Flexible parylene-based multielectrode array technology for high-density neural stimulation and recording
Introduction
Low-electrode-density neural prostheses have shown incredible promise, enabling those with severe hearing impairments to recognize speech [1] and those blind from such devastating outer retinal diseases as retinitis pigmentosa (RP) (where the photoreceptors are damaged but the remaining inner retinal circuitry remains largely intact [2]) to perceive visual data [3]. Subjects with prototype sixteen-electrode retinal prostheses can even distinguish between objects such as plates, cups, and knives, and perceive directions of movement in high-contrast environments far better than would be possible by chance alone [4]. However, there exists a need for a multielectrode array (MEA) technology that is capable of increasing the density of neural stimulation beyond its current limits, while ensuring biocompatibility and device longevity. In fact, for retinal stimulation in particular, it has been shown that room navigation could be significantly improved with an electrode array comprising one thousand or more electrodes, and furthermore such an array would likely enable facial recognition and large type reading [5]. The next-generation retinal prosthesis for patients with diseases like RP and age-related macular degeneration (AMD) (Fig. 1), then, requires a high-density flexible electrode array capable of stimulating the inner retina and a high-lead-count cable to allow for high-resolution vision. We present the first flexible parylene-based MEAs designed for functional electrical stimulation in retinal prostheses, and the extension of this technology to enable stimulation of central nervous system structures after spinal cord injury. In addition to presenting a high surface-area electroplating technology that extends stimulation electrode longevity to at least 430 million pulses, which is ample for many applications, we address the importance of a novel parylene-enabled dual-metal-layer fabrication methodology that permits complex electrode arrangements while alleviating the traditional problems of electrode crowding and electrode size restrictions caused by wire routing. Promising chronic biomechanical stability results in canine eyes and acute neural recording and stimulation results in an in vitro retinal preparation and in vivo in murine spinal cords are presented, demonstrating the ability of these parylene-based arrays to both record from and stimulate the neuronal targets of interest. All animal procedures conformed to the ARVO Statement on the Use of Animals in Ophthalmic and Vision Research.
The advantages of using parylene C as the structural material for such neuroprostheses, when compared with technologies based on the use of other materials such as PDMS, polyimide [6] and silicon [7], include parylene's pinhole-free conformality due partly to its unique room-temperature chemical vapor deposition process, its low water permeability, its chronic implantability as an ISO 10993, United States Pharmacopeia (USP) Class VI material (highest biocompatibility class for plastics in the United States), and its high flexibility and mechanical strength (Young's modulus ∼4 GPa). Since parylene is deposited at room temperature (we have verified this using Temp-Plate irreversible temperature recorders traceable to NIST (Wahl Instruments, Inc., Asheville, NC, USA)), the coating process is post-integrated-circuit (IC) compatible. Parylene C is also optically transparent, enabling the anatomy to be seen through the cable and the array during ophthalmic surgery, post-implantation examination, and follow-up. While many groups use parylene C as a coating of their arrays for many of these reasons, we have chosen to use it as the main substrate for our devices [8], [9], a paradigm that leverages these advantages to the greatest extent. A new high-temperature stable [10] and ISO 10993 biocompatible [11], [12], [13] fluorinated variant of parylene, parylene HT, that is similar in many respects to parylene C, has also been used to fabricate iridium electrode arrays. We show that while evaporation and patterning of iridium was unsuccessful on parylene C due to the high melting temperature of iridium, parylene HT lends itself to such a process, and we present this as another possible technology for ensuring good charge delivery to neural tissue.
Section snippets
Single-layer process
Single-metal-layer parylene C-based electrode arrays are fabricated as shown in Fig. 2. A photoresist sacrificial layer is optionally spun on a standard silicon wafer. Approximately 8 μm of parylene C is then vapor-deposited in a PDS2010 system (Specialty Coating Systems, Indianapolis, IN, USA) on the entire wafer. An LOR3B photoresist layer (Microchem Corporation, Newton, MA, USA) and an AZ1518 layer (AZ Electronic Materials, Branchburg, NJ, USA) are spun on top of the parylene, exposed in a
In vitro retinal recording and stimulation
Parylene C-based arrays of thin-film platinum electrodes, comprising four 200-μm-diameter stimulating electrodes and 56 recording electrodes of 10 μm diameter were fabricated according to the single-metal-layer process on a glass substrate. These were placed in a bicarbonate perfusate under a microscope and connected to a stimulus generator and preamplification board (Multi Channel Systems MCS GmbH, Reutlingen, Germany) [16]. As shown in Fig. 4, a retina isolated from larval tiger salamander (
Conclusion
Single and dual-metal-layer fabrication processes for parylene-based electrode arrays have been outlined and demonstrated as robust techniques for building flexible MEAs. These revolutionary MEAs have the ability to stimulate and record from neural tissue in the retina and spinal cord, and demonstrate excellent biostability when chronically implanted in contact with canine retinas. The parylene-enabled dual-metal-layer process allows increased electrode density while obviating many of the
Acknowledgments
This work was supported in part by the Engineering Research Centers Program of the National Science Foundation under NSF Award Number EEC-0310723, and by a fellowship from the Whitaker Foundation (D.R.). The authors especially wish to thank Dr. Jack Whalen and Ms. Aditi Ray for their help with the electroplating and electrochemical testing experiments, Dr. Saloomeh Saati for her help with the in vivo canine studies, Mr. Matthew Behrend for his work on the isolated retina setup, Ms. Ronalee Lo
Damien C. Rodger received his BS degree in electrical engineering (magna cum laude with honors) from Cornell University in 2000. He is currently an MD/PhD candidate at the Keck School of Medicine of the University of Southern California and the California Institute of Technology conducting research in bioengineering on bioMEMS for ophthalmic and neural use. He held a Whitaker Foundation Graduate Fellowship from 2003 to 2006 and is a member of the IEEE EMBS and the Association for Research in
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Damien C. Rodger received his BS degree in electrical engineering (magna cum laude with honors) from Cornell University in 2000. He is currently an MD/PhD candidate at the Keck School of Medicine of the University of Southern California and the California Institute of Technology conducting research in bioengineering on bioMEMS for ophthalmic and neural use. He held a Whitaker Foundation Graduate Fellowship from 2003 to 2006 and is a member of the IEEE EMBS and the Association for Research in Vision and Ophthalmology (ARVO).
Andy J. Fong received his MS degree in biomedical engineering at the University of California, Los Angeles in 2002. Currently he is pursuing his PhD in bioengineering at the California Institute of Technology. His dissertation research focuses on developing new technologies for treating spinal cord injury using a combination of robotically assisted physical rehabilitation, pharmacological treatments, and multi-locus electrical stimulation.
Wen Li received the BS degree in material science and engineering from Tsinghua University, Beijing, China, in 2001, the MS degree in microelectronics from Tsinghua University, Beijing, China, in 2003, and the MS degree in electrical engineering from California Institute of Technology in 2004. Currently, she is working toward a PhD in electrical engineering at the California Institute of Technology. Her research interests include flexible MEMS devices and systems for power and data transfer in retinal prostheses and other biomedical applications.
Hossein Ameri graduated from Tehran University of Medical Sciences in 1993. He received his Ophthalmology and Vitreoretinal Surgery training in Ireland and obtained his FRCSI from the Royal College of Surgeons in Ireland, and MRCOphth from the Royal College of Ophthalmologists in London in 2000. During his ophthalmology training at Cork University Hospital, he was also an official lecturer at University College Cork. He moved to the Doheny Eye Institute in Los Angeles in 2004 to pursue his research on retinal prostheses and retinal vascular disease. He is currently an assistant professor of ophthalmology at the University of Southern California.
Ashish K. Ahuja received his BS and MS degrees from Columbia University in applied physics and electrical engineering in 1999 and 2001, respectively. He worked in the Condensed Matter Physics Department at Bell Laboratories for 2 years. He then received his PhD in electrical engineering-electrophysics in 2007 from the University of Southern California. He is currently a Post-Doctoral Research Fellow at Second Sight Medical Products working towards the development of retinal prosthetic implants for the blind.
Christian Gutierrez received his BS degree in electrical engineering from the California Institute of Technology in 2005. He continued at Caltech and received his MS in electrical engineering in 2006. He is currently under fellowship pursuing a PhD in biomedical engineering at the University of Southern California. His research interest is in the development of novel MEMS devices with applications to medicine and he is currently involved in research for an intraocular retinal prosthesis.
Igor Lavrov received his MD in 1999 from Military Medical Academy and his PhD in 2002 from the Pavlov Institute of Physiology. In 2002 he joined the University of Louisville School of Medicine as a postdoctoral fellow, and in 2005 the laboratory of Dr. Edgerton at the University of California, Los Angeles. His research interests have been focused on understanding spinal cord functional organization and mechanisms of spinal cord reorganization after injury, artificial activation of spinal cord circuits responsible for locomotion, and developing rehabilitation strategies for spinal cord injury.
Hui Zhong received her MD in 1983 from Hebei Medical College. She has been at the University of California, Los Angeles since 1994. Currently, she is a project scientist in the Neuromuscular Plasticity Laboratory in the Brain Research Institute. Her research interest is neuromuscular plasticity after spinal cord injury.
Parvathy R. Menon is currently an undergraduate at the California Institute of Technology and will receive her BS in engineering and applied science in bioengineering in 2008. Prior to joining the Caltech Micromachining Group, she worked as an Axline Scholar in the Microdevices Lab of the NASA Jet Propulsion Laboratory. Additionally, she has worked in the Network Architecture Lab (NAL) of Intel Corporation and at the Oregon Graduate Institute (OGI). In the fall of 2009, she will be pursuing graduate studies in bioengineering or medicine.
Ellis Meng received her BS degree in engineering and applied science from the California Institute of Technology in 1997. She pursued her graduate studies in electrical engineering and received her MS in 1998 and PhD in 2003 at the same institution. She is now an assistant professor of biomedical engineering at the University of Southern California. In the National Science Foundation Biomimetic MicroElectronic Systems Engineering Research Center (BMES ERC) she is a Thrust Leader for Interface Technology and the Associate Director of Education and Student Diversity. She is a member of Tau Beta Pi, the American Society of Mechanical Engineers (ASME), the Society of Women Engineers (SWE), and the Association for Research in Vision and Ophthalmology (ARVO).
Joel W. Burdick received his BS in mechanical engineering from Duke University and MS and PhD degrees in mechanical engineering from Stanford University. He has been with the Department of Mechanical Engineering at the California Institute of Technology since May 1988. His current research interests include robotic locomotion, sensor based robot motion planning, multi-fingered robotic grasping, medical applications of robotics, applied nonlinear control theory, and neural prosthetics.
Roland R. Roy received the MSc and PhD degrees in exercise physiology from Michigan State University, East Lansing, in 1973 and 1976, respectively. He is currently a researcher in the Brain Research Institute, University of California, Los Angeles. His primary research interests concern the plasticity of the neuromuscular apparatus when subjected to a chronic increase (exercise, functional overload, hypergravity) or decrease (spinalization, immobilization, weightlessness, hind limb unloading, spinal cord isolation) in neuromuscular activity.
V. Reggie Edgerton received his PhD in exercise physiology from Michigan State University. He has been at the University of California, Los Angeles, since 1968 and is currently a professor in the Departments of Physiological Science and Neurobiology and a member of the Brain Research Institute. Dr. Edgerton's laboratory focuses on how, and to what extent, the nervous system controls protein expression in skeletal muscle fibers as well as how the neural networks in the lumbar spinal cord of mammals, including humans, control stepping and how this stepping pattern becomes modified by chronically imposing specific motor tasks on the limbs after complete spinal cord injury.
James D. Weiland received his BS from the University of Michigan in 1988. After 4 years in industry with Pratt & Whitney Aircraft Engines, he returned to Michigan for graduate school, earning degrees in biomedical engineering (MS 1993, PhD 1997) and electrical engineering (MS 1995). In 1999 he was appointed an assistant professor of ophthalmology at Johns Hopkins. Dr. Weiland is now the Director of the Intraocular Retinal Prosthesis Lab at the Doheny Retina Institute, and is an associate professor of ophthalmology and biomedical engineering at the University of Southern California. He is a member of the IEEE EMBS, the Biomedical Engineering Society, and the Association for Research in Vision and Ophthalmology.
Mark S. Humayun received his BS from Georgetown University in 1984, his MD from Duke University in 1989, and his PhD from the University of North Carolina, Chapel Hill in 1994. He finished his training by completing an Ophthalmology residency at Duke and a Fellowship in Vitreoretinal Diseases at Johns Hopkins Hospital. Currently, Dr. Humayun is a professor of ophthalmology, biomedical engineering, and cell and neurobiology at the University of Southern California. Dr. Humayun is the Director of the National Science Foundation Biomimetic MicroElectronic Systems Engineering Research Center (BMES ERC). He is also the Director for the Department of Energy Artificial Retina Project that is a consortium of five Department of Energy labs and four universities, as well as industry.
Yu-Chong Tai received his BS degree from National Taiwan University, and the MS and PhD degrees in electrical engineering from the University of California at Berkeley. He is currently a professor of bioengineering and executive officer and professor of electrical engineering at the California Institute of Technology, and director of the Caltech Micromachining Laboratory. His current research interests include flexible MEMS, bioMEMS, MEMS for retinal and neural implants, parylene-based integrated microfluidics, neuroprobes/neurochips, and HPLC-based labs-on-a-chip.