Overview of Retinal Prosthesis and Future Directions

Retinal prosthesis devices, also known as bionic eyes, are implantable electronic devices designed to convert light into electrical signals and transmit them to retinal tissue, the optic nerve, or the brain. These devices aim to restore vision to individuals with retinal diseases ranging from age-related causes from macular degeneration to inherited retinal diseases such as retinitis pigmentosa (RP). Irreversible loss of vision impacts quality of life and hinders the ability to perform activities of daily living. With technological advancements, patients may have the potential to regain both partial sight and a sense of independence. Patients with severe visual impairment or blindness may have the opportunity to see phosphenes, and, in the best cases, identify objects, read large letters, and navigate walking paths. This article will provide an up-to-date overview of the different types of retinal prostheses based on anatomic location (Table 1).

Table 1. Current Status of Retina Prosthesis Devices

DEVICE NAME Manufacturer/Institution/Research Team Device Stage Clinical Trial Identifier/Status	CURRENT STATUS
EPIRETINAL DESIGNS
IMIE 256 (Channel Intelligent Micro Implant Eye) Golden Eye Bionic, United States and IntelliMicro Medical, China Clinical None	The first human clinical testing occurred on 5 patients with end-stage retinitis pigmentosa. All patients underwent visual rehabilitation for 90 days and visual performance was evaluated using grating/Tumbling E visual acuity test, direction of motion, square localization, and orientation/mobility test. Results were favorable and all patients performed significantly better on all performance evaluations using the IMIE 256. Only 1 reported adverse event occurred in 1 patient with electrode array movement and low intraocular pressure.⁴ Future clinical trials with larger sample size and testing duration are under way.
EPI-RET 3 (RWTH Aachen University, Germany) Clinical None	This device was tested on 6 patients who were legally blind from retinitis pigmentosa. It was subsequently removed 1 month later per the ethics committee guidelines, due to being an experimental device. No unexpected alterations or adverse events were observed in any of the eyes. Quality of life did not worsen with the addition of the device and visual acuity ranged from light perception to hand motion.⁶
NR600 System Nano Retina, Israel Clinical NCT04295304 (terminated)	The initial trial began on January 17, 2020, and 9 patients underwent the implantation procedure. This project was recently terminated at the end of 2023 due to lack of funding, according to clinicaltrials.gov.
Argus II Second Sight Medical Products, Inc., United States Clinical NCT03418116 (terminated)	Argus II was the first FDA-approved retinal prosthesis. The initial trial began in 2006 to study the safety and efficacy in patients with end-stage retinitis pigmentosa. Since 2007, more than 350 patients were implanted with the Argus II. In 2020, Second Sight stopped its production due to financial dif-ficulties.
Polyretina Diego Ghezzi research team Preclinical None	Ex-vivo and in-vivo studies demonstrated the capability to activate retinal ganglion cells at a safe irradiance level.⁵ Overall, preclinical studies found no evidence of cytotoxicity, in addition to having a long lifetime of 2 years.⁵
SUBRETINAL DESIGNS
Prima Pixium Vision, France Clinical NCT03392324, NCT04676854, and NCT03333954 (active, not recruiting)	In the PRIMAvera study, an open-label, multicenter, prospective, single-arm pivotal trial, a total of 38 patients were implanted with Prima system. The study aimed to confirm the safety and clinical benefits provided by the Prima system.¹⁰ Most recently, a 4-year follow-up of 5 patients with geographic atrophy confirmed safety of the Prima system and demonstrated an improve-ment in visual acuity of up to 8 ETDRS lines.¹³
IMTC HARP4k Iridium Medical Technology, Taiwan Preclinical None	The retinal prosthetic is currently undergoing modifications for further devel-opment. A computer stimulation has demonstrated the safety of the device in minimizing the amount of mechanical stress on the retinal tissue, decreasing the potential risk for retinal tears.¹¹
The Boston Retinal Implant Project Commercial partners: Bionic Eye Technologies, Inc. and Visus Technology Preclinical None	This wireless power implant consists of 256+ independently configurable retinal stimulation channels. The integrated circuit chip is packaged in a titanium case attached to the sclera. Only a thin flexible electrode array enters the eye, and it is placed in the subretinal space.
SUPRACHOROIDAL DESIGNS
Bionic Eye System (generation 2) Bionic Vision Technologies (BVT) Centre for Eye Research Australia (CERA), Australia Phase 2 clinical trial completed	The results of a phase 2 clinical trial of generation 2 in 4 patients have demonstrated the safety of this device with meaningful improvements in vi-sion based on screen-based, functional assessments. The device is currently undergoing further modifications with the hopes of improving visual acuity.
Suprachoroidal-transretinal stimulation Osaka University Graduate School of Medicine, Japan Completed in vivo studies	A study in 3 patients has found a favorable safety profile but with variable functional results.
Phoenix⁹⁹ University of Sydney and Bionics Institute, Australia Preclinical	Phoenix⁹⁹ has successfully completed in vivo studies in a bovine model, which demonstrated the safety of the device.
OPTIC DISC DESIGN
Artificial vision by direct optic nerve electrode (AV-DONE) Osaka University Medical School, Japan Clinical	A clinical trial completed in 1 patient with a favorable safety profile in 2009. However, the original design became dislodged and required reinsertions. To address this concern, the group designed new device comprising of 7 stimu-lation electrodes and 1 reference electrode to facilitate 1-step implantation of the electrode tips into the disc and has demonstrated successful implantation in animal models as well as in 1 human volunteer.^16,17
CORTICAL DESIGNS
Orion visual cortex prosthetics system Cortigent (Vivani Medical Inc.), United States Clinical Second generation device under development	The Orion visual cortical prosthesis system completed the fifth year of its early feasibility study in 6 blind patients implanted with the device. Three subjects are still participating in the study and continue to use the system.²²
Cortical Vision Neuroprosthesis for the Blind Biomedical Technologies, SL, Spain Clinical NCT02983370	An early study in monkeys demonstrated successful elicitation of visual potential. A human trial in 1 patient demonstrated consistent stimulation thresholds. Further trials are under way.
Intracortical Visual Prosthesis Illinois Institute of Technology, United States Phase 1 clinical trial	A prototype was successfully implanted in 1 blind patient with a favorable safety profile. The company is currently recruiting for its phase 1 clinical trial.

Devices

Epiretinal Devices

Epiretinal prostheses capture images through an external camera that transmits the information to a video processor unit (VPU). This transmission is then converted into an electrical signal and sent to an electrode array implanted on top of the retina. A series of impulses is generated within the ganglion cell layer for the epiretinal configuration.¹ The device is surgically placed in the inner retinal surface, near the ganglion cells, which is a simpler procedure than a subretinal implant.² Challenges can arise in fixating the array and the possible distorted mapping caused by stimulation of the ganglion cell axons. Current devices include the Argus II (Second Sight Medical Products), NanoRetina 600 System (NR600; Nano Retina), 256 Channel Intelligent Micro Implant Eye (IMIE 256; Golden Eye Bionic and IntelliMicro Medical, Figure 1), Polyretina (Dr. Ghezzi’s research team), and EPI-RET 3 (RWTH Aachen University). These devices use both internal and external components with wireless communication, although the internal components are often connected by a transscleral connection.

Figure 1. Fundus photo of the 256-channel Intelligent Micro Implant Eye (Golden Eye Bionic/IntelliMicro Medical). Image courtesy of Mark Humayun MD, PhD, and Yangyi Yao, PhD.

Each device has unique features. The NR600 has an array of intraretinal penetrating microelectrodes powered wirelessly by an infrared beam that controls the stimulation parameters.³ The IMIE consists of an external VPU component and 3 internal components: an episcleral electronic implant, a transscleral cable, and a retinal electrode array of 256 electrodes.⁴ The Polyretina has moldable plasticity, allowing for full retinal surface coverage.⁵ The EPI-RET 3 incorporates a complete intraocular internal component and eliminates the transscleral connection. In this model, the transmitter coil is mounted on a pair of glasses and the receiver coil is placed within an intraocular lens along with 2 microchips that interpret the stimulation signal and produce the stimulation pulses to an epiretinal flexible microcable containing 25 microelectrodes.⁶

The Argus II was the first and only FDA-approved retina prosthesis. This device restores partial functional vision in patients with bare to no light perception due to advanced RP. It consists of an external video camera mounted in a pair of glasses that captures the images and sends them to a VPU, where the images are transformed into electrical impulses that are transmitted wirelessly using an antenna to an electrode array sitting on the macula. The electrical pulses stimulate the inner retinal cells. The most commonly reported adverse events were hypotony, conjunctival dehiscence, presumed endophthalmitis, and conjunctival erosion. More than 350 patients were implanted worldwide with the Argus II; however, in 2019, Second Sight discontinued its retinal implant due to financial difficulties (Figure 2).⁷

Figure 2. An Argus II epiretinal device (Second Sight Medical Products). Left: external components of the Argus II (video camera, video processor unit, and external coil). Center: fundus picture of the left eye demonstrating a 6 mm x 10 mm electrode array over the macula. A tack is used to fix the array to the retina. Right: optical coherence tomography of the electrode array and tack over the atrophic retina. A patient of corresponding author Sandra R. Montezuma, MD, agreed to publication of these images. — Figure 2. An Argus II epiretinal device (Second Sight Medical Products). Left: external components of the Argus II (video camera, video processor unit, and external coil). Center: fundus picture of the left eye demonstrating a 6 mm x 10 mm electrode array over the macula. A tack is used to fix the array to the retina. Right: optical coherence tomography of the electrode array and tack over the atrophic retina. A patient of corresponding author Sandra R. Montezuma, MD, has agreed to the publication of these images.

Subretinal Devices

Subretinal implantation is a more invasive approach than epiretinal implantation. The device is often positioned under the retina, in the remnants of the retinal pigmented epithelial (RPE) or photoreceptor layers. Placement stimulates the intact middle retinal processing layers (amacrine, horizontal, and bipolar cells). This approach takes advantage of the existing neural processing to stimulate ganglion cells. With this approach, the implant can be held without a tack.⁸ Placing the implant in the subretinal space might require a posterior retinotomy and temporarily detaching the retina by injecting a balanced salt solution and/or Healon in the subretinal space. These challenges could limit the implant size. In addition, the implant itself may block the fluid communication between the retina and the choroid, and there may be problems with heat dissipation.⁹ Current models include the Photovoltaic Retinal Implant (Prima) bionic vision system (Pixium Vision; Figure 3), the HARP4K Retinal Prosthesis System (Iridium Medical Technology Company) and the Boston Retinal Implant (Boston Retinal Implant Project, commercial partners Bionic Eye Technologies, Inc. and Visus Technology).^10-12 The Prima design consists of a 2x2 photovoltaic subretinal implant, which is powered by pulsed near-infrared light through a small digital projector. It is integrated into a pair of glasses. It can capture visual environmental scenes and translate them from light pulsations to electrical currents for retinal cell excitation and visual processing.¹⁰ A recent preliminary study demonstrated that implantation of Prima was not only feasible but well tolerated with no reduction of natural peripheral vision in 5 patients with geographic atrophy at 4-year follow-up.¹³ The study also showed an improvement of up to 8 ETDRS lines in visual acuity.

Figure 3. The Prima subretinal implant (Pixium Vision). Top: Fundus photos of the subretinal prosthesis in 3 patients with advanced geographic atrophy. Bottom: Optical coherence tomography images of the same patients demonstrate the placement of the prosthesis under the macula. Reprinted from open-access article: Palanker D, Le Mer Y, Mohand-Said S, Muqit M, Sahel JA. Photovoltaic restoration of central vision in atrophic age-related macular degeneration. Ophthalmology. 2020;127(8):1097-1104. doi: 10.1016/j.ophtha.2020.02.024.

Suprachoroidal Devices

Suprachoroidal devices are implanted between the choroid and sclera. Because these devices do not enter the vitreous cavity, they are less invasive and minimize the risk of retinal damage. However, devices in this location require a larger stimulation power due to the increased distance from the neurosensory retina. Additionally, these devices carry a significant risk of hemorrhage, as the choroid is well vascularized.⁹ Models currently being tested are Generation 2 by Bionic Vision Australia (consisting of 44 platinum disc electrodes that send signals to postauricular headpiece), Phoenix⁹⁹ by Bionics Institute (consisting of 98 stimulation sites returned by 1 common electrode), and suprachoroidal-transretinal stimulation by Osaka University Graduate School of Medicine (consisting of a 49-microelectrode array implanted into a scleral pocket).^14-16

These devices are successful in restoring some functional vision without significant adverse events. Preliminary data suggest that suprachoroidal devices are more limited in vision regained compared to their epiretinal and subretinal counterparts, because the greater spread of current reduces spatial resolution in final perceived vision.¹⁷

Optic Nerve Stimulation

Artificial vision by direct optic nerve electrode (AV-DONE) is an electrode-utilizing device that is implanted into the optic disc.^18,19 In 1 human volunteer, using a definition of positive perception of phosphene when more than 50% of the test was positive for perception, the subject reported localized phosphene perception via stimulation of the optic disc electrode.¹⁹ However, due to the small surface area of the optic disc, the electrode array became dislodged easily and required several repeat insertions. To address this concern, the same group in Japan developed a second-generation model that allows better fixation through the use of 7 stimulation electrodes and 1 reference electrode with 1-step implantation; this latest model has been tested in rabbit models and more recently in 1 human volunteer.¹⁸ There were no complications associated with the device. The human volunteer perceived phosphenes in 6 of the 7 electrodes implanted.

Cortical Devices

Cortical devices directly stimulate the visual cortex of the occipital lobe of the brain. By bypassing the compromised ocular anatomy, cortical devices offer the advantage of being protected from retinal damage or atrophy and corneal or lens opacities. The utility of these devices is not limited to vision loss secondary to retinal degeneration; they are intended for patients with vision loss due to glaucoma, diabetic retinopathy, optic nerve injury or disease, ocular cancer, and ocular trauma. There are currently 4 models under investigation. The Orion Visual Cortex Prosthetics system (Cortigent [Vivani Medical Inc.]) consists of a subdural electrode grid implant with 60 electrodes implanted on the medial surface of the occipital lobe, a receiver coil, and an internal circuit.^20-22 A second-generation system is being developed for use in a wide array of retinal pathologies. The Cortical Vision Neuroprosthesis for the Blind (Biomedical Technologies) comprises an electrode implant in the intracortical layer.²³ The Intracortical Visual Prosthesis (Illinois Institute of Technology) stimulates the brain through floating microelectrode arrays that receive its power and information signal wirelessly so that no connectors traverse the scalp.²⁴ Early data for all cortical devices offer promising results in restoring some degree of sight effectively. Further studies evaluating the safety profiles, as well as the full extent of utility, are under way.

Future Directions

Since the first human retinal prosthetic implantation in 2002, every subsequent step has been met with something novel and exciting.²⁵ It is remarkable that it took 20 years for the first clinically approved retinal prosthesis implantation since the first human test of retinal electrical stimulation in a blind patient with RP. However, it is important to remember that vision regained from these devices has been modest at best and largely remains well below the threshold of the legal definition of blindness. Future retina prosthesis devices will need to provide an increased safety profile, increased effectiveness in terms of visual function, and decreased cost compared to prior devices.

Nonetheless, there has been continued interest in discovering new ways to stimulate different cells or pathways to restore sight as the understanding of visual neurosciences advances.⁹As of February 2024, 14 active clinical trials are focusing on the use of stem cell therapy to repair retinal tissue and improve visual acuity, and 18 active clinical trials are exploring gene therapy for RP.²⁶ Recent advances in gene therapy and stem cell therapy have potential to restore sight, but major challenges remain. For one, adverse effects of stem cell therapy described in the literature include inflammatory response, carcinogenesis through suppression of tumor suppressor genes or stimulation of oncogenes, and retinal detachment.⁹ Adverse effects of gene therapy described in the literature include inflammatory responses, increased intraocular pressures, loss of retinal layers, and toxicity in the photoreceptor and RPE layers.²⁷ Regardless, the patient population who benefits from retinal prostheses is different from those who undergo gene therapy. The former patients are in much later disease stages.

Another area of interest has been the role of artificial intelligence in optimizing retinal prostheses and the visual processing algorithm.²⁸ Retinal prosthetics often include different parts (eg, image sensor, processing unit, and implanted photostimulator) that need to be optimized and linked for maximal visual benefit. Recently, progress has been made in the field of processing algorithms for retinal prosthetics, where the retina’s working principle is combined with computer vision models. There is continued interest in this area with the understanding of machine learning and computer algorithms advance.²⁸

Conclusion

This review describes 15 devices that have been considered in the last 2 decades since the conceptualization of the retinal prosthesis. The field of retina prostheses remains challenging. Many of these devices have achieved some visual restoration in animal and human models, but visual gains have been modest at best, limiting their clinical use. Continued progress is needed, but there are promising data that may translate to meaningful vision gain for patients. RP

Hear discussion of this article on the Retina Podcast at retinapodcast.com.

Jade Y. Moon, MD, is a second-year ophthalmology resident at the University of Minnesota in Minneapolis, Minnesota. She reports no relevant disclosures.

Richard N. Sather III, BS, is a fourth-year medical student, and will be an ophthalmology resident at the University of Minnesota department of ophthalmology and visual neurosciences in summer 2024. He reports no relevant disclosures.

Sandra R. Montezuma, MD, is a vitreoretinal surgeon, professor of ophthalmology, and the Knobloch Endowed Chair in the department of ophthalmology and visual neurosciences at the University of Minnesota. She reports past consultancy to Second Sight Medical Products and Pixium Vision. Reach her at smontezu@umn.edu.

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