IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 54, NO.

6, JUNE 2007

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An Optically Powered Single-Channel Stimulation Implant as Test System for Chronic Biocompatibility and Biostability of Miniaturized Retinal Vision Prostheses
Thomas Schanze*, Lutz Hesse, Carsten Lau, Nina Greve, Werner Haberer, Sascha Kammer, Thomas Doerge, Andreas Rentzos, and Thomas Stieglitz, Member, IEEE
I. INTRODUCTION

AbstractA microsystem based microimplant with an optically powered single-channel stimulator was designed and developed as test system for an epi-retinal vision implant. Biostability of the hybrid assembly and the encapsulation materials were evaluated in pilot experiments in chronic implantations in a cat animal model. The implant was fabricated on a exible polyimide substrate with integrated platinum electrode, interconnection lines, and contact pads for hybrid integration of electronic components. The receiver part was realized with four photodiodes connected in series. A parylene C coating was deposited on the electronic components as insulation layer. Silicone rubber was used to encapsulate the electronics in the shape of an articial intraocular lens to allow proper implantation in the eye. Pilot experiments showed the biostability of the encapsulation approach and full electric functionality of the microimplant to generate stimulation currents over the implantation period of three months in two cats. In one cat, electrical stimulation of the retina evoked neuronal responses in the visual cortex and indicated the feasibility of the system approach for chronic use.

Index TermsBlindness, BioMEMS, electrical stimulation, micromachining, neural prosthesis, neuronal activity, recording, retina implant, visual prosthesis, visual system.

Manuscript received July 3, 2006; revised December 1, 2006. This work was supported in part by the German Federal Ministry of Education, Science, Research, and Technology. Asterisk indicates corresponding author. *T. Schanze was with the Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg, Renthof 7, 35037 Marburg, Germany. He is now with CORRSYS 3D Sensors AG, CharlotteBamberg-Str. 6, 35578 Wetzlar, Germany (e-mail: th.schanze@web.de, thomas.schanze@corrsys3d.com). L. Hesse was with the Department of Ophthalmology, Philipps University Marburg, 35033 Marburg, Germany. He is now with the Eye Clinic, SLK-Kliniken Heilbronn, 74064 Heilbronn, Germany. C. Lau was with the Biomaterials Group, RWTH Aachen University, 52074 Aachen, Germany. He is now with BASF AG, 67056 Ludwigshafen, Germany. N. Greve was with the Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg, 35037 Marburg, Germany. She is now with Volkswagen AG, 38436 Wolfsburg, Germany. W. Haberer, S. Kammer, and T. Doerge are with the Fraunhofer Institute for Biomedical Engineering, 66386 St. Ingbert, Germany. A. Rentzos is with the Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg, 35037 Marburg, Germany. T. Stieglitz was with the Fraunhofer Institute for Biomedical Engineering, 66386 St. Ingbert, Germany. He is now with the Biomedical Microtechnology Laboratory, Department of Microsystems Engineering IMTEK, University of Freiburg, 79110 Freiburg, Germany. Digital Object Identier 10.1109/TBME.2007.895866

LINDNESS aficts more than one million Americans and Europeans. In Germany, 17 000 people become blind every year [1], [2]. Up to now, there is no effective treatment or cure. About 50% of all cases of blindness are caused by retinal damage. Abundant blinding diseases are retinitis pigmentosa (RP) and age related macular degeneration (AMD), which cause progressive degeneration of the outer retina. RP is the main cause of visual loss of inherited blindness and its incidence is about 1 per 4000 live births [3]. AMD is the main cause of photoreceptor loss in older adults in Western countries [4]. Fortunately, postmortem analyses of patients with RP or AMD have shown that a lot of retinal neurons, e.g., bipolar cells or ganglion cells, are retained compared to the photoreceptor cells of the outer nuclear layer [5][7]. These remaining cells are still intact and might be stimulated by electrical currents to restore vision. Although there are many examples of supporting or restoring function of defective excitable tissue by commercially available electronic devices, such as pacemakers, bladder stimulators or cochlear implants, the restoration of vision is not yet solved but research is performed on vision implants for the optic nerve, the visual cortex and the retina [8][32]. Two main approaches for retinal implants are under development. Sub-retinal implants are implanted between the pigment epithelial layer and the outer layer of the retina and try to stimulate the remaining intact retinal neuronsbipolar or horizontal cells, the initial neuronal processing stage of the retinaby currents generated from photodiodes or electrodes, respectively. Epi-retinal implants have been designed to stimulate retinal ganglion cellsthe nal and more intricate retinal processing stagewith an electrode array implanted onto the inner retinal membrane. Thus, epi-retinal implants are expected to be more complex with respect to adequate electronic processing of visual information and the related generation of stimulation currents than subretinal implants. Here, we focus on an implantable microsystem that acts as an optically powered single channel stimulator for an epi-retinal vision prosthesis. We describe its design, implantation and function with the focus on its long term biostability. The device might serve as a simple test system for future multichannel intelligent implants required for retinal vision prostheses.

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Fig. 1. Epi-retinal implant for restoring vision. (A) Both data and energy are delivered wireless, e.g., by an inductive link or optically. The external parts, energy supply, video camera, data processors and transmitter coil, are in a glass frame. The receiver coil and microelectronics are embedded in an articial intraocular lens implanted into to the eyes lens capsule. The electrode array is afxed to the retina to stimulate intact retinal neurons with electrical impulses. (B) Electrode array in close contact with the retina (inner limiting membrane). Note the lost photoreceptors due to degeneration and the still remaining intact retinal neurons (e.g., ganglion or bipolar cells).

II. METHODS The notion of our epi-retinal implant approach is to afx an electrode array onto the retinal surface and to stimulate ganglion cells by small electric currents generated by an electronic device connected with the electrodes. The wireless activation of the implant is achieved by an external transmitter which is also intended to assure an adequate data processing of visual scenes recorded by a camera (Fig. 1). Of course, the implant should be biocompatible, long-term stable and its intraocular xation must be feasible and safe. In addition, the electrodes xation on the inner retinal surface should not induce any retinal injury. Thus, the electrodes should be highly exible, smooth, light-weighted, robust, biocompatible, easily implantable, and should be capable of delivering sufcient electrical current within safe charge injection limits. Above these specications, the implants fabrication should be simple, reliable, and should give direction to more complex multichannel retina implants. On the basis of these requirements, we decided to develop an elementary retina stimulator consisting of two major functional units. The rst unit contains the electronics required for receiving energy and signals for retina stimulation. This unit will be implanted into the eye by replacing the lens; thus, we call it the intraocular lens part (IOL). The second unit consists of electrodes for epi-retinal ganglion cell stimulation. This elementary implant shall serve as a test system to evaluate the stability of microsystem based implants, hybrid assembling of electronic components and packaging and encapsulation with polymer materials. Chronic implantations in a cat animal model will be used to investigate the biostability of the implant and the functionality of the electrode-tissue interface. The results from these pilot experiments might serve as background knowledge in the development of future retinal implants. A. Design and Fabrication 1) Implant Design: We designed an intraocularly implantable one channel retina stimulator for the proof of

TABLE I PROPERTIES OF THE SR10 BP-B PHOTODIODE AT 25 C

principle using a polyimide substrate with integrated platinum electrodes and a combined parylene/silicone encapsulation to protect the electronic components against moisture, ions, and potential mechanical stress during implantation. The electronic receiver has been developed using four silicon based PIN photodiodes that have been connected in series on the polyimide substrate to reach a voltage that is sufciently high to generate a current for stimulating retinal ganglion cells with the electrodes positioned on the inner retinal surface. We chose the PIN photodiode SR10 BP-B from ELCOS (Germany) as surface mount device (SMD) component in the 1206 series with solder pads (Table I). The simplied electrical equivalent circuit of the stimulator is given as a series of four photodiodes. The

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TABLE II DIMENSIONS OF THE OPTICALLY POWERED ONE CHANNEL RETINA STIMULATOR

Fig. 2. Simplied electrical equivalent circuit of the retina stimulator. Four PIN photodiodes (SR10 BP-B, ELCOS) are connected in series. Electrode properties are modeled by a resistor and a capacitor connected in parallel. The electrical behavior of the extracellular uid between the two electrodes is approximated by a resistor.

Fig. 4. Schematic overview of the polyimide process technology for exible substrates with integrated electrodes and interconnects. (a) Bottom layer of polyimide, (b) deposition and structuring of interconnect lines, (c) deposition of electrode material (can be combined with step b), top layer of polyimide, deposition of aluminum etching mask, (d) opening of electrodes and contact pads by reactive ion etching (e), and substrate separation (f).

Fig. 3. Layout for the polyimide substrate. (A) The outline of the entire polyimide substrate. The upper part is designed for the mounting of photodiodes whereas the lower part contains the electrodes. (B) Magnications of the electrode design.

electrode-tissue interfaces were modeled as resistors parallel to capacitors with a resistive tissue component in between (Fig. 2). The layout of the stimulator substrate was designed using a commercial computer-aided design program. The substrate (Fig. 3) consists of a ring-like structure with footprints for four photodiodes to be embedded into an articial intraocular lens as required for implantation. Conductive tracks within the substrate lead to the stimulation area that will we placed onto the retina. This area has been originally designed for a manifold of electrodes [33] but for this investigation only two electrodes have been integrated. The three rings of the substrate were arranged concentrically and were connected via s-shaped interconnects that allow a 3-D adaptation to the spherical shape of the eyeball. We designed a stimulator substrate (Fig. 3, Table II) with two dot electrodes placed on the middle ring of the stimulation area of the implant. According to Brummer and Turner [34], [35], a platinum electrode voltage (versus reversible hydrogen electrode) in excess of 1.4 V can induce water electrolysis in vitro.

The use of photodiodes as electric sources has the advantage that the voltage across the electrodes is logarithmically limited to light intensity due to the diodes currentvoltage relation. The critical voltage for the stimulator is 2.8 V, which might be achieved only for high illumination densities (> 2 mW/mm ). 2) Micromachining of Substrates and Electrodes: The substrates of the implants were fabricated using micromachining technologies. We developed a polyimide based process technology for an electrode design, which overcomes the classical separation of substrate and insulation layers and allows to integrate interconnects and to generate arbitrary outer shapes [33]. The process contains the following process steps (Fig. 4): At rst, a 5- m-thick layer of polyimide resin (Pyralin PI 2611, HD Microsystems, USA/Germany) was spun onto a silicon wafer which serves as a support structure during the whole process. The polyimide was cured into a polyimide oven (PB 62, Yes, USA). A metalization layer (30 nm titanium, 300 nm platinum) for connection pads, interconnect lines, and electrode sites was deposited by sputtering (L 420 SP, Leybold, Germany) and structured using the so-called lift-off technique. A second polyimide layer with a thickness of 5 m was spun on and was cured to serve as top layer insulation. An aluminum etching mask was deposited and structured with wet etching to dene electrode sites, connection pads and the outer geometry of the devices. Reactive ion etching with a STS 320 PC generator (Surface Technology Systems, U.K.) and oxygen plasma was used to open the electrode sites and connection pads and

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to separate the devices by etching the outer shapes down to the support silicon wafer. The remaining aluminum etch mask was removed with aluminum etch solution. The wafer was cleaned with isopropanol and deionized water in an ultrasonic bath. Using tweezers, the devices were mechanically stripped from the wafer. 3) Assembling: Four SMD PIN photodiodes with solder pads (SR 10 P, 1206 Series, ELCOS, Germany) were manually aligned on the polyimide substrates with the aid of a microscope. They were mechanically xed and electrically contacted with conductive glue (Epo-Tek H20E-PFC, POLYTEC, Germany) on the metal pads of the underlying polyimide substrate. 4) Parylene Coating: Parylene has become the generic name of poly-para-xylenes [36]. Applications of parylene coatings range from encapsulation of electronic circuits under harsh environments to the insulation of implantable wires and electrodes. It has been found as a chronically stable material with excellent encapsulation and insulation properties in combination with a good in vivo biocompatibility [37][41]. Three different types of dimers are available: Parylene C, D, and N. For biomedical implants, parylene C with one chlorine atom on the benzene ring has favorable properties due to its lowest permeability to moisture and corrosive gases. Parylene lms are (theoretically) pinhole-free even at a thickness of less than 1 m. The deposition of parylene C took place in a Lab Top 3000 parylene coater (Paratec Inc., USA) that uses the standardized Gorham-process [42]. We used plasma activation (49 sccm O , 70 W, 10 s) of the polyimide substrate with the assembled photodiodes before parylene deposition to increase the adhesion between the materials. The electrodes were protected by covering them with natural caoutchouc (PC-Flex-GA, P. Jordan GmbH, Germany) on an aluminum oxide ceramic plate. The implants were mounted on a stack and a layer of 20 m parylene C was deposited in a process chamber. After parylene deposition the caoutchouc was mechanically removed. 5) Silicone Encapsulation: The silicone encapsulation of the implant mechanically protects the device during implantation and delivers a material-tissue interface with well known properties. We decided to use (Poly)dimethylsiloxane (PDMS) for encapsulation. The technology for PDMS applications is a technical standard in ophthalmologic industry [43], [44], also use for the protection of electronic devices [45], [46]. The material seems to be an excellent candidate for intraocular implant encapsulation due to its biocompatibility, inertness and transparency. For reproducible encapsulation of the implants parylene-coated electronics, an adopted vulcanization apparatus with custom-made brass casting tools (moulds), was used. The vulcanization heat and pressure could be varied systematically for optimal encapsulation. Process parameters included pressure, temperature, and duration of the vulcanization process. We used the PDMS Sylgard 184 (Dow Corning Corp., USA) for encapsulation that is a liquid two-part silicone elastomer, comprised of base and curing agents. Both components were mixed at a volume mix ratio of 10:1. The mixture was degassed in an exsiccator by means of a vacuum pump. One drop of the mixture as well as the electronics part of the implant were placed in the pit of the lower part of the mould, degassed and subsequently vulcanized for 5 h at 50 C. In the second vulcanization step, the lower part of the mould with electronics

Fig. 5. Electrode on polyimide substrate (A). Parylene coated IOL part (photodiodes) of the stimulator (B).

and the upper part of the mould were completely lled with PDMS and once again degassed. Both parts were merged in order to embed the electronics completely in the mould. The parts were compressed in the vulcanization apparatus with a pressure of 4 bar. Finally PDMS was once again vulcanized for 5 h at 50 C. After this a PDMS encapsulated implant was taken out of the vulcanization tool. In addition to this slow low-temperature vulcanization process, we performed a fast high-temperature process (1 h at 100 C). 6) Cytotoxicity of the Encapsulation: The in vitro cytotoxicity testing of PDMS was performed according to the ISO 10993 guidelines (Biological evaluation of medical devices. Part 5: Tests for cytotoxicity: in vitro methods, Part 12: Sample preparation and reference materials.) as rst mandatory step in accordance to legal requirements in the active medical device approval procedure. Direct contact and extract tests were performed using L929-cells (mouse broblast cell line according to international standards).Vitality, spreading of the cells, DNA-synthesis and mitochondria activity were investigated using different staining techniques and assays [vital staining with uorescein diacetate (FDA) and propidium iodide (PI), Mayers hemalaun as counterstain, Bradford proteine assay and XTT proliferation assay to quantify metabolic activity]. Glass was used as negative (nontoxic) control. Data for direct and extract tests were collected and analyzed from 2 control and 4 sample groups in each case. 7) External Optical Driving Unit: Electrical stimulation generally requires the generation of short voltage or current impulses transmitted extracellularly by electrodes into neural tissue. The usage of visible light impulses for implant activation during in vivo experiments has to be avoided to separate visual responses from electrical evoked potentials since experiments were performed with nonblind animals. Thus, we used a fast high-performance infrared LED with a narrow beam width (SFH484-2, Siemens, Germany). This diode has a radiation angle of 16 and provides a light radiation at 875 nm with 900 mW/sr for current impulses of 1 A amplitude and 100- s duration. The receiver photodiodes on the implant were placed circularly with an outer diameter of 6 mm (Figs. 3, 5, and 6). This arrangement leads to a simple calculation that the corresponding area of 28.3 mm can be irradiated with 55-mW infrared light under optimal conditions. This is a power density of about 2 mW/mm . Using this value, the implants photodiodes should produce a short circuit current of about 280 A (7 A at 5 mW/cm light intensity; see Table I). If we assume

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Fig. 6. Silicone encapsulated epi-retinal stimulator.

an attenuation of the infrared beam of 80% as passing through the eyes cornea and the intraocular uid, the photodiodes will produce a short circuit current of about 56 A. This value should be sufcient to be recorded in vivo by electrodes for testing the implants function and, in addition, should be sufcient to evoke cortical potentials after retinal stimulation, since recently published data show [25], [26] that the threshold for successful epi-retinal stimulation can be signicantly below 10 A. The activation of the infrared (IR) LED was performed with a current source. For this, we built up fast a voltage-current converter on the basis of a fast operational amplier (EL2070, Elantec Semiconductor Inc., USA). The converters large signal rise time of about 0.5 s ensured with the LEDs rise time of 0.6 s at 100 mA the generation of sufciently fast rising light impulses as required for producing maximum stimulation voltage gradients with the implants electrodes. B. Testing and Implantation 1) Functional Screening of the Implant Performance: In order to estimate the attenuation of the cornea and the intraocular uid, we measured the current generated by a single photodiode (SR 10 P) embedded in different optical media. We used air, ringers solution and ringers solution in combination with two explanted feline corneas. For the illumination of the photodiode, we used a single SFH484-2 LED at a distance of 3 cm and activated by short current impulses (200 s, 500 mA) of the transmitter. Function checks of 10 parylene coated implants were performed before and after silicone rubber encapsulation. The test of the nonsilicone encapsulated implants consisted of a visual control and by measuring the current generated by the photodiodes during illumination with infrared light. For this, we contacted the implants electrodes carefully with thin silver wires equipped with ball-shaped endings. Implants that had been capable of generating at least 100 A at a light intensity of 1 mW/mm (dark background) were encapsulated with silicone rubber. For testing the silicone encapsulated implants, we repeated the visual and current delivery check. Subsequently, we put the implants into Ringers solution and activated them with short impulses of infrared light (0.51 mW/mm ) for 48 h. Implants function was monitored by measuring the electrical eld induced in the solution with silver/silver-chloride electrodes during stimulation with 200- s light impulses at a rate of 1/s. An implant was declared as functional if it passed the visual and the current delivery test and if the measured

electrical eld at the end of the 48-h test scored at least 80% of the initial electrical eld. 2) Implantation: Surgical and electrophysiological procedures were performed with anaesthetized cats. The procedures were in accordance with the guidelines of the European Communities Council Directive (86/609/EEC) and were approved by an ofcial German Animal Care and Use Committee. In addition, we followed the NIH Principles of Laboratory Animal Care (Publication No. 8523, revised 1985), the OPRR Public Health Service Policy on the Human Care and Use of Laboratory Animals (revised 1986), the U.S. Animal Welfare Act, and the ARVO guidelines. Three adult cats (3 to 4 kg) received atropine sulphate (0.04 mg/kg) to reduce salivation. Anesthesia was induced by intramuscular injection of a mixture of ketamine hydrochloride (Ketanest, 1015 mg/kg) and xylazine hydrochloride (Rompun, 1 mg/kg). During surgery anesthesia was maintained by ketamine hydrochloride (Ketanest, 15 mg/kg i.m.) and/or propofol (Propofol, 0.020.05 mg/(kg h)). We controlled body temperature and the level of anesthesia by monitoring ECG and reexes. Analgesia was supported by local applications of lidocaine. The surgery for the implantation consisted of two chronological steps. In the rst step, we performed a lentectomy, the preparation of the lens capsule as required for implant xation, and a vitrectomy via corneal incisions. The incisions were closed and atropine, gentamycinsulfate, and dexamethason ointment were applied. After the animals recovery we performed the second surgical step. Prior to implantation we assured by a repeated vitrectomy a complete removement of the vitreous body and the vitreous cortex. This complete removement is essential since residuals of the vitreous body and/or the vitreous cortex will prevent a close contact between electrode and inner limiting membrane, which is indispensable for low-stimulation thresholds [18], [25], [26]. For the implantation of the epi-retinal implant, the cornea was insisted at a length of 1012 mm. The incision was made tangentially at a distance of 0.51.5 mm from the outer sulcus of the limbus. Prior to implant insertion we lled the posterior chamber of the eye with peruorodecaline up to the eyes equator. This enabled the protection of the retina during implant insertion and, in addition, the safe positioning of the electrodes onto the retinal surface. For implantation, the stimulator was guided through the tangential incision in the sulcus in front of the lens capsule. In doing so, we put the implants electrode array onto the boundary layer established by peruorodecaline and the intraocular rinsing uid (lactated Ringers solution). For the positioning of the electrodes onto the central retinal surface, we carefully replaced the peruorodecaline by Ringers solution. Stable positioning of the electrode array onto the retina surface was ensured by the restoring force of the polyimide cable that gently presses the electrode on the retina. The corneal incisions were closed with polyglactine sutures and depots of gentamycinsulfate and dexamethason were given under the conjunctiva. 3) In Vivo Testing: The in vivo testing of the epi-retinal stimulators was performed immediately after implantation and repeatedly after the animals recovery from implantation under anesthesia. Therefore, the cats were premedicated with atropine sulphate (0.04 mg/kg). Anesthesia was achieved by an

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intramuscular injection of a mixture of ketamine hydrochloride (Ketanest, 1015 mg/kg) and xylazine hydrochloride (Rompun, 1 mg/kg) and maintained by supplementary doses of ketamine hydrochloride (Ketanest, 15 mg/kg i.m. or 0.21 mg/kg i.v.). During anesthesia we controlled body temperature, ECG, and reexes. The implants were activated with infrared light irradiated from the optical driving units IR-LED positioned in front of the eye. The driving unit was controlled by a programmable wave-form generator. We used impulses of 100- and 200- s duration at different light intensity and distances between LED and eye. For the recording of the currents generated by the implanted retina stimulator (stimulation artifacts) and evoked neuronal responses, we placed a contact lens electrode onto the eye and positioned a stainless-steel electrode under the skin onto the bone above primary visual cortex at the occipital pole of the head. As a reference we used an electrode located at the rectal body temperature sensor or a tongue electrode. The electrodes were connected to differential ampliers. Stimulation waveforms and the amplied and bandpassed electrode signals (1 Hz10 kHz) were displayed on a digital oscilloscope and recorded at 50 kHz sampling rate with a PC-based data acquisition system (Multichannel Systems, Germany) for subsequent data analysis. In order to measure potential electrical interference of the electrode recordings induced by the high current impulses applied to the LED, we inserted an electrically nonconductive light barrier in between LED and eye. In addition, we tested the infrared sensitivity of the cats eyes by applying our stimulation and recording procedures to the nonimplanted eyes as control. III. RESULTS A. Stimulator Design and Fabrication Ten substrates for the retina stimulators were fabricated by means of micromachining. The electrode sites [Fig. 5(A)] had a very smooth surface. Optical inspection showed a uniform parylene C coating of the hybrid assembly of the photodiodes [Fig. 5(B)] with its high aspect ratio. The fast high-temperature silicone encapsulation procedure turned out to be inappropriate since all three implants encapsulated with this process showed severe malfunctions. The seven devices of the slow low-temperature process resulted in fully functional implants (Fig. 6). The PDMS Sylgard 184 exhibited no toxic effects in cytotoxicity testing. More than 96% of the cells were alive (Fig. 7). DNA-synthesis and mitochondria activity corresponded to the parameters of media control and negative reference of the cell culture. However, in the direct contact test, the polymers hydrophobic surface character resulted in lower adhesion of cells to the material, i.e., nearly 85% of the cells appeared in spherical shapes. B. Functional Tests and Implantation 1) Implant Performance: The in vitro measurement of light attenuation of the cats cornea and ringers solution as a substitute for intraocular uid revealed that initially assumed light transmission losses can be neglected. Actually we found, that due to less light reection loss the induced electrode currents were often larger for air/water/implant interface compared to the air/implant interface. We obtained the highest currents for

Fig. 7. L929-cells after 24 h in direct contact to Sylgard 184 (FDA + PI vital staining). More than 96% of the cells were alive (similar to a glass control). Nearly 85% of the cells appeared spheroidally in shape because of the hydrophobic surface of the silicone capsule.

Fig. 8. In vitro voltage response of an epi-retinal stimulator. The implant was immersed in Ringers solution and stimulated with infrared impulses (200 s, 1 mW/mm ). Two silver-silverchloride electrodes were positioned over stimulators electrodes at a distance of about 0.5 mm, respectively. The sharp voltage transients at stimulation light onsets are due to the electrodes capacities. They decrease for successive light impulses indicating electrode polarizations. Note the voltage reversals occurring immediately with light-off. They are due to the discharge of the electrode capacities, which is related to a reversal of the direction of the current.

the air/cornea/water/implant interface, which might be due to corneas light focusing properties. The uniform illumination of the photodiodes and a 90 angle of incidence of the infrared beam on the photodiodes delivered the best transmission results. Function testing of ten stimulators was performed after assembly and parylene C coating to verify their function. The visual and electrical function checks of the three high-temperature silicone coated implants revealed their defectiveness, which was due to detached contacts between photodiodes and platinum polyimide substrate. The low-temperature coating procedure delivered seven intact implants, i.e., 100% yield. The subsequent 48-h tests in Ringers solution during illumination with short infrared impulses revealed that all seven low-temperature silicone coated retina stimulators were functional. The activated implants show biphasic stimulation pulses after light activation (Fig. 8) due to capacitive discharge of the electrodes after the light activation. Different amplitudes resulted presumably from different on (i.e., light) and off (i.e., no light) resistive properties of the IR photodiodes or different electrode impedances.

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LED and implanted eye leading to no implant generated artifacts and no neuronal responses. IV. DISCUSSION AND CONCLUSION We designed and developed an optically powered single-channel retinal implant for epi-retinal stimulation of ganglion cells using micromachining techniques. This microsystem based implant with hybrid assembly of electronic components and polymer encapsulation has been the rst prototype being epi-retially implanted and electrically functional for up to three months. This prototype might serve as a simple test system to evaluate assembling and encapsulation approaches for more complex, high channel vision implants. Even though our pilot studies have been successful, a lot of work has to be done before such system can be transferred into human clinical trials. The stability of the assembling technology has to be improved in future implants. The use of conductive glue is quite common for SMD components. For higher integration densities and components with contacts that allow wire bonding processes, we intend to use the robust and reliable MicroFlex Interconnection (MFI) technique [47] that was developed on the basis of a modied stud ball bonding technique. The combination of gluing and the MFI technique already proved its reliability in short term retina implants [48] in animal models. The low-temperature curing of the silicone rubber resulted in a 100% yield while the high-temperature curing destroyed the hybrid assembly. The most probable failure mechanism might be the large thermal stress leading to broken contacts on the implant. The functionality of the implants with respect to optically induced stimulation current generation showed that the chosen polymer encapsulation using parylene C and silicone rubber is stable at least for some months. However, for clinical implants with a life time of some decades, accelerated life time testing of a sufcient number of devices still has to be done. Hermetic packaging of the electronic circuits on the chip size level is highly recommended to prevent system failure due degradation of the electronics in the body if polymer encapsulation is done after assembly. Material biocompatibility in general was good and the chronic material-tissue interaction does not harm the underlying retina [49] in chronic implantations. Mechanical restoring forces seem to be large enough to ensure proper electrode-tissue contact for electrical stimulation. However, this contact is quite sensitive to mechanical displacement. Retinal tacks were commonly used [48], [49] to x the implant on the retina, even though this technique is related to destruction of retinal tissue in the xation area. While this pilot study investigated the functionality of the implant and the electrode tissue contact with single channel stimulation and recording of electrical evoked potentials on the visual cortex, spatial selective activation of the visual cortex after retinal stimulation was proved with an multichannel implant based on the same substrate design and encapsulation technology in short term implantations [48] in another study. Unfortunately, the implant design of this, herein described, single-channel stimulation implant is not scalable without modications. In addition, we want to note that a simple direct generation of stimulation currents by photodiode conversion of light impulses is not sufcient for an adequate or more

Fig. 9. Implanted epi-retinal stimulator (10 min. postimplantation). The stimulator was inserted into the eye via a corneal incision. The electrodes were afxed onto the retinal surface by leverage of the platinum-polyimide cable connecting the stimulators photodiodes and electrodes.

Fig. 10. Averaged cortical response after stimulation of the retina by the implant (7 days postimplantation). For stimulation, we used a train of 10 short infrared light impulses (200 s impulse duration and 200 s interimpulse duration). The signal was recorded with an electrode placed onto the skull above primary visual cortex. The deections within 0 ms up to about 5 ms are the stimulation artifacts. The cortical response occurs about 20 ms poststimulation onset. However, the signals high-frequency noise could be reduced by adequate low-pass ltering.

2) Implantation and In Vivo Testing: Three retinal stimulators were implanted (Fig. 9) in a pilot study. The postoperative course of recovery showed that our implantation approach was sufcient to keep harm to a minimum. However, one implanted epi-retinal stimulator was not functioning postimplantation. After explantation of the implant we found that this malfunction was dedicated to the assembling. A loose contact between a photodiode and the contact pad on the polyimide substrate interrupted the electrical connection. The remaining two implants were tested three times over a period of three months. Both were able to induce stimulation artifacts, indicating the implants function. One implant was able to evoke weak neuronal responses (Fig. 10), whereas the other was not. The cortical response ocurred about 20 ms poststimulation (artifacts: 05 ms). The reason for these nonsuccessful stimulations in the second device was a dislocation of the electrode from to the retinal surface, potentially induced by movements of the stimulators IOL implanted into the eyes sulcus. Infrared stimulation of eyes without implants evoked no responses. This supports that the response measurements were unfeigned. This nding was also supported by the insertion of an electrically nonconductive light barrier in between stimulation

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physiological stimulation of retinal neurons. However, intelligent implants with active stimulation circuits, triggered by photodiode arrays, are required to solve this task irrespective of epi- or subretinal stimulation approaches. Finally, we want to note that this single-channel stimulator is suitable for basic testing of epi-retinal implant design and fabrication but not for vision restoration. Consequently, more sophisticated designs are required [15], [21], [22], [28], [31], [49]. To restore vision with an electronic device useful for object recognition and visuo-motor behavior in many in- and outdoor situations of daily life many stimulation channels ( 500) are needed [31], [50]. Thus, future high channel vision prostheses have to manage a large amount of stimulation data. Radiofrequency telemetry is capable to deliver enough energy to power up these implants but the carrier frequency determines the maximum data rate that can be transferred and thereby limits their complexity. A combination with optical transmission techniques, e.g., with IR photodiodes, might lead to powerful implant systems with high data rates. Worldwide, different concepts for vision prostheses are in competition in animal experiments and in rst human clinical trials [12], [15], [16], [20], [22], [51], [52]. The success of the different vision implants will be seen in the future. Until then, fundamental studies might help to nd highly stable substrate and electrode materials and reliable and robust assembling and encapsulation materials to deliver vision microimplants with life times, biocompatibility and functionalities that are comparable to cardiac pacemakers and cochlear implants. ACKNOWLEDGMENT The Authors to thank F. Bauerfeld, Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany, for the assistance in thin-lm technology and M. Grosch and W. Gerber, Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg, Marburg, Germany, for excellent technical help and assistance. The courtesy of R. Eckhorn, Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg, is greatly acknowledged. REFERENCES
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[31] E. Zrenner, Will retina implants restore vision?, Science, vol. 295, pp. 10221025, 2002. [32] E. Zrenner, A. Stett, W. Weiss, R. B. Aramant, E. Guenther, K. Kohler, K. D. Miliczek, M. J. Seiler, and H. Haemmerle, Can subretinal microphotodiodes successfully replace degenerated photoreceptors, Vision Res., vol. 39, pp. 25552567, 1999. [33] T. Stieglitz, H. Beutel, M. Schuettler, and J.-U. Meyer, Micromachined, polyimide-based devices for exible neural interfaces, Biomed. Microdevices, vol. 2, pp. 283294, 2000. [34] S. B. Brummer and M. J. Turner, Electrical stimulation of the nervous system: The principle of safe charge injection with noble metal electrodes, Bioelectrochem. Bioenerget., vol. 2, pp. 1325, 1975. [35] S. B. Brummer and M. J. Turner, Electrochemical considerations for safe electrical stimulation of the nervous system with platinum electrodes, IEEE Trans. Biomed. Eng., vol. BME-24, pp. 5963, 1977. [36] J. Noordegraaf, Conformal coating using parylene polymers, Med. Device Technol., vol. 8, pp. 1420, 1997. [37] G. E. Loeb, M. J. Bak, M. Salcman, and E. M. Schmidt, Parylene as a chronically stable reproducible microelectrode insulator, IEEE Trans. Biomed. Eng., vol. BME-24, pp. 121128, 1977. [38] T. G. Yuen, W. F. Agnew, and L. A. Bullara, Tissue response to potential neuroprosthetic material implanted subdurally, Biomaterials, vol. 8, pp. 138141, 1987. [39] M. F. Nichols, Flexible and insulative plasmalene wire coatings for biomedical applications, Biomed. Sci. Instrum., vol. 29, pp. 7786, 1993. [40] E. M. Schmidt, M. J. Bak, and P. Christensen, Laser exposure of parylene-C insulated microelectrodes, J. Neurosci. Meth., vol. 62, pp. 8992, 1995. [41] N. Iguchi, H. Kasanuki, N. Matsuda, M. Shoda, S. Onishi, and S. Hosoda, Contact sensitivity to polychloroparayxlene coated cardiac pacemakers, Pacing Clinic. Electrophysiol., vol. 20, pp. 372373, 1997. [42] W. F. Gorham, A new, general synthetic method for the preparation of linear poly-xylylenes, J. Polym. Sci., vol. A4, pp. 30273039, 1966. [43] J. M. Legeais and G. Renard, A second generation of articial cornea (Biokpro II, Biomaterials, vol. 19, pp. 15171522, 1998. [44] C. K. Jung, S. K. Chung, and N. H. Baek, Decentration and tilt: Silicone multifocal versus acrylic soft intraocular lenses, J. Cataract. Refract. Surg., vol. 26, pp. 582585, 2000. [45] J. C. McDonald and G. M. Whitesides, Poly(dimethylsiloxane) as a material for fabricating microuidic devices, Acc. Chem. Res., vol. 35, pp. 491499, 2002. [46] P. Walter, U. Schnakenberg, G. vom Bgel, P. Ruokonen, C. Krger, S. Dinslage, H. C. Ldtke, H. Richter, W. Mokwa, M. Diestelhorst, and G. K. Krieglstein, Development of a completely encapsulated intraocular pressure sensor, Ophthalmic Res., vol. 32, pp. 278284, 2000. [47] J.-U. Meyer, T. Stieglitz, O. Scholz, W. Haberer, and H. Beutel, High density interconnects and exible hybrid assemblies for active biomedical implants, IEEE Trans. Adv. Packag., vol. 24, no. 3, pp. 366374, Aug. 2001. [48] P. Walter, Z. F. Kisvrday, M. Grtz, N. Alteheld, G. Rssler, T. Stieglitz, and U. T. Eysel, Cortical activation with a completely implanted wireless retinal prosthesis, Inves. Ophthalmol. Vis. Sci., vol. 46, no. 5, pp. 17801785, 2005. [49] P. Walter, P. Szurman, M. Vobig, H. Berk, H.-C. Ldtke-Handjery, H. Richter, C. Mittermayer, K. Heimann, and B. Sellhaus, Successful long-term implantation of electrically inactive epi-retinal microelectrode arrays in rabbits, Retina, vol. 19, pp. 546552, 1999. [50] R. Eckhorn, M. Wilms, Th. Schanze, M. Eger, L. Hesse, U. T. Eysel, Z. F. Kisvrday, E. Zrenner, F. Gekeler, H. Schwahn, K. Shinoda, H. Sachs, and P. Walter, Visual resolution with retinal implants estimated from recordings in cat visual cortex, Vis. Res., vol. 46, pp. 26752690, 2006. [51] C. Veraart, M. C. Wanet-Defalque, B. Gerard, A. Vanlierde, and J. Delbeke, Pattern recognition with the optic nerve visual prosthesis, Artif. Organs, vol. 27, pp. 9961004, 2003. [52] H. G. Sachs, U. Bartz-Schmidt, U. Brunner, E. Zrenner, and V.-P. Gabel, Subretinal chronic active visual prostheses in blind patients: The transchoroidal surgical procedure, presented at the ARVO Conf. 3202/B570, Ft. Lauderdale, FL, 2006. Thomas Schanze was born in Kassel, Germany, in 1962. He received the Diplom-Physiker and Dr. rer. nat. degrees in physics from Philipps University Marburg, Marburg, Germany, in 1989 and 1995, respectively.

From 1987 to 2004 he was with the Applied Physics - NeuroPhysics Group, Department of Physics, Philipps University Marburg. From 1989 to 2004, he was Lecturer for electronics, physics, neurophysics, mathematics, and time series analysis at the Physics Department and the Academic Foreign ofce of Philipps University Marburg. From 1992 to 1994, he was also with Uwe Thomas Recording, Marburg, as a leading Electronics Developer. In 2005, he joined the Institute for Technology and Development of Medical Products at the Medical Faculty of RWTH Aachen University, Aachen, Germany. Since 2006, he is with CORRSYS 3D Sensors AG, Wetzlar, Germany, as a R&D project manager and works as self-employed consultant in the eld of retinal implants. His research interests include neurophysics, vision, neuronal prostheses, computational physics, time series analysis, diffractive optics and optical image processing. Dr. Schanze is member of the Society for Neuroscience (SfN), the German Society for Applied Optics (DGAO) and the German Commission for Electrical, Electronic & Information Technologies of DIN and VDE (IEC/DKE).

Lutz Hesse was born in Hannover, Germany, in 1960. He received the Dr. med. degree (summa cum laude) in medicine from the Medizinische Hochschule Hannover, in 1989. In 1992, he nished his residency in ophthalmology. From 19922002, he worked as Retinal Surgeon with the Department of Ophthalmology, Philipps University Marburg, Marburg, Germany. He qualied as a University Lecturer in intravitreal injections of tissue plasminogen activator at Philipps University Marburg, in 1998. Since 2002. He is Professor for eye surgery and since 2002 the head of the Department of Ophthalmology, SLK-Kliniken, Heilbronn, Germany.

Carsten Lau was born in Unna, Germany, in 1971. He received the Dipl.-Biol. degree with the special subject limnology from the Westfaelische WilhelmsUniversitaet, Muenster, Germany, in 1999. He received the Dr. rer. nat. degree in natural science from the RWTH Aachen University, Aachen, Germany, in 2005. After an advanced vocational training in project management biotechnology (19992000) he joined the Institute of Pathology (Biomaterials Group) in 2000 and the Institute of Technology and Development of Medical Products in 2004, at the University Hospital Aachen, Aachen, Germany. He is now with BASF AG, Ludwigshafen, Germany, working as Scientic Attendant in the student biotechnology and chemistry laboratories.

Nina Greve was born in Berlin in 1977 and studied physics at Philipps University Marburg, Marburg, Germany. She received the Diplom-Physiker degree from the Applied PhysicsNeuroPhysics Group, Department of Physics, Philipps University, in 2003. Since 2003, she is with the Department of Research and Development of Diesel Engines, Volkswagen AG, Wolfsburg, Germany

Werner Haberer was born in St. Ingbert, Germany, in 1964. Since 1997, he has been a Microsystem-Technician in the Packaging and Assembly Group, Fraunhofer Institute for Biomedical Engineering, St. Ingbert. He is specialist in design and wirebonding technologies of microsystem devices. In the past, he was involved in the development of new interconnection technologies for biomedical applications. Currently his work is focused on new approaches to integrate biosensors into microuidic devices.

Sascha Kammer was born in Germany, in 1970. He received the Electronic Technician degree from the Ford Company, Germany, in 1991. In 2001, He received the Graduate Engineer Diploma in microsystem technology from the University of Applied Science Kaiserslautern/Zweibruecken, Zweibruecken, Germany. Since 2002, he is a Graduate Engineer with the Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany. His expertise is in microsystems fabrication of exible electrodes. He is responsible for encapsulation processes and documentation management and works on the EU-Project Neurobotics and the NIH-Project Chronic Microelectrode Recording Arrays.

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Thomas Doerge was born in Germany, in 1970. In 1999, he received the Diploma degree in microsystem technology from the University of Applied Science Kaiserslautern/Zweibruecken, Zweibruecken, Germany. From 1999 to 2000, he worked as a R&D engineer at Tele Quarz GmbH & Co. KG, Hamburg, Germany. Since 2000, he is with the Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany. His expertise is on microsystems/fabrication of exible electrodes. He is responsible for the production and development of neural implants at the Fraunhofer-Institut fuer Biomedizinische Technik, St. Ingbert. Germany. He works on the EU-projects ROSANA, REBEC, Cyberhand and the German project IMEX.

Andreas Rentzos was born in Wetzlar, Germany, in 1976. He studied mathematics at University of Applied Sciences, Giessen-Friedberg, Germany. He received the degree training supervisor in physics from the Department of Physics, Philipps University Marburg, Marburg, Germany, in 2002. In 1998, he became a Neurophysics Laboratory Assistant with the Applied PhysicsNeuroPhysics Group, Department of Physics, Philipps University Marburg.

Thomas Stieglitz (M96) was born in Goslar, Germany, in 1965. He received the Dipl.-Ing. degree in electrical engineering with the specialty in biomedical engineering from the University of Technology, Karlsruhe, Germany, in 1993. He received the Dr.-Ing. degree (summa cum laude) in electrical engineering from the University of Saarland, Germany, in 1998. In 1993, he joined the Fraunhofer-Institute for Biomedical Engineering, St. Ingbert (IBMT), Germany. He qualied as a University Lecturer on approaches for long-term stability of neural prostheses and biohybrid systems at the Saarland University, Saarbr|cken, Germany, in 2002 and established the Neural Prosthesis Group and IBMT. Since October 2004, he is a full Professor of Biomedical Microtechnology with the Institute for Microsystem Technology (IMTEK), University of Freiburg, Germany. His research interests include biomedical microdevices, neural prostheses, neuromonitoring, functional electrical stimulation, and biohybrid systems. Prof. Stieglitz received the science award of the Saarland state for his work on exible, neural prostheses in 2000. He is member of the IEEE-EMBS, the International Society for Functional Electrical Stimulation (IFESS), the German Engineering Society (VDI), and the German Society for Biomedical Engineering (DGBMT) within the German Electrotechnical Society (VDE) where he holds the chair of the Neural Prostheses Section.