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An Indian Journal

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BTAIJ, 8(5), 2013 [687-691] Distinct advantages and novel applications of BioMEMS

Ying Jian Chen Research Center for Strategic Science and Technology Issues, Institute of Scientific and Technical Information of China, Beijing 100038, (CHINA) E-mail : [email protected]

ABSTRACT KEYWORDS

With the great progress of production processÿMEMS have applied to a MEMS; “fundamental lot of areas in recent yearsÿand today they have become BioMEMS; ” devices ÿwhich are comparable with the IC. In this paperÿwe first discuss IC; the main distinct advantages of MEMS as well as the important differences Sensor; between MEMS and ICÿthen some latest research progresses on Biomedical; biomedical, environmental and microfluidics applications of MEMS are Environmental; reviewed. Finally, possible future developments of BioMEMS are Microfluidics;  prospected. 2013 Trade Science Inc. - INDIA Application.

INTRODUCTION output similar to analog devices. BioMEMS are MEMS that have biological and/or biomedical functions or ap- The acronym MEMS stands for Micro Electro plications. Mechanical Systems with the focal point being the sec- Some of the key advantages of MEMS[3,4] are, “M” • ond (mechanical) and thence ultimately the con- The ability to miniaturize physical interactions to “S”. MEMS are integrated micro-scale systems ’s. cluding nearly the same degree as IC • combining electricalÿoptical or other (magnetic, me- The related ability to reduce the sample-size of chanical, thermal, fluidic, etc.) elements typically fabri- measurands. • cated using conventional batch process- The ability to integrate sensing, analysis and re ing techniques, namely, MEMS are macro-engineering sponse in a miniature package. at microscale, they have two main features: (1) design MEMS is not a single product or marketÿbut an structures/devices/systems at micro/nano scale, (2) typi- engineering tool-kit applied to a wide array of markets. cal microsystems involve multiple physical domains. Simpler, but by no means trivial, sensing devices (pres- These systems are designed to interact with the exter- sure, inertial, thermal,etc.) are finding more diverse nal environment either in a sensing or actuation mode to applications and finally emerging into consumer mar- generate state information or control it at a different kets, such as accelerometer and gyroscopic MEMS scale[1,2]. MEMS are the exotic cousins of semicon- devices for the iPhone, Wii and Playstation game con- ductors and integrated circuits (ICs), originally based trollers. Within these MEMS, we typically see integra- on silicon fabrication techniques, but adding the tion, on a single silicon substrate of not just electronic dimensions of space, flexion and continuously variable devices as on the chips, but also mechanical 688 Distinct advantages and novel applications of BioMEMS BTAIJ, 8(5) 2013 FULL PAPER

However, three points makes it very different[3,4]: ÿsensors and actuators. In addition to the com- • elements MEMS products are usually application specific, monly present materials in silicon ICs, other materials resulting in a wide range of very different products. • such as ceramics and most recently carbon nanotube, The number of MEMS products will be always less ’s. A good example CNT, arrays are also being incorporated into MEMS. than that for semiconductor IC The resulting microsystems have shown, for a variety ÿunprecedented levels of miniaturization is the inkjet printer. The four inkjet nozzles are op- of applications [5,11] erated using printed circuit boards with tens of other (reliability) and new capabilities . silicon devices. • “unit cell” (like Unlike IC manufacturing, there is no MEMS VERSUS IC the ) in MEMS technology. This leads to a more diverse technology base with more devel- MEMS are a class of physically small systems that opment and engineering work. Hence, it is more combine electronic functions with optical, mechanical, expensive and more difficult to maintain MEMS thermal and others. MEMS encompass the process- technology. based technologies used to fabricate tiny integrated Some important differences between MEMS and devices. MEMS are a logical extension of microelec- IC are summarized in TABLE 1. There is also lack of a tronics and IC technology. As an extension of IC tech- stable front-end technology (no Complementary Metal- nology, the production of MEMS devices benefits from Oxide Semiconductor) (CMOS) equivalent) in years of IC manufacturing experience. For instance, MEMS. Moreover, there is a multidimensional interac- technologies such as microlithography, chemical etch- tion space in MEMS, for instance, there is not only ing, vapor deposition, and electroplating can be used electrical connections but also optical connections. to create the microstructures of MEMS. The products MEMS are a very complicated multidisciplinary field, range in size from a few micrometers to millimeters. in which physics, chemistry, materials science, mechanics These devices/systems have the ability to sense the en- and engineering play an important role. In addition, the vironment, process and analyze information, and re- end-product functionality of MEMS is often tightly re- spond with a variety of mechanical and electrical ac- lated to the process used to make it. This can be vividly “one product, one process”. At this point tuators on the micro scale, and generate effects on the expressed as macro scale. the MEMS are completely different with the IC indus- As a manufacturing technology, MEMS has sev- try where so many products share a common process. eral distinct advantages[3,4]: • MEMS technology has the characteristics of inter- TABLE 1 : Important differences between MEMS and IC disciplinary. Its diversity of applications has led to MEMS IC an unparalleled range of devices and synergies Unit Cell No unit cell Transistor Front-end No single stable across previously unrelated fields, for instance, bio- CMOS medicine and microelectronics, semiconductor Technology technology Interaction physics and microoptics. Multidimensional Electrical • Space By MEMS technology and batch fabrication tech- Basic Physics and Multidisciplinary niques, one can produce components and devices Disciplines engineering Process or Many products with higher performance and reliability, such prod- One product, one Fabrication share a common process ucts have obvious advantages with small size, light Technology process weight and low cost. • MEMS technology provides the basis for the fab- Therefore, the current research is evolving toward “MEMS unit” that is not a single “unit cell” (e.g. tran- rication of products that cannot be manufactured a by other methods. Hence, MEMS have become a sistor in IC), but small, specifically designed, compo- universally applicable technology such as IC mi- nents libraries that could be refined over time to be- “standard building blocks” for each MEMS de- come BiicoroTcehicph. nollogy An Indian Journal BTAIJ, 8(5) 2013 Ying Jian Chen 689 FULL PAPER • vice domain. Polymerase chain reaction(PCR) for DNA repli- MEMS technology is a enchanting and far-reach- cation. ing area. It has played and will continue to play a very In particular, pressure sensors in biomedical field vital role in both science and human society. Especially, have the following applications: • it has translated physical properties and material char- Blood pressure sensors. • acteristics into structures and devices that can have a Intracranial pressure sensors. ’s everyday life. • large positive impact on people Pressure sensors in endoscopes. • Sensors for infusion pumps. SOME RECENT APPLICATIONS Main differences between MEMS and BioMEMS OF BioMEMS are summarized in TABLE 2. BioMEMS are being re- searched for possible applications in a variety of areas, Until recently, sensors are a major application for but have already led to multiple applications in the fol- MEMS devices. Today, BioMEMS have become the lowing areas[13-15]: largest and most diverse applications of MEMS de- TABLE 2 : Comparing MEMS with BioMEMS vices. Applications for BioMEMS devices exist in clinical medicine, environmental, biological and chemical analy- MEMS BioMEMS Silicon based Biocompatible Material sis. Applications from one area often overlap with other Material areas. Applications can be broadly placed into the fol- Electrical & Biomolecular & physical lowing categories[12-16]: Mechanical parameter • clinical diagnostics and therapeutics, interface, (electrical,mechanical,optical ) • integration transducer integration environmental applications, Moving part in • Motion medium in passive food safety, and micromachining —— —— substrate microfluidic driving • system active bioprocessing. force MEMS technology is an engineering solution for component • biomedical problems. From component aspect, Detection. • BioMEMS is the research of microfabricated devices Analysis. • for biomedical applications. BioMEMS usually contains Diagnosis. • sensors, actuators, mechanical structures and electron- Therapeutics. • ics. Such systems are being developed as diagnostic Drug delivery. • and analytical devices at diagnostic and analytical de- Cell culture. vices. BioMEMS is expected to revolutionize the field BioMEMS encompasses all interfaces and inter- of medicine. Clinical applications of BioMEMS include sections of the life sciences and clinical disciplines with both diagnostic (utilizing MEMS sensors and transduc- microsystems and nanotechnology. Main related areas ers) and therapeutic (such as drug delivery actuators) are the following[16]: • applications. Micro and nanotechnology for drug delivery. • Tissue engineering, harvesting, manipulation. In medical field MEMS have the following appli- • [12] Microfluidics and miniaturized total analysis systems. cations : • Nano-scale imaging, and integrated systems. • • Precise dispensers for small amounts of liquids found Biomolecular amplification. • in needleless injectors and drug delivery systems. Sequencing of nucleic acids. • • Sub-dermal glucose for monitoring monitor glucose Molecular assembly. • levels and delivery of the insulin. Proteomics. • • DNA microarrays for testing of genetic diseases Biosensors. and other biological markers. • In the remaining part of this section, we focus Medical diagnostics for blood analysis, cells counts on some new applications of BioMEMS in three and urinalysis. fields. BiioTechnollogy An Indian Journal 690 Distinct advantages and novel applications of BioMEMS BTAIJ, 8(5) 2013 FULL PAPER

BIOMEDICAL APPLICATIONS For example, a gene from a firefly is added to mamma- OF BioMEMS lian cells so that the cells glow when exposed to the toxin dioxin. As the amount of dioxin increases, the cells BioMEMS sensor placement depends on the de- glow more brightly. This assay provides a quick and vice and its application. A sensor can be[12,16] simple test for dioxin. The figure shows how the firefly • topical (applied to skin or placed in the mouth) luciferase reporter gene luminesces to test for the pres- • externally connected (in vitro or external with in ence of dioxin in environmental samples. Another ap- vivo or internal device) plication uses cultured mammalian cells to predict lethal • implanted devices (totally in vivo) toxicity of chemicals in humans. The initial application Topical sensors used a micropipette tip to hold the cells. This assay can be adapted to a MEMS device[17]. They are applied to skin or placed in the mouth. Both environmental scientists and homeland secu- One familiar device is the thermometer used for mea- rity personnel are interested in the rapid detection and suring body temperature. Thick-film disposable ther- identification of bacteria and pathogens. Researchers mistors and infrared ear thermometers have largely re- have developed microsystems which concentrate com- placed the mercury thermometer. ponents specific to certain pathogens, then release these Externally connected sensors to a micro gas chromatography unit so that the compo- They contain both an in vivo part and an external nents can be separated. The separate components are part. An example of such a device is the cochlear im- passed to a surface acoustic wave sensor array (SAW) plant. These devices contain a microphone, a speech pro- for component identification. A working example of such cessor, a transmitter and receiver/stimulator, and an elec- a system was developed by Sandia National Labs. This trode array. The implant does not restore normal hear- device will provide portable, rapid detection and early ing, but it does give a deaf person a useful representation warning of the presence of pathogens in air or water. of his environment and helps him understand speech. Another example is the glucometer. These devices have MICROFLUIDICS AND BioMEMS an implanted glucose sensor that communicates with ex- APPLICATIONS ternal components, such as a and micropump. Another MEMS platform used in diagnostic Implanted devices BioMEMS makes use of microfluidic components. In- This area of BioMEMS has numerous possibilities, tegrated fluidic microchips allow separations, chemical but few of these devices have made it to market. Im- reactions, and calibration-free analytical measurements plantable BioMEMS that have been on the market for to be directly performed in very small quantities of com- years are defibrillators and pacemakers. Other emerging plex samples such as whole blood and contaminated applications for implantable devices include neural im- environmental samples. This technology lends itself to plants and spinal cord stimulators to treat intractable pain applications such as clinical diagnostics (including tu- and spasticity. The implantable microelectrodes for neu- mor marker screening) and environmental sensing in ral applications are based on thin-film polymer foils with remote locations. Lab-on-a-Chip (LOC) systems en- embedded microelectrodes for both recording and stimu- able sample handling, mixing, dilution, electrophoresis lation. Implantable pressure sensors are being tested that and chromatographic separation, staining and detec- can be used in cardiovascular monitoring, glaucoma tion on single, micro-integrated systems[18]. monitoring, and monitoring of intracranial pressure. BioLOC is developing a lab on a disk to perform ELISAs (Enzyme-linked Immunosorbent Assays) on a ENVIRONMENTAL APPLICATIONS polymeric compact disk. ELISAs use antibodies as OF BioMEMS biosensors. They have been widely used for detection and quantification of biological agents (mainly proteins ’s high selectivity and sen- BiiTohTeye cahren ao gllroogwying part of the BioMEMS field. and polypeptides). An ELISA An Indian Journal BTAIJ, 8(5) 2013 Ying Jian Chen 691 FULL PAPER sitivity draw great interests in clinical, food safety, and Guide to Design, Analysis and Applications, Springer, environmental applications. (2006). [2] A.R.Jha; MEMS and Nanotechnology-Based Sen- FUTURE DEVELOPMENTS OF BioMEMS sors and Devices for Communications, Medical and Aerospace Applications, CRC Press, (2008). [3] Mohamed Gad-el-Hak; The MEMS Handbook: MEMS products have successfully made the com- MEMS Applications, CRC Press, (2006). plete transition into the consumer space. Today, liter- [4] Reza Ghodssi, Pinyen Lin; MEMS Materials and ally billions of MEMS devices are manufactured every Processes Handbook, Springer, (2011). year for a wide variety of consumer applications, and [5] Nava Setter; Electroceramic-based MEMS: Fabri- MEMS developers have begun to turn their attention cation-Technology and Applications, Springer, more and more to BioMEMS. Today, there are pre- (2009). cious few successful BioMEMS devices on the mar- [6] Allyson.L.Hartzell, Mark.G.da Silva, ket. Herbert.R.Shea; MEMS Reliability, Springer, In the area of implantable devices, CardioMEMS (2010). has an implantable pressure sensor for monitoring an- [7] Evgeni Gusev, Eric Garfunkel, Arthur Dideikin; eurysms. Cochlear implants are routine, allowing deaf Advanced Materials and Technologies for Micro/ Nano-Devices, Sensors and Actuators, Springer, people to hear. In the area of microfluidics, companies (2010). such as Caliper and Cepheid manufacture chips and [8] Priyanka Aggarwal, Zainab Syed, Aboelmagd plastic fluidic components for biochemical analysis and Noureldin, Naser El-Sheimy; MEMS-Based Inte- diagnostics. However, there are many much more im- grated Navigation, Artech House, (2010). portant and much more impactful devices on the hori- [9] Andrew McWilliams; MEMS: Biosensors and zon, such as retinal implants, health monitoring systems, Nanosensors, BCC Research, (2011). protein detection arrays, and continuous, implantable [10] Volker Kempe; Inertial MEMS: Principles and Prac- chemical sensing. Over the next 10 years, this next gen- tice, Cambridge, (2011). eration of BioMEMS innovations will transform medi- [11] Edward.B.Magrab; Vibrations of Elastic Systems: cine as we currently practice it and understand it[12-17]. With Applications to MEMS and NEMS, Springer, In addition, national security is of increased impor- (2012). [12] Wanjun Wang, A.Steven Soper; BioMEMS: Tech- tance related to the growing fear from terrorist attacks nologies and Applications, CRC Press, (2007). and outbreaks of infectious human or animal diseases. [13] Teena James, Manu Sebastian Mannoor, V.Dentcho –Advancing the Frontiers of This drives a need for small multi parameter instruments Ivanov; BioMEMS to test water, air, blood and so on for microbiological Medicine, Sensors, 8, 6077-6107 (2008). threats[19]. [14] Stergios Logothetidis; Nanomedicine and On the other hand, there is a tendency to develop Nanobiotechnology, Springer, (2012). more flexible and cheaper production technologies. It [15] Ajay Kumar Mishra; Nanomedicine for Drug De- is expected that this tendency will be driven by the pro- livery and Therapeutics, Wiley, (2013). duction research into typical low cost, large surface area [16] Shekhar Bhansali, Abhay Vasudev; MEMS for Bio- devices (for instance, solar cell, displays, wearable elec- medical Applications, Woodhead Publishing, (2012). tronics) and disposable diagnostics devices. [17] Zhaoying Zhou, Zhonglin Wang, Liwei Lin; Microsystems and Nanotechnology, Springer, Finally, a huge number of products will originate (2012). from the large amount of nanotechnology research in- [18] Francis.E.H.Tay; Microfluidics and BioMEMS vestments, in many cases MEMS will act as an inter- Applications, Springer, (2002). [7,9,11,14] face between the nano and human size world . [19] Mohammad Ilyas, Imad Mahgoub; Smart Dust: Sensor Network Applications, Architecture and REFERENCES Design, CRC Press, (2006). 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