sign in sign up
<<
Home , Microfabrication, Sensor, Surface micromachining

BIOMEDICAL APPLICATIONS OF MEMS

Jack W. Judy University of California, Los Angeles 68-121 IV, Box 159410 Los Angeles, CA 90095-1594 Tel: (310) 206-1371 [email protected]

Abstract – Micromachining and MEMS For a discussion of the early work in MEMS, technologies can be used to produce complex including many of the seminal papers, the interested electrical, mechanical, fluidic, thermal, optical, reader is directed to reference [1]. For a and magnetic structures, devices, and systems comprehensive discussion of micromachining on a scale ranging from organs to subcellular processes and MEMS devices, the interested reader organelles. This miniaturization ability has is directed to the texts by Kovacs [2] and Madou [3]. enabled MEMS to be applied in many areas of , medicine, and biomedical engineering – a field generally referred to as BioMEMS. The future looks bright for BioMEMS to realize (1) Although many of the microfabrication techniques microsensor arrays that act as an electronic and materials used to produce MEMS have been nose or tongue, (2) microfabricated neural borrowed from the IC industry, the field of MEMS has systems capable of controlling motor or sensory also driven the development and refinement of other prosthetic devices, (3) painless microsurgical microfabrication processes and non-traditional tools, and (4) complete microfluidic systems for materials. total chemical or genetic analyses. Conventional IC Processes and Materials: INTRODUCTION - ; ; dopant diffusion; implantation; LPCVD; PECVD; Microelectromechanical systems (MEMS) is a evaporation; sputtering; wet ; plasma technology of miniaturization that has been largely etching; reactive-ion etching; ion milling adopted from the (IC) industry and applied to the miniaturization of all systems (i.e., not - ; ; silicon nitride; aluminum only electrical systems but also mechanical, optical, fluidic, magnetic, etc). Miniaturization is Additional Processes and Materials used in MEMS: accomplished with microfabrication processes, such - anisotropic wet etching of single-crystal silicon; as micromachining, that typically use , deep reactive-ion etching or DRIE; x-ray although other non-lithographic precision lithography; ; low-stress LPCVD microfabrication techniques exist (FIB, EDM, laser films; thick-film resist (SU-8); spin casting; machining). Due to the enormous breadth and micromolding; batch microassembly diversity of the field of MEMS, the acronym is not a particularly apt one. However, it is used almost - piezoelectric films such as PZT; magnetic films universally to refer to the entire field (i.e., all devices such as Ni, Fe, Co, and rare earth alloys; high produced by micromachining). Other names for this materials such as SiC and ceramics; general field include “microsystems”, popular in mechanically robust aluminum alloys; stainless Europe, and “micromachines”, popular in Asia. steel; platinum; gold; sheet ; such as PVC and PDMS The methods used to integrate multiple patterned typically the case for ). materials together to fabricate a completed MEMS Exploiting the predictable anisotropic etching device are just as important as the individual characteristics of single-crystal silicon, many high- processes and materials themselves. The two most precision complex 3-D shapes, such as V-grooves, general methods of MEMS integration are described channels, pyramidal pits, membranes, vias, and in the next two sub-sections: surface micromachining nozzles, can be formed [5]. An illustration of a typical and bulk micromachining. bulk micromachining process is given in Figure 2.

Surface Micromachining (100) Silicon Simply stated, surface micromachining is a method p+ Silicon of producing MEMS by depositing, patterning, and etching a sequence of thin films, typically ~1 µm Silicon Nitride Film thick. One of the most important processing steps that is required of dynamic MEMS devices is the selective removal of an underlying film, referred to as a sacrificial layer, without attacking an overlaying film, referred to as the structural layer, used to create the mechanical parts. Figure 1 illustrates a typical {111 Planes} surface micromachining process [4]. Surface micromachining has been used to produce a wide variety of MEMS devices for many different applications. In fact, some of them are produced commercially in large volumes (> million parts per month). Through Membrane V-Groove Hole Anchor Sacrificial Layer

Substrate Figure 2: Bulk micromachining.

Structural Layer Substrate Bonding

Silicon, glass, metal and polymeric substrates can be bonded together through a variety of processes (i.e., fusion bonding, anodic bonding, eutectic bonding, and adhesive bonding). Typically at least one of the Release Etch bonded substrates has been previously micromachined. Substrate bonding is typically done to achieve a structure that is difficult to form otherwise (i.e., large cavities that may be hermetically sealed or a complex system of enclosed channels) or simply to add mechanical support and protection [2]. Figure 1: Surface micromachining and the sacrificial layer technique. Non-Silicon Microfabrication

Bulk Micromachining The development of MEMS has contributed significantly to the improvement of non-silicon Bulk micromachining differs from surface microfabrication techniques. Two prominent micromachining in that the substrate material, which examples are LIGA and from is typically single-crystal silicon, is patterned and micromachined substrates. shaped to form an important functional component of the resulting device (i.e., the silicon substrate does not simply act as a rigid mechanical base as is LIGA comprehensive discussion of all the different and their applications is beyond the scope of this LIGA is a German acronym standing for lithographie, paper. Instead, a discussion of several classes of galvanoformung (plating), and abformung (molding) microsensors and an overview of their applications [6]. However, in practice LIGA essentially stands for will be given. a process that combines extremely thick-film resists (often >1 mm) and x-ray lithography, which can Microsensors for Biomechanics pattern thick resists with high fidelity and results in vertical sidewalls. Although some applications may Studies of the forces created by and imposed on the require only the tall patterned resist structures body benefit from increasing the sensitivity of themselves, other applications benefit from using the mechanical stress and strain sensors while also thick resist structures as plating molds (i.e., material reducing their size and cost. The following are can be quickly deposited into the mold by examples of microsensors used to study electroplating). A drawback to LIGA is the need for biomechanics. high-energy x-ray sources (e.g., synchrotrons or linear accelerators) that are very expensive and rare Strain Gauges (i.e., only several such sources exist in the U.S.). Strain gauges are used to characterize the forces in SU-8 the body. Since silicon is known to be an excellent piezoresistive material (i.e., it’s resistance changes Recently a cheap alternative to LIGA, with nearly the as a function of applied force), it can be easily same performance, has been developed. The micromachined to form sub-millimeter multi-axis solution is to use a special epoxy-resin-based optical strain gauges [10]. Applications of such miniaturized resist, called SU-8, that can be spun on in thick strain gauges include orthopedic research and the layers (>500 µm), patterned with commonly available study of muscles. Although the understanding of contract lithography tools, and yet still achieves muscle function and structure is well understood at vertical sidewalls [7]. the whole-muscle and cellular levels, muscles have not been well characterized in the region in between. Plastic Molding with PDMS An improved understanding at this level would allow for the development of improved locomotion Polydimethylsiloxane (PDMS) is a transparent therapies and prosthetic devices. elastomer that can be poured over a mold (e.g., a wafer with a pattern of tall SU-8 structures), Accelerometers polymerized, and then removed simply by peeling it off of the mold substrate [8]. The advantages of this One class of microsensors that MEMS technology process include (1) many inexpensive PDMS parts has had the most positive impact on are inertial can be fabricated from a single mold, (2) the PDMS sensors (i.e., accelerometers and gyros). Since will faithfully reproduce even sub-micron features in inertial devices typically consist of a proof mass, the mold, (3) PDMS is biocompatible and thus can mechanical flexure, and displacement , be used in a variety of BioMEMS applications, and MEMS technology is well suited to integrate each of (4) since PDMS is transparent, tissues, cells, and these sensor elements into a single chip. In fact, it is other materials can be easily imaged through it. also possible to integrate ICs with the micro- Common uses of PDMS in biomedical applications mechanical elements to add amplification and include: microstamping of biological compounds (to filtration capability to the chip-scale sensor [11]. observe geometric behavior of cells and tissues) and Inertial microsensors are useful to determine impact systems [9][8]. level and patient posture.

BIOMEDICAL MICROSENSORS Microsensors for Pneumatic Biosystems

The majority of MEMS used in biomedical Since much of the human body is a complex system applications act as sensors. Examples include of pumps, valves, vessels, and interconnects, critical sensors used during surgery (i.e., measuring pressure in many parts of the body is an important intravascular pressure), long-term sensors for parameter to indicate the health and well being of a prosthetic devices, and highly sophisticated sensor patient. Pressure sensors are used in medicine in arrays for rapid lab-quality diagnosis at home. A many applications: blood pressure, bladder pressure, and cerebral spinal fluid pressure to name a few. In doped with conductive particles, addition to performance requirements, the size of conductive polymers, and some metal oxides. The pressure sensors, particularly those inserted into the challenges common to impedance-based chemical body must be small and ideally disposable. MEMS sensors include identifying single , quantifying technology is well positioned to deliver solutions to concentration, dealing with gas mixtures, this opportunity. In fact, a good example is the sensitivity to water vapor, sensitivity to temperature commercially successful low-cost disposable changes, and microfabrication of arrays of uniquely medical developed by Lucas sensitive sensors. NovaSensor NPC-107 (Figure 3) [12]. In it a silicon micromachined sensing element is used to meet or -Based Gas Sensors exceed all industry requirements (e.g., sensitivity within +/-1% and linearity better than 1%). Another Many polymers will geometrically swell reversibly micromachined silicon pressure sensor produced by when exposed to certain gases. Conductive NovaSensor is made small enough (1 mm x 0.7 mm polymers, such as polypyrrole, can be used directly x 0.175 mm thick) to be inserted into a catheter and as a viable . To use insulating inserted into arteries. polymers, they are doped with conductive particles to reduce their impedance (e.g., carbon black). When doped, the overall resistance of the doped polymer will change as a function of the chemically specific and concentration-dependent swelling [13]. One difficulty is that the polymers will swell to a greater or lesser extent when exposed to a variety of gases. To identify specific gases, the response pattern of many different polymers is needed. In addition to resistive measurements of geometric swelling, configurations that capacitively detect swelling have also been used. In these sensors the insulating polymers are not doped. Since it is known that certain diseases cause the body to generate specific gases that are not normally present, gas sensors have been used to help diagnose patient health.

In order to microfabricate arrays of sensors with Figure 4: Micromachined pressure sensor die with unique polymers, the integration process must smallest having dimensions (175×700×1000 µm3). contend with the large volume of solvent that is typically present during polymer deposition. Furthermore, the microfabrication technique must Microsensors for Chemical Biosystems not damage previously deposited polymers. One strategy is to use a removable mask to selectively Since living organisms are extremely sophisticated deposit each polymer into a specific area. This chemical processing systems, there are many technique has difficulty forming sub-millimeter biomedical applications for chemical sensors (e.g., sensors due to poor adhesion to the substrate when medical diagnostic instruments, drug screening, the mask is removed (i.e., the polymers adhere more implantable sensors for prostheses, and strongly to the mask than to the substrate). Another environment ). Although the strategy is to use a permanent microwell structure to micromachining of chemical sensors is typically contain the polymer-solvent solution in a well-defined simple, other components sometimes used in a sub-millimeter area without disturbing previously complete chemical sensor system (i.e., sample deposited polymers. An example of a polymeric preparation and delivery, reaction control, and waste impedance-based gas sensor that uses an SU-8 disposal) are more difficult to integrate together. microwell structure is given in Figure 5.

Impedance Sensors Metal Oxides

The conductivity of some materials is affected by the The conductivity of certain metal oxides, most presence and relative concentration of certain gases commonly SnO2, is known to vary as a function of or vapors. Examples of these materials include the concentration of specific gasses (e.g., O2, H2, CO, CO2, NO2, and H2S) when the metal oxide is solution. In addition, the simple construction of a heated sufficiently to induce a chemical reaction that typical electrochemical sensor (i.e., a partially is detected. There are several mechanisms that insulated metal trace on a substrate) allows ICs to be cause the resistance of the metal oxide to vary [2]. easily integrated with the electrode. The ICs can be The microfabrication of these sensors can be used to provide on-chip and relatively straightforward, unless additional amplification. micromachined features are added to improve sensor response and power consumption (i.e., Molecular-Specific Sensors integrating microfabricated heaters, thermal isolation structures (e.g., membranes) that require far less Chemical sensors that respond only to certain power to heat, and CMOS signal detection, or molecules can be extremely selective. Among the amplification, and filtering circuitry. most selective are the interactions between complex organic molecules, such as antigens and . One caveat is that often very selective sensors are also less reversible and thus may require special packaging to protect the sensors until they are needed. A prominent example of a molecularly sensitive amperometric sensor is one that uses a oxidase enzyme to detect glucose. The enzyme, which is typically immobilized on or near electrodes, reacts with glucose and alters the local pH, concentration, and peroxide concentration – events that can be electrochemically detected.

ISFETs

Field effect transistors (FETs) are very sensitive to variations in the amount of charge on their controlling Figure 5: Microfabricated polymer carbon-black gas electrodes (i.e., gate). If an ionic solution acts as the sensor with SU-8 microwell for solvent containment gate of a FET, the device will be tremendously (from [14]). sensitive to the overall ion concentration of the solution (i.e., not selective to specific ions). A good Electrochemical Sensors pH sensor can be made this way and indeed one exists [15]. By coating the gate of the FET with a The oxidation and reduction of chemical species on compound that will selectively bind or allow to pass a conducting electrode can be observed by only specific ions or molecules, an ion-sensitive FET, measuring the movement of charge. There are two or ISFET, can be realized. Common difficulties with primary methods of sensing electrochemical , as with all chemical sensors, are drift and reactions: potentiometric and amperometric. repeatability. Potentiometric sensors can be used to measure the equilibrium potential established between the Resonant Sensors electrode material and the solution, a potential that is dependent on the involved. Amperometric The resonant frequency of a mechanical element is sensors measure the current generated by a strongly dependent on its geometry, mechanical reaction and thus give a measure of reaction rates. properties, and mass. By coating a resonating By controlling the potential of the electrode relative to mechanical element, such as a beam or membrane, the solution and measuring the charge flow induced, with a compound that will selectively bind to only the presence of specific ions can be determined by specific ions or molecules, the mass of the observing the potential at which they undergo mechanical element will increase with their oxidation or reduction. This is a process known as concentration. The ion-concentration dependent voltammetry. mass loading can be determined by measuring the corresponding shift in the resonant frequency. Micromachining processes can be used to accurately and reliable define the area, number, and relative position of electrodes that are exposed to The most common resonant chemical sensors use gram (ERG). These bioelectrical are typically acoustic waves driven along surfaces of a solid (i.e., transduced with either external or internal electrodes. surface acoustic waves, SAW) or in a thin With MEMS technology, many electrodes can be co- membrane (i.e., flexural plate waves, FPW) [2],[16]. fabricated onto a single substrate so that both Acoustic-wave sensors have been used to detect precise temporal and spatial can be liquid density, viscosity, specific gas vapors. Design obtained. MEMS technology can also be used to challenges include (1) temperature sensitivity of the shape the substrate into either arrays of microprobes mechanical flexure, (2) selectivity of the binding capable of penetrating neural tissue (Figure 7) compound, and (3) reversibility of the binding and [19][21] or into a perforated membrane through mass loading process. MEMS technology impacts which regenerating neural tissue can grow and then resonant chemical gas sensors by allowing miniature be monitored [20]. In the U.S. the University of sensors to be produced at low cost. Michigan [22], Stanford University [23], and the University of Utah [24] have spent years developing Cell-Based Sensors and improving various MEMS-based neural- electronic interfaces. An innovative microsensor uses a cell as the primary transduction mechanism. An advantage of using cells to detect chemicals is that cells are microscopic chemical laboratories that can amplify a chemical signal (i.e., the detection a few molecules can lead to the production of many so called “second messanger” molecules) – essentially biological gain [17]. The amplified cell signal can be monitored by either detecting a chemical change within the cell or inferring the change by monitoring other parameters, such the electrical activity. One sensor uses chick myocardial cells to detect the presence of epinephrine, verapamil, and tetrodotoxin in the cell environment (Figure 6) [18]. Limitations of cell-based sensors include the lifetime and robustness of the cells.

Figure 7: Microfabricated silicon neural probe arrays. Top: Close-up of the probes and electrodes [19].

The implications of MEMS technologies for neuroscience are revolutionary. We now have the potential to develop arrays of microsystems, which can be tailored to the physical and temporal dimensions of individual cells. Neuroscientists can

now realistically envision sensing devices that allow Figure 6: Cell-based with microelectrode real-time measurements at the cellular level. array [18]. Information from such sensors could be monitored, analyzed, and used as a basis of experimental or Microsensors for Electrical Biosystems medical intervention, again at a cellular level. Another example is the use of micromachined neural sensors and stimulators to control prosthetic limbs The central and peripheral nervous systems are the with processed signals recorded from the brain or primary electrical biosystems of interest. Many spinal column. sensors and probes have been used to measure the electrical signals generated by neural tissue. Example include electrocardiogram (ECG), electroencephalogram (EEG), electroneurogram (ENG), electromyogram (EMG), and electroretino- BIOMEDICAL MICROACTUATORS Surgical Microinstruments

Microactuators are useful in biomedical applications The capability of most microactuators to surgically when biological objects or their environment need to interact with biological tissues is hindered by their be controlled on the microscopic scale. Furthermore, inability to withstand forces on the scale of ~1 mN. the ability to integrate many microactuators as easily The most successful uses of microactuation in as only one makes it feasible to produce complex surgical devices employ high-force small- microsystems capable of controlling many displacement stepper motors or resonant parameters. microstructures. MEMS technology can be used to add a variety of capabilities to surgical Micromanipulators microinstruments (e.g., microheaters, microsensors, fluid delivery, fluid extraction, feedback and control). To manipulate cells, tissues, and other biological objects, micromanipulators must be driven by a A scalpel driven by a piezoelectric microactuator is microactuation mechanism capable of operating in a an innovative example of using MEMS technology in conductive solution. Good candidates include surgical tools (Figure 10) [27]. The piezoelectric magnetic, pneumatic, thermal, and shape-memory stepper motor allows the position the scalpel to be alloy actuation. The magnetic microactuator shown precisely controlled. By integrating an ability to in Figure 8 has been used to manipulate single-cell measure the stresses experienced by the scalpel protozoa in saline [25]. The shape memory alloy during cutting, the actual cutting force can be microactuator shown in Figure 9 is capable of quantified and controlled. grasping tissues during endoscopic surgical procedures [26]. A second-generation device constructed with polymers is being commercialized by Micrus, Inc. and is presently in human trials.

Figure 10: Piezoelectrically driven force sensitive scalpel (see [27]).

Figure 8: Magnetic microactuator manipulating a single-cell protozoa (from [25]). An ultrasonic cutting tool fabricated by bulk micromachining is another good example of using MEMS technology in surgical devices. Again, piezoelectric material is attached to the cutter to resonante the tip of the tool at ultrasonic frequencies. Only when activated will the device easily and rapidly cut through even tough tissues (e.g., the hardened lenses of patients with cataracts) [28]. The devices shown in Figure 11, includes a imbedded microchannel through which fluid and surgical debris can be extracted while cutting .

Figure 9: Surgical microgripper actuated by shape- memory-alloy forces (from [26]). Microfilters

The process used to produce conventional filters capable of screening micron-scale objects results in an unacceptably broad statistical distribution of the size of objects that can pass. Micromachining and MEMS technology has been used to realize filters that are precisely and uniformly machined, which greatly reduces the statistical variation in objects that pass through [30].

Figure 11: Micromachined ultrasonic cutting tool [28].

Micropumps, and Microvalves, Microfilters, and Microneedles Figure 12: Silicon micromachined precision filter Clearly the need to precisely control gas and fluid (from [30]). flow is critical for diagnostic, surgical, and therapeutic biomedical systems. With this as Microvalves motivation, there have been many efforts to develop viable reliable low-cost high-precision microneedles, Several different types of microvalves have been microfilters, microvalves and micropumps. microfabricated, including normally-open and normally-closed valves either for controlling gasses Microneedles or fluids. A complete discussion of the specifics involved in the development of each valve type is The reduction in pain caused by needle insertion is beyond the scope of this paper. Instead, the options important for patient satisfaction and health. This is and trade-offs of valve design in general will be particularly true for patients suffering from diabetes described. who inject themselves with insulin at least a few times a day. It is then no surprise that the smallest A leader in the commercialization of microvalves has needles presently available are the 30-gauge been Redwood Microsystems of Menlo Park, CA needles used by diabetics (Figure 11 - left). [31]. They have designed many different valves, but Micromachining and MEMS technology has been each has many common characteristics. First off, the used to produce silicon microneedles that are much actuation mechanism used in each valve is the same sharper than exisiting needles (Figure 11 - right) [29]. – a small quantity of inert fluid is heated with an integrated resistor until a phase change is induced that exerts a tremendous force (Figure 11). Although the microfabrication process that precisely traps a fluid inside a microcavity is not trivial, it can be commercialized. The performance of microvalves compares favorably with macroscopic solenoid valves. In particular, microvalves typically operate faster and have a longer operational lifetime than macro-scale valves. Figure 11: Left: Smallest conventional needle (30 gauge). Right: Microfabricated silicon needle. The size scale of both images is the same (from [29]).

The electrodes are fabricated inside a second isolated cavity formed above the deformable pumping membrane so that they are sealed away from the conductive solutions being pumped (Figure 12). Although the micropump works well, high voltages (>100 V) are required for significant pumping to occur [33].

Figure 11: Microvalves designed by Redwood Microsystems, Inc [31].

The TiNi corporation has also commercialized a micromachined pressure sensor driven by shape- Figure 12: Electrostatic micropump with two one-way memory alloys. HP and NovaSensor have designed, check valves (from [33]). fabricated, and tested microvalves driven by the linear thermal expansion of solid materials. Despite When designing micropumps for biomedical the good performance, the HP valves have not yet applications, attention must be paid to the media been commercialized due to business reasons and being pumped. Some fluids, such as insulin, cannot the NovaSensor valves are in the final phase of tolerate aggressive pumping mechanisms without development. degrading.

The performance of microvalves compares favorably BIOMEDICAL MICROSYSTEMS with macroscopic solenoid valves. In particular, microvalves typically operate faster and have a The ability to miniaturize entire biomedical systems, longer operational lifetime. However, since such as DNA analysis, chemical analysis, drug microvalves are typically driven by thermal actuators development, and neural prosthetics, has the their power consumption is still relatively high potential to reduce the cost of health-care (0.1-2.0 W). Care must be taken to prevent the valve management. For example, reducing the cost and temperature to exceed that tolerated by the fluid or complexity of performing DNA screening and gas media being controlled. chemical analysis to the point that tests can be performed rapidly on the desktop, would reduce the Micropumps infrastructure required for the test without compromising capability. This would enable remote Several methods of microactuation have been used or small-scale clinics to offer fast high-quality tests. to drive micropumps: electrostatic forces, magnetic forces, and piezoelectric. One example is a Microfluidic Systems miniaturized gear pump that consists of LIGA microgears that are magnetically actuated It has Chemical, pharmaceutical, and genetic analysis been commercialized by MEMStek Products, LLC, of systems require the precise handling of fluids (i.e., Vancouver, Washington [32]. Another example is an sampling, mixing, heating, cooling, reacting, and electrostatically driven micropump produced by separating). Conventional fluidic analyses are bonding multiple bulk micromachined silicon wafers typically performed with relatively macroscopic fluidic together. The bonding process creates a pumping systems (>25 µL). Miniaturization and integration of cavity with a deformable membrane and two one- fluidic systems offers the following advantages: (1) way check valves. smaller typical operating fluid volume, (2) precise control of sample volumes, (3) ability to perform sensors into the same chip to allow for improved massively parallel tests, (4) take advantage of the temperature control. effect of scaling on fluidic, electrical, and thermal behavior, (5) possible reduction in system size, and (6) possible reduction in system cost. One important caveat with miniaturizing fluidic analysis systems is the fact that reducing the sample size requires a corresponding increase in sensor sensitivity. In addition, micro-scale fluid flow is almost completely laminar (i.e., there is very little turbulence and thus mixing can be problematic).

Micro Total Analysis Systems (µTAS)

The ability to electrically control fluid flow in Figure Micromachined PCR chamber (from [36]). micromachined channels (i.e., pumping and valving) without any moving parts has enabled the realization Gene Chips of complex micro total analysis systems [34]. With multiple independently controlled flow channels, Separation by electrophoresis can be used to detect complex sample preparation, mixing, and testing the size of a DNA molecule, but another method is procedures can be established. The electrically needed to determine its precise code. One method controlled pumping and valving mechanism is either exploits the highly selective hybridization process electroosmotic flow or electrophoretic flow [2]. Liquid that allows DNA fragments to bind only with their chromatography (i.e., a method of separating liquids complimentary sequence. In order to test for many based on their different mobility in a long flow specific sets of DNA sequences (i.e., for genetic channel) can be used to perform a precise chemical screening), a large number of unique oligonucleotide analysis in microfabricated flow channels. Sensors probes need to be constructed and compared to the integrated at the end of the flow channel will reveal a amplified DNA. One novel method of constructing time-domain spectrum of the fluid composition. oligonucleotide probes employs the same Micromachined electrophoretic devices have been lithographic techniques used to construct MEMS. used to separate ions and DNA molecules from 70 to Specifically, a substrate is coated with a compound 1000 bases in under 2 minutes – much faster than that is protected by a photochemically cleavable or conventional capillary electrophoresis systems [35]. photolabile protecting group (e.g., nitroveratryloxy- The detection of each ion or molecule species can carbonyl). be accomplished with electrochemical measure- ments, fluorescence, or optical absorption. When this film is exposed to a pattern of light, the illuminated regions will become unprotected and can Microsystems for Genetic Analysis be conditioned to receive a specific nucleotide / photolabile protecting group pair. By continuing the The analysis of genetic material typically calls for first processes with a new mask pattern each time, very the amplification of the DNA sample and then its large arrays of unique combinations of nucleotide detection. The amplification of a DNA sample can be can be rapidly formed. The process is repeated until accomplished by polymerase chain reaction (PCR). the desired oligonucleotides are constructed. After The PCR process begins by heating the DNA tagging the sample DNA with a fluorescent probe, it sample above the temperature at which the two is then distributed over the array of oligonucleotide strands separate or “melt” (~90 to 95ºC). If the DNA probes. Subsequent optical inspection of the polymerase enzyme and the building blocks of DNA distribution of fluorescence clearly indicates which (i.e., nucleotide triphosphates) are present during oligonucleotides in the array match with a section of cooling, the DNA polymerase will then reconstruct the sample DNA. Miniaturization of this detection each double helix resulting in a doubling of the system enabled massively parallel screening (i.e., number of DNA stands. A major advantage of 40,000 different compounds can be tested on a miniaturizing PCR systems is the fact that the much single 1 cm chip with 50 µm oligonucleotide probe lower thermal mass of the reaction chamber allows areas. Affymetrix, Inc, has commercialized a DNA for more rapid heating and cooling and thus a much detection scheme based on this technology [37]. faster process overall. Furthermore, it is even possible to integrate heaters and temperature CONCLUSIONS [10] Y. Kanda, “Piezoresistance Effect of Silicon”, Sensors and Actuators A, vol. 28, 1991, Micromachining and MEMS technologies are pp. 83-91. powerful tools for enabling the miniaturization of [11] B. Boser, “ for Micromachined Inertial devices useful in biomedical engineering. Although Sensors”, Proceedings of International Solid- silicon micromachined pressure sensors presently State Sensors and Actuators Conference possess the largest share of the BioMEMS market in ( '97), Chicago, IL, USA, June, terms of volume and sales, it is anticipated that the 1997, pp. 1169-1172. market share of MEMS-enabled chemical sensing [12] Data Sheet: NPC–107 Series Disposable and microfluidic systems will grow tremendously. In Medical Pressure Sensor, Lucas NovaSensor, addition, MEMS will continue to be applied to 1055 Mission Court, Fremont, CA 94539, biomedical engineering in new research activities http://www.novasensor.com/. that push our understanding of cells, organs, the [13] M. C. Lonergan, E. J. Severin, B. J. Doleman, S. brain, the body, and the world around us. A. beaber, R. H. Grubbs, and N. S. Lewis, “Array-Based Vapor Sensring Using Chemically REFERENCES Sensitive, Carbon Black-Polymber Resistors,” Chem. Mater., vol. 8, 1996, pp. 2298-2312. [14] F. Zee and J. W. Judy, “MEMS Chemical Gas [1] Micromechanics and MEMS: Classic and Sensor Using a Polymer-Based Array”, Seminal Papers to 1990, W. Trimmer (Ed.), Proceedings of International Solid-State Sensors IEEE Press, New York, NY, 1996, ISBN and Actuators Conference (Transducers '99), 0-7803-1085-3. Sendai, Japan, June, 1999, pp. 1169-1172. [2] G. T. A. Kovacs, Micromachined Transducers [15] http://www.beckman.com/beckman/biorsrch/prod Sourcebook. WCB/McGaw-Hill, 1998, ISBN info/electro/echome.asp 0-07-290722-3. [16] A. D’Amico, C. Di Natale, and E. Verona, [3] M. Madou, Fundamentals of Microfabrication. “Acoustic Devices,” in Handbook of Boca Raton, FL: CRC Press, Inc., 1997, ISBN and Electronic Noses, E. Kress-Rogers editor, 0-8493-9451-1. CRC Press, Inc., Boca Raton, FL, 1997, pp. 197- [4] J. Bustillo, R. T. Howe, and R. S. Muller, 223, ISBN 0-8493-8905-4. “Surface micromachining for microelectro- [17] H. Stieve, “Sensors of Biological Organisms – mechanical systems”, Proceedings of the IEEE, Biological Transducers”, Sensors and Actuators, vol. 86, no. 8, August 1998, pp. 1552-1574. vol. 4, no. 4, Dec. 1983, pp. 689-704. [5] K. E. Petersen, “Silicon as a Mechanical [18] D. A. Borkholder, “Cell-Based Biosensors using Material”, Proceedings of the IEEE, vol. 70, Microelectrodes”, Ph.D. Thesis, Electrical no. 5, May 1982, pp. 420-457. Engineering Department, Stanford University, [6] W. Ehrfeld et al., “Fabrication of Microstructures Stanford, CA, 1998. using the LIGA Process”, Proceedings IEEE [19] D.T. Kewley, M.D Hills, D.A. Borkholder, I.E. Micro Robots and Teleoperators Workshop, Opris, N.I. Maluf, C.W. Storment, J.M. Bower, November, 1987. Available in Micromechanics and G.T.A. Kovacs, "Plasma-Etched Neural and MEMS: classic and seminal paper to 1990, Probes," Sensors and Actuators A, vol. 58, no. 1, W. S. Timmer editor, IEEE Press, New York, Jan. 1997, pp. 27 - 35. 1997, ISBN 0-7803-1085-3, pp. 623-633. [20] G.T.A. Kovacs, C.W. Storment, M. Halks-Miller, [7] H. Lorenz, M. Despont, N. Fahrnl, N. LaBianca, C.R. Belczynski, C.C.D. Santina, E.R. Lewis, Renaud, and P. Vettiger, “SU-8: a low-cost N.I. Maluf, “Silicon-substrate micro-electrode negative resist for MEMS”, Journal of arrays for parallel recording of neural activity in Micromechanics and Microengineering, vol. 7, peripheral and cranial nerves”, IEEE no. 3, September 1997, pp. 121-124. Transactions on Biomedical Engineering, vol. 41, [8] Y. Xia and G. M. Whitesides, “Soft Lithography”, no. 6, June 1994, pp. 567-577. Angew. Chem. Int. Ed., vol. 37, 1998, [21] K. Najafi, “Solid-state microsensors for cortical pp. 550-575. nerve recordings”, IEEE Engineering in Medicine [9] D. C. Duffy, O. J. A. Schueller, S. T. Brittain, and and Biology Magazine, vol. 13, no. 3, June-July G. M. Whitesides, “Rapid prototyping of 1994, pp. 375-387. microfluidic in poly(dimethyl siloxane) [22] University of Michigan Center for Neural and their actuation by electro-osmotic flow”, Communication Technology (Funded by NIH): Journal of Micromechanics and Micro- http://www.engin.umich.edu/facility/cnct/ engineering, vol.9, no.3, IOP Publishing, September 1999, pp. 211-217. [23] Stanford University research on microprobes: and Actuators (Transducers 93), Yokohama, http://transducers.stanford.edu/stl/Projects.html Japan, June 7-10, 1993, pp. 924-926. [24] University of Utah, Bioengineering Department: [37] http://www.affymetrix.com/ http://www.bioen.utah.edu/faculty/RAN/ [25] J. W. Judy, R. S. Muller, and H. H. Zappe, "Magnetic microactuation of polysilicon flexure structures," IEEE Journal of Microelectromechanical Systems, vol. 4, no. 4, pp. 162-169, 1995. [26] A. P. Lee, D. R. Ciarlo, P. A. Krulevitch, S. Lehew, J. Trevino, and M. A. Northrup, “A Practical Microgripper by Fine Alignment, Eutectic Bonding and SMA Actuation”, Proceedings of International Solid-State Sensors and Actuators Conference (Transducers '95), Stockholm, Sweden, June, 1995, pp. 368-371. [27] U.S. Patent 5,629,577 – Piezoelectric microactuator useful in a force-balanced scalpel. [28] A. Lal, “Silicon-based ultrasonic surgical actuators”, Proceedings of the 20th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, vol. 20, Hong Kong, China, 29 Oct. 1998, pp. 2785-2790. [29] N.H. Talbot and A.P. Pisano, “Polymolding: two wafer polysilicon micromolding of closed-flow passages for microneedles and microfluidic devices”, Solid-State Sensor and Actuator Workshop Technical Digest, Hilton Head Island, SC, USA, 8-11 June 1998, pp. 265-268. [30] W.-H. Chu, R. Chin, T. Huen, and M. Ferrari, “Silicon membrane nanofilters from sacrificial oxide removal”, Journal of Microelectro- mechanical Systems, vol. 8, no. 1, IEEE, March 1999, pp. 34-42. [31] http://www.redwoodmicro.com/ [32] http://www.mems.com/ [33] R. Zengerle, J. Ulrich, S. Kluge M. Richter, A. Richter, “A bidirectional silicon micropump”, Sensors and Actuators A (Physical), vol. A50, no. 1-2, Aug. 1995, pp. 81-86. [34] N. Chiem, C. Colyer, and D.J. Harrison, “Microfluidic systems for clinical diagnostics”, International Conference on Solid-State Sensors and Actuators Digest of Technical Papers (Transducers '97), Chicago, IL, USA, 16-19 June 1997, pp. 183-186. [35] A. T. Woolley and R. A. Mathies, “Ultra-High Speed DNA Fragment Separations Using Microfabricated Capillary Array Electrophoresis Chips", Proceedings of the National Academy of Science, vol. 91, Nov. 1994, pp. 11348-11352. [36] M.A. Northrup, M.T. Ching, R.M. White, and R.T. Lawton, “DNA Amplification with a Microfabricated Reaction Chamber”, International Conference on Solid-State Sensors