Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays

Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission

Enhanced Tearing by Electrical Stimulation of the Anterior Ethmoid Nerve

PURPOSE. Electrical neurostimulation enhances tear secretion, and can be applied to treatment of dry eye disease. Using a chronic implant, we evaluate the effects of stimulating the anterior ethmoid nerve on the aqueous, lipid, and protein content of secreted tears. METHODS. Neurostimulators were implanted beneath the nasal mucosa in 13 New Zealand white rabbits. Stimulations (2.3-2.8 mA pulses of 75-875 ls in duration repeated at 30-100 Hz for 3 minutes) were performed daily, for 3 weeks to measure changes in tear volume (Schirmer test), osmolarity (TearLab osmometer), lipid (Oil-Red-O staining), and protein (BCA assay, mass spectrometry). RESULTS. Stimulation of the anterior ethmoid nerve in the frequency range of 30 to 90 Hz increased tear volume by 92% to 133% (P 0.01). Modulating the treatment with 50% duty cycle (3 seconds of stimulation repeated every 6 seconds) increased tear secretion an additional 23% above continuous stimulation (P 0.01). Tear secretion returned to baseline levels within 7 minutes after stimulation ended. Tear film osmolarity decreased by 7 mOsmol/ L, tear lipid increased by 24% to 36% and protein concentration increased by 48% (P 0.05). Relative abundance of the lacrimal gland proteins remained the same, while several serum and corneal proteins decreased with stimulation (P 0.05). CONCLUSIONS. Electrical stimulation of the anterior ethmoid nerve increased aqueous tear volume, reduced tear osmolarity, added lipid, and increased the concentration of normal tear proteins. Human studies with an intranasal stimulator should verify these effects in patients with aqueous-and lipid-deficient forms of dry eye disease

Photovoltaic restoration of sight with high visual acuity

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration

Photodiode circuits for retinal prostheses

Photodiode circuits show promise for the development of high-resolution retinal prostheses. While several of these systems have been constructed and some even implanted in humans, existing descriptions of the complex optoelectronic interaction between light, photodiode, and the electrode/electrolyte load are limited. This study examines this interaction in depth with theoretical calculations and experimental measurements. Actively biased photoconductive and passive photovoltaic circuits are investigated, with the photovoltaic circuits consisting of one or more diodes connected in series, and the photoconductive circuits consisting of a single diode in series with a pulsed bias voltage. Circuit behavior and charge injection levels were markedly different for platinum and sputtered iridium-oxide film (SIROF) electrodes. Photovoltaic circuits were able to deliver 0.038 mC/cm2 (0.75 nC/phase) per photodiode with 50- μm platinum electrodes, and 0.54-mC/cm2 (11 nC/phase) per photodiode with 50-μ m SIROF electrodes driven with 0.5-ms pulses of light at 25 Hz. The same pulses applied to photoconductive circuits with the same electrodes were able to deliver charge injections as high as 0.38 and 7.6 mC/cm2 (7.5 and 150 nC/phase), respectively. We demonstrate photovoltaic stimulation of rabbit retina in-vitro, with 0.5-ms pulses of 905-nm light using peak irradiance of 1 mW/mm2. Based on the experimental data, we derive electrochemical and optical safety limits for pixel density and charge injection in various circuits. While photoconductive circuits offer smaller pixels, photovoltaic systems do not require an external bias voltage. Both classes of circuits show promise for the development of high-resolution optoelectronic retinal prostheses

Photovoltaic retinal prosthesis with high pixel density

Retinal degenerative diseases lead to blindness due to loss of the ‘image capturing’ photoreceptors, while neurons in the ‘image-processing’ inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating the surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems that deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation is produced in normal and degenerate rat retinas, with pulse durations of 0.5–4 ms, and threshold peak irradiances of 0.2–10 mW mm−2, two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 µm bipolar pixel, demonstrating the possibility of a fully integrated photovoltaic retinal prosthesis with high pixel density

Photovoltaic retinal prosthesis for restoring sight to the blind

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the developed world, with an incidence of 1:500 in patients aged 55–64, and 1:8 in patients over 85 [1]. Retinitis pigmentosa (RP) is an inherited disease blinding about 1 in every 4000 individuals much earlier in life [2]. In both of these conditions the photoreceptor layer degenerates, while the inner retinal neurons survive to a large extent [3–5]. Electrically activating these neurons provides an alternative route for visual information and raises hope for the restoration of sight to the blind. In a normal retina, photoreceptors convert light into neural signals that are processed by inner retinal neurons, leading to generation of action potentials in the retinal ganglion cells (RGCs). These signals travel to the brain through the optic nerve and serve as the basis for visual perception. Electrical stimulation of the retina with microelectrodes can also produce action potentials in RGCs, creating spatially patterned percepts of light called phosphenes. Indeed, recent clinical trials with retinal prosthetic electrode arrays have restored visual acuity to subjects blinded by retinal degeneration up to 20/1200 using epiretinal placement (facing the ganglion cell side) [6], and up to 20/550 with subretinal implantation [7]. While this serves as an important proof of concept with clinically useful implications, existing retinal prosthesis designs have a number of shortcomings