Subretinal Electrical Stimulation Research Articles

Asymmetric Activation of ON and OFF Pathways in the Degenerated Retina.

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the rd10 and wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the rd10 retina, compared with that in the wt retina.

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina.

Vision restoration strategies aim to reestablish vision by replacing the function of lost photoreceptors with optoelectronic hardware or through gene therapy. One complication to these approaches is that retinal circuitry undergoes remodeling after photoreceptor loss. Circuit remodeling following perturbation is ubiquitous in the nervous system and understanding these changes is crucial for treating neurodegeneration. Spontaneous oscillations that arise during retinal degeneration have been well-studied, however, other changes in the spatiotemporal processing of evoked and spontaneous activity have received less attention. Here we use subretinal electrical stimulation to measure the spatial and temporal spread of both spontaneous and evoked activity during retinal degeneration. We found that electrical stimulation synchronizes spontaneous oscillatory activity, over space and through time, thus leading to increased correlations in ganglion cell activity. Intriguingly, we found that spatial selectivity was maintained in rd10 retina for evoked responses, with spatial receptive fields comparable to wt retina. These findings indicate that different biophysical mechanisms are involved in mediating feed forward excitation, and the lateral spread of spontaneous activity in the rd10 retina, lending support toward the possibility of high-resolution vision restoration.

Decoding network-mediated retinal response to electrical stimulation: implications for fidelity of prosthetic vision

Objective. Patients with photovoltaic subretinal implant PRIMA demonstrated letter acuity ∼0.1 logMAR worse than sampling limit for 100 μm pixels (1.3 logMAR) and performed slower than healthy subjects tested with equivalently pixelated images. To explore the underlying differences between natural and prosthetic vision, we compare the fidelity of retinal response to visual and subretinal electrical stimulation through single-cell modeling and ensemble decoding. Approach. Responses of retinal ganglion cells (RGCs) to optical or electrical white noise stimulation in healthy and degenerate rat retinas were recorded via multi-electrode array. Each RGC was fit with linear–nonlinear and convolutional neural network models. To characterize RGC noise, we compared statistics of spike-triggered averages (STAs) in RGCs responding to electrical or visual stimulation of healthy and degenerate retinas. At the population level, we constructed a linear decoder to determine the accuracy of the ensemble of RGCs on N-way discrimination tasks. Main results. Although computational models can match natural visual responses well (correlation ∼0.6), they fit significantly worse to spike timings elicited by electrical stimulation of the healthy retina (correlation ∼0.15). In the degenerate retina, response to electrical stimulation is equally bad. The signal-to-noise ratio of electrical STAs in degenerate retinas matched that of the natural responses when 78 ± 6.5% of the spikes were replaced with random timing. However, the noise in RGC responses contributed minimally to errors in ensemble decoding. The determining factor in accuracy of decoding was the number of responding cells. To compensate for fewer responding cells under electrical stimulation than in natural vision, more presentations of the same stimulus are required to deliver sufficient information for image decoding. Significance. Slower-than-natural pattern identification by patients with the PRIMA implant may be explained by the lower number of electrically activated cells than in natural vision, which is compensated by a larger number of the stimulus presentations.

The Effects of Phase Durations on the Spatial Responses of Retinal Ganglion Cells to Epi- and Sub-Retinal Electrical Stimulation.

Retinal prostheses have the potential to restore vision to blind patients that have retinitis pigmentosa or similar hereditary degenerative disorders, by electrically stimulating surviving retinal neurons through implanted electrode arrays. Current retinal prostheses provide limited visual acuity and one challenge is to spatially control neural activation following electrical stimulation. Most of the retinal prostheses are either epi-retinal - in front of the retinal ganglion cell layer, or sub-retinal - behind photoreceptor layer. In this study, we performed calcium imaging of ganglion cells from whole mounted retinas and compared the spread of neural activation between epi-retinal stimulation with a fiber electrode and sub-retinal stimulation with a disk electrode. We investigated the effects of phase durations on the spatial resolution of biphasic stimulation. Our results suggest that with fiber electrode epi-retinal stimulation, the axon bundles activation can lead to significant spread of stimulation, and cannot be avoided simply by changing the phase durations. However, sub-retinal stimulation with very short pulses (phase duration 0.033ms) can effectively confine the activation of retinal ganglion cells.

Foveal eccentricity can influence activation threshold in subretinal electrical stimulation

Purpose: Retinal prosthetic devices have been trialled in patients and encouraging results have been reported. Various factors including retinal disease state and effective electrode placement during surgery, would affect the outcome of retinal prosthesis implementation. In this study, we explore the possible effect of implant foveal eccentricity on retinal activation threshold using computational modelling. Method: Five healthy and five early stage dry age-related macular degeneration human volunteers were scanned using optical coherence tomography. The 3D retinal structure of each individual was extracted from the images and smoothly meshed. A set of five hexapolar electrode configurations was placed in the sub-foveal, 1 mm and 2 mm eccentricity positions from the centre of the retina within the subretinal space. The activation threshold for individual electrodes at all three sites of stimulation were simulated, using bidomain finite element modelling, and compared for all subjects. Results: We found that sub-foveal pit electrode placement required the lowest activation threshold, followed by the 1 mm eccentricity electrode placement. The 2 mm eccentricity electrode placement required the highest activation threshold. Conclusion: Our simulations indicate that clinically minute changes in foveal eccentricity of the subretinal implant can increase activation threshold and therefore, with a given stimulus current, retinal prosthetic performance drops with foveal eccentricity. Translational Relevance: Retinal prosthetic devices have been introduced as a potential therapy for patients suffering from outer retinal diseases. Human subjects with retinal implants demonstrated a varying range of responses to these devices. In this study, we introduce an anatomically-based patient-specific model of the human retina, using it to explore the effect of foveal eccentricity on activation threshold.

In Vivo Photovoltaic Performance of a Silicon Nanowire Photodiode-Based Retinal Prosthesis.

PurposeFor more than 20 years, there has been an international, multidisciplinary effort to develop retinal prostheses to restore functional vision to patients blinded by retinal degeneration. We developed a novel subretinal prosthesis with 1512 optically addressed silicon nanowire photodiodes, which transduce incident light into an electrical stimulation of the remaining retinal circuitry. This study was conducted to evaluate the efficacy of optically driving the subretinal prosthesis to produce visual cortex activation via electrical stimulation of the retina.MethodsWe measured electrically evoked potential responses (EEPs) in rabbit visual cortex in response to illumination of the subretinal nanowire prosthesis with pulsed 852-nm infrared (IR) light. We compared the EEP responses to visually evoked potential responses (VEPs) to pulsed 532-nm visible light (positive control) and pulsed 852-nm IR light (negative control).ResultsActivating the devices with IR light produced EEP responses with a significantly higher trough-to-peak amplitude (54.17 ± 33.4 μV) than IR light alone (24.07 ± 22.1 μV) or background cortical activity (23.22 ± 17.2 μV). EEP latencies were significantly faster than focal VEP latencies. Focal VEPs produced significantly higher amplitudes (94.88 ± 43.3 μV) than EEPs. We also demonstrated how an electrode placed on the cornea can be used as a noninvasive method to monitor the function of the implant.ConclusionsThese results show that subretinal electrical stimulation with nanowire electrodes can elicit EEPs in the visual cortex, providing evidence for the viability of a subretinal nanowire prosthetic approach for vision restoration.

Biophysical basis of the linear electrical receptive fields of retinal ganglion cells

Responses of retinal ganglion cells to direct electrical stimulation have been shown experimentally to be well described by linear–nonlinear models. These models rely on the simplifying assumption that retinal ganglion cell responses to stimulation with an array of electrodes are driven by a simple linear weighted sum of stimulus current amplitudes from each electrode, known as the ‘electrical receptive field’. Objective. This paper aims to demonstrate the biophysical basis of the linear–nonlinear model and the electrical receptive field to facilitate the development of improved stimulation strategies for retinal implants. Approach. We compare the linear–nonlinear model of subretinal electrical stimulation with a multi-layered, biophysical, volume conductor model of retinal stimulation. Main results. Our results show that the linear electrical receptive field of the linear–nonlinear model matches the transmembrane currents induced by electrodes (the activating function) at the site of the high-density sodium channel band with only minor discrepancies. The discrepancies are mostly eliminated by including axial current flow originating from adjacent cell compartments. Furthermore, for cells where a single linear electrical receptive field is insufficient, we show that cell responses are likely driven by multiple sites of action potential initiation with multiple distinct receptive fields, each of which can be accurately described by the activating function. Significance. This result establishes that the biophysical basis of the electrical receptive field of the linear–nonlinear model is the superposition of transmembrane currents induced by different electrodes at and near the site of action potential initiation. Together with existing experimental support for linear–nonlinear models of electrical stimulation, this provides a firm basis for using this much simplified model to generate more optimal stimulation patterns for retinal implants.

Electrode-size dependent thresholds in subretinal neuroprosthetic stimulation

Objective. Retinal prostheses have shown promising results in restoring some visual perception to blind patients but successful identification of objects of different size remains a challenge. Here we investigated electrode-size specific stimulation thresholds and their variability for subretinal electrical stimulation. Our findings indicate the range of charge densities required to achieve identification of small objects and the object—size-specific scaling of stimulation threshold. Approach. Using biphasic voltage—limited current stimuli provided by a light-sensitive microchip, we determined threshold charge densities for stimulation with variable electrode sizes. The stimulated activation of the retinal network was identified by recording the spiking of retinal ganglion cells in photoreceptor-degenerated mouse rd10 retinas. Stimulation thresholds were determined for cells with saturating stimulus response relationships (SRRs) but not for cells characterized by monotonically increasing or decreasing SRRs. Main results. Stimulation thresholds estimated in rd10 retinas ranged between 100–900 µC cm−2 for stimulation with small electrodes (30 µm diameter). Threshold charge density decreased with increasing electrode size and plateaued at 20 µC cm−2 for an electrode diameter larger than 300 µm. This trend of decreasing threshold down to a plateau value was confirmed in wild-type mouse retina suggesting an underlying physiological source. Significance. Our results suggest the following guidelines for retinal prosthetics employing biphasic current pulses. The encoding of small objects may be achieved through the activation of a confined set of different retinal ganglion cells, with individual stimulation thresholds spanning a wide range of charge densities. The encoding of increasing object sizes may be achieved by decreasing stimulation charge density.

Differential stimulation of the retina with subretinally injected exogenous neurotransmitter: A biomimetic alternative to electrical stimulation.

Subretinal stimulation of the retina with neurotransmitters, the normal means of conveying visual information, is a potentially better alternative to electrical stimulation widely used in current retinal prostheses for treating blindness from photoreceptor degenerative diseases. Yet, no subretinal electrical or chemical stimulation study has stimulated the OFF and ON pathways differentially through inner retinal activation. Here, we demonstrate the feasibility of differentially stimulating retinal ganglion cells (RGCs) through the inner nuclear layer of the retina with glutamate, a primary neurotransmitter chemical, in a biomimetic way. We show that controlled pulsatile delivery of glutamate into the subsurface of explanted wild-type rat retinas elicits highly localized simultaneous inhibitory and excitatory spike rate responses in OFF and ON RGCs. We also present the spatiotemporal characteristics of RGC responses to subretinally injected glutamate and the therapeutic stimulation parameters. Our findings could pave the way for future development of a neurotransmitter-based subretinal prosthesis offering more naturalistic vision and better visual acuity than electrical prostheses.

Subretinal electrical stimulation reveals intact network activity in the blind mouse retina.

Retinal degeneration (rd) leads to progressive photoreceptor cell death, resulting in vision loss. Stimulation of the inner-retinal neurons by neuroprosthetic implants is one of the clinically approved vision-restoration strategies, providing basic visual percepts to blind patients. However, little is understood as to what degree the degenerating retinal circuitry and the resulting aberrant hyperactivity may prevent the stimulation of physiological electrical activity. Therefore, we electrically stimulated ex vivo retinas from wild-type (wt; C57BL/6J) and blind (rd10 and rd1) mice using an implantable subretinal microchip and simultaneously recorded and analyzed the retinal ganglion cell (RGC) output with a flexible microelectrode array. We found that subretinal anodal stimulation of the rd10 retina and wt retina evoked similar spatiotemporal RGC-spiking patterns. In both retinas, electrically stimulated ON and a small percentage of OFF RGC responses were detected. The spatial selectivity of the retinal network to electrical stimuli reveals an intact underlying network with a median receptive-field center of 350 μm in both retinas. An antagonistic surround is activated by stimulation with large electrode fields. However, in rd10 and to a higher percentage, in rd1 retinas, rhythmic and spatially unconfined RGC patterns were evoked by anodal or by cathodal electrical stimuli. Our findings demonstrate that the surviving retinal circuitry in photoreceptor-degenerated retinas is preserved in a way allowing for the stimulation of temporally diverse and spatially confined RGC activity. Future vision restoration strategies can build on these results but need to avoid evoking the easily inducible rhythmic activity in some retinal circuits.

A 3D-continuum bidomain model of retinal electrical stimulation using an anatomically detailed mesh.

A continuum bidomain model of sub-retinal electrical stimulation on an anatomically detailed mesh of retina is presented. The underlying geometry is made up of 256 B-scans of optical coherence tomography (OCT) images of a healthy human retina, covering approximately 6×2 mm(2) centered on the macula. The OCT images are initially segmented and digitized into five major retinal layers comprising passive and active retinal cell types. This computational mesh is then used to model a subretinal hexapolar biphasic electrical stimulation. Our results indicate that the ultra-structure of the retina results in an asymmetric spatial extracellular potential distribution, leading to an irregular pattern of retinal ganglion cell activation. This finding is in contrast to focal circular activation previously reported in retinal electrical stimulation modeling with a uniform mesh.

Simultaneous recording of mouse retinal ganglion cells during epiretinal or subretinal stimulation.

We compared response patterns and electrical receptive fields (ERF) of retinal ganglion cells (RGCs) during epiretinal and subretinal electrical stimulation of isolated mouse retina. Retinas were stimulated with an array of 3200 independently controllable electrodes. Four response patterns were observed: a burst of activity immediately after stimulation (Type I cells, Vision Research (2008), 48, 1562-1568), delayed bursts beginning >25ms after stimulation (Type II), a combination of both (Type III), and inhibition of ongoing spike activity. Type I responses were produced more often by epiretinal than subretinal stimulation whereas delayed and inhibitory responses were evoked more frequently by subretinal stimulation. Response latencies were significantly shorter with epiretinal than subretinal stimulation. These data suggest that subretinal stimulation is more effective at activating intraretinal circuits than epiretinal stimulation. There was no significant difference in charge threshold between subretinal and epiretinal configurations. ERFs were defined by the stimulating array surface area that successfully stimulated spikes in an RGC. ERFs were complex in shape, similar to receptive fields mapped with light. ERF areas were significantly smaller with subretinal than epiretinal stimulation. This may reflect the greater distance between stimulating electrodes and RGCs in the subretinal configuration. ERFs for immediate and delayed responses mapped within the same Type III cells differed in shape and size, consistent with different sites and mechanisms for generating these two response types.

Effects of Subretinal Electrical Stimulation in Mer-KO Mice

Subretinal electrical stimulation (SES) from microphotodiode arrays protects photoreceptors in the RCS rat model of retinitis pigmentosa. The authors examined whether mer(kd) mice, which share a Mertk mutation with RCS rats, showed similar neuroprotective effects from SES. Mer(kd) mice were implanted with a microphotodiode array at postnatal day (P) 14. Weekly electroretinograms (ERGs) followed by retinal histology at week 4 were compared with those of age-matched controls. RT-PCR for fibroblast growth factor beta (Fgf2), ciliary nerve trophic factor (Cntf), glial-derived neurotrophic factor (Gdnf), insulin growth factor 1 (Igf1), and glial fibrillary acidic protein (Gfap) was performed on retinas at 1 week after surgery. Rates of degeneration using ERG parameters were compared between mer(kd) mice and RCS rats from P28 to P42. SES-treated mer(kd) mice showed no differences in ERG a- and b-wave amplitudes or photoreceptor numbers compared with controls. However, the expression of Fgf2 and Cntf was greater (6.5 ± 1.9- and 2.5 ± 0.5-fold, respectively; P < 0.02) in SES-treated mer(kd) retinas. Rates of degeneration were faster for dark-adapted maximal b-wave, log σ, and oscillatory potentials in mer(kd) mice than in RCS rats. Although SES upregulated Fgf2 in mer(kd) retinas, as reported previously for RCS retinas, this was not accompanied by neuroprotection of photoreceptors. Comparisons of ERG responses from mer(kd) mice and RCS rats across different ages showed inner retinal dysfunction in mer(kd) mice but not in RCS rats. This inner retinal dysfunction and the faster rate of degeneration in mer(kd) mice may produce a retinal environment that is not responsive to neuroprotection from SES.

Repeated transchoroidal implantation and explantation of compound subretinal prostheses: An exploratory study in rabbits

For human trials with retinal prostheses it is mandatory to develop procedures to safely explant and possibly reimplant the devices. This prompted us to investigate in a small exploratory study the safety of repeated transchoroidal implantation and explantation procedures of complex subretinal devices in laboratory animals. Repeated transchoroidal surgery was performed in four rabbits. The rabbits were examined by clinical examination and funduscopy. Function was assessed by electroretinography and cortical recordings following light and subretinal electrical stimulation. Sections of the retina and of the implantation channel were examined by light microscopy. Using the same access route, repeated transchoroidal subretinal implantation surgery was successfully performed in all cases. Fixation of implants was stable for up to 13 months; retinas remained attached at all examination dates. Electroretinograms and visual evoked cortical potential proved retinal and visual pathway integrity. Subretinal electrical stimulation elicited retinal and cortical responses. While retinal morphology at earlier stages was found to be essentially unaltered, atrophic disorganization in the region of the subretinal channel was observed after 10 months and after subretinal electrical stimulation. Repeated transchoroidal surgery can be safely performed for implantation, explantation, and reimplantation of subretinal devices in rabbits. With modifications, we believe the technique can be applied in human surgery.

Retinal Expression ofFgf2in RCS Rats with Subretinal Microphotodiode Array

To test the hypothesis that subretinal electrical stimulation from a microphotodiode array (MPA) exerts a neuroprotective effect in Royal College of Surgeons (RCS) rats through the induction of growth factors. At postnatal day 21, RCS rats were divided into four groups in which one eye per rat received treatment: (A) active MPA, (M) minimally active MPA, (S) sham surgery, or (C) no surgery and the opposite eye was unoperated. Dark- and light-adapted ERGs were recorded 1 week after surgery. A second set of A-, M-, and C-treated RCS rats had weekly ERG recordings for 4 weeks. Real-time RT-PCR was used to measure relative expression of mRNAs (Bdnf, Fgf2, Fgf1, Cntf, Gdnf, and Igf1) in retina samples collected 2 days after the final ERG. One week after surgery, there was a slight difference in dark-adapted ERG b-wave at the brightest flash intensity. Mean retinal Fgf2 expression in the treated eye relative to the opposite eye was greater for the A group (4.67 +/- 0.72) than for the M group (2.80 +/- 0.45; P = 0.0501), S group (2.03 +/- 0.45; P < 0.01), and C group (1.30 +/- 0.22; P < 0.001). No significant change was detected for Bdnf, Cntf, Fgf1, Gdnf, and Igf1. Four weeks after surgery, the A group had significantly larger dark- and light-adapted ERG b-waves than for the M and C groups (P < 0.01). Simultaneously, mean relative Fgf2 expression was again greater for the A group (3.28 +/- 0.61) than for the M (1.28 +/- 0.32; P < 0.05) and C (1.05 +/- 0.04; P < 0.05) groups. The results show subretinal implantation of an MPA induces selective expression of Fgf2 above that expected from a retina-piercing injury. Preservation of ERG b-wave amplitude 4 weeks after implantation is accompanied by elevated Fgf2 expression. These results suggest that Fgf2 may play a role in the neuroprotection provided by subretinal electrical stimulation.

Compound subretinal prostheses with extra-ocular parts designed for human trials: successful long-term implantation in pigs

Subretinal implants aim to replace photoreceptor function in patients suffering from degenerative retinal disease like retinitis pigmentosa by topically applying electrical stimuli in the subretinal space. This study-as a last step before upcoming human trials-explored a newly developed surgical technique for permanent implantation of complex subretinal implants with extra-ocular parts. The implant consisted of a microphoto-diode array (MPDA) with 1550 electrodes and a 4x4 array of gold electrodes for direct electrical stimulation; both were mounted onto a polyimide foil for transscleral placement into the subretinal space. The foil carried connection lanes to a silicone cable that was implanted under the skin and led to a stimulator box in the animal's neck. Surgery was performed in 11 domestic pigs. Improved vitreo-retinal surgical technique consisted of a 180 degrees peripheral retinotomy and use of diathermy to penetrate the choroid in order to avoid choroidal haemorrhage. Subretinal forceps were used to place the implant safely onto the retinal pigment epithelium before the retina was flattened, peripheral laser photocoagulation was applied and the eye was filled with silicon oil. The implant was stabilized by a scleral fixation patch, use of a metal clamp with bone screws on the animal's skull and a tissue ring under the animal's skin in the neck. Behaviour was observed in the freely moving animals after direct subretinal electrical stimulation and funduscopy, optical coherence tomography, fluorescein angiography and histology were performed. All implants were successfully placed subretinally. In three animals a proliferative vitreo-retinopathy was observed after approximately 2 weeks. Otherwise, funduscopy and OCT demonstrated complete retinal attachment and FA showed no retinal vascular abnormalities over and around the implant. The animals showed clear behavioural reactions to electrical stimulation over the whole examination period. Histological examination failed to show any voltage-induced alteration in the cellular architecture of the retina overlying the stimulation electrodes. This study demonstrates the feasibility of a new surgical procedure for highly safe and controlled implantation of complex subretinal devices with extra-ocular parts. The new implant design proved to be safely implantable in free-moving pigs for an observation period of 4 weeks.

CMOS artificial subretinal chip for natural light illumination

A novel CMOS oscillating pixel array for subretinal prosthesis used in natural light illumination is presented. Its prototype chips are fabricated in a standard 0.6 µm CMOS technology. Experimental results show the device can deliver effective self-oscillation for subretinal electrical stimulation.

Implantation of Stimulation Electrodes in the Subretinal Space to Demonstrate Cortical Responses in Yucatan Minipig in the Course of Visual Prosthesis Development

Purpose During the course of the development of visual prostheses, subretinal stimulation films were implanted in micropigs in order to prove the feasibility of subretinal electrical stimulation with subsequent cortical response. One aim was to demonstrate that epidural recording of visual evoked potentials is possible in the micropig. Methods Film-bound stimulation electrode arrays were placed in the subretinal space of micropigs. This enabled the retina to be stimulated subretinally. Since conventional visual evoked potential (VEP) measuring is virtually impossible in the pig from the neurosurgical point of view, epidural recording electrode arrays were positioned over the visual cortex as permanent electrodes. Results The feasibility of temporary implantation of film-bound stimulation electrode arrays was successfully demonstrated in the micropig model. On stimulation with monopolar voltage pulses (1000 to 3000 mV), reproducible epidural VEP measurements (5 to 10 μV) were detected. Conclusions The feasibility of subretinal stimulation of the retina was demonstrated in a retinal model that is similar to the human retina. This animal model therefore offers a suitable means of studying the tolerability of stimulation situations in the course of visual prosthesis development.

Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

Neuroprotective Effect of Subretinal Implants in the RCS Rat

Retinal prosthetics have been designed to interface with the neural retina by electrically stimulating the remaining retinal circuits after photoreceptor degeneration. However, the electrical stimulation provided by the subretinal implant may also stimulate neurotrophic factors that provide neuroprotection to the retina. This study was undertaken to determine whether electrical stimulation from a subretinal photodiode-based implant has a neuroprotective effect on photoreceptors in the RCS rat, a model of photoreceptor degeneration. Eyes of RCS rats were implanted with an active or inactive device or underwent sham surgery before photoreceptor degeneration. Outer retinal function was assessed with electroretinogram (ERG) recordings weekly until 8 weeks after surgery, at which time retinal tissue was collected and processed for morphologic assessment, including photoreceptor cell counts and retinal layer thickness. At 4 to 6 weeks after surgery, the ERG responses in the active-implant eyes were 30% to 70% greater in b-wave amplitude than the responses from eyes implanted with inactive devices, those undergoing sham surgery, or the nonsurgical control eyes. At 8 weeks after surgery the ERG responses from active-implant eyes were not significantly different from the control groups. However, the number of photoreceptors in eyes implanted with the active or inactive device was significantly greater in the regions over and around the implant versus sham-surgical and nonsurgical control eyes. These results suggest that subretinal electrical stimulation provides temporary preservation of retinal function in the RCS rat. In addition, implantation of an active or inactive device into the subretinal space causes morphologic preservation of photoreceptors in the RCS rat until 8 weeks after surgery. Further studies are needed to determine whether the correlation of neuropreservation with subretinal implantation is due to electrical stimulation and/or a mechanical presence of the implant in the subretinal space.