Spatially Selective Retinal Ganglion Cell Activation Using Low Invasive Extraocular Temporal Interference Stimulation.

Conventional retinal implants involve complex surgical procedures and require invasive implantation. Temporal Interference Stimulation (TIS) has achieved noninvasive and focused stimulation of deep brain regions by delivering high-frequency currents with small frequency differences on multiple electrodes. In this study, we conducted in silico investigations to evaluate extraocular TIS's potential as a novel visual restoration approach. Different from the previously published retinal TIS model, the new model of extraocular TIS incorporated a biophysically detailed retinal ganglion cell (RGC) population, enabling a more accurate simulation of retinal outputs under electrical stimulation. Using this improved model, we made the following major discoveries: (1) the maximum value of TIS envelope electric potential ([Formula: see text] showed a strong correlation with TIS-induced RGC activation; (2) the preferred stimulating/return electrode (SE/RE) locations to achieve focalized TIS were predicted; (3) the performance of extraocular TIS was better than same-frequency sinusoidal stimulation (SSS) in terms of lower RGC threshold and more focused RGC activation; (4) the optimal stimulation parameters to achieve lower threshold and focused activation were identified; and (5) spatial selectivity of TIS could be improved by integrating current steering strategy and reducing electrode size. This study provides insights into the feasibility and effectiveness of a low-invasive stimulation approach in enhancing vision restoration.

Adhesion of retinal cells to gold surfaces by biomimetic molecules.

Background: Neural cell-electrode coupling is crucial for effective neural and retinal prostheses. Enhancing this coupling can be achieved through surface modification and geometrical design to increase neuron-electrode proximity. In the current research, we focused on designing and studying various biomolecules as a method to elicit neural cell-electrode adhesion via cell-specific integrin mechanisms. Methods: We designed extracellular matrix biomimetic molecules with different head sequences (RGD or YIGSR), structures (linear or cyclic), and spacer lengths (short or long). These molecules, anchored by a thiol (SH) group, were deposited onto gold surfaces at various concentrations. We assessed the modifications using contact angle measurements, fluorescence imaging, and X-ray Photoelectron Spectroscopy (XPS). We then analyzed the adhesion of retinal cells and HEK293 cells to the modified surfaces by measuring cell density, surface area, and focal adhesion spots, and examined changes in adhesion-related gene and integrin expression. Results: Results showed that YIGSR biomolecules significantly enhanced retinal cell adhesion, regardless of spacer length. For HEK293 cells, RGD biomolecules were more effective, especially with cyclic RGD and long spacers. Both cell types showed increased expression of specific adhesion integrins and proteins like vinculin and PTK2; these results were in agreement with the adhesion studies, confirming the cell-specific interactions with modified surfaces. Conclusion: This study highlights the importance of tailored biomolecules for improving neural cell adhesion to electrodes. By customizing biomolecules to foster specific and effective interactions with adhesion integrins, our study provides valuable insights for enhancing the integration and functionality of retinal prostheses and other neural implants.

Implantable antennas for biomedical applications: a systematic review.

This review presents an in-depth examination of implantable antennas for various biomedical purposes. The development of implantable antennas, including their designs, materials, and operating principles, are introduced at the beginning of the discussion. An overview of the many kinds of implantable antennas utilized in implantable medical devices (IMDs) are presented in this study. The article then discusses the important factors to consider when developing implantable antennas for biomedical purposes, including implant placement, frequency range, and power needs. This investigation additionally examines the challenges and limitations encountered with implantable antennas, including the limited space available within the human body, the requirement for biocompatible materials, the impact of surrounding tissue on antenna performance, tissue attenuation, and signal interference. This review also emphasizes the most recent advances in implanted antenna technology, such as wireless power transmission, multiband operation, and miniaturization. Furthermore, it offers illustrations of several biomedical uses for implantable antennas, including pacemaker, capsule endoscopy, intracranial pressure monitoring, retinal prostheses, and bone implants. This paper concludes with a discussion of the future of implantable antennas and their possible use in bioelectronic medicine and novel medical implants. Overall, this survey offers a thorough analysis of implantable antennas in biomedical applications, emphasizing their importance in the development of implantable medical technology.

Explainable machine learning predictions of perceptual sensitivity for retinal prostheses.

Objective.Retinal prostheses evoke visual precepts by electrically stimulating functioning cells in the retina. Despite high variance in perceptual thresholds across subjects, among electrodes within a subject, and over time, retinal prosthesis users must undergo 'system fitting', a process performed to calibrate stimulation parameters according to the subject's perceptual thresholds. Although previous work has identified electrode-retina distance and impedance as key factors affecting thresholds, an accurate predictive model is still lacking.Approach.To address these challenges, we (1) fitted machine learning models to a large longitudinal dataset with the goal of predicting individual electrode thresholds and deactivation as a function of stimulus, electrode, and clinical parameters ('predictors') and (2) leveraged explainable artificial intelligence (XAI) to reveal which of these predictors were most important.Main results.Our models accounted for up to 76% of the perceptual threshold response variance and enabled predictions of whether an electrode was deactivated in a given trial with F1 and area under the ROC curve scores of up to 0.732 and 0.911, respectively. Our models identified novel predictors of perceptual sensitivity, including subject age, time since blindness onset, and electrode-fovea distance.Significance.Our results demonstrate that routinely collected clinical measures and a single session of system fitting might be sufficient to inform an XAI-based threshold prediction strategy, which has the potential to transform clinical practice in predicting visual outcomes.

An update on visual prosthesis.

PURPOSE: To review the available evidence on the different retinal and visual prostheses for patients with retinitis pigmentosa and new implants for other indications including dry age-related macular degeneration. METHODS: The PubMed, GoogleScholar, ScienceDirect, and ClinicalTrials databases were the main resources used to conduct the medical literature search. An extensive search was performed to identify relevant articles concerning the worldwide advances in retinal prosthesis, clinical trials, status of devices and potential future directions up to December 2022. RESULTS: Thirteen devices were found to be current and were ordered by stimulation location. Six have active clinical trials. Four have been discontinued, including the Alpha IMS, Alpha AMS, IRIS II, and ARGUS II which had FDA and CE mark approval. Future directions will be presented in the review. CONCLUSION: This review provides an update of retinal prosthetic devices, both current and discontinued. While some devices have achieved visual perception in animals and/or humans, the main issues impeding the commercialization of these devices include: increased length of time to observe outcomes, difficulties in finding validated meaures for use in studies, unknown long-term effects, lack of funding, and a low amount of patients simultaneously diagnosed with RP lacking other comorbid conditions. The ARGUS II did get FDA and CE mark approval so it was deemed safe and also effective. However, the company became more focused on a visual cortical implant. Future efforts are headed towards more biocompatible, safe, and efficacious devices.

Optimizing the fabrication of a 3D high-resolution implant for neural stimulation.

BACKGROUND: Tissue-integrated micro-electronic devices for neural stimulation hold great potential in restoring the functionality of degenerated organs, specifically, retinal prostheses, which are aimed at vision restoration. The fabrication process of 3D polymer-metal devices with high resolution and a high aspect-ratio (AR) is very complex and faces many challenges that impair its functionality. APPROACH: Here we describe the optimization of the fabrication process of a bio-functionalized 3D high-resolution 1mm circular subretinal implant composed of SU-8 polymer integrated with dense gold microelectrodes (23µm pitch) passivated with 3D micro-well-like structures (20µm diameter, 3µm resolution). The main challenges were overcome by step-by-step planning and optimization while utilizing a two-step bi-layer lift-off process; bio-functionalization was carried out by N2 plasma treatment and the addition of a bio-adhesion molecule. MAIN RESULTS: In-vitro and in-vivo investigations, including SEM and FIB cross section examinations, revealed a good structural design, as well as a good long-term integration of the device in the rat sub-retinal space and cell migration into the wells. Moreover, the feasibility of subretinal neural stimulation using the fabricated device was demonstrated in-vitro by electrical activation of rat's retina. CONCLUSIONS: The reported process and optimization steps described here in detail can aid in designing and fabricating retinal prosthetic devices or similar neural implants.

SpikeSEE: An energy-efficient dynamic scenes processing framework for retinal prostheses.

Intelligent and low-power retinal prostheses are highly demanded in this era, where wearable and implantable devices are used for numerous healthcare applications. In this paper, we propose an energy-efficient dynamic scenes processing framework (SpikeSEE) that combines a spike representation encoding technique and a bio-inspired spiking recurrent neural network (SRNN) model to achieve intelligent processing and extreme low-power computation for retinal prostheses. The spike representation encoding technique could interpret dynamic scenes with sparse spike trains, decreasing the data volume. The SRNN model, inspired by the human retina's special structure and spike processing method, is adopted to predict the response of ganglion cells to dynamic scenes. Experimental results show that the Pearson correlation coefficient of the proposed SRNN model achieves 0.93, which outperforms the state-of-the-art processing framework for retinal prostheses. Thanks to the spike representation and SRNN processing, the model can extract visual features in a multiplication-free fashion. The framework achieves 8 times power reduction compared with the convolutional recurrent neural network (CRNN) processing-based framework. Our proposed SpikeSEE predicts the response of ganglion cells more accurately with lower energy consumption, which alleviates the precision and power issues of retinal prostheses and provides a potential solution for wearable or implantable prostheses.

Explainable Machine Learning Predictions of Perceptual Sensitivity for Retinal Prostheses.

To provide appropriate levels of stimulation, retinal prostheses must be calibrated to an individual's perceptual thresholds ('system fitting'), despite thresholds varying drastically across subjects, across electrodes within a subject, and over time. Although previous work has identified electrode-retina distance and impedance as key factors affecting thresholds, an accurate predictive model is still lacking. To address these challenges, we 1) fitted machine learning (ML) models to a large longitudinal dataset with the goal of predicting individual electrode thresholds and deactivation as a function of stimulus, electrode, and clinical parameters ('predictors') and 2) leveraged explainable artificial intelligence (XAI) to reveal which of these predictors were most important. Our models accounted for up to 77% of the perceptual threshold response variance and enabled predictions of whether an electrode was deactivated in a given trial with F1 and AUC scores of up to 0.740 and 0.913, respectively. Deactivation and threshold models identified novel predictors of perceptual sensitivity, including subject age, time since blindness onset, and electrode-fovea distance. Our results demonstrate that routinely collected clinical measures and a single session of system fitting might be sufficient to inform an XAI-based threshold prediction strategy, which may transform clinical practice in predicting visual outcomes.

Artificial intelligence techniques for retinal prostheses: a comprehensive review and future direction.

Objective. Retinal prostheses are promising devices to restore vision for patients with severe age-related macular degeneration or retinitis pigmentosa disease. The visual processing mechanism embodied in retinal prostheses play an important role in the restoration effect. Its performance depends on our understanding of the retina's working mechanism and the evolvement of computer vision models. Recently, remarkable progress has been made in the field of processing algorithm for retinal prostheses where the new discovery of the retina's working principle and state-of-the-arts computer vision models are combined together.Approach. We investigated the related research on artificial intelligence techniques for retinal prostheses. The processing algorithm in these studies could be attributed to three types: computer vision-related methods, biophysical models, and deep learning models.Main results. In this review, we first illustrate the structure and function of the normal and degenerated retina, then demonstrate the vision rehabilitation mechanism of three representative retinal prostheses. It is necessary to summarize the computational frameworks abstracted from the normal retina. In addition, the development and feature of three types of different processing algorithms are summarized. Finally, we analyze the bottleneck in existing algorithms and propose our prospect about the future directions to improve the restoration effect.Significance. This review systematically summarizes existing processing models for predicting the response of the retina to external stimuli. What's more, the suggestions for future direction may inspire researchers in this field to design better algorithms for retinal prostheses.

[Modern concepts of bionic vision]. / Sovremennye kontseptsii bionicheskogo zreniya.

Loss of vision is a pressing medical and social problem leading to profound disability, loss of ability to work, serious alterations in the psycho-emotional state, and a decline of the quality of life. When conservative or surgical treatment can not help restore vision, the use of visual prosthesis - bionic eye - can be an effective solution. This review covers the main modern approaches to the development of visual prosthetic systems. Analysis of publications revealed that there are several main approaches to visual prosthesis differing primarily by the anatomical structure targeted for stimulation in order to activate visual sensations. The most significant among them are retinal prostheses, optic nerve stimulation, and cortical visual prostheses. Currently, retinal prostheses such as ARGUS II demonstrate the most successful results, since the stimulation of the surviving neural structures of the retina is a relatively easy task, but their field of application is limited to diseases associated with pathological changes in photoreceptors. The development of cortical visual prostheses is more difficult, but in the future they may allow using more stimulation channels to obtain a more detailed visual perception. In addition, cortical visual prostheses are universal, as they do not require preservation of any structures of the visual organ, only the primary visual cortex.

Virtual reality validation of naturalistic modulation strategies to counteract fading in retinal stimulation.

Objective. Temporal resolution is a key challenge in artificial vision. Several prosthetic approaches are limited by the perceptual fading of evoked phosphenes upon repeated stimulation from the same electrode. Therefore, implanted patients are forced to perform active scanning, via head movements, to refresh the visual field viewed by the camera. However, active scanning is a draining task, and it is crucial to find compensatory strategies to reduce it.Approach. To address this question, we implemented perceptual fading in simulated prosthetic vision using virtual reality. Then, we quantified the effect of fading on two indicators: the time to complete a reading task and the head rotation during the task. We also tested if stimulation strategies previously proposed to increase the persistence of responses in retinal ganglion cells to electrical stimulation could improve these indicators.Main results. This study shows that stimulation strategies based on interrupted pulse trains and randomisation of the pulse duration allows significant reduction of both the time to complete the task and the head rotation during the task.Significance. The stimulation strategy used in retinal implants is crucial to counteract perceptual fading and to reduce active head scanning during prosthetic vision. In turn, less active scanning might improve the patient's comfort in artificial vision.

Retinal prostheses: Where to from here?

Researchers have been working towards the development of retinal prostheses, so called "bionic eyes" since the 1960s in an effort to restore functional vision to severely visually impaired patients. Groups from all around the world are involved in this research but in particular, groups from the United States, Germany, France, Japan and Australia have conducted clinical trials of these devices and three of these devices have achieved either FDA HDE (U.S. Food and Drug Administration Humanitarian Device Exception) or CE mark approval for commercial production. Despite this, all three of these devices are now not in commercial production. There are many challenges to overcome to develop devices suitable to implant in human patients and then reach commercial distribution. This is an exacting process and many hurdles need to be overcome to reach this point so that leaving the market after achieving this goal is a significant decision. Ongoing research is exploring the possibility of less complicated surgery with better visual processing algorithms to provide more useful visual information for our patients to provide a commercial alternative.

Neuromodulation using electroosmosis.

Objective.Our laboratory has proposed chemical stimulation of retinal neurons using exogenous glutamate as a biomimetic strategy for treating vision loss caused by photoreceptor (PR) degenerative diseases. Although our previousin-vitrostudies using pneumatic actuation indicate that chemical retinal stimulation is achievable, an actuation technology that is amenable to microfabrication, as needed for anin-vivoimplantable device, has yet to be realized. In this study, we sought to evaluate electroosmotic flow (EOF) as a mechanism for delivering small quantities of glutamate to the retina. EOF has great potential for miniaturization.Approach.An EOF device to dispense small quantities of glutamate was constructed and its ability to drive retinal output tested in anin-vitropreparation of PR degenerate rat retina.Main results.We built and tested an EOF microfluidic system, with 3D printed and off-the-shelf components, capable of injecting small volumes of glutamate in a pulsatile fashion when a low voltage control signal was applied. With this device, we produced excitatory and inhibitory spike rate responses in PR degenerate rat retinae. Glutamate evoked spike rate responses were also observed to be voltage-dependent and localized to the site of injection.Significance.The EOF device performed similarly to a previously tested conventional pneumatic microinjector as a means of chemically stimulating the retina while eliminating the moving plunger of the pneumatic microinjector that would be difficult to miniaturize and parallelize. Although not implantable, the prototype device presented here as a proof of concept indicates that a retinal prosthetic based on EOF-driven chemical stimulation is a viable and worthwhile goal. EOF should have similar advantages for controlled dispensing of charged neurochemicals at any neural interface.

Multisensory perception in Argus II retinal prosthesis patients: Leveraging auditory-visual mappings to enhance prosthesis outcomes.

Crossmodal mappings associate features (such as spatial location) between audition and vision, thereby aiding sensory binding and perceptual accuracy. Previously, it has been unclear whether patients with artificial vision will develop crossmodal mappings despite the low spatial and temporal resolution of their visual perception (particularly in light of the remodeling of the retina and visual cortex that takes place during decades of vision loss). To address this question, we studied crossmodal mappings psychophysically in Retinitis Pigmentosa patients with partial visual restoration by means of Argus II retinal prostheses, which incorporate an electrode array implanted on the retinal surface that stimulates still-viable ganglion cells with a video stream from a head-mounted camera. We found that Argus II patients (N = 10) exhibit significant crossmodal mappings between auditory location and visual location, and between auditory pitch and visual elevation, equivalent to those of age-matched sighted controls (N = 10). Furthermore, Argus II patients (N = 6) were able to use crossmodal mappings to locate a visual target more quickly with auditory cueing than without. Overall, restored artificial vision was shown to interact with audition via crossmodal mappings, which implies that the reorganization during blindness and the limitations of artificial vision did not prevent the relearning of crossmodal mappings. In particular, cueing based on crossmodal mappings was shown to improve visual search with a retinal prosthesis. This result represents a key first step toward leveraging crossmodal interactions for improved patient visual functionality.

Innovative strategies for treating retinal diseases.

OBJECTIVE: The aim of this comprehensive paper is to acquaint the readers with innovative approaches in the treatment of retinal diseases, which could in the coming years to get into clinical practice. Retinal prostheses, retinal pigment epithelial (RPE) transplantation, gene therapy and optogenetics will be described in this paper. METHODOLOGY: Describing the basic characteristics and mechanisms of different types of therapy and subsequently literary minireview clarifying the current state of knowledge in the area. RESULTS: Retinal prostheses, RPE transplantation, gene therapy and optogenetics offer yet unexplored possibilities and are considered as the future of treatment of retinal diseases where classical pharmacotherapy or surgical treatment are no longer sufficient. However, all these methods challenge not only in the innovative technical implementation itself, but also for the ethical, administrative and economic demands. CONCLUSION: There will be certainly interesting development in the treatment of retinal diseases, but it is not possible to fully estimate which modality of treatment will be dominant in the future.

Stimulus waveform design for decreasing charge and increasing stimulation selectivity in retinal prostheses.

Retinal degenerative diseases, such as retinitis pigmentosa, begin with damage to the photoreceptor layer of the retina. In the absence of presynaptic input from photoreceptors, networks of electrically coupled AII amacrine and cone bipolar cells have been observed to exhibit oscillatory behaviour and result in spontaneous firing of ganglion cells. This ganglion cell activity could interfere with external stimuli provided by retinal prosthetic devices and potentially degrade their performance. In this work, the authors computationally investigate stimulus waveform designs, which can improve the performance of retinal prostheses by suppressing undesired spontaneous firing of ganglion cells and generating precise temporal spiking patterns. They utilise a multi-scale computational model for electrical stimulation of degenerated retina based on the admittance method and NEURON simulation environments. They present a class of asymmetric biphasic pulses that can generate precise ganglion cell firing patterns with up to 55% lower current requirements compared to traditional symmetric biphasic pulses. This lower current results in activation of only proximal ganglion cells, provides more focused stimulation and lowers the risk of tissue damage.

Bionic eye review - An update.

PURPOSE: To date, reviews of bionic eye have concentrated on implants which were used in human trials in the developed countries. This is the main restriction of this systematic review examines, however this review discusses worldwide advances in retinal prosthetic research, assesses engineering features and clinical progress of recent implant trials, and identifies potential future research areas in the field of bionic implants. METHODS: A literature review searching PubMed, Google Scholar, and IEEExplore was performed using the PRISMA Guidelines for Systematic Review. We included peer-reviewed papers in the review which demonstrated progress in human or animal trials and papers with described innovative bionic eye engineering design. For each trial, a characteristic of the device, engineering solution, and latest clinical outcomes were presented. RESULTS: Eleven prosthetic projects fulfilled met our inclusion criteria and were ordered by stimulation location. Four have recently finished human trials, three are having conducted multi- or singlecenter human trials, and three are in preclinical animal testing stage. FDA has approved Argus II (FDA 2013, CE 2011); the Alpha-IMS (CE 2013) has been approved and obtained BCVA with Landolt-C test has taken into a multicenter clinical research. New approaches will be presented using alternating magnetic fields, low-intensity focused ultrasounds, optogenetics, implementing ionic gradients across neural cell membranes or influencing neurotransmitter levels will be presented in the review. CONCLUSION: Several bionic eye have successfully achieved visual perception in animals and/or humans. However, many things need to be improved and engineering difficulties are to be resolved before bionic eye will be capable of fully and safely bring back vision functions. New approaches could improve medical outcome of future bionic eye.

Stimulation Strategies for Improving the Resolution of Retinal Prostheses.

Electrical stimulation using implantable devices with arrays of stimulating electrodes is an emerging therapy for neurological diseases. The performance of these devices depends greatly on their ability to activate populations of neurons with high spatiotemporal resolution. To study electrical stimulation of populations of neurons, retina serves as a useful model because the neural network is arranged in a planar array that is easy to access. Moreover, retinal prostheses are under development to restore vision by replacing the function of damaged light sensitive photoreceptors, which makes retinal research directly relevant for curing blindness. Here we provide a progress review on stimulation strategies developed in recent years to improve the resolution of electrical stimulation in retinal prostheses. We focus on studies performed with explanted retinas, in which electrophysiological techniques are the most advanced. We summarize achievements in improving the spatial and temporal resolution of electrical stimulation of the retina and methods to selectively stimulate neurons with different visual functions. Future directions for retinal prostheses development are also discussed, which could provide insights for other types of neuromodulatory devices in which high-resolution electrical stimulation is required.

3D Diamond Electrode Array for High-Acuity Stimulation in Neural Tissue.

Innovations in micro- and nanofabrication technologies enable the manufacture of multielectrode arrays for use in neuromodulation and neural recording. Multielectrode arrays make possible medical implants such as pacemakers, deep-brain stimulators, or visual and hearing aids, to treat numerous neural disorders. An optimal neural interface requires a high density of electrodes to precisely record from and stimulate the nervous system while minimizing the overall size of the array. For example, people with retinal degenerative diseases can benefit from retinal prostheses implanted inside the eye. However, at present the visual acuity provided by such implants is well below the threshold for functional vision, mainly due to the limited spatial resolution. In this work, we present a design of 3D nanostructured conductive diamond electrodes, integrated within a polycrystalline diamond housing, offering a high electrode density and count, which simultaneously satisfies spatial resolution and biocompatibility goals. The array is composed of height adjustable pillar electrodes that are 80 µm in diameter and separated by 150 µm. A holistic characterization of the electrodes was performed and the device tested for stimulation performance in a whole-mounted retina. Electrochemical testing showed impedance of 20 kΩ and a wide water window of 2.47 V. The pillar structure allows the distance between the electrodes and the retinal ganglion cells to be reduced which is key to more confined stimulation at lower current levels, leading to potentially higher-acuity stimulation without damaging retinal tissue.

Recent Progress in Wireless Sensors for Wearable Electronics.

The development of wearable electronics has emphasized user-comfort, convenience, security, and improved medical functionality. Several previous research studies transformed various types of sensors into a wearable form to more closely monitor body signals and enable real-time, continuous sensing. In order to realize these wearable sensing platforms, it is essential to integrate wireless power supplies and data communication systems with the wearable sensors. This review article discusses recent progress in wireless technologies and various types of wearable sensors. Also, state-of-the-art research related to the application of wearable sensor systems with wireless functionality is discussed, including electronic skin, smart contact lenses, neural interfaces, and retinal prostheses. Current challenges and prospects of wireless sensor systems are discussed.