Eyal Margalit

Retinal prosthesis for the blind

Most of current concepts for a visual prosthesis are based on neuronal electrical stimulation at different locations along the visual pathways within the central nervous system. The different designs of visual prostheses are named according to their locations (i.e., cortical, optic nerve, subretinal, and epiretinal). Visual loss caused by outer retinal degeneration in diseases such as retinitis pigmentosa or age-related macular degeneration can be reversed by electrical stimulation of the retina or the optic nerve (retinal or optic nerve prostheses, respectively). On the other hand, visual loss caused by inner or whole thickness retinal diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory processes etc.), or diseases of the central nervous system (not including diseases of the primary and secondary visual cortices) can be reversed by a cortical visual prosthesis. The intent of this article is to provide an overview of current and future concepts of retinal and optic nerve prostheses. This article will begin with general considerations that are related to all or most of visual prostheses and then concentrate on the retinal and optic nerve designs. The authors believe that the field has grown beyond the scope of a single article so cortical prostheses will be described only because of their direct effect on the concept and technical development of the other prostheses, and this will be done in a more general and historic perspective.

Effects of indocyanine green injection on the retinal surface and into the subretinal space in rabbits.

Purpose To evaluate the effects of indocyanine green (ICG) injection on the retinal surface and into the subretinal space of rabbit eyes. Methods Twenty-two Dutch-belted rabbits underwent two-port vitrectomy followed by injection of ICG (5 mg/mL) on the retinal surface and into the subretinal space. Balanced salt solution (BSS) was also injected subretinally. The locations where ICG was delivered (both epiretinal and subretinal) were exposed to light from an endoilluminator for 7 minutes. The animals were examined at 1, 7, and 14 days after surgery. The eyes were studied by fluorescein angiography as well as light and electron microscopy. Results No damage was observed after epiretinal ICG injection, but subretinal ICG injection resulted in damage to the outer nuclear layer, photoreceptor inner and outer segments, and retinal pigment epithelium. This damage was more severe with longer follow-up. Control experiments without ICG, in which balanced salt solution was injected into the subretinal space or light was delivered on the epiretinal surface, demonstrated only damage to the photoreceptor outer segments. Conclusion Subretinal delivery of ICG (5 mg/mL) in rabbits induces retinal pigment epithelium, photoreceptor inner and outer segment, and outer nuclear layer damage. These mechanisms of damage may explain the retinal pigment epithelium changes that are sometimes seen after ICG-assisted internal limiting membrane peeling in humans.

Effects of intravitreal indocyanine green injection in rabbits.

Purpose To report the clinical, electrophysiologic, and histologic findings of different concentrations of indocyanine green (ICG) injected into the vitreous cavity of rabbit eyes. Methods Forty-two rabbits underwent intravitreal injection of 0.1 mL of ICG in three different concentrations: 0.5 mg/mL (250 mOsm), 5 mg/mL (270 mOsm), and 25 mg/mL (170 mOsm). Fellow eyes were injected with 0.1 mL of balanced salt solution. Biomicroscopy, ophthalmoscopy, electroretinography, fluorescein angiography, and histologic evaluation were performed. Results Eyes injected with 0.5 mg/mL of ICG showed b-wave latency delay on the first day after injection. Eyes injected with 5 mg/mL of ICG showed b-wave latency delay and decreased b-wave amplitude on the first and seventh days after injection; delayed a-wave latency on the first day after injection was also observed. Eyes injected with 25 mg/mL of ICG showed b- and a-wave amplitude and latency abnormalities during the entire follow-up. Direct correlation of increasing retinal edema proportional to the progressively increasing ICG concentrations was shown on histologic evaluation. Conclusion Intravitreal ICG injection in rabbit eyes may impair retinal function and morphology proportional to the progressively increasing ICG dosages.

Retinal pigment epithelial abnormalities after internal limiting membrane peeling guided by indocyanine green staining.

X-linked retinoschisis (XLRS) is a rare genetic disorder associated with stellate maculopathy in all affected patients and peripheral schisis in one-half of affected patients. 1 Although the pathophysiology of the disease remains largely unknown, histopathologic reports have focused on the breakdown of Müller cells and the schisis at the level of the nerve fiber layer in the periphery. 2 Optical coherence tomography is capable of high-resolution cross-sectional imaging in vivo. We used optical coherence tomography to examine the macular findings of two patients with XLRS.

Comparison of electrical stimulation thresholds in normal and retinal degenerated mouse retina

PurposeTo compare the threshold for electrically elicited action potentials of retinal ganglion cells in normal mouse retina and photoreceptor degenerated (rd) mouse retina.MethodsMicroelectrode recordings were made from retinal ganglion cells of normal and rd mice. Mice with a genetically based retinal degeneration (rd mice) were grown to the age of 16 weeks, when light-evoked responses could no longer be recorded. A bare wire was placed in the vitreous to stimulate the retina with charge-balanced current pulses. The following pulse shapes were investigated: single, square biphasic pulse, single sine wave, and biphasic pulse trains.ResultsNormal mice had significantly lower stimulus thresholds than rd mice for all pulse shapes. In normal and rd mice, short pulses were more efficient with respect to total charge used, but required a higher current. In normal mice, sine wave stimulation was significantly more efficient than a biphasic pulse of the same duration. No difference was noted between sine wave and square wave stimulation in rd mice. Pulse trains offered little benefit over single pulses.ConclusionThe amount of electrical charge required to elicit an action potential is dependent on the condition of the retina and the shape of the stimulus pulse used to deliver the charge.

Electrical stimulation in normal and retinal degeneration (rd1) isolated mouse retina.

Stimulus threshold and response latencies were measured for electrically elicited retinal ganglion cell responses in retina isolated from the eyes of normal and retinal degenerate (rd1) mice. Stimulation of the ganglion cell-side in normal retina yielded a significantly lower mean threshold and shorter latency when compared with stimulation of the photoreceptor side in normal retina. The latency of the ganglion cell-side stimulation in normal retina also proved to be significantly shorter than the latency for stimulation of the ganglion cell side in rd1 retina. Thus both the electrode positioning as well as the health of the retinal tissue play a role in the stimulating current required to elicit a retinal response.

Bioadhesives for intraocular use.

Background/Purpose: A safe, effective adhesive could be useful in the management of retinal holes or tears and selected complicated retinal detachments, as well as for attaching a small electronic device (retinal prosthesis) to the retina. In this study, we examined nine commercially available compounds for their suitability as intraocular adhesives. Methods: The following materials were studied: commercial fibrin sealant, autologous fibrin. Cell‐Tak, three photocurable glues, and three different polyethylene glycol hydro‐ gels. An electronic strain gauge measured the adherence forces between different glues and the retina. The stability of hydrogels at body temperature and the impermeability of the hydrogel adhesive to dextran blue were examined. Long‐term biocompatibility testing of the most promising glues in terms of adhesive force, consistency, and short‐term safety (hydrogels) were done in rabbits. Funduscopy, electroretinogram, and histology of the retina were performed. Results: Hydrogels had 2 to 39 times more adhesive force (measured in mN) than the other glues tested. They liquefied at body temperature after 3 days to a few months. Hydrogels were impermeable to dextran blue. One type of hydrogel proved to be nontoxic to the retina. Conclusions: Hydrogels proved to be superior for intraocular use in terms of consis‐tency, adhesiveness, stability, impermeability, and safety.

Heat Effects on the Retina

BACKGROUND AND OBJECTIVE To study the heat and power dissipation effect of anintraocular electronic heater on the retina. The determination of thermal parameters that are nonharmful to the retina will aid in the development of an implantable intraocular electronic retinal prosthesis. MATERIALS AND METHODS In dogs, five different retinal areas were touched with a custom intraocular heater probe (1.4 x 1.4 x 1.0 mm) for 1 second while the heater dissipated 0 (control), 10, 20, 50, or 100 mW. In a second protocol, the heater was mechanically held in the vitreous cavity while dissipating 500 mW for 2 hours while monitoring intraocular temperature. The animals were observed for 4 weeks with serial fundus photography and electroretinography. The procedure was then repeated in the fellow eye. The dogs were killed and both eyes were enucleated and submitted for histology. RESULTS In experiments using protocol 1, heater settings of 50 mW or higher caused an immediate visible whitening of the retinal tissue. Histologically, this damage was evident only if the eyeswere immediately enucleated. Permanent damage was caused by heater settings of 100 mW or higher. Under protocol 2, no ophthalmologic, electroretinography, or histologic differences were noted between the groups. Temperature increases of 5 degrees C in the vitreous and 2 degrees C near the retina were noted. CONCLUSIONS The liquid environment of the eye acts as a heat sink that is capable of dissipating a significant amount of power. An electronic chip positioned away from the retina can run at considerably higher powers than a chip positioned on the retinal surface.

Inner and outer retinal mechanisms engaged by epiretinal stimulation in normal and rd mice

Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, the retinal circuitry that is activated by epiretinal stimulation is not well characterized. Whole-cell patch clamp recordings were obtained from ganglion cells in normal and rd mice using flat-mount and retinal slice preparations. A stimulating electrode was positioned along the ganglion cell side of the preparation at different distances from the stimulated tissue. Pulses of cathodic current evoked action potentials in ganglion cells and less frequently evoked sustained inward currents that appeared synaptic in origin. Sustained currents reversed around E(Cl) and were inhibited by blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-proprionate (AMPA)-type glutamate receptors with 2,3-dihydroxy-6-nitro-sulfamoyl-benzo(f)-quinoxaline-2,3-dione (NBQX), γ aminobutyric acid a/c (GABA(a/c)) receptors with picrotoxinin, or glycine receptors with strychnine. This suggests that epiretinal stimulation activates glutamate release from bipolar cell terminals, which in turn evokes release of GABA and glycine from amacrine cells. Synaptic current thresholds were lower in ON ganglion cells than OFF cells, but the modest difference did not attain statistical significance. Synaptic currents were rarely observed in rd mice lacking photoreceptors compared to normal retina. In addition, confocal calcium imaging experiments in normal mice retina slices revealed that epiretinal stimulation evoked calcium increases in the outer plexiform layer. These results imply a contribution from photoreceptor inputs to the synaptic currents observed in ganglion cells. The paucity of synaptic responses in rd mice retina slices suggests that it is better to target retinal ganglion cells directly rather than to attempt to engage the inner retinal circuitry.

Electrical Stimulation in Isolated Rabbit Retina

Experiments were conducted to assess the effect of stimulating electrode parameters (size, position, and waveform shape) on electrically elicited ganglion cell action potentials from isolated rabbit retina. Thirty-eight isolated rabbit retinas were stimulated with bipolar stimulating electrodes (either 125 or 25 mum in diameter) positioned on either the ganglion or the photoreceptor side. Recording electrodes were placed between the optic disc and the stimulating electrodes. Cathodic-first, biphasic, current waveforms of varying pulse durations (0.1, 0.5, 1 ms) were used. For the four conditions tested (125- electrode and 25-mum electrode, ganglion cell, and photoreceptor positions) threshold currents ranged from 6.7 to 23.6 muA, depending on location and pulse duration. With 1-ms pulse duration, no statistically significant difference was seen between threshold currents when either size electrode was used to stimulate either the ganglion cell side or the photoreceptor side. For all groups, the threshold currents using the 1-ms pulse were lower than those using 0.1 ms, but the 0.1-ms pulses used less charge. These experiments provide a number of valuable insights into the relative effects of several stimulation parameters critical to the development of an implanted electronic retinal prosthesis