Micro-Fabrication of Components for a High-Density Sub-Retinal Visual Prosthesis.

We present a retrospective of unique micro-fabrication problems and solutions that were encountered through over 10 years of retinal prosthesis product development, first for the Boston Retinal Implant Project initiated at the Massachusetts Institute of Technology and at Harvard Medical School's teaching hospital, the Massachusetts Eye and Ear-and later at the startup company Bionic Eye Technologies, by some of the same personnel. These efforts culminated in the fabrication and assembly of 256+ channel visual prosthesis devices having flexible multi-electrode arrays that were successfully implanted sub-retinally in mini-pig animal models as part of our pre-clinical testing program. We report on the processing of the flexible multi-layered, planar and penetrating high-density electrode arrays, surgical tools for sub-retinal implantation, and other parts such as coil supports that facilitated the implantation of the peri-ocular device components. We begin with an overview of the implantable portion of our visual prosthesis system design, and describe in detail the micro-fabrication methods for creating the parts of our system that were assembled outside of our hermetically-sealed electronics package. We also note the unique surgical challenges that sub-retinal implantation of our micro-fabricated components presented, and how some of those issues were addressed through design, materials selection, and fabrication approaches.

Implantation and Extraction of Penetrating Electrode Arrays in Minipig Retinas.

Purpose: This work was motivated by the goals of demonstrating methods to fabricate and implant large numbers of penetrating arrays into the retina and the feasibility of extraction. Methods: Arrays of inactive, three-dimensional (3D) SU-8 structures were microfabricated onto 13-µm polyimide substrates. Standard vitreoretinal surgical techniques were used with an ab externo approach for subretinal implantation of arrays in 12 mini-pigs. In the first three surgeries, different post-geometries were explored, while a preferred design (128-µm tall, 30-µm diameter, 200-µm spacing) was used for the remaining nine implantations. Two arrays were extracted. Funduscopy, optical coherence tomography (OCT) and immunohistochemistry of the retinae were performed. The unoperated eyes and tissue far from implantation served as controls. A thirteenth pig was implanted with a planar array. Results: Ten implant surgeries had no significant complication, and two arrays were successfully extracted. One retinal tear occurred after implantation due to too long posts in an early surgery. In "successful" cases, OCT showed close apposition of the arrays to the retina and integration of the posts, the tops of which were positioned at the junction of the inner plexiform and ganglion cells, without significant gliosis. Conclusions: These results provide a proof-of-concept that relatively large numbers of 3D posts can be implanted into, and extracted from, the retina of mini-pigs. Our surgical numbers were relatively small, especially for the extractions, and our conclusions must be viewed with that limitation. Our methods are applicable for human surgeries. Translational Relevance: This study provides results of implantation and extraction of relatively large numbers of 3D posts from the retina of minipig eyes. If similar technology were used in humans, a 3D array of this type should lower perceptual thresholds, provide safer long-term stimulation, and perhaps provide better perceptual outcomes.

ASIC design and data communications for the Boston retinal prosthesis.

We report on the design and testing of a custom application-specific integrated circuit (ASIC) that has been developed as a key component of the Boston retinal prosthesis. This device has been designed for patients who are blind due to age-related macular degeneration or retinitis pigmentosa. Key safety and communication features of the low-power ASIC are described, as are the highly configurable neural stimulation current waveforms that are delivered to its greater than 256 output electrodes. The ASIC was created using an 0.18 micron Si fabrication process utilizing standard 1.8 volt CMOS transistors as well as 20 volt lightly doped drain FETs. The communication system receives frequency-shift keyed inputs at 6.78 MHz from an implanted secondary coil, and transmits data back to the control unit through a lower-bandwidth channel that employs load-shift keying. The design's safety is ensured by on-board electrode voltage monitoring, stimulus charge limits, error checking of data transmitted to the implant, and comprehensive self-test and performance monitoring features. Each stimulus cycle is initiated by a transmitted word with a full 32-bit error check code. Taken together, these features allow researchers to safely and wirelessly tailor retinal stimulation and vision recovery for each patient.

Communication and Control System for a 15-Channel Hermetic Retinal Prosthesis.

A small, hermetic, wirelessy-controlled retinal prosthesis has been developed for pre-clinical studies in Yucatan minipigs. The device was attached conformally to the outside of the eye in the socket and received both power and data wirelessly from external sources. Based on the received image data, the prosthesis drove a subretinal thin-film polyimide array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing a 15-channel stimulator and receiver chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by power amplifiers. Power was delivered by a 125 KHz carrier, and data were delivered by amplitude shift keying of a 15.5 MHz carrier at 100 Kbps. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. The final assembly was tested in vitro in physiological saline and in vivo in two minipigs for up to five and a half months by measuring stimulus artifacts generated by the implant's current drivers.

A hermetic wireless subretinal neurostimulator for vision prostheses.

A miniaturized, hermetically encased, wirelessly operated retinal prosthesis has been developed for preclinical studies in the Yucatan minipig, and includes several design improvements over our previously reported device. The prosthesis attaches conformally to the outside of the eye and electrically drives a microfabricated thin-film polyimide array of sputtered iridium oxide film electrodes. This array is implanted into the subretinal space using a customized ab externo surgical technique. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete circuit components. Feedthroughs in the case connect the stimulator chip to secondary power and data receiving coils on the eye and to the electrode array under the retina. Long-term in vitro pulse testing of the electrodes projected a lifetime consistent with typical devices in industry. The final assembly was tested in vitro to verify wireless operation of the system in physiological saline using a custom RF transmitter and primary coils. Stimulation pulse strength, duration, and frequency were programmed wirelessly from a Peripheral Component Interconnect eXtensions for Instrumentation (PXI) computer. Operation of the retinal implant has been verified in two pigs for up to five and a half months by detecting stimulus artifacts generated by the implanted device.

Overview of the boston retinal prosthesis: challenges and opportunities to restore useful vision to the blind.

A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers.

Development of the boston retinal prosthesis.

A small, hermetic, wirelessly-controlled retinal prosthesis was developed for pre-clinical studies in Yucatan mini-pigs. The device was implanted on the outside of the eye in the orbit, and it received both power and data wirelessly from external sources. The prosthesis drove a sub-retinal thin-film array of sputtered iridium oxide stimulating electrodes. The implanted device included a hermetic titanium case containing the 16-channel stimulator chip and discrete circuit components. Feedthroughs in the hermetic case connected the chip to secondary power- and data-receiving coils, which coupled to corresponding external power and data coils driven by a power amplifier. Power was delivered by a 500 KHz carrier, and data were delivered by frequency shift keying. Stimulation pulse strength, duration and frequency were programmed wirelessly from an external computer system. Through an 'outbound' telemetry channel, electrode impedances were monitored by an on-board analog to digital converter that sampled the output voltage waveforms. The final assembly was tested in vitro in physiological saline and in vivo in two mini-pigs for up to three months by measuring stimulus artifacts generated by the implant's current drivers.

Contribution of oxygen reduction to charge injection on platinum and sputtered iridium oxide neural stimulation electrodes.

The extent to which oxygen reduction occurs on sputtered iridium oxide (SIROF) and platinum neural stimulation electrodes was quantified by cyclic voltammetry and voltage-transient measurements in oxygen-saturated physiological saline. Oxygen reduction was the dominant charge-admittance reaction on platinum electrodes during slow-sweep-rate cyclic voltammetry, contributing approximately 12 mC/cm(2) (88% of total charge) to overall cathodal charge capacity. For a 300-nm-thick SIROF electrode, oxygen reduction was a minor reaction contributing 1.3 mC/cm(2), approximately 3% of total charge. During current pulsing with platinum electrodes, oxygen reduction was observed at a level of 7% of the total injected charge. There was no indication of oxygen reduction on pulsed SIROF electrodes. A sweep-rate-dependent contribution of oxygen reduction was observed on penetrating SIROF microelectrodes (nominal surface area 2000 microm(2)) and is interpreted in terms of rate-limited diffusion of oxygen in electrolyte that penetrates the junction between the insulation and electrode shaft. For typical neural stimulation pulses, no oxygen reduction could be observed on penetrating SIROF microelectrodes. Based on the in vivo concentration of dissolved oxygen, it is estimated that oxygen reduction on platinum microelectrodes will contribute less than 0.5% of the total injected charge and considerably less on SIROF electrodes.

Realization of a 15-channel, hermetically-encased wireless subretinal prosthesis for the blind.

A miniaturized, hermetically-encased, wirelessly-operated retinal prosthesis has been developed for implantation and pre-clinical studies in Yucatan mini-pig animal models. The prosthesis conforms to the eye and drives a microfabricated polyimide stimulating electrode array with sputtered iridium oxide electrodes. This array is implanted in the subretinal space using a specially-designed ab externo surgical technique that affixes the bulk of the prosthesis to the surface of the sclera. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete power supply components. Feedthroughs from the case connect to secondary power- and data-receiving coils. In addition, long-term in vitro pulse testing was performed on the electrodes to ensure their stability for the long lifetime of the hermetic case. The final assembly was tested in vitro to verify wireless operation of the system in biological saline using a custom RF transmitter circuit and primary coils. Stimulation pulse strength, duration and frequency were programmed wirelessly using a custom graphical user interface. Operation of the retinal implant has been verified in vivo in one pig for more than three months by measuring stimulus artifacts on the eye surface using a contact lens electrode.

Development and implantation of a minimally invasive wireless subretinal neurostimulator.

A wirelessly operated, minimally invasive retinal prosthesis was developed for preclinical chronic implantation studies in Yucatan minipig models. The implant conforms to the outer wall of the eye and drives a microfabricated polyimide stimulating electrode array with sputtered iridium oxide electrodes. This array is implanted in the subretinal space using a specially designed ab externo surgical technique that fixes the bulk of the prosthesis to the outer surface of the sclera. The implanted device is fabricated on a host polyimide flexible circuit. It consists of a 15-channel stimulator chip, secondary power and data receiving coils, and discrete power supply components. The completed device is encapsulated in poly(dimethylsiloxane) except for the reference/counter electrode and the thin electrode array. In vitro testing was performed to verify the performance of the system in biological saline using a custom RF transmitter circuit and primary coils. Stimulation patterns as well as pulse strength, duration, and frequency were programmed wirelessly using custom software and a graphical user interface. Wireless operation of the retinal implant has been verified both in vitro and in vivo in three pigs for more than seven months, the latter by measuring stimulus artifacts on the eye surface using contact lens electrodes.

Sputtered iridium oxide films for neural stimulation electrodes.

Sputtered iridium oxide films (SIROFs) deposited by DC reactive sputtering from an iridium metal target have been characterized in vitro for their potential as neural recording and stimulation electrodes. SIROFs were deposited over gold metallization on flexible multielectrode arrays fabricated on thin (15 microm) polyimide substrates. SIROF thickness and electrode areas of 200-1300 nm and 1960-125,600 microm(2), respectively, were investigated. The charge-injection capacities of the SIROFs were evaluated in an inorganic interstitial fluid model in response to charge-balanced, cathodal-first current pulses. Charge injection capacities were measured as a function of cathodal pulse width (0.2-1 ms) and potential bias in the interpulse period (0.0 to 0.7 V vs. Ag|AgCl). Depending on the pulse parameters and electrode area, charge-injection capacities ranged from 1-9 mC/cm(2), comparable with activated iridium oxide films (AIROFs) pulsed under similar conditions. Other parameters relevant to the use of SIROF on nerve electrodes, including the thickness dependence of impedance (0.05-10(5) Hz) and the current necessary to maintain a bias in the interpulse region were also determined.