip 131
Description 131
Affymetrix: Combinatorial DNA Analysis 132
Orchid BioSciences-SNP Analysis On A Chip.134
Genometrix; Inc. . 135
Berkeley: Microcantilevers Detect Cancer On A Chip 136
Beckman Instruments; Inc. .137
Motorola; Packard; and Argonne: Find One Genetic Variation
Among Three Billion DNA Bases in a Matter of Minutes 138
Differential Gene Expression or Copy Number On A Chip .140
NEN Life Science .140
Incyte Pharmaceuticals Inc. .140
Vysis: Microarrays for gene copy numbers. 140
Harvard University: ?eProtein Chips?f Probe Protein Function 142
Hoffman-La Roche: Bacteria Chips to Study Antibiotics .144
Ciphergen Biosystems: Biomarkers 145
Beyond Proteomics: Glycomics. 145
DNA Chips for Agricultural Studies .145

5. Enabling Technologies 147

Introduction 147
Sensors 147
Biosensors . 147
Biointegrated Circuits as Chemical Sensors . 147
Microphysiometry?Intracellular Sensing153
Milli Sensors Systems and Actuators Inc: Motion Sensing 157
Microphotonics 158
Northwestern University: Microphotonic Resonator .158
Nanogen: Photonic Energy Transfer .158
University of Arizona 158
Fiber-Optic Sensors . 160
Los Alamos: Fiber-Optic pH Sensor .160
Tufts University: Fiber-Optic Sensor Arrays 161
Illumina . 161
Sandia National Labs: Pattern Recognition System for Sensors
On A Chip 163
Sandia Labs: Tiny Acoustic Wave Sensors Detect Minute
Traces of Dangerous Chemicals 164
Integrated Sensing Systems 165
Johns Hopkins University: Visual Sensor On A Chip 166
Cyrano Sciences Inc and Hewlett-Packard 167
University of Texas at Austin 169
Berkeley MicroInstruments. 170
Oak Ridge National Lab: Microcantilevers Put Sensor
Array on Chip 171
MEMS and Microelectronics .172
University of Michigan: MEMS Resonator for LOC
Gyroscopes; Internal Clocks? .172
?gXYZ On A Chip?h Initiative Seeks Novel Applications for
Microelectronics .173
Harvard University: Refrigerator On A Chip 174
Oak Ridge: Photosynthesis Can Power Nanomachines .175
Brigham Young University: Get Battery Down to MEMS Scale . 176
UCSD: DNA Glues Optoelectronics Components .177
Technion: DNA Helps Connect Nano Electronics 178
Sandia Labs: A Silicon Micromotor. 180
Lucent Technologies: Micromechanical Mirrors Route
Light Signals .182
Sandia: MEMS Clock Times System On A Chip 183
University of Wales at Bangor: Electrokinetic Analysis of Cells . 184
Selective and Non-Selective Dielectrophoresis Traps. .185
Directional TWD Junctions 186
Electrorotation Units .186
Micropumps and Microvalves 189
Fraunhofer Institute: Silicon Micro-Diaphragm Pump 189
University of Washington: Nonmoving Tesla Microvalves
Help Pump 191
Johns Hopkins University: Pumping With Tiny Bubbles:
Vapor Pushes Liquid through Micro Devices .192
Fraunhofer Insititute: Micromechanical Pneumatic Valve 193
Louisiana State University: Micropump Has No Moving Parts 194
Fabrication Technologies .195
Cornell University: Artificial Gels Could Speed DNA
Sequencing 195
Rockefeller University: Build Biochips A Molecule at
A Time With Optical Tweezers 197
Purdue and Scripps: Studying Biomolecules With Porous Silicon 198
De Montfort University (UK): Porous Silicon Enables
Next-Generation Biochips 201
University of Michigan : Plastic Capillary Channels .202
NIST: Plastic-Coated Microfluid Devices . 202
Micromolding in Capillaries (MI MIC) 204
Pulsed Laser Deposition .204
Glass-Glass Microbonding Technique .204
Glass-Silicon Bonding 205
Lithography . 205
University of Neuchatel: Tiny Lenses Make Tiny
Chip Featuress .205
Harvard: Soft Lithography?Microfabrication based on
printing of self-assembled monolayers 206

6. Appendices .211

Appendix A: Contact Information .211
Contact Information 211
Appendix B: Selected Patents .222
Organizations Involved in MEMS And Microfuidics R&D 260
MCNC: MUMPS Program .261
NIST/USC: MOSIS 261
Analog Devices; Inc. 262
DARPA?fs MicroFluidic Molecular Systems Program .262
David Sarnoff Research Center .263
Lawrence Livermore National Laboratory; Microtechnology
Center 264
Micralyne (formerly the Alberta Microelectronics Centre) 264
Other MEMS Organizations .265
Appendix D: Readings .266
Readings . 266
Appendix E: Useful Website URLs 274
Useful Website URLs 274
TAS (MICRO TOTAL ANALYSIS SYSTEMS) 278