OBJECTIVE:To describe the histological findings 7 weeks and 18 months after subretinal implantation of the PRIMA photovoltaic array in eyes with geographic atrophy. DESIGN:Comparative case series SUBJECTS: and controls: Four globes of two deceased study participants from the prospective PRIMAvera study were analyzed. METHODS:The subretinal implant was removed after horizontal sectioning of the globe. Serial sections were performed and stained with hematoxylin-eosin, Masson trichrome as well as periodic acid Schiff for histopathologic analysis. Selected sections were immunohistochemically stained for CD68, CD163, GFAP, CD31, CK18, ARR3, RPBMS, and TRPM1. Both study and fellow eyes were analyzed. MAIN OUTCOME MEASURES:The histopathological analysis focused on the anatomical implant localization, wound healing processes, potential inflammatory reactions adjacent to the implant and at the retinotomy site, the development of retinal gliosis and retinal atrophy as well as a potential encapsulation. RESULTS:Both implants could be removed in toto without obvious retinal trauma. Histologically, the implants were located at the level of the outer plexiform layer, as intended, close to the inner nuclear layer. A tissue layer was identified beneath the implant, consisting of a basement membrane deposit and cellular components. A small rupture of Bruch's membrane was detected (in the globe with an 18 months follow-up) associated with localized subretinal fibrosis. At the implant-retina interface, there was only a minimal tissue response without pseudocapsule formation. Furthermore, no significant inflammatory response was detected. The retina overlying the implant was comparable to the fellow eyes in most areas, with limited focal atrophy of the inner retina 18 months after PRIMA implantation. At the retinotomy site, a full thickness scar was noted with mild atrophic changes in the implant insertion area. CONCLUSIONS:The wireless subretinal PRIMA implant demonstrated good biocompatibility with no significant encapsulation or surrounding inflammatory response. At seven weeks and eighteen months after implantation, retina overlying the implant was viable and layered as in control areas. Histopathologic analysis following innovative surgical techniques can provide important information in addition to in vivo findings.

Augmented reality glasses typically have poor optical efficiency (<1%), which is detrimental for high power applications, such as prosthetic vision. Maxwellian view optics are a candidate for increasing efficiency, but suffer from a very limited exit pupil and thus field of view. Many approaches to extend the eyebox inherently decrease the optical power. We present a design that uses a high-density VCSEL array and eye tracking to create an extended eyebox without sacrificing the advantages of a Maxwellian view display. Our system achieves a 20 degree field of view, a resolution 48.8 LP/mm (10 μm), and an end-to-end optical efficiency of 83%

Photovoltaic subretinal prosthesis can restore central vision in patients blinded by age-related macular degeneration with letter acuity matching its 100 µm pixel size. Improving resolution requires smaller pixels, but to still reach the target neurons, electric field should be less confined. However, wide-spreading field may engage adjacent photoreceptors and alter the visual perception. We studied the effects of residual photoreceptors on retinal responses to electrical stimulation using monopolar and bipolar photovoltaic arrays implanted subretinally in Long Evans rats with local photoreceptor loss, and compared that to RCS rats lacking all photoreceptors. Patterned retinal activation (880 nm, 0.5 to 10 ms) was assessed using visually evoked potentials under scotopic and photopic conditions, with and without the intravitreal injection of neurotransmitter blockers. Results were analyzed using a computational model of photoreceptor activation by various electric field configurations. We observed two mechanisms of photoreceptors engagement in electrical activation of the degenerate retina: 1) Dark-adapted photoreceptors near the implant can be simulated directly by a negative electric potential of the common return electrode along the edge of the array. 2) Light-adapted photoreceptors can reduce the stimulation threshold of bipolar cells within about 100 mm from the implant's edge. Both effects may lead to reduced perceptual uniformity. Bipolar pixels with local return electrodes generate better confined electric fields than monopolar arrays and thus are less affected by the nearby photoreceptors. However, even such implants should be placed a few hundred micrometers from the edge of scotoma to minimize the unintended percepts.

Retinal prostheses aim at restoring sight to patients blinded by atrophy of photoreceptors using electrical stimulation of the inner retinal neurons. Bipolar cells can be targeted using subretinal implants, and their responses are then relayed to the central visual pathways via the retinal neural network, preserving many features of natural signal processing. Epiretinal implants stimulate the output retinal layer-ganglion cells-and encode visual information directly in spiking patterns.Several companies and academic groups have demonstrated that electrical stimulation of the degenerate retina can elicit visual percepts. However, most failed to consistently and safely achieve an acceptable level of performance. Recent clinical trials demonstrated that subretinal photovoltaic arrays in patients visually impaired by age-related macular degeneration can provide letter acuity matching their 100 μm pixel pitch, corresponding to 20/420 acuity. Electronic zoom enabled patients to read smaller fonts. This review describes the concepts, technologies, and clinical outcomes of current systems and provides an outlook into future developments.

Vision begins with conformational changes in photopigments. The associated electrical signature, called an early receptor potential (ERP), in rods is limited to contribution of a small fraction of rhodopsin embedded in plasma membrane. Optoretinography (ORG), using phase-sensitive optical coherence tomography, detects nanoscale deformations of retinal cells associated with physiological processes. In previous ORG studies, focused primarily on cones, deformation related to ERP was largely obscured by osmotic swelling and long stimuli. Here, we demonstrate a robust electromechanical signature of photoisomerization in rods. A green flash induces a sub-millisecond contraction of the outer segments by hundreds of nanometers, while a subsequent UV flash reverts the activated molecules, producing an opposite response of similar magnitude. ORG surpasses the sensitivity of electrical methods by integrating the response across all the discs in rod outer segments and it opens the door to fundamental studies of visual transduction in-vivo and to more specific clinical diagnosis.

Patients with age-related macular degeneration (AMD) implanted with the PRIMA photovoltaic subretinal prosthesis demonstrated letter acuity closely matching the device’s 100 µm pixel size. Improving visual acuity requires smaller pixels, which, in turn, require relaxation of electric field confinement to maintain effective stimulation of bipolar cells. Eliminating local return electrodes broadens the electric field but may inadvertently engage residual photoreceptors adjacent to the implant, thereby altering electrically evoked visual percepts. Here we quantify the contribution of residual photoreceptors to electrically evoked retinal responses across various implant configurations. Monopolar photovoltaic arrays with 20 µm pixels and bipolar arrays with 100 µm pixels were implanted subretinally in Long Evans rats, resulting in local degeneration of photoreceptors directly above the device. Responses were compared with those obtained in RCS rats, which lack functional photoreceptors. Implants were activated by patterns of 880 nm laser at pulse durations varying from 0.5 to 10 ms. Visually evoked potentials were measured in scotopic and photopic conditions, with and without the intravitreal application of mGluR6 agonist L-AP4 to block photoreceptor-driven ON pathways. Experimental thresholds were interpreted using a computational model of retinal network activation in distinct electric field geometries. In locally degenerate retina stimulated with monopolar arrays, blocking photoreceptor input yielded a rheobase (0.06 mW/mm²) and chronaxie (∼3 ms) of the stimulation threshold, matching that measured in fully degenerate RCS retina, indicating direct activation of bipolar cells. In contrast, when photoreceptor input was intact, stimulation thresholds decreased significantly, and dark adaptation further modulated the threshold in a pulse-duration dependent manner. Bipolar arrays provided identical thresholds in locally degenerate and fully degenerate retina (0.2 mW/mm²) when stimulation was confined to the implant center; however, shifting stimulation to the implant’s edge lowered the thresholds, revealing a contribution from adjacent photoreceptors. These findings demonstrate that residual photoreceptors can substantially influence responses evoked by subretinal prostheses in a degenerate retina, with direct consequences for perceptual uniformity in patients, such as edge brightening. These results provide guidance for design of the next-generation higher-resolution implants, supporting the use of local return electrodes to maximize resolution while minimizing the effect of photoreceptors in clinical applications.

Objective.Clinical trials of the photovoltaic subretinal prosthesis PRIMA demonstrated feasibility of prosthetic central vision with resolution matching its 100µm pixel width. To improve prosthetic acuity further, pixel size should be decreased. However, there are multiple challenges, one of which is related to accommodating a compact shunt resistor within each pixel that discharges the electrodes between stimulation pulses and helps increase the contrast of the electric field pattern. Unfortunately, standard materials used in integrated circuit resistors do not match the resistivity required for small photovoltaic pixels. Therefore, we used a novel material-doped amorphous silicon (a-Si) and integrated it into photovoltaic arrays with pixel sizes down to 20µm.Approach.To fit within a fewµm2area of the pixels and provide resistance in the MΩ range, the material should have sheet resistance of a few 100 kΩ sq-1, which translates to resistivity of a few Ω * cm. The a-Si layer was deposited by low-pressure chemical vapor deposition and its resistivity was adjusted by PH3doping before encapsulating the resistors between SiO2and SiC for stabilityin-vivo. Main results.High-resolution retinal implants with integrated shunt resistors were fabricated with values ranging from 0.75 to 4 MΩ on top of the photovoltaic pixels of 55, 40, 30 and 20µm in size. Photoresponsivity with all pixel sizes was approximately 0.53 A W-1, as high as in the arrays with no shunt resistor. The shunts shortened electrodes discharge time, with the average electric potential in electrolyte decreasing by only 21%-31 % when repetition rate increased from 2 to 30 Hz, as opposed to a 54%-55 % decrease without a shunt. Similarly, contrast of a Landolt C pattern increased from 16%-22 % with no shunt to 22%-34 % with a shunt. Further improvement in contrast is expected with pillar electrodes and local returns within each pixel.Significance.Miniature shunt resistors in a MΩ range can be fabricated from doped a-Si in a process compatible with manufacturing of photovoltaic arrays. The shunt resistors improved current injection and spatial contrast at video frame rates, without compromising the photoresponsivity. These advances are critical for scaling pixel sizes below 100 µm to improve visual acuity of prosthetic vision.

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.

BACKGROUND:Geographic atrophy due to age-related macular degeneration (AMD) is the leading cause of irreversible blindness and affects more than 5 million persons worldwide. No therapies to restore vision in such persons currently exist. The photovoltaic retina implant microarray (PRIMA) system combines a subretinal photovoltaic implant and glasses that project near-infrared light to the implant in order to restore sight to areas of central retinal atrophy. METHODS:We conducted an open-label, multicenter, prospective, single-group, baseline-controlled clinical study in which the vision of participants with geographic atrophy and a visual acuity of at least 1.2 logMAR (logarithm of the minimum angle of resolution) was assessed with PRIMA glasses and without PRIMA glasses at 6 and 12 months. The primary end points were a clinically meaningful improvement in visual acuity (defined as ≥0.2 logMAR) from baseline to month 12 after implantation and the number and severity of serious adverse events related to the procedure or device through month 12. RESULTS:A total of 38 participants received a PRIMA implant, of whom 32 were assessed at 12 months. Of the 6 participants who were not assessed, 3 had died, 1 had withdrawn, and 2 were unavailable for testing. Among the 32 participants who completed 12 months of follow-up, the PRIMA system led to a clinically meaningful improvement in visual acuity from baseline in 26 (81%; 95% confidence interval, 64 to 93; P<0.001). Using multiple imputation to account for the 6 participants with missing data, we estimated that 80% (95% CI, 66 to 94; P<0.001) of all participants would have had a clinically meaningful improvement at 12 months. A total of 26 serious adverse events occurred in 19 participants. Twenty-one of these events (81%) occurred within 2 months after surgery, of which 20 (95%) resolved within 2 months after onset. The mean natural peripheral visual acuity after implantation was equivalent to that at baseline. CONCLUSIONS:In this study involving 38 participants with geographic atrophy due to AMD, the PRIMA system restored central vision and led to a significant improvement in visual acuity from baseline to month 12. (Funded by Science Corporation and the Moorfields National Institute for Health and Care Research Biomedical Research Centre; PRIMAvera ClinicalTrials.gov number, NCT04676854.).

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.

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/mm 2 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/mm 2 . Such threshold is significantly lower than 1.8 mW/mm 2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Small animals, such as rodents, are attractive options for investigating the intrinsic process of retinal degeneration. In this study, we used phase-sensitive optical coherence tomography to explore the comprehensive dynamics of rats' outer retinas in response to visual stimuli. By calculating the temporal phase difference between different outer retinal bands, we revealed highly reproducible retinal dynamics, on the order of tens of nanometers, related to different parts of the outer retina. Our approach may pave the way for preclinical optoretinography study in small animals, facilitating clinical translations for the early detection of neurodegenerative diseases.

ObjectiveTo assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation.DesignFirst-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954).SubjectsFive patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 (20/400-20/1000) in their worse-seeing “study” eye.MethodsIn patients subretinally implanted with a photovoltaic neurostimulation array containing 378 pixels of 100 μm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The system’s external components, augmented reality glasses and pocket computer, provide image processing capabilities, including zoom.Main Outcome MeasuresVA using ETDRS charts with and without the system, as well as light sensitivity in the central visual field, measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post-implantation.ResultsAll five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery, nor during the 48 months follow-up period (p=0.08).ConclusionsSubretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Prosthetic central vision provided by photovoltaic neurostimulation enabled patients to reliably recognize letters and sequences of letters, and with zoom it improved VA of up to eight ETDRS lines.

Phototransduction involves changes in concentration of ions and other solutes within photoreceptors and in subretinal space, which affect osmotic pressure and the associated water flow. Corresponding expansion and contraction of cellular layers can be imaged using optoretinography (ORG), based on phase-resolved optical coherence tomography (OCT). Until now, ORG could reliably detect only photoisomerization and phototransduction in photoreceptors, primarily in cones under very bright stimuli. By employing a novel subpixel bulk motion correction algorithm, which enabled imaging of the nanometer-scale tissue dynamics during minute-long recordings, and unsupervised learning of spatiotemporal patterns, we discovered optical signatures of the other retinal structures’ response to visual stimuli. These include inner and outer segments of rod photoreceptors, retinal pigment epithelium, and subretinal space in general. High sensitivity of our technique enabled detection of the retinal responses to very dim stimuli: down to 0.01% bleach level, corresponding to natural levels of scotopic illumination. We also demonstrated that with a single flash, the optoretinogram can map retinal responses across a 12°field of view, potentially replacing multifocal electroretinography, with its long acquisition time and low spatial resolution. This new technique expands the diagnostic capabilities and practical applicability of optoretinography, providing a more complete replacement of electroretinography, while combining structural and functional retinal imaging in the same OCT machine.