Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

Spatiotemporal characteristics of retinal response to network-mediated photovoltaic stimulation.

Subretinal prostheses aim at restoring sight to patients blinded by photoreceptor degeneration using electrical activation of the surviving inner retinal neurons. Today, such implants deliver visual information with low-frequency stimulation, resulting in discontinuous visual percepts. We measured retinal responses to complex visual stimuli delivered at video rate via a photovoltaic subretinal implant and by visible light. Using a multielectrode array to record from retinal ganglion cells (RGCs) in the healthy and degenerated rat retina ex vivo, we estimated their spatiotemporal properties from the spike-triggered average responses to photovoltaic binary white noise stimulus with 70-µm pixel size at 20-Hz frame rate. The average photovoltaic receptive field size was 194 ± 3 µm (mean ± SE), similar to that of visual responses (221 ± 4 µm), but response latency was significantly shorter with photovoltaic stimulation. Both visual and photovoltaic receptive fields had an opposing center-surround structure. In the healthy retina, ON RGCs had photovoltaic OFF responses, and vice versa. This reversal is consistent with depolarization of photoreceptors by electrical pulses, as opposed to their hyperpolarization under increasing light, although alternative mechanisms cannot be excluded. In degenerate retina, both ON and OFF photovoltaic responses were observed, but in the absence of visual responses, it is not clear what functional RGC types they correspond to. Degenerate retina maintained the antagonistic center-surround organization of receptive fields. These fast and spatially localized network-mediated ON and OFF responses to subretinal stimulation via photovoltaic pixels with local return electrodes raise confidence in the possibility of providing more functional prosthetic vision. NEW & NOTEWORTHY Retinal prostheses currently in clinical use have struggled to deliver visual information at naturalistic frequencies, resulting in discontinuous percepts. We demonstrate modulation of the retinal ganglion cells (RGC) activity using complex spatiotemporal stimuli delivered via subretinal photovoltaic implant at 20 Hz in healthy and in degenerate retina. RGCs exhibit fast and localized ON and OFF network-mediated responses, with antagonistic center-surround organization of their receptive fields.

Dielectrophoretic bead-droplet reactor for solid-phase synthesis.

Solid-phase synthesis underpins many advances in synthetic and combinatorial chemistry, biology, and material science. The immobilization of a reacting species on the solid support makes interfacing of reagents an important challenge in this approach. In traditional synthesis columns, this leads to reaction errors that limit the product yield and necessitates excess consumption of the mobile reagent phase. Although droplet microfluidics can mitigate these problems, its adoption is fundamentally limited by the inability to controllably interface microbeads and reagent droplets. Here, we introduce Dielectrophoretic Bead-Droplet Reactor as a physical method to implement solid-phase synthesis on individual functionalized microbeads by encapsulating and ejecting them from microdroplets by tuning the supply voltage. Proof-of-concept demonstration of the enzymatic coupling of fluorescently labeled nucleotides onto the bead using this reactor yielded a 3.2-fold higher fidelity over columns through precise interfacing of individual microreactors and beads. Our work combines microparticle manipulation and droplet microfluidics to address a long-standing problem in solid-phase synthesis with potentially wide-ranging implications.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective.Retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables increasing prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigated 3-dimensional (3d) structures on top of photovoltaic arrays for enhanced penetration of the electric field, permitting higher resolution implants.Approach.3D COMSOL models of subretinal photovoltaic arrays were developed to accurately quantify the electrodynamics during stimulation and verified through comparison to flat photovoltaic arrays. Models were applied to optimize the design of 3D electrode structures (pillars and honeycombs). Return electrodes on honeycomb walls vertically align the electric field with bipolar cells for optimal stimulation. Pillars elevate the active electrode, thus improving proximity to target neurons. The optimized 3D structures were electroplated onto existing flat subretinal prostheses.Main results.Simulations demonstrate that despite exposed conductive sidewalls, charge mostly flows via high-capacitance sputtered iridium oxide films topping the 3D structures. The 24µm height of honeycomb structures was optimized for integration with the inner nuclear layer cells in the rat retina, whilst 35µm tall pillars were optimized for penetrating the debris layer in human patients. Implantation of released 3D arrays demonstrates mechanical robustness, with histology demonstrating successful integration of 3D structures with the rat retinain-vivo.Significance. Electroplated 3D honeycomb structures produce vertically oriented electric fields, providing low stimulation thresholds, high spatial resolution, and high contrast for pixel sizes down to 20µm. Pillar electrodes offer an alternative for extending past the debris layer. Electroplating of 3D structures is compatible with the fabrication process of flat photovoltaic arrays, enabling much more efficient retinal stimulation.

Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ.

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100µm pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22µm pixels increased the grating acuity from the 100µm capability of PRIMA implants to 28µm, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

3D electronic implants in subretinal space: Long-term follow-up in rodents.

Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 µm pixel size. Since scaling the pixels below 75 µm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 32-36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12-16 weeks. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 12-16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective: High-resolution retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables an increase in prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigate 3-dimensional structures on top of the photovoltaic arrays for enhanced penetration of electric field to permit higher-resolution implants. Approach: We developed 3D COMSOL models of subretinal photovoltaic arrays that accurately quantify the device electrodynamics during stimulation and verified it experimentally through comparison with the standard (flat) photovoltaic arrays. The models were then applied to optimise the design of 3D electrode structures (pillars and honeycombs) to efficiently stimulate the inner retinal neurons. The return electrodes elevated on top of the honeycomb walls surrounding each pixel orient the electric field inside the cavities vertically, aligning it with bipolar cells for optimal stimulation. Alternatively, pillars elevate the active electrode into the inner nuclear layer, improving proximity to the target neurons. Modelling results informed a microfabrication process of electroplating the 3D electrode structures on top of the existing flat subretinal prosthesis. Main results: Simulations demonstrate that despite the conductive sidewalls of the 3D electrodes being exposed to electrolyte, most of the charge flows via the high-capacitance sputtered Iridium Oxide film that caps the top of the 3D structures. The 24 µm height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 µm height of the pillars was optimized for penetrating the debris layer in human patients. Release from the wafer and implantation of the 3D arrays demonstrated that they are mechanically robust to withstand the associated forces. Histology demonstrated successful integration of the 3D structures with the rat retina in-vivo. Significance: Electroplated 3D honeycomb structures produce a vertically oriented electric field that offers low stimulation threshold, high spatial resolution and high contrast for the retinal implants with pixel sizes down to 20µm in width. Pillar electrodes offer an alternative configuration for extending the stimulation past the debris layers. Electroplating of the 3D structures is compatible with the fabrication process of the flat photovoltaic arrays, thereby enabling much more efficient stimulation than in their original flat configuration.

3D electronic implants in subretinal space: long-term follow-up in rodents.

Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 µm pixel size. Since decreasing the pixel size below 75 µm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats.

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 µm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 µm pixels matches the pixel pitch, while with 20 µm pixels, it reaches the 28 µm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.

Vertical-junction photodiodes for smaller pixels in retinal prostheses.

Objective.To restore central vision in patients with atrophic age-related macular degeneration, we replace the lost photoreceptors with photovoltaic pixels, which convert light into current and stimulate the secondary retinal neurons. Clinical trials demonstrated prosthetic acuity closely matching the sampling limit of the 100µm pixels, and hence smaller pixels are required for improving visual acuity. However, with smaller flat bipolar pixels, the electric field penetration depth and the photodiode responsivity significantly decrease, making the device inefficient. Smaller pixels may be enabled by (a) increasing the diode responsivity using vertical p-n junctions and (b) directing the electric field in tissue vertically. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field.Approach.Arrays of silicon photodiodes of 55, 40, 30, and 20µm in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically using a common return electrode at the edge of the device. Optical and electronic performance of the diodes was characterizedin-vitro, and retinal stimulation threshold measured by recording the visually evoked potentials in rats with retinal degeneration.Main results.The photodiodes exhibited sufficiently low dark current (<10 pA) and responsivity at 880 nm wavelength as high as 0.51 A W-1, with 85% internal quantum efficiency, independent of pixel size. Field mapping in saline demonstrated uniformity of the pixel performance in the array. The full-field stimulation threshold was as low as 0.057±0.029mW mm-2with 10 ms pulses, independent of pixel size.Significance.Photodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20µm. Vertically oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of scaling down the photovoltaic pixels for subretinal stimulation.

Honeycomb-shaped electro-neural interface enables cellular-scale pixels in subretinal prosthesis.

High-resolution visual prostheses require small, densely packed pixels, but limited penetration depth of the electric field formed by a planar electrode array constrains such miniaturization. We present a novel honeycomb configuration of an electrode array with vertically separated active and return electrodes designed to leverage migration of retinal cells into voids in the subretinal space. Insulating walls surrounding each pixel decouple the field penetration depth from the pixel width by aligning the electric field vertically, enabling a decrease of the pixel size down to cellular dimensions. We demonstrate that inner retinal cells migrate into the 25 µm deep honeycomb wells as narrow as 18 µm, resulting in more than half of these cells residing within the electrode cavities. Immune response to honeycombs is comparable to that with planar arrays. Modeled stimulation threshold current density with honeycombs does not increase substantially with reduced pixel size, unlike quadratic increase with planar arrays. This 3-D electrode configuration may enable functional restoration of central vision with acuity better than 20/100 for millions of patients suffering from age-related macular degeneration.

Characteristics of prosthetic vision in rats with subretinal flat and pillar electrode arrays.

OBJECTIVE: Retinal prostheses aim to restore sight by electrically stimulating the surviving retinal neurons. In clinical trials of the current retinal implants, prosthetic visual acuity does not exceed 20/550. However, to provide meaningful restoration of central vision in patients blinded by age-related macular degeneration (AMD), prosthetic acuity should be at least 20/200, necessitating a pixel pitch of about 50 µm or lower. With such small pixels, stimulation thresholds are high due to limited penetration of electric field into tissue. Here, we address this challenge with our latest photovoltaic arrays and evaluate their performance in vivo. APPROACH: We fabricated photovoltaic arrays with 55 and 40 µm pixels (a) in flat geometry, and (b) with active electrodes on 10 µm tall pillars. The arrays were implanted subretinally into rats with degenerate retina. Stimulation thresholds and grating acuity were evaluated using measurements of the visually evoked potentials (VEP). MAIN RESULTS: With 55 µm pixels, we measured grating acuity of 48 ± 11 µm, which matches the linear pixel pitch of the hexagonal array. This geometrically corresponds to a visual acuity of 20/192 in a human eye, matching the threshold of legal blindness in the US (20/200). With pillar electrodes, the irradiance threshold was nearly halved, and duration threshold reduced by more than three-fold, compared to flat pixels. With 40 µm pixels, VEP was too low for reliable measurements of the grating acuity, even with pillar electrodes. SIGNIFICANCE: While being helpful for treating a complete loss of sight, current prosthetic technologies are insufficient for addressing the leading cause of untreatable visual impairment-AMD. Subretinal photovoltaic arrays may provide sufficient visual acuity for restoration of central vision in patients blinded by AMD.

Optimization of pillar electrodes in subretinal prosthesis for enhanced proximity to target neurons.

OBJECTIVE: High-resolution prosthetic vision requires dense stimulating arrays with small electrodes. However, such miniaturization reduces electrode capacitance and penetration of electric field into tissue. We evaluate potential solutions to these problems with subretinal implants based on utilization of pillar electrodes. APPROACH: To study integration of three-dimensional (3D) implants with retinal tissue, we fabricated arrays with varying pillar diameter, pitch, and height, and implanted beneath the degenerate retina in rats (Royal College of Surgeons, RCS). Tissue integration was evaluated six weeks post-op using histology and whole-mount confocal fluorescence imaging. The electric field generated by various electrode configurations was calculated in COMSOL, and stimulation thresholds assessed using a model of network-mediated retinal response. MAIN RESULTS: Retinal tissue migrated into the space between pillars with no visible gliosis in 90% of implanted arrays. Pillars with 10 µm height reached the middle of the inner nuclear layer (INL), while 22 µm pillars reached the upper portion of the INL. Electroplated pillars with dome-shaped caps increase the active electrode surface area. Selective deposition of sputtered iridium oxide onto the cap ensures localization of the current injection to the pillar top, obviating the need to insulate the pillar sidewall. According to computational model, pillars having a cathodic return electrode above the INL and active anodic ring electrode at the surface of the implant would enable six times lower stimulation threshold, compared to planar arrays with circumferential return, but suffer from greater cross-talk between the neighboring pixels. SIGNIFICANCE: 3D electrodes in subretinal prostheses help reduce electrode-tissue separation and decrease stimulation thresholds to enable smaller pixels, and thereby improve visual acuity of prosthetic vision.

SiC protective coating for photovoltaic retinal prosthesis.

OBJECTIVE: To evaluate plasma-enhanced, chemically vapor deposited (PECVD) amorphous silicon carbide (α-SiC:H) as a protective coating for retinal prostheses and other implantable devices, and to study their failure mechanisms in vivo. APPROACH: Retinal prostheses were implanted in rats sub-retinally for up to 1 year. Degradation of implants was characterized by optical and scanning electron microscopy. Dissolution rates of SiC, SiN x and thermal SiO2 were measured in accelerated soaking tests in saline at 87 °C. Defects in SiC films were revealed and analyzed by selectively removing the materials underneath those defects. MAIN RESULTS: At 87 °C SiN x dissolved at 18.3 ± 0.3 nm d(-1), while SiO2 grown at high temperature (1000 °C) dissolved at 0.104 ± 0.008 nm d(-1). SiC films demonstrated the best stability, with no quantifiable change after 112 d. Defects in thin SiC films appeared primarily over complicated topography and rough surfaces. SIGNIFICANCE: SiC coatings demonstrating no erosion in accelerated aging test for 112 d at 87 °C, equivalent to about 10 years in vivo, can offer effective protection of the implants. Photovoltaic retinal prostheses with PECVD SiC coatings exhibited effective protection from erosion during the 4 month follow-up in vivo. The optimal thickness of SiC layers is about 560 nm, as defined by anti-reflective properties and by sufficient coverage to eliminate defects.

Photovoltaic Pixels for Neural Stimulation: Circuit Models and Performance.

Photovoltaic conversion of pulsed light into pulsed electric current enables optically-activated neural stimulation with miniature wireless implants. In photovoltaic retinal prostheses, patterns of near-infrared light projected from video goggles onto subretinal arrays of photovoltaic pixels are converted into patterns of current to stimulate the inner retinal neurons. We describe a model of these devices and evaluate the performance of photovoltaic circuits, including the electrode-electrolyte interface. Characteristics of the electrodes measured in saline with various voltages, pulse durations, and polarities were modeled as voltage-dependent capacitances and Faradaic resistances. The resulting mathematical model of the circuit yielded dynamics of the electric current generated by the photovoltaic pixels illuminated by pulsed light. Voltages measured in saline with a pipette electrode above the pixel closely matched results of the model. Using the circuit model, our pixel design was optimized for maximum charge injection under various lighting conditions and for different stimulation thresholds. To speed discharge of the electrodes between the pulses of light, a shunt resistor was introduced and optimized for high frequency stimulation.

Contrast Sensitivity With a Subretinal Prosthesis and Implications for Efficient Delivery of Visual Information.

PURPOSE: To evaluate the contrast sensitivity of a degenerate retina stimulated by a photovoltaic subretinal prosthesis, and assess the impact of low contrast sensitivity on transmission of visual information. METHODS: We measure ex vivo the full-field contrast sensitivity of healthy rat retina stimulated with white light, and the contrast sensitivity of degenerate rat retina stimulated with a subretinal prosthesis at frequencies exceeding flicker fusion (>20 Hz). Effects of eye movements on retinal ganglion cell (RGC) activity are simulated using a linear-nonlinear model of the retina. RESULTS: Retinal ganglion cells adapt to high frequency stimulation of constant intensity, and respond transiently to changes in illumination of the implant, exhibiting responses to ON-sets, OFF-sets, and both ON- and OFF-sets of light. The percentage of cells with an OFF response decreases with progression of the degeneration, indicating that OFF responses are likely mediated by photoreceptors. Prosthetic vision exhibits reduced contrast sensitivity and dynamic range, with 65% contrast changes required to elicit responses, as compared to the 3% (OFF) to 7% (ON) changes with visible light. The maximum number of action potentials elicited with prosthetic stimulation is at most half of its natural counterpart for the ON pathway. Our model predicts that for most visual scenes, contrast sensitivity of prosthetic vision is insufficient for triggering RGC activity by fixational eye movements. CONCLUSIONS: Contrast sensitivity of prosthetic vision is 10 times lower than normal, and dynamic range is two times below natural. Low contrast sensitivity and lack of OFF responses hamper delivery of visual information via a subretinal prosthesis.

Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration.

PURPOSE: Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration. METHODS: Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns. RESULTS: We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina. CONCLUSIONS: Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.

Performance of photovoltaic arrays in-vivo and characteristics of prosthetic vision in animals with retinal degeneration.

Loss of photoreceptors during retinal degeneration leads to blindness, but information can be reintroduced into the visual system using electrical stimulation of the remaining retinal neurons. Subretinal photovoltaic arrays convert pulsed illumination into pulsed electric current to stimulate the inner retinal neurons. Since required irradiance exceeds the natural luminance levels, an invisible near-infrared (915 nm) light is used to avoid photophobic effects. We characterized the thresholds and dynamic range of cortical responses to prosthetic stimulation with arrays of various pixel sizes and with different number of photodiodes. Stimulation thresholds for devices with 140 µm pixels were approximately half those of 70 µm pixels, and with both pixel sizes, thresholds were lower with 2 diodes than with 3 diodes per pixel. In all cases these thresholds were more than two orders of magnitude below the ocular safety limit. At high stimulation frequencies (>20 Hz), the cortical response exhibited flicker fusion. Over one order of magnitude of dynamic range could be achieved by varying either pulse duration or irradiance. However, contrast sensitivity was very limited. Cortical responses could be detected even with only a few illuminated pixels. Finally, we demonstrate that recording of the corneal electric potential in response to patterned illumination of the subretinal arrays allows monitoring the current produced by each pixel, and thereby assessing the changes in the implant performance over time.

Cortical responses elicited by photovoltaic subretinal prostheses exhibit similarities to visually evoked potentials.

We have previously developed a wireless photovoltaic retinal prosthesis, in which camera-captured images are projected onto the retina using pulsed near-IR light. Each pixel in the subretinal implant directly converts pulsed light into local electric current to stimulate the nearby inner retinal neurons. Here we report that implants having pixel sizes of 280, 140 and 70 µm implanted in the subretinal space in rats with normal and degenerate retina elicit robust cortical responses upon stimulation with pulsed near-IR light. Implant-induced eVEP has shorter latency than visible light-induced VEP, its amplitude increases with peak irradiance and pulse duration, and decreases with frequency in the range of 2-20 Hz, similar to the visible light response. Modular design of the arrays allows scalability to a large number of pixels, and combined with the ease of implantation, offers a promising approach to restoration of sight in patients blinded by retinal degenerative diseases.

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 surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems, which 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 was produced in normal and degenerate rat retinas, with pulse durations from 0.5 to 4 ms, and threshold peak irradiances from 0.2 to 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.