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Unlabelled: Degenerative diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) primarily affect the photoreceptors, ultimately resulting in significant loss of vision. Retinal prostheses aim to elicit neural activity in the remaining retinal cells by detecting and converting light into electrical stimuli that can then be delivered to the retina. The concept of visual prostheses has existed for more than 50 years and recent progress shows promise, yet much remains to be understood about how the visual system will respond to artificial input after years of blindness that necessitate this type of prosthesis. This review focuses on 3 major areas: the histopathologic features of human retina affected by AMD and RP, current results from clinical trials, and challenges to overcome for continued improvement of retinal prostheses., Financial Disclosure(s): Proprietary or commercial disclosures may be found after the references., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Epiretinal prostheses used to treat degenerative retina diseases apply stimulus via an electrode array fixed to the ganglion cell side of the retina. Mechanical pressure applied by these arrays to the retina, both during initial insertion and throughout chronic use, could cause sufficient retinal damage to reduce the device's effectiveness. In order to understand and minimize potential mechanical damage, we have used finite element analysis to model mechanical interactions between an electrode array and the retina in both acute and chronic loading configurations. Modeling indicates that an acute tacking force distributes stress primarily underneath the tack site and heel edge of the array, while more moderate chronic stresses are distributed more evenly underneath the array. Retinal damage in a canine model chronically implanted with a similar array occurred in correlating locations, and model predictions correlate well with benchtop eyewall compression tests. This model provides retinal prosthesis researchers with a tool to optimize the mechanical electrode array design, but the techniques used here represent a unique effort to combine a modifiable device and soft biological tissues in the same model and those techniques could be extended to other devices that come into mechanical contact with soft neural tissues.

The purpose of this paper is to present a wide field electrode array that may increase the field of vision in patients implanted with a retinal prosthesis. Mobility is often impaired in patients with low vision, particularly in those with peripheral visual loss. Studies on low vision patients as well as simulation studies on normally sighted individuals have indicated a strong correlation between the visual field and mobility. In addition, it has been shown that an increased visual field is associated with a significant improvement in visual acuity and object discrimination. Current electrode arrays implanted in animals or human vary in size; however, the retinal area covered by the electrodes has a maximum projected visual field of about 10 degrees. We have designed wide field electrode arrays that could potentially provide a visual field of 34 degrees, which may significantly improve the mobility. Tests performed on a mechanical eye model showed that it was possible to fix 10 mm wide flexible polyimide dummy electrode arrays onto the retina using a single retinal tack. They also showed that the arrays could conform to the inner curvature of the eye. Surgeries on an enucleated porcine eye model demonstrated feasibility of implantation of 10 mm wide arrays through a 5 mm eye wall incision.

Retinal prosthesis recipients may still have degraded vision, such that additional information about their surroundings may help them perform certain tasks. We evaluate a system that provides cues that point towards important objects. Using a simulated vision grid of 6 x 10 pixels, subjects perform object location and mobility tasks with and without the help of cues. The velocity of head movement in degrees per second and the time taken by subjects to finish the tasks are recorded. Results show that a cueing system may help to reduce and organize the head movements of the subjects, whereas a time benefit exists in object location but not in mobility tasks.

Simulations of artificial vision suggest that 1000 electrodes may be required to restore vision to individuals with diseases of the outer retina. In order to achieve such an implant, new technology is needed, since the state-of-the-art implantable neural stimulator has at most 22 contacts with neural tissue. A critical component of this system is the multi-channel, stimulating electrode array. This array must meet very challenging, competing requirements for manufacturing, integration, surgical handling, and biocompatibility. Our lab has evaluated 3 polymers as retinal prosthesis substrates: polyimide, parylene, and silicone.

Purpose: The goal was to evaluate how perceptual thresholds are related to electrode impedance, electrode size, the distance of electrodes from the retinal surface, and retinal thickness in six subjects blind as a result of retinitis pigmentosa, who received epiretinal prostheses implanted monocularly as part of a U.S. Food and Drug Administration (FDA)-approved clinical trial., Methods: The implant consisted of an extraocular unit containing electronics for wireless data, power recovery, and generation of stimulus current, and an intraocular unit containing 16 platinum stimulating electrodes (260- or 520-microm diameter) arranged in a 4 x 4 pattern. The electrode array was held onto the retina by a small tack. Stimulation was controlled by a computer-based external system that allowed independent control over each electrode. Perceptual thresholds (the current necessary to see a percept on 79% of trials) and impedance were measured for each electrode on a biweekly basis. The distance of electrodes from the retinal surface and retinal thickness were measured by optical coherence tomography on a less regular basis., Results: Stimulation thresholds for detecting phosphenes correlated with the distance of the electrodes from the retinal surface, but not with electrode size, electrode impedance, or retinal thickness., Conclusions: Maintaining close proximity between the electrode array and the retinal surface is critical in developing a successful retinal implant. With the development of chronic electrode arrays that are stable and flush on the retinal surface, it is likely that the influence of other factors such as electrode size, retinal degeneration, and subject age will become more apparent. (ClinicalTrials.gov number, NCT00279500.).

Epiretinal prostheses are being developed to bypass a degenerated photoreceptor layer and excite surviving ganglion and inner retinal cells. We used custom microfabricated multielectrode arrays with 200-microm-diameter stimulating electrodes and 10-microm-diameter recording electrodes to stimulate and record neural responses in isolated tiger salamander retina. Pharmacological agents were used to isolate direct excitation of ganglion cells from excitation of other inner retinal cells. Strength-duration data suggest that, if amplitude will be used for the coding of brightness or gray level in retinal prostheses, shorter pulses (200 micros) will allow for a smaller region in the area of the electrode to be excited over a larger dynamic range compared with longer pulses (1 ms). Both electrophysiological results and electrostatic finite-element modeling show that electrode-electrode interactions can lead to increased thresholds for sites half way between simultaneously stimulated electrodes (29.4 +/- 6.6 nC) compared with monopolar stimulation (13.3 +/- 1.7 nC, p < 0.02). Presynaptic stimulation of the same ganglion cell with both 200- and 10-microm-diameter electrodes yielded threshold charge densities of 12 +/- 6 and 7.66 +/- 1.30 nC/cm2, respectively, while the required charge was 12.5 +/- 6.2 and 19 +/- 3.3 nC.

Purpose: To assess visual task performance in three blind subjects implanted with epiretinal prostheses., Design: Prospective, investigational device exemption trial., Methods: Three subjects with light perception or no light perception vision were enrolled at a single center. All subjects had retinitis pigmentosa (RP). Main inclusion criteria: light perception or worse vision in one eye and some visual experience as an adult before blindness. Main exclusion criteria included other ophthalmic problems. A prototype retinal prosthesis was implanted in the eye with worse light sensitivity. The prosthesis had 4 x 4 array of platinum electrodes tacked to the epiretinal surface. The prosthesis was wirelessly controlled by a computer or by a head-worn video camera. Visual function testing was performed in single masked or double masked fashion. Scores from the visual task were compared to chance to determine statistical significance., Results: The subjects performed significantly better than chance in 83% of the tests. Using the video camera, subjects scored as follows on simple visual tasks: locate and count objects (77% to 100%), differentiate three objects (63% to 73%), determine the orientation of a capital L (50% to 77%), and differentiate four directions of a moving object (40% to 90%). A subset of tests compared camera settings using multipixels vs single pixels. Using multipixel settings, subjects performed better (17%) or equivalent (83%) in accuracy and better (25%) or equivalent (75%) in reaction time., Conclusions: Three RP implant subjects used epiretinal prostheses to perform simple visual tasks. Multipixel settings proved slightly more effective than single pixel settings.

A critical element of a retinal prosthesis is the stimulating electrode array, which is placed in close proximity to the retina. It is via this retinal-electrode interface that a retinal prosthesis electrically stimulates nerve cells to produce the perception of light. The impedance load seen by the current driver consists of the tissue resistance and the complex electrode impedance. The results in this paper show that the tissue resistance of the retina is significantly greater than that of the vitreous humor in the eye. Circuit models of the electrode-retina interface are used to parameterize the different contributors to the overall impedance.

An epiretinal prosthesis, consisting of an extraocular microelectronic stimulator and an intraocular electrode array, was implanted in one eye of three blind and three sighted dogs. Three dogs (2 blind, 1 normal) were stimulated for 120 days, and two dogs (both normal) for 60 and 103 days respectively for 8-10 h/day at levels of 0.1 mC cm(-2) and 0.05 mC cm(-2), with each stimulus level presented to half of the array. One blind dog was kept as an inactive implant control. During the study period, electroretinograms (ERG) and fundus photographs were recorded. At the end of the study period, the dogs were sacrificed and histological and morphometric evaluation was made of the retina. No inflammatory reaction, neovascularization or hemorrhage was observed during the follow-up examinations. ERGs were unchanged. Stimulus levels used were of sufficient amplitude to elicit cortical evoked potentials. Histological evaluation showed no inflammatory infiltrates or changes in retina morphometry related to electrical stimulation when compared to the unstimulated control eye. Morphometric analysis revealed no consistent differences relating to electrical stimulation. In summary, chronic electrical stimulation of the dog retina at up to 0.1 mC cm(-2) with an epiretinal prosthesis does not appear to adversely affect the retina.

Loss of photoreceptor cells is one of the major causes of blindness. Several groups are exploring the functional replacement of photoreceptors by a retinal prosthesis. The goal of this study was to simulate the vision levels that recipients of retinal prostheses with 4 x 4, 6 x 10, and 16 x 16 electrode arrays may experience, and to test the functionality of this vision. A PC video camera captured images that were converted in real time into dots ("pixels"). The PC monitor and a head-mounted display worn by test subjects displayed the pixelized images. To assess performance of normally sighted individuals with each array, we designed a set of tasks including: four-choice orientation discrimination of a Sloan letter E, object recognition and discrimination, a cutting task, a pouring task, symbol recognition, and two reading tasks. In the letter E task, subjects were found to have visual acuities of 20/1,810, 20/1,330, and 20/420 with the 4 x 4, 6 x 10, and 16 x 16 arrays, respectively. Most subjects were able to read fonts as small as 36 point with the 16 x 16 array, corresponding with a visual acuity of 20/600 in our system. The test subjects partially overcame the visual limitation of the system by scanning the video camera over the letters allowing spatial and temporal integration of visual information. In all categories, subjects performed best with the 16 x 16 array and least well with the 4 x 4 array. Even with the lowest resolution array, however, some subjects could recognize simple objects and symbols.

Visual prostheses are based on neuronal electrical stimulation at different locations along the visual pathway (ie, cortical, optic nerve, epiretinal, subretinal). In terms of retinal prostheses, advances in microtechnology have allowed for the development of sophisticated, high-density integrated circuit devices that may be implanted either in the subretinal or epiretinal space. Analogous to the cochlear implants for some forms of deafness, these devices could restore useful vision by converting visual information into patterns of electrical stimulation that would excite the remaining spared inner retinal neurons in patients with diseases such as retinitis pigmentosa and age-related macular degeneration. The different types of implants and recent results are discussed, but special emphasis is given to retinal implants.

Purpose: To determine the best candidates (ie, those requiring lowest current levels delivered to the retina to elicit visual perceptions) for long-term implantation of a microelectronic retinal implant through a series of preoperative visual, psychophysical, and electrophysiological tests., Methods: This study protocol was granted an investigational device exemption by the Food and Drug Administration and was approved by the institutional review board at the University of Southern California. After informed consent was obtained, all subjects underwent the following preoperative tests: dark-adapted bright flash and 30-Hz flicker electroretinograms, electrical evoked responses (EERs) using a Burian-Allen corneal electrode to stimulate the globe, and psychophysical tests to evaluate the light and electrically elicited visual perceptions. Intraocular stimulation (IOS) of the retina was performed by an array of electrodes positioned on the internal limiting lamina., Results: Lower vision correlated with less sensitive psychophysical responses (P<.0001). Lower vision and less sensitive psychophysical tests correlated with higher EER values for stimulus pulse widths of 2 ms (P<.0008) and 4 ms (P<.0002). Lower IOS currents correlated with more sensitive psychophysical responses (P<.02) and lower EER values at 4 ms (P<.04)., Conclusions: Preoperative testing, especially psychophysical and electrophysiological tests to assess light and electrically driven visual responses, can help in evaluating patients for suitability for receiving a permanent microelectronic retinal implant. Further study is warranted.