Repeated in vivo electrochemical activation and the biological effects of microelectromechanical systems drug delivery device Rebecca S. Shawgo, 1 Gabriela Voskerician, 2 Hong Linh Ho Duc, 1 Yawen Li, 1 Aaron Lynn, 2 Matthew MacEwan, 2 Robert Langer, 3 James M. Anderson, 2,4 Michael J. Cima 1 1 Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 2 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106 3 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 4 Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106 Received 26 January 2004; accepted 16 February 2004 Published online 26 October 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30050 Abstract: The repeated activation of a microelectrome- chanical systems (MEMS) drug delivery device was studied in vivo in rats to examine the effect of implantation on the device operation and the effect of electrochemical activation on the inflammatory and wound-healing response. The MEMS devices were fabricated from a silicon wafer into which reservoirs were etched and covered with gold mem- branes. The membranes were electrochemically removed when an anodic voltage was applied. Devices were im- planted subcutaneously both with and without stainless steel mesh cages for 4, 7, 14, 21, or 28 days before activation. Devices were activated every other day for five activations. Leukocyte concentrations indicated that both the application of voltage and the gold corrosion products elevated the inflammatory response which was resolved within 48 h after each activation. The efficiency of gold membrane removal was not impaired throughout the implantation, although a bimodal distribution of background current densities was observed after long implantation times. The thickness of the fibrous capsule surrounding the MEMS devices was similar between activated and control devices explanted at each time point. It was concluded that the repeated activation of MEMS drug delivery devices was successful and the activa- tion produced an acceptable biological response that re- solved promptly. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 559 –568, 2004 Key words: MEMS; drug delivery; biocompatibility; volt- ammetry; inflammatory response INTRODUCTION Stimulating electrodes are necessary components of several medical devices, including pacemakers, bio- sensors, and neural implants. The electrode interac- tion with the body is considered the weakest link in the long-term reliability of both pacemakers and bio- sensors. 1–3 Researchers have studied the biocompat- ibility of electrodes and electrode materials in a vari- ety of circumstances as well as the effect of electric fields on cells and tissues. Few in vivo studies of elec- trode behavior have produced any quantitative data, however. The in vivo implantation of electrodes for medical applications results in a host-initiated inflammatory and wound-healing response. During this process, the local biological environment isolates the implanted device through the development of a fibrous capsule. The fibrous capsule surrounding an electrode will be influenced by the lead size, shape, smoothness, and materials as well as by the electric field produced by a stimulating electrode. 4 The fibrous capsules may aid in fixing the lead in place, but the fibrosis may affect the electrical properties of the lead. A technique using lasers to remove leads with the surrounding fibrous tissue intact has recently been developed 5 ; immuno- histochemistry revealed that the fibrous tissue was generally devoid of inflammatory and immune cells after an average implantation time of 5.6 years. This indicated that the inflammatory response around Correspondence to: M. J. Cima, Ceramics Processing Re- search Laboratory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Room 12-011, Cambridge, MA 02139; e-mail: mjcima@mit.edu Contract grant sponsor: National Institutes of Health; con- tract grant number: 1 R24 AI47739-01 © 2004 Wiley Periodicals, Inc.