BIOMEDICAL MICROSYSTEMS

E L L I S M E N G

(rrtC) CRC Press \ V * J Taylor &. Francis Group

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

Contents

Preface xi Acknowledgments xiii Author xv

1. Introduction 1 1.1 Evolution of MEMS 1 1.2 Applications of MEMS 3 1.3 BioMEMS Applications 5 1.4 MEMS Resources 5 1.5 Text Goals and Organization 6 1.6 Miniaturization and Scaling 7

1.6.1 Geometrical Scaling 7 1.6.1.1 Scaling in Nature 8

1.6.2 Scaling of Forces 9 1.6.2.1 Notation 9 1.6.2.2 Implications 10

1.6.3 Scaling of Phenomena 12 1.6.3.1 Electricity 12 1.6.3.2 Mechanical Systems 15 1.6.3.3 Fluidic Systems 15 1.6.3.4 Heat Transfer 16

1.7 Problems 17 References 19

2. BioMEMS Materials 21 2.1 Traditional MEMS and Microelectronic Materials 21

2.1.1 Classification of Electronic Materials 22 2.1.2 Silicon 22

2.1.2.1 Crystal Structure 22 2.1.2.2 Single Crystal Silicon Fabrication 26 2.1.2.3 Properties of Silicon 30

2.1.3 Properties of Thin Films 37 2.1.3.1 Adhesion 37 2.1.3.2 Stress 37 2.1.3.3 Resistivity 39

2.1.4 Silicon Compounds 40 2.1.4.1 Polycrystalline Silicon 40 2.1.4.2 Silicon Dioxide 40 2.1.4.3 Silicon Nitride 41

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2.1.5 Piezoelectric Crystals 42 2.1.6 Metals 43

2.2 Polymeric Materials for MEMS 44 2.2.1 Polydimethylsiloxane (Silicone Rubber) 45 2.2.2 Polyimide 45 2.2.3 SU-8 46 2.2.4 Parylene 46 2.2.5 Conductive Polymers 47

2.3 Biomaterials 48 2.3.1 Material Selection for Biological and

Medical Applications 49 2.3.2 Food and Drug Administration and

Medical Device Regulation 50 2.3.3 Biocompatibility 52 2.3.4 Sterilization 55

2.4 Problems 58 References 59

3. Microfabrication Methods and Processes forBioMEMS 61 3.1 Introduction 61 3.2 Microlithography 63

3.2.1 Photolithography Process 63 3.2.1.1 Surface Preparation 64 3.2.1.2 Spin Coating 64 3.2.1.3 Soft Baking 65 3.2.1.4 Exposure 65 3.2.1.5 Development 66 3.2.1.6 Descum 67 3.2.1.7 Hard Baking and Post Baking 67

3.2.2 Photoresists 67 3.2.3 Photolithography Tools and Resolution 69

3.2.3.1 Contact and Proximity Printings 69 3.2.3.2 Projection 70 3.2.3.3 Resolution 70 3.2.3.4 Double-Sided Lithography 73 3.2.3.5 Multilayer Resists 73 3.2.3.6 Other Lithography Methods 74

3.2.4 Photomasks 74 3.2.4.1 Mask Layout 74 3.2.4.2 Producing a Photomask 74 3.2.4.3 Mask Alignment 75

3.2.5 Cleanroom Processing 76 3.3 Doping 77

Contents v

3.3.1 Diffusion 78 3.3.2 Ion Implantation 79

3.4 Micromachining 80 3.4.1 Subtractive Processes 80

3.4.1.1 Wet Etching 81 3.4.1.2 Dry Etching 84

3.4.2 Additive Processes 89 3.4.2.1 Oxidation 90 3.4.2.2 Chemical Vapor Deposition 92 3.4.2.3 Physical Vapor Deposition 96 3.4.2.4 Epitaxy 100 3.4.2.5 Electrochemical Deposition 101

3.4.3 Bulk and Surface Micromachining 102 3.4.3.1 Bulk Micromachining 102 3.4.3.2 Surface Micromachining 106

3.4.4 LIGA 108 3.4.5 Micromolding and Imprint Lithography 109

3.4.5.1 Casting and Soft Lithography 110 3.4.5.2 Injection Molding I l l 3.4.5.3 Compression Molding 112

3.4.6 Other Micromachining Techniques 112 3.4.6.1 Microstereolithography 112 3.4.6.2 Probe-Based Lithographic Techniques 113 3.4.6.3 Chemical Mechanical Polishing 114

3.5 Wafer Bonding, Assembly, and Packaging 114 3.5.1 Dicing 115 3.5.2 Wafer Bonding Methods 115

3.5.2.1 Fusion Bonding 116 3.5.2.2 Anodic Bonding 117 3.5.2.3 Low-Temperature Glass Bonding 117 3.5.2.4 Eutectic Bonding 118 3.5.2.5 Adhesive Bonding 118

3.5.3 Hermeticity and Sealing 119 3.5.4 Assembly 120 3.5.5 Electrical Packaging 121 3.5.6 Microfluidic Packaging 122 3.5.7 Medical Packaging Requirements 122

3.6 Surface Treatment 123 3.6.1 Stiction 123 3.6.2 Surface Modification 124

3.7 Conversion Factors for Energy and Intensity Units 125 3.8 Problems 126 3.9 Laboratory Exercises 130 References 134

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4. Microfluidics 137 4.1 Introduction and Fluid Properties 137

4.1.1 Fluids 137 4.1.2 Fluid as a Continuum 137 4.1.3 Properties of a Fluid 138

4.1.3.1 Pressure 138 4.1.3.2 Density 138 4.1.3.3 Temperature • 139 4.1.3.4 Viscosity 139 4.1.3.5 Thermal Conductivity 142 4.1.3.6 Surface Tension 142 4.1.3.7 Contact Angle 143

4.2 Concepts in Microfluidics 144 4.2.1 Capillarity 144 4.2.2 Fluid Flow 145 4.2.3 CouetteFlow 145 4.2.4 Poiseuille Flow 146 4.2.5 Hydraulic Resistance 148 4.2.6 Hydrodynamic Capacitance 150 4.2.7 Hydrodynamic Inductance 150 4.2.8 Fluidic Circuit Theory 150 4.2.9 Stokes Drag 151

4.3 Fluid-Transport Phenomena and Pumping 151 4.3.1 Diffusion 151 4.3.2 Electrowetting 153 4.3.3 Electrokinetics 154

4.3.3.1 Electric Double Layers 154 4.3.3.2 Electroosmosis 157 4.3.3.3 Electrophoresis 158 4.3.3.4 Dielectrophoresis 160

4.3.4 Magnetophoresis 162 4.4 Flow Control 163

4.4.1 Microchannels 163 4.4.2 Laminar Flow in Microchannels .....165 4.4.3 Valving 166

4.4.3.1 Passive Valves 167 4.4.3.2 Actuation Methods and Active Valves 168

4.4.4 Pumping 173 4.4.4.1 Passive Pumps 173 4.4.4.2 Active Pumps: Mechanical 174 4.4.4.3 Active Pumps: Nonmechanical 175

4.4.5 Mixing 177 4.5 Problems 179

Contents vii

4.6 Laboratory Exercise 181 References 184

5. Lab-on-a-Chip or Micro Total Analysis Systems 187 5.1 Microanalytical Systems in Chemistry and Biology 187 5.2 Sample Pretreatment 189

5.2.1 Filtration 190 5.2.1.1 Filtration Structures 191 5.2.1.2 Filtration Membranes 193 5.2.1.3 Dialysis 194

5.2.2 Extraction 196 5.2.2.1 Liquid-Phase Extraction 196 5.2.2.2 Solid-Phase Extraction 198

5.3 Sample Introduction 201 5.3.1 Electrokinetic Injection 201 5.3.2 Hydrodynamic Injection 205

5.4 Separations 206 5.4.1 Separation Performance 206 5.4.2 Chromatography 208

5.4.2.1 High-Performance Liquid Chromatography ... 209 5.4.2.2 Hydrodynamic Chromatography 211 5.4.2.3 Affinity Chromatography 212 5.4.2.4 Field Flow Fractionation ! 212

5.4.3 Electrophoresis 215 5.4.3.1 Capillary Electrophoresis and Capillary Gel

Electrophoresis 216 5.4.3.2 Isoelectric Focusing 217

5.5 Problems.... 218 References 220

6. Sensing and Detection Methods 223 6.1 Sensing and Detection 223 6.2 Sensor Characteristics 225 6.3 Principles of Physical Sensing 228

6.3.1 Resistive Sensors 228 6.3.2 Capacitive Sensors 231 6.3.3 Inductive Sensors 231 6.3.4 Resonant Sensors 232 6.3.5 Sensor Examples: Pressure Sensing 233

6.4 Biological and Chemical Detection Methods 238 6.4.1 Biological Sensors 238 6.4.2 Electrochemical Methods 238

6.4.2.1 Amperometry 239

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6.4.2.2 Voltammetry 241 6.4.2.3 Potentiometry 242 6.4.2.4 Conductometry 243

6.4.3 Optical Detection Methods 245 6.4.3.1 Fluorescence 245 6.4.3.2 Absorbance 248 6.4.3.3 Chemiluminescence 249 6.4.3.4 Other Optical Detection Methods 251

6.4.4 Mass Spectrometry 251 6.4.4.1 Electrospray Ionization 252 6.4.4.2 Matrix-Assisted Laser Desorption

Ionization 259 6.5 Problems 263 References 266

7. Applications to Cells, Nucleic Acids, and Proteins 269 7.1 Cells 269

7.1.1 Cell Culture Reactors 269 7.1.2 Cell Adhesion 271 7.1.3 Retention: Filters, Weirs, and Polymer Matrix 275 7.1.4 Cell Manipulation 281 7.1.5 Electroporation 283 7.1.6 Cell Lysis 288 7.1.7 Cell-Based Sensors 289

7.2 Nucleic Acids 292 7.2.1 Purification 293 7.2.2 Amplification: Polymerase Chain Reaction 294 7.2.3 Hybridization: MicroChannel and Microarray 299 7.2.4 Sequencing 300 7.2.5 Integrated Genetic Analysis Systems 304

7.3 Proteins 306 7.3.1 Immunoassays 307 7.3.2 Enzymatic Assays 310

7.4 Problems 310 References 311

8. Clinical Monitoring 317 8.1 Flow Cytometry 317 8.2 Microdialysis 322 8.3 Catheter-Based Sensors 324 8.4 Endoscopy 330 8.5 Point of Care 333 8.6 Problems 341 References 341

Contents ix

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9. MEMS Implants and Bioelectric Interfaces 345 9.1 Implantable MEMS 345 9.2 Microelectrodes and Neural Probes 345 9.3 Implantable Sensors 359 9.4 Drug Delivery 363 9.5 Tissue Engineering 371 9.6 Problems 376 References 377

Index 383

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