Testing of Newly Developed Wide-Field Dual-Array Suprachoroidal-Transretinal Stimulation Prosthesis in Dogs.

Purpose: This study was conducted to investigate the feasibility of a newly developed wide-field dual-array suprachoroidal-transretinal stimulation (STS) prosthesis in dogs and to examine its biocompatibility and stability over a 4-month period. Methods: Three types of STS dual arrays were designed and tested. The STS dual-array was implanted into a scleral pocket of the left eye of six healthy beagle dogs. Ophthalmic examinations, fundus photography, fluorescein angiography (FA), electroretinography (ERG), and functional testing of this system were conducted postoperatively. The dogs were euthanatized at the end of the experiment, and their eyes were enucleated and histologically examined. Results: All prostheses were successfully implanted without complications, and no serious adverse event occurred during the postoperative period. Fundus photographs and FA showed no serious damage in the retina surrounding the arrays. The ERGs recorded from the implanted eyes showed no significant differences from those from control eyes. Histological evaluations demonstrated good preservation of the retina over the array. However, system failure occurred in 50% of the dogs owing to dog-specific habits. Conclusions: Implantation of this prosthesis system in dogs is feasible and can be performed without significant damage to the eye. The biocompatibility and stability of the array were good during the observation period, but the low durability of the system against dogs (not humans) is an issue to be resolved in the future. Translational Relevance: This study suggests that this wide-field dual-array prosthesis might widen the visual field and might be useful for patients with retinitis pigmentosa.

One-Year Outcome of 49-Channel Suprachoroidal-Transretinal Stimulation Prosthesis in Patients With Advanced Retinitis Pigmentosa.

PURPOSE: To determine the feasibility of a 49-channel suprachoroidal-transretinal stimulation (STS) retinal prosthesis that was implanted for 1 year. METHODS: Three patients with advanced retinitis pigmentosa (RP) and with less than or equal to hand motion (HM) vision were studied. A 49-channel STS system was implanted in a scleral pocket, and the stability of the prosthesis, adverse events, and its efficacy were investigated. RESULTS: The electrode array was implanted in a scleral pocket located under the parafoveal area through a scleral incision at 14 mm in patient (Pt) 1, 16 mm in Pt 2, and 18 mm in Pt 3 from the sclerocorneal limbus. No complications occurred during surgery in all cases. During the follow-up period, iridocyclitis developed in Pt 2 and Pt 3, which was successfully treated with topical medications. The implanted devices continued functioning and elicited phosphenes in all cases. The results of localization tests (P < 0.05) and table tests (P < 0.05) were significantly better with the prosthesis turned on than turned off in Pt 3. The deviations of the walking tests were smaller with the prosthesis turned on than off in Pt 2 and Pt 3 at multiple times after the implantation. CONCLUSIONS: The 49-channel STS retinal prosthesis was able to elicit phosphenes in all patients with advanced RP for the entire 1-year experimental period without major complications. Better results on visual tasks were found in the eyes in which the electrode array was implanted closer to the fovea centralis.

Safety assessment of semichronic suprachoroidal electrical stimulation to rabbit retina.

Confirming safety of chronic electrical stimulation is of prime importance for the practical use of visual prostheses. Here we applied electrical stimulation to eyes of freely-moving rabbits eight hour per day for one month. Examinations including fundus photo, optical coherence tomography (OCT), electrically evoked potentials (EEPs) were performed before and after one-month stimulation to detect tissue damage. No adverse effect caused by electrical stimulation was observed in electrophysiological and histological evaluation. We also found that there was no sign of morphological and electrochemical degradation of stimulating electrodes.

Implantation of a newly developed direct optic nerve electrode device for artificial vision in rabbits.

The purpose of this study was to investigate the surgical procedures involved in the implantation of a newly developed direct optic nerve electrode device for inducing artificial vision. The electrode device comprised seven wire stimulation electrodes and a return electrode (diameter 50 µm), one manipulation rod (diameter 100 µm), and a cylindrical silicone board (diameter 2.0 mm). The stimulation electrodes and the manipulation rod protruded through the board to allow implantation of the electrode tips into the optic disc of the rabbit eye. The surgical procedures required to insert the device into the vitreous cavity and implant the device into the optic disc were evaluated. When the electrodes were stimulated, electrically evoked potentials (EEPs) were recorded at the visual cortex. The electrode device was inserted into the vitreous cavity with no damage using a trocar through a scleral incision. The device was easily manipulated using vitreoretinal forceps in the vitreous cavity, and the electrode tips were implanted into the optic disc in a single insertion after vitrectomy. When electrical stimulation was applied, EEPs were recorded from all electrode pairs. The newly developed electrode device was inserted into the eye and implanted into the optic nerve disc smoothly and safely, suggesting that these surgical procedures are useful for our artificial vision system.

Chronic implantation of newly developed suprachoroidal-transretinal stimulation prosthesis in dogs.

PURPOSE: To investigate the feasibility of implanting a newly developed suprachoroidal-transretinal stimulation (STS) prosthesis in dogs and to determine its biocompatibility and stability over a 3-month period. METHODS: The STS prosthesis system consisted of an array of 49 electrodes (nine were active), an intravitreal return electrode, and an extraocular microstimulator. The 49-electrode array was implanted into a scleral pocket of each of three healthy beagle dogs. Color fundus photography, fluorescein angiography, electroretinography, and functional testing of the STS system were performed postoperatively. The dogs were euthanatized 3 months after the implantation, and the retinas were evaluated histologically. RESULTS: All the prostheses were successfully implanted without complications, and no serious complications occurred during the 3-month postoperative period. The fixation of the implant was stable throughout the experimental period. Fluorescein angiography showed that the entire retina, including the area on the electrode array, remained well perfused without intraocular inflammation. Electroretinograms recorded from the eyes with the prosthesis did not differ significantly from those recorded from control eyes. Functional testing of the STS system showed that this system performed well for the 3-month experimental period. Histologic evaluations showed good preservation of the retina over the electrode array. CONCLUSIONS: Implantation of a newly developed STS retinal prosthesis into a scleral pocket of beagle dogs is surgically feasible and can be performed without significant damage to the retina or the animal. The biocompatibility and stability of the system were good for the 3-month observation period.

Biocompatibility and durability of Teflon-coated platinum-iridium wires implanted in the vitreous cavity.

Teflon-coated platinum-iridium wires are placed in the vitreous as electrodes in artificial vision systems. The purpose of this study was to determine whether these wires have toxicity in the vitreous cavity, and to examine the durability of their coating when grasped by forceps. Rabbits were implanted with platinum-iridium wires that were 50 µm in diameter and coated with Teflon to a total diameter of 68 or 100 µm. To examine the biocompatibility, electroretinograms (ERGs) and fluorescein angiography (FA) were performed before and 1 week, 1, 3, and 6 months after the implantation of the electrode. After 6 months, the eyes were histologically examined with light microscopy. To check the durability, the surface of a coated wire was examined with scanning electron microscopy after grasping with different types of forceps. At all times after the implantation the amplitudes and implicit times of the ERGs recorded were not significantly different from those recorded before the implantation (P > 0.05). FA showed no notable change during the follow-up periods. Histological studies showed that the retinas were intact after 6 months of implantation. There was no damage to the Teflon-coated wire after grasping the wire with forceps with silicon-coated tips, while surface damage of the Teflon that did not extend to the platinum-iridium wire was found when grasped by vitreoretinal forceps. We conclude that Teflon-coated platinum-iridium wire is highly biocompatible in the vitreous for at least 6 months. Wires should be handled with vitreoretinal forceps with silicone-coated tips in order to avoid causing damage during wire manipulation.

Testing of semichronically implanted retinal prosthesis by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa.

PURPOSE: To examine the safety and effectiveness of a retinal prosthesis that is implanted semichronically in two patients with advanced retinitis pigmentosa (RP). METHODS: Two eyes of two patients with advanced RP had a retinal prosthesis implanted in a sclera pocket of one eye. The visual acuity of both eyes before the implantation was bare light perception. Phosphenes were elicited by suprachoroidal-transretinal stimulation (STS). The internal devices of the STS were implanted under the skin on the temporal side of the head, and the 49 electrode-array was implanted in the scleral pocket of one eye. Biphasic electrical pulses (duration, 0.5 ms; frequency, 20 Hz) were delivered through nine active electrodes. The threshold current was determined by currents ≤1 mA. Behavioral tasks were used to determine the functioning of the prosthesis. RESULTS: The surgery was completed without a retinal detachment and retinal/vitreous hemorrhage. The implanted STS system remained functional for the 4-week test period. Phosphenes were elicited by currents delivered through six electrodes in Patient 1 and through four electrodes in Patient 2. The success of discriminating two bars was better than the chance level in both patients. In Patient 2, the success of a grasping task was better than the chance level, and the success rate of identifying a white bar on a touch panel increased with repeated testing. CONCLUSIONS: Semichronic implantation of a microelectrode-STS system showed that it was safe and remained functional for at least 4 weeks in two patients with advanced RP. (www.umin.ac.jp/ctr number, R000002690.).

Artificial vision by direct optic nerve electrode (AV-DONE) implantation in a blind patient with retinitis pigmentosa.

The purpose of this study was to evaluate the efficacy and safety of artificial vision by using a direct optic nerve electrode (AV-DONE) in a blind patient with retinitis pigmentosa (RP). This device, comprising three wire electrodes (0.05 mm in diameter), was implanted into the optic disc of a patient with RP with no light perception vision and the device was left implanted. Six months later, visual sensations were elicited by electrical stimulation through each electrode and the thresholds for the phosphene perception elicited by pulses of 0.25-ms duration/phase and a pulse frequency of 320 Hz were 30, 5, and 70 microA for each electrode. The phosphenes, which ranged in size from that of a match head to an apple, were round, oval, or linear, primarily yellow, and focally distributed. The area of the phosphenes changed when the electrical stimulation was supplied from different electrodes. No complications arose during the follow-up period. Localized visual sensations were produced in a blind patient with advanced RP, suggesting that our system could lead to the development of a useful visual prosthesis system.

Evaluation of phosphenes elicited by extraocular stimulation in normals and by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa.

BACKGROUND: To determine the efficient parameters to evoke electrical phosphenes is essential for the development of a retinal prosthesis. We studied the efficient parameters in normal subjects and investigated if suprachoroidal-transretinal stimulation (STS) is effective in patients with advanced retinitis pigmentosa (RP) using these efficient parameters. METHODS: The amplitude of pupillary reflex (PR) evoked by transcorneal electrical stimulation (TcES) was determined at different frequencies in eight normal subjects. The relationship between localized phosphenes elicited by transscleral electrical stimulation (TsES) and the pulse parameters was also examined in six normal subjects. The phosphenes evoked by STS were examined in two patients with RP with bare light perception. Biphasic pulses (cathodic first, duration: 0.5 or 1.0 ms, frequency: 20 Hz) were applied through selected channel(s). The size and shape of the phosphenes perceived by the patients were recorded. RESULTS: The maximum PR was evoked by TcES with a frequency of 20 Hz. The brightest phosphene was elicited by TsES with a pulse train of more than 10 pulses, duration of 0.5-1.0 ms and a frequency of 20 to 50 Hz. In RP patients, localized phosphenes were elicited with a current of 0.3-0.5 mA (0.5 ms) in patient 1 and 0.4 mA (1.0 ms) in patient 2. Two isolated or dumbbell-shaped phosphenes were perceived when the stimulus was delivered through two adjacent channels. CONCLUSION: Biphasic pulse trains (> or =10 pulses) with a duration of 0.5-1.0 ms and a frequency of 20-50 Hz were efficient for evoking phosphenes by localized extraocular stimulation in normal subjects. With these parameters, STS is a feasible method to use with a retinal prosthesis even in advanced stages of RPs.

Threshold suprachoroidal-transretinal stimulation current resulting in retinal damage in rabbits.

The purpose of this study is to determine the threshold suprachoroidal-transretinal stimulation (STS) current that results in retinal damage in rabbits. Biphasic STS pulses (anodic first, frequency 20 Hz) were used to stimulate the retina of pigmented rabbits (n = 18) continuously for 1 h using a 100 microm diameter platinum wire electrode. The STS current that induced retinal damage after 1 h was determined by ophthalmoscopy or by fluorescein angiography (FA) independently. The effect of the pulse duration on the threshold current was investigated. Histological studies were performed after electrical stimulation experiments. The threshold for a safe current to the retina was 0.6 mA for a duration of 0.5 ms. The threshold for a safe charge increased approximately linearly with an increase of stimulus duration but the threshold for a safe current decreased logarithmically with an increase of duration. The threshold for a safe electrical energy remained almost constant for all durations. Histological examination showed severe retinal damage when the current exceeded the threshold, with more damage in the inner layers compared with the outer layers of the retina. The threshold for the safe current was higher than that reported for direct stimulation of neural tissues, suggesting that the STS method was safe and able to be used with a retinal prosthesis. Because the threshold for the safe charge was lower with shorter pulse durations, care should be taken using pulses of short durations.

The development of a multichannel electrode array for retinal prostheses.

The development of a multielectrode array is the key issue for retinal prostheses. We developed a 10 x 10 platinum electrode array that consists of an 8-microm polyimide layer sandwiched between 5-microm polymonochloro-para-xylylene (parylene-C) layers. Each electrode was formed as a 30-microm-high bump by Pt/Au double-layer electroplating. We estimated the charge delivery capability (CDC) of the electrode by measuring the CDCs of two-channel electrode arrays. The dimensions of each electrode of the two-channel array were the same as those of each electrode formed on the 10 x 10 array. The results suggest that for cathodic-first (CF) pulses, 80% of electrodes surpassed our development target of 318 microC/cm2, which corresponds to the charge density of pulses of 500 micros duration and 200 microA amplitude for a 200-microm-diameter planar electrode.

Neuroprotective effect of PACAP against kainic acid-induced neurotoxicity in rat retina.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is well known to protect delayed neuronal cell death in the brain of rodents. In order to investigate the neuroprotective action of PACAP in the retina, we examined the effects of PACAP on kainic acid (KA)-induced neurotoxicity in the rat retina. Many ganglion cells in the retina died after KA injection in the control group and PACAP treatment significantly promoted cell survival. These findings strongly suggest that PACAP plays very important roles in preventing cell death in the retina.