A BioMEMS Review: MEMS Technology for Physiologically Integrated Devices AMY C. RICHARDS GRAYSON, REBECCA S. SHAWGO, AUDREY M. JOHNSON, NOLAN T. FLYNN, YAWEN LI, MICHAEL J. CIMA, AND ROBERT LANGER Invited Paper MEMS devices are manufactured using similar microfabrica- I. INTRODUCTION tion techniques as those used to create integrated circuits. They often, however, have moving components that allow physical Microelectromechanical systems (MEMS) devices are or analytical functions to be performed by the device. Although manufactured using similar microfabrication techniques as MEMS can be aseptically fabricated and hermetically sealed, those used to create integrated circuits. They often have biocompatibility of the component materials is a key issue for moving components that allow a physical or analytical MEMS used in vivo. Interest in MEMS for biological applications function to be performed by the device in addition to (BioMEMS) is growing rapidly, with opportunities in areas such as biosensors, pacemakers, immunoisolation capsules, and drug their electrical functions. Microfabrication of silicon-based delivery. The key to many of these applications lies in the lever- structures is usually achieved by repeating sequences of aging of features unique to MEMS (for example, analyte sensitivity, photolithography, etching, and deposition steps in order to electrical responsiveness, temporal control, and feature sizes produce the desired configuration of features, such as traces similar to cells and organelles) for maximum impact. In this paper, (thin metal wires), vias (interlayer connections), reservoirs, we focus on how the biological integration of MEMS and other valves, or membranes, in a layer-by-layer fashion. The implantable devices can be improved through the application of microfabrication technology and concepts. Innovative approaches interested reader is directed to [1]–[3] for a review of for improved physical and chemical integration of systems with the microfabrication techniques. Microelectronics fabrication body are reviewed. An untapped potential for MEMS may lie in techniques routinely produce well-controlled features that the area of nervous and endocrine system actuation, whereby the range in size from millimeters to submicrometers, while ability of MEMS to deliver potent drugs or hormones, combined soft lithography techniques were recently used to produce with their precise temporal control, may provide new treatments features below 100 nm [4]. Although a vast assortment of for disorders of these systems. MEMS components and devices, including microreservoirs, Keywords—Biomedical engineering, biomedical materials, micropumps, cantilevers, rotors, channels, valves, sensors, biomedical transducers, drug delivery systems, microelectrome- and other structures, have been fabricated and tested in the chanical devices, micromachining, microneedles, microparticles, laboratory environment, most devices are designed for in cardiac pacemakers, surface modification, tissue engineering. vitro diagnostics. Interest in using MEMS and microfabrication technolo- gies for in vivo applications, however, is growing. MEMS can be aseptically fabricated and hermetically sealed, and Manuscript received February 3, 2003; revised April 10, 2003. This work was supported by National Institutes of Health Bioengineering Research the biocompatibility of materials used in MEMS fabrication Partnership under Grant R24-AI47739. is being investigated. The manufacturing techniques used in A. C. R. Grayson is currently with the School of Chemical and Biomolec- the microelectronics industry may lead to greater uniformity ular Engineering and the Biomedical Engineering Program, Cornell Univer- sity, Ithaca, NY 14853 USA (e-mail: [email protected]). and reproducibility of implantable devices than is currently R. S. Shawgo, Y. Li, and M. J. Cima are with the Department of available to the biomedical and pharmaceutical industries. Materials Science and Engineering, Massachusetts Institute of Technology, MEMS offer great potential advantages over other types Cambridge, MA 02139 USA (e-mail: [email protected]; [email protected]; of implantable systems for certain applications due to their [email protected]; [email protected]). A. M. Johnson and R. Langer are with the Department of Chemical En- small size scale, electrical nature, and ability to operate gineering, Massachusetts Institute of Technology, Cambridge, MA 02139 on short time scales. The development of retinal implants USA (e-mail: [email protected]; [email protected]; [email protected]). to treat blindness, neural implants for stimulation and N. T. Flynn is with the Department of Chemistry, Wellesley College, Wellesley, MA 02481 USA. recording from the central nervous system, and micronee- Digital Object Identifier 10.1109/JPROC.2003.820534 dles for painless vaccination are examples of applications 0018-9219/04$20.00 © 2004 IEEE 6 PROCEEDINGS OF THE IEEE, VOL. 92, NO. 1, JANUARY 2004 Authorized licensed use limited to: University of Maryland College Park. Downloaded on February 8, 2009 at 16:17 from IEEE Xplore. Restrictions apply. in which features unique to MEMS, such as optical and II. IMPLANTABLE MEMS electrical sensitivity or feature size comparable to relevant A variety of implantable electronic devices are based upon biological structures, are being leveraged for maximum or use MEMS technology, including sensors, immunoisola- impact. tion capsules, and drug delivery microchips. These topics, as The digital capabilities of MEMS may allow potentially greater temporal control in the area of drug delivery than well as a novel application of microfabrication technology to can currently be achieved with polymer-based systems. stents, are briefly reviewed here. Additionally, the incorporation of optical, electrical, or chemical sensing components into MEMS devices can A. Biosensors allow the delivery of drugs to be attuned to changes in Much has been done in the application of MEMS tech- the physiological environment surrounding the device. A nology to biosensors and the adaptation of various types of number of researchers have pursued a similar strategy for sensors to in vivo diagnostics. However, at the intersection the incorporation of sensing components into responsive of these fields, namely, implantable MEMS biosensors, polymeric systems for drug delivery, including systems there are few examples. This is due in part to the formidable that can be triggered by the application of ultrasound [5], challenges faced in the more general field of implantable [6], changes in pH [7]–[12], temperature [13]–[18], analyte biosensors. The goal of short-term sensing of pH, analytes, concentrations [19]–[21], and electric [22]–[27] or magnetic and pressure in blood, tissue, and body fluids has largely [28], [29] fields. While these systems are useful and inter- been achieved, but stable sensors for long-term implantation esting in their own right, we will not discuss them in detail, continue to elude researchers [30]–[34]. Long-term in vivo as they largely fall outside the scope of this paper. sensing is a critical component of the ideal closed-loop drug The small size of MEMS, coupled with their ability to delivery or monitoring system, but the issue of implant bio- achieve precise control over the timing of drug delivery, may compatibility and biofouling must be addressed in order to prove to be of great utility in the area of actuation of physi- achieve long-term in vivo sensing. Although it is important ological systems within the human body. Molecules such as to avoid adverse tissue responses to any implant, the degree hormones or growth factors are often quite potent, and their of biocompatibility must be greater for a sensor. effect is strongly influenced by their temporal administra- Even those materials generally considered to be biocom- tion. These potent molecules affect signaling and regulatory patible produce some degree of tissue response, usually systems in the body, such as the endocrine and nervous sys- resulting in the partial isolation of the implant from the body. tems. The ability of MEMS to act on a short time scale and Although this typically does not impede the function of drug under physiologically relevant conditions, coupled with their delivery, orthopedic, or other implants whose function is ability to deliver an electrical stimulus and/or drugs from a essentially mechanical in nature, implant isolation leads to device, offer the potential for these devices to actuate sys- reduced sensitivity and increased delay time for a sensor. tems in the body. The same biocompatibility challenge must be overcome We focus in this paper on the idea of physiological inte- in vivo gration of MEMS, which encompasses two main concepts. by any MEMS biosensor for use, as the intimate First, we will examine how the physiological integration interaction of sensor and analyte is intrinsic to the operation of MEMS and other implantable devices can be improved of all sensors. Efforts are under way to use microfabricated through the application of microfabrication technology and biosensors in vivo, especially for the less problematic concepts, and we review the current state of the art in the short-term sensing applications. Sensing strategies for assessment and improvement of MEMS biocompatibility. In biosensors include optical [35], mechanical [36], magnetic some cases, such as the microtexturing of surfaces for better [37], and electrochemical [38], [39] detection methods, cell adhesion, greater physical integration