Retinal Prosthesis Research Articles

PRPF31-retinitis pigmentosa: Challenges and opportunities for clinical translation

Mutations in pre-mRNA processing factor 31 cause autosomal dominant retinitis pigmentosa (PRPF31-RP), for which there is currently no efficient treatment, making this disease a prime target for the development of novel therapeutic strategies. PRPF31-RP exhibits incomplete penetrance due to haploinsufficiency, in which reduced levels of gene expression from the mutated allele result in disease. A variety of model systems have been used in the investigation of disease etiology and therapy development. In this review, we discuss recent advances in both in vivo and in vitro model systems, evaluating their advantages and limitations in the context of therapy development for PRPF31-RP. Additionally, we describe the latest approaches for treatment, including AAV-mediated gene augmentation, genome editing, and late-stage therapies such as optogenetics, cell transplantation, and retinal prostheses.

2D Semiconductor‐Based Optoelectronics for Artificial Vision

AbstractArtificial retina technologies aim to restore visual function by mimicking the natural processes of the eye. These biomimetic devices can convert light into electrical signals that the brain can interpret as visual information, bypassing damaged or non‐functional cells of the eye. To be effective, these devices should possess high sensitivity to light, high spatial resolution, biocompatibility, power efficiency, and so on. Recently, 2D semiconductor materials have appeared as a promising candidate for artificial retinal devices, thanks to their excellent optoelectronic properties, ultrathin body, flexible nature, and biocompatibility. Here the recent developments in the field of 2D semiconductors‐based optoelectronics for visual function recovery are reviewed and their potential applications are discussed. The photodetector, optoelectronic memory, and artificial synapse mechanisms and devices utilized in artificial systems that are based on 2D semiconductor materials are summarized. Additionally, a range of application scenarios for devices that are inspired by retinal cells and vision systems is explored. Finally, it is concluded with an overview of the critical technical challenges and strategies that must be addressed for the successful development of artificial retina technologies. It also highlights the potential for new applications in other fields, such as robotics and artificial intelligence.

Invited Session I: Vision restoration: The New Generation of Visual Cortical Prosthetics.

Since the 1960s, the prospect of developing a visual cortical prosthesis for restoration of useful vision to the blind has tantalized scientists, engineers, and clinicians. After two decades of relative inactivity, interest in this approach has been renewed. There are now multiple active efforts to develop next generation visual prostheses and to bring these devices to clinical implementation. We will review the current state of the field, with a particular emphasis on our own work, and will highlight advances in the field as well challenges that must be overcome to produce a clinically useful prosthetic device.

The Use of Dog Guides for Orientation and Mobility by Individuals With the Argus II Retinal Prosthesis: A Case Series

The Use of Dog Guides for Orientation and Mobility by Individuals With the Argus II Retinal Prosthesis: A Case Series

Surgical Observations From the First 120 Cases of Subretinal Gene Therapy for Inherited Retinal Diseases.

To report surgical observations formulated during the first 120 cases of subretinal gene therapy in patients with inherited retinal degenerations (IRDs). A two-surgeon team compiled surgical observations and formulated surgical pearls based on the consecutive cases of subretinal viral vector injection in patients enrolled in clinical trials focusing on choroideremia, achromatopsia, and RP GTPase regulator associated retinitis pigmentosa, as well as patients with retinal pigment epithelium-specific-65-kDa (RPE65) associated Leber congenital amaurosis receiving Food and Drug Administration-approved voretigene neparvovec-rzyl therapy. One hundred twenty subretinal surgeries were performed by a two-surgeon team. Key anatomical features pertinent to surgical management were noted and are described in this article. Surgical decision making for successful subretinal administration of viral vectors and management of potential surgical challenges were formulated. Lessons learned during subretinal gene therapy cases may be helpful to other surgeons entering clinical trials or performing postapproval gene therapy administration. Surgical pearls outlined in this article may also be helpful for other targeted subretinal therapies, such as cellular transplantation or retinal prosthesis implantation.

Invited Session I: Vision restoration: Deep learning-based stimulus optimization for prosthetic vision.

Visual neuroprostheses are emerging as a promising technology to restore a rudimentary form of vision to people living with incurable blindness. However, phosphenes elicited by current devices often appear artificial and distorted. Although current computational models can predict the neural or perceptual response to an electrical stimulus, an optimal stimulation strategy needs to solve the inverse problem: what is the required stimulus to produce a desired response? Here we frame this as an end-to-end optimization problem, where a deep neural network encoder is trained to invert a psychophysically validated phosphene model that predicts phosphene appearance as a function of stimulus amplitude, frequency, and pulse duration. As a proof of concept, we show that our strategy can produce high-fidelity, patient-specific stimuli representing handwritten digits and segmented images of everyday objects that drastically outperform conventional encoding strategies by relying on smaller stimulus amplitudes at the expense of higher frequencies and longer pulse durations. Overall, this work is an important first step towards improving visual outcomes in visual prosthesis users across a wide range of stimuli.

Strengthen motor imagery for motor disorders patients in metaverse through brain computer interfaces

Both brain-computer interface (BCI) and metaverse technology are emerging research fields involving computer science, neuroscience, psychological, cognitive science, biomedical engineering, mathematics, signal processing, clinical medicine, automatic control, etc. This paper focuses on the role of both in the medical field for patients with motor disorders (MD). MD is mostly caused by neurological diseases or accidental trauma, which often results in the death of nerve cells, loss of synapses and localised neuronal conduction blockage, thereby damaging the neural network’s structural and functional integrity in the brain and disrupting the brain’s information processing processes, resulting in motor paralysis of the limbs. Approximately 3% of the world’s population is currently suffering from severe disabilities, and approximately 110-190 million people are unable to live independently. Of these, nearly 100 million suffer from motor paralysis caused by stroke, cerebrospinal cord injury and amyotrophic lateral sclerosis, which has a serious impact on their daily work and life. Scientists are already using BCI to help people with paralysis caused by neurological damage to the brain, with a lesser contribution from the metaverse. This paper draws on past BCI and biological experiments to logically reason about methodologies such as neurofeedback, motor imagery, visual prosthesis implantation and training to explore future possibilities for treating MD in the interactive world of BCI and the Metaverse.

Contributed Session III: Characteristics of electrically-induced visual percepts in the first human with the Intracortical Visual Prosthesis.

The Intracortical Visual Prosthesis (ICVP) consists of multiple wireless floating microelectrode arrays (WFMAs), each with 16 stimulating electrodes. Stimulation of these electrodes can potentially provide artificial vision for people who are blind. Twenty-five WFMAs were implanted in the right occipital visual cortex of a participant in an FDA-approved, NIH-sponsored Phase 1 clinical trial (NCT04634383). Here, we report characteristics of visual percepts elicited by the WFMAs (frequency: 200 Hz, cathodic phase duration: 200 µs, amplitude and train length up to 60 µA and 900 ms). Stimulation of single electrodes in 10 WFMAs and groups of 4 or more electrodes in 7 additional WFMAs consistently produced percepts during >10 sessions across approximately 3 months of testing. Phosphenes generated within a single WFMA were typically similar in appearance. Descriptions included configurations of rings, bright or dark dots, and constant or flickering bars, with sizes of 0.3-12° across. Phosphenes appeared as blueish-white, or occasionally orange, red, or having an iridescent texture. Ten WFMAs produced phosphenes within a 4° cluster centered 4° below and to the left of fixation. Phosphenes from 4 other WFMAs were located 4° below or 20° left of the cluster. When using these phosphenes to scan a virtual line, the participant was able to discriminate horizontal and vertical lines (46/51 correct, p < 10^-8, binomial test), and 45° and 135° diagonal lines (12/14 correct, p < 0.01).

Flexible optoelectronic synaptic transistors for neuromorphic visual systems

Neuromorphic visual systems that integrate the functionalities of sensing, memory, and processing are expected to overcome the shortcomings of conventional artificial visual systems, such as data redundancy, data access delay, and high-energy consumption. Neuromorphic visual systems based on emerging flexible optoelectronic synaptic devices have recently opened up innovative applications, such as robot visual perception, visual prosthetics, and artificial intelligence. Various flexible optoelectronic synaptic devices have been fabricated, which are either two-terminal memristors or three-terminal transistors. In flexible optoelectronic synaptic transistors (FOSTs), the synaptic weight can be modulated by the electricity and light synergistically, which endows the neuromorphic visual systems with versatile functionalities. In this Review, we present an overview of the working mechanisms, device structures, and active materials of FOSTs. Their applications in neuromorphic visual systems for color recognition, image recognition and memory, motion detection, and pain perception are presented. Perspectives on the development of FOSTs are finally outlined.

Room-temperature-processed transparent hemispherical optoelectronic array for electronic eyes

Bio-inspired electronic eyes mimicking the geometry and function of natural light-sensing organs are highly attractive in next-generation miniaturized imaging systems. The processing of electronic eyes usually adopts complex and equipment-intensive techniques, involving vacuum-based materials growth, doping, deposition and patterning. Here, we report an electronic eye system with a fully transparent artificial retina by a simple solution-based method at room-temperature. The artificial retina contains a flexible 16 × 16 photodetector array, which composes of a ZnO nanoparticle-MoS2 nanosheet composite film as the light sensing unit and the patterned silver nanowires as conductive paths within 1 cm2. It shows a reliable ultra-violet response and high transparence across the visible and near-infrared range, and hence allows the artificial retina to perceive light from all directions without weakening the photo-response. Demonstrations of two kinds of electronic eye prototypes (concave and convex hemispheres) in a single device configuration show the possibility for double-sided imaging. This work provides a simple, rapid and high-throughput processing route for bio-inspired electronic eye that could be used for integration of various functional materials with different properties, which opens a new avenue for the multifunctional electronic eye devices.

Calcium Imaging In Electrically Stimulated Flat-Mounted Retinas.

Retinal dystrophies are a leading cause of blindness worldwide. Extensive efforts are underway to develop advanced retinal prostheses that can bypass the impaired light-sensing photoreceptor cells in the degenerated retina, aiming to partially restore vision by inducing visual percepts. One common avenue of investigation involves the design and production of implantable devices with a flexible physical structure, housing a high number of electrodes. This enables the efficient and precise generation of visual percepts. However, with each technological advancement, there arises a need for a reliable and manageable ex vivo method to verify the functionality of the device before progressing to in vivo experiments, where factors beyond the device's performance come into play. This article presents a comprehensive protocol for studying calcium activity in the retinal ganglion cell layer (GCL) following electrical stimulation. Specifically, the following steps are outlined: (1) fluorescently labeling the rat retina using genetically encoded calcium indicators, (2) capturing the fluorescence signal using an inverted fluorescence microscope while applying distinct patterns of electrical stimulation, and (3) extracting and analyzing the calcium traces from individual cells within the GCL. By following this procedure, researchers can efficiently test new stimulation protocols prior to conducting in vivo experiments.

Current Assistive Devices Usage and Recommendations for a Future Artificial Vision Prosthesis among Patients with Severe Visual Impairment Due to Inherited Retinal Diseases.

Patients with inherited retinal diseases (IRDs) utilize various adaptive techniques and devices designed to assist them with activities of daily living (ADLs). The purpose of this study was to assess the assistive devices used by patients with IRDs, the difficulties they face despite these devices, and their recommendations for a future visual prosthesis. In collaboration with blind patients, an online survey was developed and administered to adults with IRDs and visual acuities of 20/400 to no light perception in the better-seeing eye. We analyzed data from 121 survey respondents (aged 18 to >80 years). Five respondents were Argus II prosthesis recipients. The most commonly used aids were cellular phones/tablets for reading (63.6%) as well as a sighted guide (75.0%) and a cane (71.4%) for mobility. Despite current assistive devices, participants reported continued difficulty with ADLs. Improved navigation, reading, and facial recognition were ranked the most desirable features for future visual prostheses. Argus II recipients suggested technology with improved ability to recognize objects and obstacles, detect movement, and cut out busy backgrounds. These insights are valuable in shaping the design of future prosthetic devices tailored to the needs of IRD patients.

A novel simulation paradigm utilising MRI-derived phosphene maps for cortical prosthetic vision

Objective. We developed a realistic simulation paradigm for cortical prosthetic vision and investigated whether we can improve visual performance using a novel clustering algorithm. Approach. Cortical visual prostheses have been developed to restore sight by stimulating the visual cortex. To investigate the visual experience, previous studies have used uniform phosphene maps, which may not accurately capture generated phosphene map distributions of implant recipients. The current simulation paradigm was based on the Human Connectome Project retinotopy dataset and the placement of implants on the cortices from magnetic resonance imaging scans. Five unique retinotopic maps were derived using this method. To improve performance on these retinotopic maps, we enabled head scanning and a density-based clustering algorithm was then used to relocate centroids of visual stimuli. The impact of these improvements on visual detection performance was tested. Using spatially evenly distributed maps as a control, we recruited ten subjects and evaluated their performance across five sessions on the Berkeley Rudimentary Visual Acuity test and the object recognition task. Main results. Performance on control maps is significantly better than on retinotopic maps in both tasks. Both head scanning and the clustering algorithm showed the potential of improving visual ability across multiple sessions in the object recognition task. Significance. The current paradigm is the first that simulates the experience of cortical prosthetic vision based on brain scans and implant placement, which captures the spatial distribution of phosphenes more realistically. Utilisation of evenly distributed maps may overestimate the performance that visual prosthetics can restore. This simulation paradigm could be used in clinical practice when making plans for where best to implant cortical visual prostheses.

Double-Glued Multi-Focal Bionic Compound Eye Camera.

Compound eye cameras are a vital component of bionics. Compound eye lenses are currently used in light field cameras, monitoring imaging, medical endoscopes, and other fields. However, the resolution of the compound eye lens is still low at the moment, which has an impact on the application scene. Photolithography and negative pressure molding were used to create a double-glued multi-focal bionic compound eye camera in this study. The compound eye camera has 83 microlenses, with ommatidium diameters ranging from 400 μm to 660 μm, and a 92.3 degree field-of-view angle. The double-gluing structure significantly improves the optical performance of the compound eye lens, and the spatial resolution of the ommatidium is 57.00 lp mm-1. Additionally, the measurement of speed is investigated. This double-glue compound eye camera has numerous potential applications in the military, machine vision, and other fields.

A multi-scale simulation of retinal physiology

We present a detailed physiological model of the (human) retina that includes the biochemistry and electrophysiology of phototransduction, neuronal electrical coupling, and the spherical geometry of the eye. The model is a parabolic–elliptic system of partial differential equations based on the mathematical framework of the bi-domain equations, which we have generalized to account for multiple cell-types. We discretize in space with non-uniform finite differences and step through time with a custom adaptive time-stepper that employs a backward differentiation formula and an inexact Newton method. A refinement study confirms the accuracy and efficiency of our numerical method. Numerical simulations using the model compare favorably with experimental findings, such as desensitization to light stimuli and calcium buffering in photoreceptors. Other numerical simulations suggest an interplay between photoreceptor gap junctions and inner segment, but not outer segment, calcium concentration. Applications of this model and simulation include analysis of retinal calcium imaging experiments, the design of electroretinograms, the design of visual prosthetics, and studies of ephaptic coupling within the retina.

Computational analysis of efficient organic solar cell-based retinal prosthesis using plasmonic gold nanoparticles.

Photovoltaic restoration of vision, especially in conjunction with the use of silicon photodiodes, has gained attention for use in patients affected by blindness due to retinal layer disease. Although the use of silicon photodiodes offers miniaturization of the implant unit and increase in the stimulation channel, the implant unit may suffer from the fracture of these brittle photodiodes when mechanical pressure exerted. We present an organic solar cell (OSC)-based retinal prosthesis in which spherical gold nanoparticles (AuNPs) are embedded into the active layer to increase the efficiency of the bioelectric interface. We demonstrate computationally that a modeled OSC incorporating spherical AuNPs has three times higher efficiency than that of a bare OSC presented before for retinal prostheses. Our AuNP based OSC was able to activate the neuron at the minimum light intensity of 0.26 mW/mm2, which is lower than that of the bare OSC. The use of AuNPs in OSC allows device miniaturization or lowering of the light exposure required for neural activation using a photovoltaic retinal prosthesis, which can generally be applied in a broad range of neural prostheses.

Low dead space encapsulation and integration of circuits for retinal prosthesis based on cyclic olefin copolymer.

A retinal prosthesis is a device that can provide artificial vision to people who have lost their sight from certain retinal disorder. Because the device needs to be inserted into the body, high flexibility and reliability is required. Recently, devices using thermoplastic polymers such as LCP and COC as substrates have been studied. Being a highly functional integrated device, retinal prosthesis poses many design challenges. Among them, the stimulation chip embedding can be a particularly important task. Although it is common to use a wire bonding method for chip embedding, there are several limitations that are difficult to apply to implantable device. In this investigation, a novel approach is developed for high spaceefficient electrical connections and perform reliable encapsulation of integrated circuits to replace wire bonding. Since designing and manufacturing the stimulator chip used in retinal prosthesis requires non-negligible cost, a silicon die with the identical shape was selected as a substitute for testing purposes.

Transformer-based light-evoked retinal spiking activity prediction.

Retinal visual prosthetic devices aim to restore vision via electrical stimulation delivered on the retina. While a number of devices have been commercially available, the stimulation strategies applied have not met the expectations of end-users. These stimulation strategies involve the neurons being activated based on their spatial properties, regardless of their functions, which may lead to lower visual acuity. The ability to predict light-evoked neural activities thus becomes crucial for the development of a retinal prosthetic device with better visual acuity. In addition to temporal nonlinearity, the spatial relationship between the 2-dimensional light stimulus and the spiking activity of neuron populations is the main barrier to accurate predictions. Recent advances in deep learning offer a possible alternative for neural activity prediction tasks. With proven performance on nonlinear sequential data in fields such as natural language processing and computer vision, the emerging transformer model may be adapted to predict neural activities. In this study, we built and evaluated a deep learning model based on the transformer to explore its predictive capacity in light-evoked retinal spikes. Our preliminary results show that the model is possible to achieve good performance in this task. The high versatility of deep learning models may allow us to make retinal activity predictions in more complex physiological environments and potentially enhance the visual acuity of retinal prosthetic devices in the future by enabling us to anticipate the desired neural responses to electrical stimuli.

The direct influence of retinal degeneration on electrical stimulation efficacy: Significant implications for retinal prostheses.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Development of a rabbit model of Adenosine triphosphate-induced monocular retinal degeneration for optimization of retinal prostheses.

Optimization of retinal prostheses requires preclinical animal models that mimic features of human retinal disease, have appropriate eye sizes to accommodate implantable arrays, and provide options for unilateral degeneration so as to enable a contralateral, within-animal control eye. In absence of a suitable non-human primate model and shortcomings of our previous feline model generated through intravitreal injections of Adenosine Triphosphate (ATP), we aimed in the present study to develop an ATP induced degeneration model in the rabbit. Six normally sighted Dutch rabbits were monocularly blinded with this technique. Subsequent retinal degeneration was assessed with optical coherence tomography, electroretinography, and histological assays. Overall, there was a 42% and 26% reduction in a-wave and oscillatory potential amplitudes in the electroretinograms respectively, along with a global decrease in retinal thickness, with increased variability. Qualitative inspection also revealed that there were variable levels of retinal degeneration and remodeling both within and between treated eyes, mimicking the disease heterogeneity observed in retinitis pigmentosa. These findings confirm that ATP can be utilized to unilaterally induce blinding in rabbits and, potentially present an ideal model for future cortical recording experiments aimed at optimizing vision restoration strategies.Clinical Relevance- A rapid, unilaterally induced model of retinal degeneration in an animal with low binocular overlap and large eyes will allow for clinically valid recordings of downstream cortical activity following retinal stimulation. Such a model would be highly beneficial for the optimization of clinically appropriate vision restoration approaches.