Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration.

A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to partially restore vision in patients with retinal diseases that have resulted in the loss of photoreceptors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been major breakthroughs in retinal prosthesis technology, with the creation of numerous types of implants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate the remaining cells in the retina with electric signals to create a visual sensation. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying electronic retinal prostheses. Engineering aspects are explored, including electrode-retina alignment, electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events, visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing debate over whether implantable retinal devices still offer a promising approach for the treatment of retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as optogenetics. This review compares retinal prostheses with these alternative therapies, providing a balanced perspective on their advantages and limitations. The recent advancements in retinal prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of retinal prostheses. While acknowledging the challenges and complexities of the technology, this article highlights the significant potential of retinal prostheses for vision restoration in individuals with retinal diseases and calls for continued research and development to refine and enhance their performance, ultimately improving patient outcomes and quality of life.

Improved performance and safety from Argus II retinal prosthesis post-approval study in France.

PURPOSE: To evaluate the post-approval long-term outcomes of the Argus II Retinal Prosthesis, with a specific focus on its functional visual benefit in patients' daily activities. METHODS: Eighteen patients with bare light perception due to end-stage retinitis pigmentosa were included in a French prospective, multicentre, single-arm study and followed for 2 years. Visual benefit in patients' daily activities was monitored through the use of the Functional Low-vision Observer Rated Assessment (FLORA), and the final score at 2 years was the primary effectiveness outcome. Standardized visual assessments were also performed. Device- or procedure-related adverse events were recorded. RESULTS: Seventeen subjects completed the study. Positive impacts of the Argus II system on functional vision and well-being were demonstrated for over 70% of subjects on the FLORA. Among the daily activities/tasks tested, finding doorways was one of the most statistically significantly improved tasks (p < 0.001), along with estimating the size of an obstacle (p < 0.001), visually locating a place setting on a dining table (p < 0.001) and visually locating people in a non-crowded setting (p < 0.001). Visual function was improved on most standardized tests. Only two device- or procedure-related serious adverse events were observed (one vitreous haemorrhage and one endophthalmitis, both resolved with treatment). No explantation was required. CONCLUSION: This first report of a completed post-approval study of Argus II with a two-year follow-up demonstrates the safety and effectiveness of the Argus II System in a real-world cohort of patients and further highlights its real functional benefit in implanted patients' daily activities.

Improved visual acuity using a retinal implant and an optimized stimulation strategy.

OBJECTIVE: Retinal prosthetic devices hold great promise for the treatment of retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Through electrical stimulation of the surviving retinal neurons, these devices evoke visual signals that are then relayed to the brain. Currently, the visual prostheses used in clinical trials have few electrodes, thus limiting visual acuity. Electrode arrays with high electrode densities have been developed using novel technologies, including diamond growth and laser machining, and these may provide a more promising route to achieve high visual acuity in blind patients. APPROACH: Here, we studied the potential spatial resolution of electrical stimulation using diamond electrodes. We did this by labeling retinal ganglion cells in whole mount retina with a calcium indicator in wild-type rats and those with retinal degeneration. We imaged the ganglion cell responses to a range of stimulation parameters, including pulse duration and return electrode configuration. MAIN RESULTS: With sub-retinal stimulation, in which electrodes were in contact with the intact or degenerated photoreceptor layer, we found that biphasic pulses of 0.1 ms phase duration and a local return configuration was the most effective in confining the retinal ganglion cell activation patterns, while also remaining within the safety limits of the materials and providing the best power efficiency. SIGNIFICANCE: These results provide an optimized stimulation strategy for retinal implants, which if implemented in a retinal prosthetic is expected to improve the achievable visual acuity.

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.

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.

An optimized content-aware image retargeting method: toward expanding the perceived visual field of the high-density retinal prosthesis recipients.

OBJECTIVE: Retinal prosthesis devices have shown great value in restoring some sight for individuals with profoundly impaired vision, but the visual acuity and visual field provided by prostheses greatly limit recipients' visual experience. In this paper, we employ computer vision approaches to seek to expand the perceptible visual field in patients implanted potentially with a high-density retinal prosthesis while maintaining visual acuity as much as possible. APPROACH: We propose an optimized content-aware image retargeting method, by introducing salient object detection based on color and intensity-difference contrast, aiming to remap important information of a scene into a small visual field and preserve their original scale as much as possible. It may improve prosthetic recipients' perceived visual field and aid in performing some visual tasks (e.g. object detection and object recognition). To verify our method, psychophysical experiments, detecting object number and recognizing objects, are conducted under simulated prosthetic vision. As control, we use three other image retargeting techniques, including Cropping, Scaling, and seam-assisted shrinkability. MAIN RESULTS: Results show that our method outperforms in preserving more key features and has significantly higher recognition accuracy in comparison with other three image retargeting methods under the condition of small visual field and low-resolution. SIGNIFICANCE: The proposed method is beneficial to expand the perceived visual field of prosthesis recipients and improve their object detection and recognition performance. It suggests that our method may provide an effective option for image processing module in future high-density retinal implants.

Electrophysiological testing of visual function after mirror telescope implantation: a case report.

PURPOSE: The implantation of an intraocular telescope increases life quality in patients with end-stage age-related macular degeneration (AMD). The present study monitored changes in electrophysiological markers of visual processing before and during seventeen months after a novel mirror telescope implantation in two patients (OV-male 90 years, MZ-female 70 years) with the final-stage form of AMD. METHODS: Visual evoked potentials were recorded to high-contrast pattern-reversal (PR-VEP for check size 40' and 10'), low-contrast motion-onset stimuli (in visual periphery M-VEP M20°, and in central part M-VEP C8°), and event-related potentials (ERPs) in the oddball visual paradigm. RESULTS: MZ's more systematic responses showed attenuation and prolongation of the M-VEP M20° and the PR-VEP 40' immediately after the telescope implantation with a slow amplitude recovery with unchanged prolonged latency. The implantation completely eradicated the M-VEP C8° without any restoration. The PR-VEP 10' were not readable. Only a part of OV's PR-VEP 40' and M-VEP M20' were of a repeatable and expected morphology. These OV's VEPs were consistent with MZ's findings. The ERPs did not show any effect of implantation in both patients. Post-implantation visual acuity and reaction time overcame the pre-implantation levels. CONCLUSIONS: The mirror telescope preserved peripheral vision in contrast to classic telescopes; however, the telescope concurrently reduced the luminance of the magnified retinal image, which was likely responsible for the prolongation of the VEP latencies.

Long-term evaluation of a liquid crystal polymer (LCP)-based retinal prosthesis.

OBJECTIVE: The aim of this study is to evaluate the long-term reliability of a recently presented liquid crystal polymer (LCP) -based retinal prosthesis in vitro as well as in vivo. Because an all-polymer implant introduces another intrinsic leak type due to gas permeation, for which the traditional helium leak test for metallic packages was not designed to quantify, a new method to investigate its durability is required. APPROACH: We designed and carried out a series of reliability tests specifically for all-polymer implants by quantitatively investigating moisture ingress through various pathways of the polymer surface, and the polymer-polymer and polymer-metal adhesions. Moisture permeation through the bulk material was estimated by analytic calculation, while water ingress through the adhesively sealed LCP-LCP and LCP-metal interfaces was investigated using the separate parts of an electrode array and a package in an accelerated aging condition. In vivo tests were done in rabbits to examine the long-term biocompatibility and implantation stability by fundus observation and optical coherence tomography (OCT) imaging. MAIN RESULTS: The analytic calculation estimated good barrier properties of the LCP. Samples of the LCP-based electrode array failed after 114 days in 87 °C saline as a result of water penetration through the LCP-metal interface. An eye-conformable LCP package survived for 87 days in an accelerated condition at 87 °C. The in vivo results confirmed that no adverse effects were observed around the retina 2.5 years after the implantation of the device. SIGNIFICANCE: These long-term evaluation results show the potential for the chronic use of LCP-based biomedical implants to provide an alternative to traditional metallic packages.

Eye movements as a marker for visual prosthesis spatial mapping - A feasibility study using a blind patient implanted with the Argus II retinal prosthesis.

Spatial mapping, the location in space of a perceived location due to an implanted electrode's electrical stimulation is important in the design of visual prostheses. Generally, a visual prosthesis system consists of an implanted electrode array, an external camera that acquires the image, and a transmitter that sends the information to the implanted electrodes. In cortical visual implant, the layout of the implanted array in most cases does not match the retinotopic map and it is necessary to find the location of the percept of each electrode in world coordinates. Herein, we show the feasibility of using eye movements as markers to construct the spatial map of the implanted electrodes. A blind patient implanted with the Argus II retinal prosthesis was instructed to conduct an eye movement to the location of a percept generated by an electrical stimulation at different retinal locations. By analyzing the eye movements triggered by the electrical stimulation, we were able to reconstruct the spatial map of the electrodes. Our experiment demonstrates that a blind person still maintains control of eye movements that can be used to map the percept location of the implanted electrodes.

Oculomotor behavior of blind patients seeing with a subretinal visual implant.

Electronic implants are able to restore some visual function in blind patients with hereditary retinal degenerations. Subretinal visual implants, such as the CE-approved Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany), sense light through the eye's optics and subsequently stimulate retinal bipolar cells via ∼1500 independent pixels to project visual signals to the brain. Because these devices are directly implanted beneath the fovea, they potentially harness the full benefit of eye movements to scan scenes and fixate objects. However, so far, the oculomotor behavior of patients using subretinal implants has not been characterized. Here, we tracked eye movements in two blind patients seeing with a subretinal implant, and we compared them to those of three healthy controls. We presented bright geometric shapes on a dark background, and we asked the patients to report seeing them or not. We found that once the patients visually localized the shapes, they fixated well and exhibited classic oculomotor fixational patterns, including the generation of microsaccades and ocular drifts. Further, we found that a reduced frequency of saccades and microsaccades was correlated with loss of visibility. Last, but not least, gaze location corresponded to the location of the stimulus, and shape and size aspects of the viewed stimulus were reflected by the direction and size of saccades. Our results pave the way for future use of eye tracking in subretinal implant patients, not only to understand their oculomotor behavior, but also to design oculomotor training strategies that can help improve their quality of life.

Assessing the utility of visual acuity measures in visual prostheses.

There are presently several ongoing clinical trials to provide usable sight to profoundly visually impaired patients by means of electrical stimulation of the retina. Some of the blind patients implanted with retinal prosthesis reported un-patterned perception and yet benefit from the device in many activities of daily living, seemingly because they adopt active scanning strategies. The aim of the present work is to evaluate if and under what conditions a measured visual acuity level is truly an indication that the brain perceived a patterned image from the electrical stimulation of the visual prosthesis. Sighted subjects used a pixelized simulator in which they perceived either a low resolution sub-sampling of the original image ("normal mode"--patterned vision) or an image that was solely a function of the brightness and size of the original image ("brightness mode"--no patterned vision). Results show that subjects were able to adopt a head scanning strategy that enabled acuity beyond the resolution set by a static view of the stimulus. In brightness mode, i.e. without patterned vision, most subjects achieved a measurable acuity level better than the limit set by the geometrical resolution of the entire array but worse than the limit set by the distance between neighboring simulated pixels. In normal mode all subject achieved acuity level that is better than the geometrical resolution of the simulated pixels. Thus, visual acuity levels comparable with the electrodes/pixels resolution implies that the patient perceives an image with spatial patterns.

High-fidelity reproduction of spatiotemporal visual signals for retinal prosthesis.

Natural vision relies on spatiotemporal patterns of electrical activity in the retina. We investigated the feasibility of veridically reproducing such patterns with epiretinal prostheses. Multielectrode recordings and visual and electrical stimulation were performed on populations of identified ganglion cells in isolated peripheral primate retina. Electrical stimulation patterns were designed to reproduce recorded waves of activity elicited by a moving visual stimulus. Electrical responses in populations of ON parasol cells exhibited high spatial and temporal precision, matching or exceeding the precision of visual responses measured in the same cells. Computational readout of electrical and visual responses produced similar estimates of stimulus speed, confirming the fidelity of electrical stimulation for biologically relevant visual signals. These results suggest the possibility of producing rich spatiotemporal patterns of retinal activity with a prosthesis and that temporal multiplexing may aid in reproducing the neural code of the retina.

Chronic electrical stimulation with a suprachoroidal retinal prosthesis: a preclinical safety and efficacy study.

PURPOSE: To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. METHODS: Seven normally-sighted feline subjects were implanted for 96-143 days with a suprachoroidal electrode array and six were chronically stimulated for 70-105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. RESULTS: All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11-15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. CONCLUSIONS: Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.

Safety ensuring retinal prosthesis with precise charge balance and low power consumption.

Ensuring safe operation of stimulators is the most important issue in neural stimulation. Safety, in terms of stimulators' electrical performances, can be related mainly to two factors; the zero-net charge transfer to tissue and the heat generated by power dissipation at tissue. This paper presents a safety ensuring neuro-stimulator for retinal vision prostheses, featuring precise charge balancing capability and low power consumption, using a 0.35 µm HV (high voltage) CMOS process. Also, the required matching accuracy of the biphasic current pulse for safe stimulation is mathematically derived. Accurate charge balance is achieved by employing a dynamic current mirror at the output of a stimulator. In experiments, using a simple electrode model (a resistor (R) and a capacitor (C) in parallel), the proposed stimulator ensures less than 30 nA DC current flowing into tissue over all stimulation current ranges (32 µA-1 mA), without shorting. With shorting enabled, further reduction is achieved down to 1.5 nA. Low power consumption was achieved by utilising small bias current, sharing of key biasing blocks, and utilising a short duty cycle for stimulation. Less than 30 µW was consumed during stand-by mode, mostly by bias circuitry.

A standardized obstacle course for assessment of visual function in ultra low vision and artificial vision.

We describe an indoor, portable, standardized course that can be used to evaluate obstacle avoidance in persons who have ultralow vision. Six sighted controls and 36 completely blind but otherwise healthy adult male (n=29) and female (n=13) subjects (age range 19-85 years), were enrolled in one of three studies involving testing of the BrainPort sensory substitution device. Subjects were asked to navigate the course prior to, and after, BrainPort training. They completed a total of 837 course runs in two different locations. Means and standard deviations were calculated across control types, courses, lights, and visits. We used a linear mixed effects model to compare different categories in the PPWS (percent preferred walking speed) and error percent data to show that the course iterations were properly designed. The course is relatively inexpensive, simple to administer, and has been shown to be a feasible way to test mobility function. Data analysis demonstrates that for the outcome of percent error as well as for percentage preferred walking speed, that each of the three courses is different, and that within each level, each of the three iterations are equal. This allows for randomization of the courses during administration.

Performance of conducting polymer electrodes for stimulating neuroprosthetics.

OBJECTIVE: Recent interest in the use of conducting polymers (CPs) for neural stimulation electrodes has been growing; however, concerns remain regarding the stability of coatings under stimulation conditions. These studies examine the factors of the CP and implant environment that affect coating stability. The CP poly(ethylene dioxythiophene) (PEDOT) is examined in comparison to platinum (Pt), to demonstrate the potential performance of these coatings in neuroprosthetic applications. APPROACH: PEDOT is coated on Pt microelectrode arrays and assessed in vitro for charge injection limit and long-term stability under stimulation in biologically relevant electrolytes. Physical and electrical stability of coatings following ethylene oxide (ETO) sterilization is established and efficacy of PEDOT as a visual prosthesis bioelectrode is assessed in the feline model. MAIN RESULTS: It was demonstrated that PEDOT reduced the potential excursion at a Pt electrode interface by 72% in biologically relevant solutions. The charge injection limit of PEDOT for material stability was found to be on average 30× larger than Pt when tested in physiological saline and 20× larger than Pt when tested in protein supplemented media. Additionally stability of the coating was confirmed electrically and morphologically following ETO processing. It was demonstrated that PEDOT-coated electrodes had lower potential excursions in vivo and electrically evoked potentials (EEPs) could be detected within the visual cortex. SIGNIFICANCE: These studies demonstrate that PEDOT can be produced as a stable electrode coating which can be sterilized and perform effectively and safely in neuroprosthetic applications. Furthermore these findings address the necessity for characterizing in vitro properties of electrodes in biologically relevant milieu which mimic the in vivo environment more closely.