MEMS devices for biomedical applications By Dr. Ramesh Ramadoss, Formfactor, San Jose, CA Micro-Electro-Mechanical Systems (MEMS) are a class of miniature devices and systems fabricated by micromachining processes. MEMS devices have critical dimensions in the range of 100 nm to 1000 µm (or 1 mm). MEMS technology is a precursor to the relatively more popular field of Nanotechnology, which refers to science, engineering and technology below 100 nm down to the atomic scale. Occasionally, MEMS devices with dimensions in the millimeter-range are referred to as meso-scale MEMS devices. Figure 1 shows relevant dimensional scale alongside biological matter. Figure 1. Dimensional scale of MEMS and Nanotechnology. (Adapted from Nguyen et al. ). Initially, MEMS technology was based on silicon using bulk micromachining and surface micromachining processes. Figure 2 shows an SEM image of a surface micromachining based polysilicon MEMS device, an electrostatic motor, which consists of twelve fixed stator electrodes and a rotor that spins around the pivot at its center. Gradually, other materials such as glass, ceramics and polymers have been adapted for MEMS. Especially, polymers are attractive for biomedical applications due to their bio-compatibility, low cost, and suitability for rapid prototyping. Other micromachining processes employed for fabrication of MEMS include dry plasma etching, electroplating, laser machining, micromilling, micromolding, stereolithography, and inkjet printing. Figure 2. An SEM image of a MEMS electrostatic motor. (Source: https://www.mems-exchange.org/). MEMS devices can actuate or sense on a micro-scale. MEMS devices can function individually or in combination with other devices to generate effects of meso- or macro- scale. Some advantages of MEMS devices include small size, light weight, low power consumption and high functionality compared to conventional devices. Further, MEMS technology offers cost reduction due to batch processing techniques similar to semiconductor Integrated Circuit (IC) manufacturing. Initially, MEMS technology emerged as an offshoot of the semiconductor industry and eventually established itself as a specialized field of study with a significant market share. According to Yole Développement, the MEMS industry market in 2012 was $11 billion, which is a 10 percent growth from the previous year. MEMS applications MEMS applications in various functional domains are shown in Figure 3. The term “functional domain” is used to refer to a domain in which the MEMS device performs a function such as sensing or actuation. In the early stages, MEMS proved to be a revolutionary technology in various fields of the physical domain such as Mechanical (e.g., Pressure sensors, Accelerometers, and Gyroscopes), Microfluidics (e.g., Inkjet nozzles), Acoustics (e.g., Microphone), RF MEMS (e.g., Switches and Resonators), and Optical MEMS (e.g., Micromirrors). Gradually, MEMS technology has demonstrated unique solutions and delivered innovative products in chemical, biological and medical domains as well. MEMS have penetrated into consumer electronics, home appliances, automotive industry, aerospace industry, biomedical industry, recreation and sports . Figure 3. MEMS applications in various functional domains. Typically, electronics are used to interface MEMS devices from its functional domain (i.e., Physical, Chemical, or Biological) to the electrical domain for signal transduction and/or recording. It should be pointed out that the term MEMS was originally coined to refer to miniature sensors and actuators operating between electrical and mechanical domains. Gradually, the term MEMS has evolved to encompass a wide variety of other microdevices fabricated by micromachining. For example, a micromachined electrochemical sensor is referred to as a MEMS device even though there is no functional role played by this device in the mechanical domain. Similarly, the term “BioMEMS” is used to refer to the science and technology of microdevices fabricated by micromachining for biological and medical applications. BioMEMS may or may not include any electrical or mechanical functions. BioMEMS application areas include biomedical transducers, microfluidics, medical implants, microsurgical tools, and tissue engineering. As shown in Figure 4, the global BioMEMS market is expected to almost triple in size, from $1.9 billion in 2012 to $6.6 billion in 2018 . Figure 4. BioMEMS market forecast by Yole Développement . (Source: http://www.yole.fr/). BioMEMS applications In this section, a few representative BioMEMS applications are presented. A survey of all products available on the market is beyond the scope of this article. a) MEMS Pressure Sensors The first MEMS devices to be used in the biomedical industry were reusable blood pressure sensors in the 1980s. MEMS pressure sensors have the largest class of applications including disposable blood pressure, intraocular pressure (IOP), intracranial pressure (ICP), intrauterine pressure, and angioplasty. Some manufacturers of MEMS pressure sensors for biomedical applications include CardioMEMS, Freescale semiconductors, GE sensing, Measurement Specialties, Omron, Sensimed AG and Silicon Microstructures. According to World Health Organization (WHO), Glaucoma is the second leading cause of blindness in the world after cataracts. MEMS implantable pressure sensors are used for continuous IOP monitoring in Glaucoma patients. A normal eye maintains a positive IOP in the range of 10-22 mmHg. Abnormal elevation (> 22 mmHg) and fluctuation of IOP are considered the main risk factors for glaucoma. Glaucoma, often without any pain or significant symptoms, can cause an irreversible and incurable damage to the optic nerve. This initially affects the peripheral vision and possibly leads to blindness without timely lifetime treatment. Therefore, it is critical to accurately monitor IOP and provide prompt treatments at the early stages of glaucoma development. Sensimed’s TriggerfishTM implantable MEMS IOP sensor is shown in Figure 5. It consists of a disposable contact lens with a MEMS strain-gage pressure sensor element, an embedded loop antenna (golden rings), and an ASIC microprocessor (2mmx2mm chip). The MEMS sensor includes a circular active outer ring and passive strain gages to measure corneal curvature changes in response to IOP. The loop antenna in the lens receives power from the external monitoring system and sends information back to the system. Figure 5. Sensimed’s TriggerfishTM implantable MEMS IOP sensor. (Source: http://www.sensimed.com/). b) MEMS Inertial Sensors MEMS accelerometers are used in defibrillators and pacemakers. Some patients exhibit unusually fast or chaotic heart beats and thus are at a high risk of cardiac arrest or a heart attack. An implantable defibrillator restores a normal heart rhythm by providing electrical shocks to the heart during abnormal conditions. Some peoples’ hearts beat too slowly, and this may be related to the natural aging process or a genetic condition. A pacemaker maintains a proper heart beat by transmitting electrical impulses to the heart. Conventional pacemakers were fixed rate. Modern pacemakers employ MEMS accelerometers and are capable of adjusting heart rate in accordance with the patient’s physical activity. Medtronic is a leading manufacturer of MEMS based defibrillators and pacemakers. Figure 6 shows a MEMS accelerometer-based Medtronic’s SureScanTM pacemaker and implantation of a pacemaker inside the body next to the heart. This pacemaker is designed to be compatible with magnetic resonance imaging (MRI). Figure 6a. MEMS inertial sensors (accelerometers and gyroscopes) were employed to develop one of the most unique wheelchairs, the iBOTTM Mobility system, shown in Figure 7. A combination of multiple inertial sensors in this system enables the user to operate the wheelchair and lift to a standing height just balancing on two wheels. This allows the wheelchair user to interact with others face-to-face. The iBOTTM system was developed by Dean Kamen in a partnership between DEKA and Johnson and Johnson’s Independence Technology division. Unfortunately, it is no longer available for sale from Independence Technology. Another related example is the Segway PT, a two-wheeled, self-balancing, battery-powered electric vehicle, also invented by Dean Kamen. It is produced by Segway Inc. of New Hampshire, USA. Figure 7. Independence Technology’s iBOTTM mobility system. (source: http://www.ibotnow.com/). c) MEMS Hearing-Aid Transducer A hearing-aid is an electroacoustic device used to receive, amplify and radiate sound into the ear. The goal of a hearing aid is to compensate for the hearing loss and thus make audio communication more intelligible for the user. In the US, hearing aids are considered medical devices and are regulated by the FDA. According to NIH, approximately 17 percent (36 million) of American adults report some degree of hearing loss. There is a strong relationship between age and reported hearing loss. Also, about 2 to 3 out of every 1,000 children in the United States are born deaf or hard-of-hearing. According to statistics, 80% of those who could benefit from a hearing-aid chose not to use one. The reasons include reluctance to recognize hearing loss and social stigma associated with common misconceptions about wearing hearing aids. Thus, it is highly desirable to miniaturize hearing-aids without compromising performance. MEMS technology enables reduction of form factor, cost, and power consumption compared to conventional hearing-aid solutions. Figure 8 shows Analog Devices small size (7.3 mm3) MEMS microphone suitable for hearing-aid applications. Figure 8. Analog Devices MEMS microphone for hearing-aid applications. (Source: http://www.analog.com/). d) Microfluidics for diagnostics Microfluidics involve movement, mixing and control of small volumes (nanoliters) of fluids. A typical microfluidic system is comprised of needles, channels, valves, pumps, mixers, filters, sensors, reservoirs, and dispensers. Microfluidics enable bedside or at the point-of-care (POC) medical diagnosis. Especially, POC diagnosis is important in developing countries where access to centralized hospitals is limited and expensive. A POC diagnostic microfluidic system uses bodily fluids (saliva, blood, or urine samples) to perform sample preconditioning, sample fractionation, signal amplification, analyte detection, data analysis, and results display. In 1985, Unipath introduced the first POC microfluidic device, ClearBlueTM, for pregnancy test from urine sample and is still available on the market. Recently, a comprehensive review article on the commercialization of microfluidic devices for POC diagnostics was published by Chin et al. . One of the world’s most significant public health challenges, particularly in low- and middle- income countries, remains to be HIV/AIDS. According to WHO, 34 million people are living with HIV, and around 7 million eligible people are waiting for antiretroviral therapy. POC diagnosis is very crucial for the enumeration of absolute numbers of T-helper cells, commonly referred to as a CD4 count, for monitoring the course of immunosuppression caused by HIV and the initiation of antiretroviral therapy. The Alere Pima™ CD4 test system, shown in Figure 9, offers a revolutionary POC solution by providing an absolute CD4 count from either a fingerstick or a venous whole blood sample. The test requires approximately 25 microliters of whole blood sample to be loaded into the cartridge capillary. All test reagents are sealed within the disposable cartridge. On insertion of the cartridge into the analyzer, the test process automatically begins and displays direct CD4 measurement within 20 minutes. Figure 9. Alere’s PimaTM point-of-care CD4 test system: a) disposable cartridge, and b) analyzer with a slot for cartridge insertion. (Source: http://alere-technologies.com/). e) Microfluidics for drug delivery Microfluidics enable advanced drug delivery technologies such as triggered release, timed release and targeted delivery. Some applications include transdermal drug delivery (e.g., microneedle arrays and needle-less jet-based system), implantable drug delivery systems (e.g., drug-eluting stents and insulin pump), and drug delivery vehicles (e.g., micro- and nano– particles). In the US, Diabetes mellitus has a mortality of 180,000 per year. It can be managed through proper diet and exercise, glucose-lowering oral medications and/or insulin therapy. One of the most notable insulin delivery systems for diabetes therapy, JewelPUMPTM, is shown in Figure 10. This system was developed by Debiotech in collaboration with STMicroelectronics. The MEMS nanopumpTM mounted on a disposable skin patch provides continuous insulin through jet-based infusion delivery. The whole system weighs only 25 grams and holds up to 500 units of insulin and can be used for a 7 day period without any need for refill or replacement. The JewelPUMPTM is directly programmed from a large display remote controller. It can be attached to the body using a disposable skin patch and can be detached when necessary, thereby offering more freedom to the patient. Figure 10b. Attachment of the system to the body using a disposable skin patch (left) JewelPUMPTM (middle) and programmable remote controller (right) (Source: http://www.debiotech.com/). f) Micromachined needles Micromachining enables fabrication of needles smaller than 300 µm, which is the limit of conventional machining methods. Typically, the length of the MEMS-based microneedles is less than 1 mm. Microneedles have been used for drug delivery, bio-signal recording electrodes, blood extraction, fluid sampling, cancer therapy, and microdialysis. Frequently, microneedles are integrated and used in conjunction with microfluidic systems. Solid and hollow microneedles have been fabricated out of silicon, glass, metals, and polymers using micromachining processes. Microneedles have been demonstrated with various body shapes (cylindrical, canonical, pyramid, candle, spike, spear, square, pentagonal, hexagonal, octagonal and rocket shape) and tip shapes (volcano, snake fang, cylindrical, canonical, micro-hypodermis and tapered). Figure 11 shows solid microneedles fabricated by reactive ion etching of silicon  and hollow microneedles fabricated by laser machining of a polymer. Figure 11a. Micromachined needles: silicon based solid needles. (Source: Henry et al. ). Figure 11a. Micromachined needles: polymer based hollow needles. (Source: http://www.lasermicromachining.com/). g) Microsurgical tools Surgery is treatment of diseases or other ailments through manual and instrumental methods. In surgery, the majority of trauma to the patient is caused by the surgeon’s incisions to gain access to the surgical site. Minimally invasive surgical (MIS) procedure aims to provide diagnosis, monitoring, or treatment of diseases by performing operations with very small incisions or sometimes through natural orifices. Advantages of MIS over conventional open surgery includes less pain, minimal injury to tissues, minimal scarring, reduced recovery time, shorter hospital visits, faster return to normal activities and often lower cost to the patient. Common MIS procedures include angioplasty, catheterization, endoscopy, laparoscopy, and neurosurgery. MEMS based microsurgical tools have been identified as a key enabling technology for MIS . A pair of silicon MEMS based microtweezers and metal MEMS based biopsy forceps are shown in Figure 12. It should be noted that some of these feasibility demonstrations have yet to be qualified for clinical applications. Figure 12a. Micromachined surgical tools: a pair of silicon MEMS tweezers. (Source: http://www.memspi.com/). Figure 12b. Micromachined surgical tools: a pair of metal MEMS biopsy forceps. (Source: http://www.microfabrica.com/). Cardiovascular disease continues to be the leading cause of death in the United States. One of the common fatal cardiovascular conditions is narrowing of blood vessels due to accumulation of plaque that can lead to heart attack, stroke and other serious issues. Angioplasty is a procedure designed to restore normal blood flow through clogged or blocked arteries. A cardiac stent is inserted into a blood vessel via a catheter and then expanded to enlarge the vessel. There are two general types of stents: Metal stents and polymer stents. Metal stents are the conventional type. Two main types of polymer stents are resorbable and nonresorbable. The former type is attractive as it may be absorbed or dissolved inside the body. Figure 13 shows a stent fabricated on a bio-resorbable polymer by laser micromachining. Figure 13. Micromachined resorbable polymer stent. (Source: http://resonetics.com/). Other BioMEMS applications include tissue engineering  and microfluidics for cell biology, proteomics, and genomics . A comprehensive coverage of various BioMEMS applications can be found in the recent books  and . In the 21st century, BioMEMS devices are anticipated to revolutionize the biomedical industry similar to that of semiconductor devices to the electronics industry in the last century. As evident from the market trend, there are tremendous opportunities for MEMS in the biomedical industry. However, FDA approval process necessary for certain applications can cause significant delays for new BioMEMS devices entering the market. References 1. N.-T. Nguyen, S. A. M. Shaegh, N. Kashaninejad, and D.-T. Phan, “Design, fabrication and characterization of drug delivery systems based on lab-on-a-chip technology,” Advanced drug delivery reviews (2013). 2. M. Bourne, A Consumer’s Guide to MEMS & Nanotechnology, Bourne Research LLC, 1st edition, 2007. 3. BioMEMS 2013: Microsystem Device Market for Healthcare Applications, Yole Developpment, France, Feb. 2013. 4. C.D. Chin, V. Linder, and S. K. Sia. “Commercialization of microfluidic point-of-care diagnostic devices,” Lab on a Chip 12.12 (2012): 2118-2134. 5. S. Henry, D. V. Mc Allister, M. G. Allen and M. R. Prausnitz, “Microfabricated Microneedles: A Novel Approach to Transdermal Drug Delivery,” Journal of Pharmaceutical Sciences, 1998, 87, pp. 922-925. 6. K. Rebello, “Applications of MEMS in Surgery,” Proceedings of the IEEE, vol. 92, no. 1, Jan. 2004, pp. 43-55. 7. C. M. Puleo, H. C. Yeh, T. H. Wang, “Applications of MEMS technologies in tissue engineering,” Tissue Engineering, 13(12), 2007, pp. 2839-2854. 8. F. A. Gomez, Biological Applications of Microfluidics, Wiley-Interscience, 1st edition, 2008. 9. A. Folch, Introduction to BioMEMS, CRC Press, 1st edition, 2013. 10. Shekhar Bhansali (Editor), and Abhay Vasudev (Editor), MEMS for Biomedical Applications, Woodhead Publishing, 1st edition, 2012. Dr. Ramesh Ramadoss is currently employed as a Senior Manager in the MicroProbe Product Group of FormFactor Inc., San Jose, California. He received his B.E. degree from Thiagarajar College of Engineering, Madurai, India in May 1998 and Ph.D. degree in Electrical Engineering from the University of Colorado at Boulder in May 2003. From June 2003 to Dec. 2007, he was employed as an Assistant Professor in the Department of Electrical and Computer Engineering at Auburn University, Auburn, Alabama. From Jan. 2008 to Mar. 2012, he was employed as a Program Manager, MEMS R&D, FormFactor Inc., Livermore, California. Since April 2012, he has been employed at MicroProbe, San Jose, CA (Acquired by FormFactor Inc.). He is the author or coauthor of 3 book chapters and 53 papers in the MEMS field (Google Scholar Citations: 476, h-index: 14, and i10-index: 17). He has conducted MEMS R&D projects for DARPA, NASA, US Army, AOARD, Sandia National Labs, Motorola Labs, Foster-Miller Inc. and FormFactor Inc.