Symbols and Units xi

Acronyms xvii

Preface xxv

1 Introduction to BioMEMS 1

1.1 What are BioMEMS? 1

1.2 The Driving Force Behind Biomedical Applications 4

1.3 Biocompatibility 7

1.4 Reliability Considerations 7

1.5 Regulatory Considerations 8

1.6 Other Organizations 12

1.7 Education 13

1.8 Review Questions 14

References 14

2 Silicon Microfabrication 19

2.1 Hard Fabrication Considerations 20

2.2 Lithography 26

2.3 Etching Methods 38

2.4 Thin-Film Deposition Processes 45

2.5 Ion Implantation 53

2.6 Wet-Bulk Surface Micromachining 54

2.7 Dry-Bulk Surface Micromachining 63

2.8 HEXIL Process 65

2.9 Electroplating 65

2.10 Substrate Bonding 68

2.11 Review Questions 69

References 70

3 �Soft� Fabrication Techniques 75

3.1 Introduction 75

3.2 Biomaterials 76

3.3 Soft Lithography 78

3.4 Micromolding 79

3.5 Three-Dimensional Photopolymerization 86

3.6 Smart Polymers and Hydrogels 89

3.7 Nanomedicine 94

3.8 Thick-Film Technologies 97

3.9 Review Questions 98

References 98

4 Polymer Materials 107

4.1 Polymers 107

4.2 Physical Properties 111

4.3 Copolymers 116

4.4 Review Questions 118

References 118

5 Microfluidic Principles 119

5.1 Introduction 120

5.2 Transport Processes 126

5.3 Electrokinetic Phenomena 137

5.4 Microvalves 148

5.5 Micromixers 152

5.6 Micropumps 153

5.7 Review Questions 158

References 160

6 Sensor Principles and Microsensors 167

6.1 Introduction 168

6.2 Fabrication 172

6.3 Basic Sensors 173

6.4 Optical Fibers 187

6.5 Piezoelectricity and SAW Devices 192

6.6 Electrochemical Detection 197

6.7 Applications in Medicine 204

6.8 Review Questions 213

References 214

7 Microactuators and Drug Delivery 219

7.1 Introduction 219

7.2 Activation Methods 220

7.3 Microactuators for Microfluidics 230

7.4 Equivalent Circuit Representation 232

7.5 Drug Delivery 234

7.6 Review Questions 243

References 243

8 Clinical Laboratory Medicine 249

8.1 Introduction 250

8.2 Chemistry 255

8.3 Hematology 261

8.4 Immunology 266

8.5 Microbiology 269

8.6 Urinalysis 270

8.7 Coagulation Assays 271

8.8 Arterial Blood Gases 272

8.9 Review Questions 274

References 275

9 Micro-Total-Analysis Systems (mTAS) 283

9.1 Lab-on-a-Chip 284

9.2 Capillary Electrophoresis Arrays (CEA) 287

9.3 Cell, Molecule, and Particle Handling 290

9.4 Surface Modification 295

9.5 Microspheres 306

9.6 Cell-Based Bioassay Systems 309

9.7 Review Questions 309

References 310

10 Detection and Measurement Methods 315

10.1 Introduction 315

10.2 Detection Schemes 316

10.3 Measurement Systems 322

10.4 Review Questions 329

References 329

11 Genomics and DNA Microarrays 341

11.1 Introduction to Genomics 341

11.2 Polymerase Chain Reaction (PCR) 351

11.3 Gene Expression Profiling 353

11.4 DNA-LOC Devices 355

11.5 DNA Microarrays 356

11.6 Pharmacogenomics 373

11.7 Review Questions 374

References 374

12 Proteomics and Protein Microarrays 377

12.1 Introduction to Proteomics 377

12.2 Mass Spectrometry (MS) 382

12.3 Protein LOC Devices 392

12.4 Protein Microarrays 393

12.5 Bioinformatics 406

12.6 Review Questions 407

References 408

13 Emerging BioMEMs Technology 413

13.1 Introduction 414

13.2 Minimally Invasive Surgery 414

13.3 Point-of-Care Clinical Diagnosis 415

13.4 Cardiovascular 418

13.5 Diabetes 422

13.6 Endoscopy 424

13.7 Neurosciences 425

13.8 Oncology 431

13.9 Ophthalmology 432

13.10 Dermabrasion 435

13.11 Tissue Engineering 436

13.12 Cell-Based Biosensors 437

13.13 Homeland Security 438

13.14 Review Questions 441

References 442

14 Packaging, Power, Data, and RF Safety 449

14.1 Packaging 449

14.2 Electronic Assembly and Packaging 458

14.3 Power Systems 463

14.4 Data transmission 470

14.5 Radio Frequency (RF) Safety 472

14.6 Review Questions 477

References 478

15 Biocompatibility, FDA, and ISO 10993 483

15.1 Introduction 484

15.2 FDA Guidance 485

15.3 International Organization for Standardization 485

15.4 Cytotoxicity 493

15.5 Sensitization 495

15.6 Irritation 498

15.7 Systemic Toxicity 499

15.8 Genotoxicity, Carcinogenicity and Reproduction 500

15.9 Implantation 501

15.10 Hemocompatibility 504

15.11 Degradation 506

15.12 Biocompatibility of Polymers 508

15.13 Biofouling 511

15.14 Biocompatibility of Other Materials 512

15.15 Review Questions 516

References 517

Appendix A: Common BioMEMS Polymers 527

Appendix B: Medical Imaging 545

Appendix C: FDA Blue Book Memorandum #G95-1 557

Glossary 561

Index 595

Preface

BioMEMS stands for biomedical microelectromechanical systems. Although perhaps not an ideal term, since electromechanical evokes an image of electrically driven coils, solenoids, and machined parts, it has caught on to encompass some of the most interesting new technologies today.

It is a matter of perspective, for micro places us in a new realm altogether, and allows us to conceptualize electromechanical as any physical, electrochemical, biochemical, or fluidic phenomenon that accomplishes work at the microscale. This work includes microsensing, microactuation, microassaying, micromoving, and microdelivery.

BioMEMS is a science that includes more than simply finding biomedical applications for MEMS devices. It represents an expansion into a host of new polymer materials, microfluidic physics, surface chemistries and modification, �soft� fabrication techniques (including polymers and biological components), biocompatibility, and cost-effective solutions to biomedical problems. It brings together the creative talents of electrical, mechanical, optical, and chemical engineers, materials specialists, clinical laboratory scientists, and physicians. BioMEMS devices are the platform upon which nanomedicine will be delivered for the betterment of the human condition. It is also the quintessential science for genomics, the study of sets of genes, gene products, and their interactions; and proteomics, the study of proteins, the expression of genes in health and disease.

Designing, modeling, and fabricating medical microdevices will increase enormously in the next ten years, and the need for people involved in this activity to communicate their ideas, needs, and capabilities requires specialized training that bridges diverse backgrounds, and introduces the terminology and potential of the field.

Many professional organizations, including SPIE�The International Society for Optical Engineering, Materials Research Society, Institute of Electrical and Electronic Engineers, American Society of Mechanical Engineers and American Institute of Chemical Engineers, have sponsored and published symposia proceedings or other works in bioMEMS. In addition, bioMEMS should be featured among the advanced curricula of biomedical engineering programs, along with functional genomics, cell/tissue engineering, computational biology and bio-imaging.

It is necessary for the medical community to take a serious look at including bioMEMS and medical microdevices as prerequisite training for entry into medical school, as a research elective during medical training or as part of a combined M.D. and Ph.D. program. There are innumerable medical problems that can be solved with these devices, but there exists a shortage of medical specialists in the field. It is also prudent for the biomedical engineering community to consider holding medical case presentations to become more aware of medicine and design opportunities.

There may be as many device solutions to medical problems twenty years from now as there are pharmaceutical solutions today, and I would not be surprised to find a book titled Physician�s Reference to Biomedical Devices on the desk of every practitioner. Hospitals and large clinics in the future may need to employ biomedical engineering doctorates in device management much as they employ doctorates in pharmacy. This specialization seems inevitable as I have witnessed advances in pacemakers and implantable defibrillators, insulin pumps, and other devices beyond the knowledge base of primary care physicians.

There will be an explosion of new implantable devices based on bioMEMS technology, and it is foreseeable that new standards will emerge, governing interconnectivity, power, and data telemetry so that all implantable devices will have conforming features. This will allow small companies to enter the market and focus on one or more aspects of more complex systems.

United States and foreign patents help recoup investments in bioMEMS devices by allowing a company to develop, manufacture, and market a new device, or license the technology as they see fit. Investors must be aware that the road for a newly patented device to market is a difficult and expensive journey not unlike the development of a new medication. There may be biocompatibility issues to resolve, clinical trials to perform, and Federal Drug Administration (FDA) requirements to satisfy.

In the end someone will need to pay for the new technology, including facilities that buy bioMEMS-based equipment, and the patients who require evaluation and therapy. Ultimately it will be the payers�HMOs, Medicare, private insurers and patients�who will decide the fate of even the most promising and useful device. New devices intended for medical care will require advocacy from the medical community and demonstration of superiority over existing methods.

This book is the first dedicated to bioMEMS and medical microdevice training, and is suitable for a single semester course for upper senior and graduate students, or as an introduction to others interested or already working in the field. Topics include (1) microfabrication of silicon, glass, and polymer devices; (2) microfluidics and electrokinetics; (3) sensors, actuators, and drug-delivery systems; (4) micro-total- analysis-systems (mTAS) and lab-on-a-chip devices (LOC); (5) an introduction to clinical laboratory medicine; (6) detection and measuring systems; (7) genomics, proteomics, DNA, and protein microarrays; (8) emerging applications in medicine, research, and homeland security; (9) packaging, power systems, data communication, and RF safety; and (10) biocompatibility, FDA guidance, and ISO 10993 biological evaluations.

The book is written to appeal to the diversity of training and background of its readers, and includes introductory material, advanced concepts, and current research. The foundations for conceiving, designing, and applying bioMEMS and medical microdevices at both the research and clinical level are addressed. An extensive glossary covers both the engineering and healthcare terminology.

I am very appreciative of the staff at SPIE, including its editorial staff and reviewers, and of all the others who made this book possible. I am especially grateful to Merry Schnell and Cassie McClellan for their invaluable assistance. I am also grateful to my students and colleagues, and for the opportunity to lecture on this subject in the Department of Biomedical Engineering at the University of Minnesota, under the leadership of Robert Tranquillo.

There are many individuals who through the years have provided me with the necessary background and inspiration to complete this book, and I would like to express my sincere gratitude. I would also like to thank the many authors and investigators whose works I have relied on in completing this book.

Comments and suggestion for future editions are always welcome. Instructors at educational institutions may inquire about Power Point presentations by sending me an e- mail. I have prepared about 600 slides divided into 18 lectures, suitable as an introductory course when used in conjunction with the book.

Steven S. Saliterman MD, FACP
Chief of Medicine Methodist Hospital
Department of Biomedical Engineering
Faculty, Nano & Microsystems Applications Center
University of Minnesota
www.tc.umn.edu/~drsteve
drsteve@umn.edu
November 17, 2005