Chapter 1

Introduction to BioMEMS
1.1

1.2

1.3
1.4
1.5

1.6

1.7

1.8

1.1

What is BioMEMS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.1 Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.2 Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.3 Goal of this book . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The Driving Force Behind Biomedical Applications . . . . . . . . . . . . . . .
1.2.1 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.2 Drug-delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.3 Tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.4 Minimally invasive procedures . . . . . . . . . . . . . . . . . . . . . . . . . .
Biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reliability Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Regulatory Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5.1 Food and Drug Administration (FDA) . . . . . . . . . . . . . . . . . . . .
1.5.2 Clinical Laboratory Improvement Amendment (CLIA) . . . . . .
1.5.3 Joint Commission on Accreditation of Healthcare
Organizations (JCAHO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.6.1 United States Pharmacopeia (USP) . . . . . . . . . . . . . . . . . . . . .
1.6.2 The American Society for Testing and Materials (ASTM) . . .
1.6.3 Underwriter’s Laboratories (UL) . . . . . . . . . . . . . . . . . . . . . . . . .
Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.7.1 Accreditation Board for Engineering and Technology (ABET)
and the Biomedical Engineering Society (BMES) . . . . . . . . . .
1.7.2 Programs in biomedical engineering . . . . . . . . . . . . . . . . . . . . .
Review Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14

What is BioMEMS?

BioMEMS, or biomedical microelectromechanical systems, has emerged as a
subset of MEMS devices for applications in biomedical research and medical

1

1. and drug-delivery systems Micro-total-analysis systems (mTAS) and lab-on-a-chip devices (LOC) Clinical laboratory medicine Detection and measuring systems Genomics.CHAPTER 1 2 microdevices.1 Fabrication Traditional fabrication techniques previously imported from integrated circuit manufacturing to MEMS devices have undergone yet another transition for bioMEMS devices. and protein microarrays Emerging applications in medicine. glass. proteomics. and bonding that are essential for mass production with reproducibility and functional reliability at low cost. the 3D construction of bioMEMS devices. FDA. and as detection schemes become incorporated into the device itself. and biological materials. For the purpose of teaching bioMEMS. and RF safety Biocompatibility.  In Europe the term microsystem or microstructure technology (MST) is used instead of MEMS. once thought better left to side-by-side devices in the MEMS realm. In addition. chemical. actuators. and ISO 10993 biological evaluations The bioMEMS industry is increasing rapidly with a growth rate of 11. the following subjects will be covered: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) Microfabrication of silicon. In addition. Modification of surfaces for biomedical assays and biocompatibility has emerged as a complex science. inertial masses. not just in shape but in the embodiment of electromechanical.4%. and homeland security Packaging. glass. and diaphragms of typical MEMS devices. New techniques are being developed for molding. Merging traditional MEMS devices with discussion of bioMEMS is essential. and ceramics. with an increased awareness of microfluidic physics and the surface science of silicon. research.1. with abundant opportunities for creating novel techniques and applications that can be patented and ultimately brought to market. are now becoming essential as microreactor chambers. casting. and polymer devices Microfluidics and electrokinetics Sensors. polymers. power systems. replication. because some readers will not have engineering backgrounds or familiarity with MEMS technology. reaches beyond the basic concepts of cantilevers. with projected revenues of $850 million in 2003 to over $1 billion in 2006 [Rebello. Fabrication process steps are becoming more complex as integrated electronics. . DNA. both of which are vital to the medical disposables market. data communication. 2004]. packaging for safety and biocompatibility poses a significant challenge for the bioMEMS engineer.

or elective study for anyone in related fields. and discarding of waste products. and for applying them to research and medicine. . precise control of mixing. Implanted devices may be part of a distributed system such as fiber optic sensors that provide continuous information via light from various parts of the body to a central medical device. and designing bioMEMS and medical microdevices.1. Although this book is suitable for a one-semester course at the graduate level. reacting. self-assembled monolayers (SAMs). You will also develop an understanding of biocompatibility based on the ISO 10993 Standard. reproducibility. and reagent use. and sensor and actuator concepts. dielectrophoresis. 1. and have self-contained or external power sources. this book may serve as useful extension for a MEMS engineering class.2 Structure BioMEMS devices can typically be considered as having at least one feature’s dimension in the submicron to micron range (100 nm– 200 mm). This includes fabrication with silicon. but more typically they are integrated with other components and perform one or more functions in a chain of operations connected by tubing or other conduits. instructors may additionally incorporate a laboratory experience to provide handson design and fabrication of a bioMEMS device. and polymers substrates. and operate as either an open-ended (sensor or actuator) system or a closed-loop system (autoregulation).1. and the options for powering and packaging devices to obtain optimal performance and safety. small sample size. They may operate in vivo or in vitro (inside or outside a living system). glass. Among the advantages of biochip miniaturization are lower manufacturing costs. while on the other end they may be the key component to a much larger device such as a medical imaging machine. Improved signal-tonoise ratio. technology management course. covalent and noncovalent surface modifications. electrophoresis. in-line or embedded detection methods. and high throughput are also advancges of miniaturized biochips.3 Goal of this book Upon completing this book you will have acquired an understanding of the many necessary skills for conceiving.INTRODUCTION TO BIOMEMS 3 1. They may be all encompassing devices. On one end of the application scale they may be the platform for nanotechnologies. transport processes such as laminar flow and electrokinetic phenomena (electro-osmosis. and basic genomics and proteomics as a prelude to DNA and protein microarrays. and other dimensions of up to several millimeters. improved response time. Moreover. and electrowetting). Next you will learn about micro-total-analysis systems (mTAS) and lab-on-achip (LOC) devices. They may be smart systems with integrated microprocessors.

. . . . . . . . . . . . . . . . . . . . . . . . .2 Chemical analysis . . . . . . . . . . . . . . .3 Isoelectric focusing (cIEF) . . . . . . . . . . .3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. .3. . . . 283 284 284 284 287 287 288 290 290 290 291 292 292 293 294 295 297 297 299 304 306 306 306 306 309 309 310 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . . . . . . . . . . . 9. . . . . . . .1 9. . . . . . . . . . . Microspheres . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . 9. . . .6 Optical tweezers and scissors . . . References . . 9. . .1 Mechanical separation . . . . . . . . . . . . . .7 Hydrogels .1. . . . . .3 Semipermeable membranes . . . 9. . . . . . . . . . . . .2. . . . . . . . . . . . . 9. . . . . . . . . . . . . . . . . . . . .3 Applications . . . .4. . . . .2. . . . . . . 9. . . . . . Cell. . . . . . . . . . . . . . . . . Surface Modification . . .2 Polymer substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 9. . 9. . . . .5. . . .1. . . . .3. . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 Dielectrophoresis . . . . . . . . . . . . . . . . . . . . .5. . . . . . . . Capillary Electrophoresis Arrays (CEA) . . . . . . . .4 9. . .3. . . . . . . . . .4. . . . .1 Introduction . . Review Questions . . . . . 9. . . . . . . . . . . . Molecule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . . . . . . . . . . . . . . . 9. . . . . .3. . . .2 Fabrication . . . . . . . . . . . . . . . . . . . . . . .5 Protein adhesive rolling . . . . . .3 Immobilization strategies . . . . . . . .2 9. . . . . 9. . . . . . . . . . . . . . . . . 9. . .5. . . . . . . . . . . . . . . . . . . . . . 9. . . . . . . .4. . . . . . . . . . . Cell-Based Bioassay Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Glass and silicon substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. . . . 9. . . . . . .2 Linear and radial arrays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3. . . . . . . . . . . . . . . and Particle Handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Lab-on-a-Chip . . . . .Chapter 9 Micro-Total-Analysis Systems (mTAS) 9.5 9. . . . . .2 Impedance counting and sizing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Capillary electrophoresis (CE) . . . . . .3. . . . . . . . . . . . . . . . . .1 Characteristics . . . . . . . . . . .2. . . . . . . . . . . . .3 9. . . . . . . . . . .

1 Introduction Micro-total-analysis systems (mTAS). and customized surfaces created by chemical modification or coatings with inorganic and organic materials. derive from application of “hard” and “soft” fabrication techniques for the manufacture of miniaturized devices that perform all or part of a biochemical analysis. and detectors into single devices. 2001].1. hence. Improved throughput of analytes occurs as a consequence of miniaturization and integration. Microspheres and beads are also integral to numerous LOC devices. separators. and the subset of devices referred to as lab-on-a-chip (LOC). electrodes. while LOC refers more specifically to a microfluidic chip or other device that performs a well-defined analytical task [Guber et al. mTAS may be hybrids of multiple chips. reactions chambers. and integration of channels. reduced reagent consumption. have been the catalyst for LOC devices. and the history of these devices have been discussed in previous chapters.CHAPTER 9 284 9. mixers. The definition of these terms varies with different authors and may be used interchangeably. efficient cells. much of the discussion here derives from current research efforts. 2004]. DNA chips (for the study of DNA and RNA) include both DNA LOC devices and DNA microarrays. not all techniques are reported. While certain representative works have been selected to introduce basic concepts. These are discussed in Chapters 11 and 12. especially for DNA analysis..1 Lab-on-a-Chip 9. molecular and particle separation. 9. fabrication techniques. Biochips more generically include the LOC devices and microarray devices. microactuators. new technologies have emerged for continuous and . Most of the techniques employed for mTAS and LOC devices are investigational.2 Chemical analysis Although electrophoretic methods.1.. and immobilization. Microanalysis devices can be broadly classified as either microfluidic-based or microarray-based microdevices [Krishnan et al. The goal of mTAS and LOC devices is to achieve increased efficiency through smaller scales and to undertake analysis that cannot be done conveniently by other means. smaller sample requirements and carrier volumes. and much can be gained by going directly to the literature and searching a topic of interest. Advantages of smaller scales include the following: (1) (2) (3) (4) (5) improved transport through use of electrokinetic effects and miniaturized pumps. LOC devices may incorporate microfluidic components. Commonly used materials. and external supports. microsensors. while protein chips include both LOC devices and protein microarrays. integrated electronics.

and that surface area to volume is proportional to the scale of the microchannel. As the scale decreases.1 shows the scale dependence of the molecular transportation time and the specific interface area. and cell analysis. for example. is shown in Fig. surface area to volume increases. while time for diffusion decreases. 20-nm thick Cr and 100-nm thick Au layers were deposited on the substrates by physical vapor deposition. Applications include chemical analysis. and incorporate either novel electrokinetic effects or pressure-driven systems for movement of fluids and solids. [Reprinted with permission from Sato et al. suitable for a variety of inorganic. (2003). The bare glass surface with the microchannel pattern was etched with a 50% HF solution at an etching rate of 13 mm/min.1 Scale dependence of the molecular transportation time and the specific interface area. organic. 9. Figure 9. The photoresist was developed and a pattern with 10-mm wide lines was obtained. the channel size of 150– 250 mm means diffusion across the channel may occur in seconds.] . Figure 9. The Au and Cr layers were etched with I2/NH4I and Ce(NH4)2(NO3)6 solutions. Recall from the discussion on diffusion in Chapter 5 that the mean-square displacement of a particle from its origin is proportional to time. the remaining photoresist was removed in acetone and metals were removed in I2/NH4I and Ce(NH4)2(NO3)6 solutions. UV light was exposed through a photomask by using a mask aligner to transfer the microchannel pattern onto the photoresist.2. These devices are typically microfluidic in design.7-mm thick Pyrex glass plates were used (top and bottom plates). After glass etching. Pressure-driven continuous-flow chemical processing chips with stabilized laminar flow. and protection of the substrates during glass etching. 2-mm thick positive photoresist was spin-coated on the Au metal layer and baked at 908C for 30 minutes. Inlet and outlet holes were drilled by ultrasonic sandblasting on the top plate. (2003). immunoassays. and physical chemistry reactions. The following summarizes the process steps required to fabricate this chip: Mechanically polished 0. are described by Sato et al. copyright Elsevier. For good contact between the substrates and the photoresist.MICRO-TOTAL-ANALYSIS SYSTEMS (mTAS) 285 sequential chemical processing. In LOC devices. An immunoassay chip. multi-ion sensing.

forming a stable liquid-liquid interface. [Reprinted with permission from Sato et al.] . Surface-chemical modification with octadecylsilane stabilized liquid flow in organic solvent carrying channels. [Reprinted with permission from Sato et al. copyright Elsevier. Figure 9.286 CHAPTER 9 Figure 9. (2003).3).2 Immunoassay chip.] Microchannels were designed with guide structures (Fig. (2003). copyright Elsevier. 9. These required three photomasks and three independent etching cycles.3 Microchannels with guide structures forming a stable liquid-liquid interface.

copyright Elsevier.4 A microfluidic system for capillary electrophoresis. The sample is driven through the short sample channel across the separation channel by application of a potential. this immunoassay chip is able to measure ultra-trace amounts of human carcinoembryonic antigen (CEA) (a serum colon cancer marker) and interferon. and the Figure 9. The methodology employs antibody-coated polystyrene beads packed in the microchannels and thermal-lens microscopy for detection.] . 9.1 Capillary electrophoresis (CE) A microfluidic system for capillary electrophoresis (CE) is shown in Fig.2.4. (a) Sample introduction and electrophoretic separation are accomplished in each of two crossing channels. where sample introduction and electrophoretic separation are accomplished in each of two crossing channels.2 Capillary Electrophoresis Arrays (CEA) 9. (2004). [Reprinted with permission from Guber et al. (b) The sample is driven through the short sample channel across the separation channel by application of a potential. and (c) the “plug” is electrophoretically separated by application of another potential.MICRO-TOTAL-ANALYSIS SYSTEMS (mTAS) 287 As an alternative to traditional ELISA. 9.

. . . . . . . . . . . . . . .6 11. . . . . . . . . . . . . . . . . . DNA Microarrays . . . 11. . . . .5. . . . . . . . . . . . . References . .3 RT-PCR . . . . . . . .3 cDNA chip experimentation . . . . . . . .3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Microarray data analysis . . . . and the exchange and recombination of genetic material. . . . . . . . . . . . . . and (4) bioinformatics. . . . . . . . . . . . . . . . . .1 Introduction to Genomics 11. . . . . . . . . . . . . . . . . . . . Polymerase Chain Reaction (PCR) . . . . . . . . . . . . . . . .1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 11. 11. . . . . . . . . . .1 Definition The science of genomics includes (1) understanding the mechanism of DNA replication. . . . . . . . . . . . . . . . . . . . . . . . . . . .2 A brief history of genetics . . . . . . . . . . . .3. 11. . . . . . . . . . . . . . . .1 Technology requirements . . . . . . .3 The human genome . .5.5. . . . . . . .1. . . . . . . .4 Oligo chip experimentation . . . . .Chapter 11 Genomics and DNA Microarrays 11. . and interpreting of data [Baldi and Hatfield. . . . . . . . . . . . . . . . . . .5. . . . .1. . .5 11. 11. . . . .2 Measuring transcript levels . . . . . . . . . . .4 11. . . . Functional genomics is the overall effort of deconstructing the genome to assign 341 . . . . . . . . . . . DNA-LOC Devices . . . . . .4 Molecular genetics . . . . . . . . . . . . . . Gene Expression Profiling . . . . . . . . . . . . . . . . . . . . . . . 11. . . . . . . . . . . . . . . . . . . 11. . . . . . . . . . . . . . .1. . 11. . . . . . . . . . . . . . . . . . . protein synthesis. . . . . . . . . . .1 Definition . . . 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . gene expression. . . . . . . . . . . . . .5. . . . . . . . . . . . . . 341 341 343 344 345 351 353 353 354 354 355 355 355 363 367 370 370 373 373 374 11. . . . . . . . . . . . . . . . . . . . .3 11. . 11. . . . . . . . . . . . . . . . . . . . .1. . . . Review Questions . . . . . . . . . . . . . .2 11. . . . . . . . . . . . . Pharmacogenomics . . . . . . . . . . . . . . . . 11.2 Fabrication . . . . .3. . . . . . . . . . . . . . . . . . . . . . .1. . . . . . . . . . . . . . . . . . . . 11. . . . . . . . . . . . . . . . . . . . . . . . .7 Introduction to Genomics . . . . . . the storing. . . . . . . . . (2) the understanding of restriction endonucleases and DNA ligases capable of cutting and rejoining DNA at sequence specific sites. . . . . . . . . . analyzing. . . . . . . . . . (3) technical advances such as PCR and automatic DNA sequencing.1 11. . . . . 2002]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

With genome data from humans and other organisms. it is necessary to have some background in molecular genetics. and cytosine). 2003]. and (2) facilitation of modeling of molecular interactions ( phemonics).000 to 25. As a cautionary note. with about 20. and deletion of base pairs) to be studied. it is now possible to systematically deconstruct how the genetically programmed behavior of an organism’s physiology is related to the constituent genes that makes its individual version of its species’ genome. The consequence is that many reports will not be substantiated in follow-up studies. gene expression. including cellular and subcellular messaging. gene maps. It includes (1) the establishment of informational databases for the storage and retrieval of molecular sequence and structure information. Not all diseases . 2002]. Available biological information includes DNA sequence.” published in the Mayo Clinic Proceedings between August 2002 and March 2004. There are about 3 billion such bases in the human genome. Genomics permits us to understand the total characteristics displayed. have evolved and disseminated faster than the computation skills and analytical techniques required to properly interpret the data. Haploid refers to a nucleus. Moreover. such as gametes (reproductive spermatozoa and oocytes). gene polymorphisms. and protein interaction effects. While the following discussion offers some insight. and chromosomes are contained within the nucleus of the cell. The function of a genome is to drive the generation of molecules (mostly proteins) for structural integrity and response to the environment. or phenotype. the large amount of expression data has involved data mining specialists. or organism possessing a single set of unpaired chromosomes. as measured by the number of entries into databases such as GenBank. groups of genes. It also allows the effects of single nucleotide polymorphisms (SNPs) and mutations (substitution. and gene expression data. is increasing far more rapidly than our knowledge about these genes as measured by the number of articles appearing in the biomedical literature [Kohane et al. and statisticians. both animal and plant. There are 23 pairs of chromosomes in the human genome. cell. Diploid refers to chromosomes in homologous pairs. To appreciate what has already been accomplished and prepare for future devices.342 CHAPTER 11 biological function to genes. machine learners. A genome is composed of a series of nitrogenous DNA bases (adenine. thymine. protein structure. physical maps. with one chromosome from each parent. such as microarray-based expression profiling. This has involved computer scientists with special skills in string processing. guanine. The function of only about 15. In addition.000 genes. and computer graphics. There are a number of mTAS opportunities in genomics and proteomics. Genes that provide the code for all living things. by an organism under a particular set of environmental factors... the comprehensive genomic measurement technologies. are located on chromosomes. and particular gene interactions. insertion. Bioinformatics is a science that addresses the challenge of knowledge acquisition from genomic data. and is cited several times below.000 of these genes is known [Lorentz et al. and the specific order of base pairs provides the genetic code. computational geometry. a thorough understanding and link to the original literature can be obtained in the multipart series “Primer on Medical Genomics. raw genomic data.

1. Chargaff (1951) discovered the ratio of purines to pyrimidines (adenine to thymine. and soon afterward chromosome syndromes were identified. as did an understanding of sex-linked traits and the linear arrangement of genes on chromosomes.GENOMICS AND DNA MICROARRAYS 343 stem from single gene disorders with Mendelian inheritance patterns. There are many abnormalities that show a familial recurrence and have a clear genetic component. Aristotle. BioMEMS includes cDNA chips and oligo chips discussed below. Tijo and Levan determined that humans had 46 chromosomes. Genomics facilitates an understanding of these complex diseases as well [van Heyningen and Yeyati. The DNA double helix was described by Watson and Crick in 1953.2. and Baltimore (1970) . In 1865. In 1960. Temin and Mitzutani (1970). and soon after Crick introduced the concept that DNA makes RNA (ribonucleic acid). The first attempts to cultivate plants and domesticate animals can be traced back to ancient Babylonians and Assyrians from 5000 BC. (1953) showed the helical structure of the DNA molecule.1 Inheritance The earliest understanding of inheritance began long ago when humans realized that specific traits were shared between parent and child.2 A brief history of genetics 11. An understanding of biochemical disorders based on genetic defects followed. In 1859. Greek philosophers Hippocrates. which in-turn makes proteins. Nowell and Hungerford discovered that an abnormality of chromosome 22 was associated with chronic myeloid leukemia.1. and Plato wrote about the inheritance of human traits between 460 and 322 BC. quinine to cytosine) was 1:1. In the late nineteenth century it was recognized that chromosomes were located in the nucleus and were the basis of heredity. and over the next two centuries it was recognized that cells with nuclei were the fundamental units of life and were formed by the division of other cells. Darwin published On the Origin of Species with his theory of natural selection. Cells were discovered by Hooke in 1665. 11. Mendel published “Experiments in Plant Hybridization.1. 2004].2 Genetics The term genetics was coined by Bateson (1900) at the beginning of the twentieth century in advocation of Darwin’s theory based on Mendel’s principles of hereditary. X-ray diffraction patterns by Franklin and Gosling (1953) and Wilkins et al. 11.2. but do not show Mendelian segregation patterns. These are rapidly evolving devices. In 1956. and consulting the manufacturer’s current product sheets is essential for realizing their full potential. leading to the birth of cancer cytogenetics.” introducing the principles of heredity and the concept of dominant and recessive genes.

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