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Dalrymple AN, Jones ST, Fallon JB, Shepherd RK, Weber DJ. Overcoming failure: improving acceptance and success of implanted neural interfaces. Bioelectron Med 2025; 11:6. [PMID: 40083033 PMCID: PMC11907899 DOI: 10.1186/s42234-025-00168-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/06/2025] [Indexed: 03/16/2025] Open
Abstract
Implanted neural interfaces are electronic devices that stimulate or record from neurons with the purpose of improving the quality of life of people who suffer from neural injury or disease. Devices have been designed to interact with neurons throughout the body to treat a growing variety of conditions. The development and use of implanted neural interfaces is increasing steadily and has shown great success, with implants lasting for years to decades and improving the health and quality of life of many patient populations. Despite these successes, implanted neural interfaces face a multitude of challenges to remain effective for the lifetime of their users. The devices are comprised of several electronic and mechanical components that each may be susceptible to failure. Furthermore, implanted neural interfaces, like any foreign body, will evoke an immune response. The immune response will differ for implants in the central nervous system and peripheral nervous system, as well as over time, ultimately resulting in encapsulation of the device. This review describes the challenges faced by developers of neural interface systems, particularly devices already in use in humans. The mechanical and technological failure modes of each component of an implant system is described. The acute and chronic reactions to devices in the peripheral and central nervous system and how they affect system performance are depicted. Further, physical challenges such as micro and macro movements are reviewed. The clinical implications of device failures are summarized and a guide for determining the severity of complication was developed and provided. Common methods to diagnose and examine mechanical, technological, and biological failure modes at various stages of development and testing are outlined, with an emphasis on chronic in vivo characterization of implant systems. Finally, this review concludes with an overview of some of the innovative solutions developed to reduce or resolve the challenges faced by implanted neural interface systems.
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Affiliation(s)
- Ashley N Dalrymple
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
- Department of Physical Medicine and Rehabilitation, University of Utah, Salt Lake City, UT, USA.
- NERVES Lab, University of Utah, Salt Lake City, UT, USA.
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
- NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA.
| | - Sonny T Jones
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
- NERVES Lab, University of Utah, Salt Lake City, UT, USA
| | - James B Fallon
- Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Melbourne, VIC, Australia
| | - Robert K Shepherd
- Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia
| | - Douglas J Weber
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA
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Petoe MA, Abbott CJ, Titchener SA, Kolic M, Kentler WG, Nayagam DAX, Baglin EK, Kvansakul J, Barnes N, Walker JG, Karapanos L, McGuinness MB, Ayton LN, Luu CD, Allen PJ. A Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis: A Single-Arm Clinical Trial of Feasibility. OPHTHALMOLOGY SCIENCE 2025; 5:100525. [PMID: 39328823 PMCID: PMC11426041 DOI: 10.1016/j.xops.2024.100525] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/14/2024] [Accepted: 03/18/2024] [Indexed: 09/28/2024]
Abstract
Purpose To assess the feasibility of a second-generation (44-channel) suprachoroidal retinal prosthesis for provision of functional vision in recipients with end-stage retinitis pigmentosa (RP) over 2.7 years. Design Prospective, single-arm, unmasked interventional clinical trial. Participants Four participants, with advanced RP and bare-light perception vision. Methods The 44-channel suprachoroidal retinal prosthesis was implanted in the worse-seeing eye. Device stability, functionality, and adverse events were investigated at approximately 12-week intervals up to 140 weeks (2.7 years) postdevice activation. Main Outcome Measures Serious adverse event (SAE) reporting, visual response outcomes, functional vision outcomes, and quality-of-life outcomes. Results All 4 participants (aged 39-66 years, 3 males) were successfully implanted in 2018, and there were no device-related SAEs over the duration of the study. A mild postoperative subretinal hemorrhage was detected in 2 recipients, which cleared spontaneously within 2 weeks. OCT confirmed device stability and position under the macula. Improvements in localization abilities were demonstrated for all 4 participants in screen-based, tabletop, and orientation and mobility tasks. In addition, 3 of 4 participants recorded improvements in motion discrimination and 2 of 4 participants recorded substantial improvements in spatial discrimination and identification of tabletop objects. Participants reported their unsupervised use of the device included exploring new environments, detecting people, and safely navigating around obstacles. A positive effect of the implant on participants' daily lives in their local environments was confirmed by an orientation and mobility assessor and participant self-report. Emotional well-being was not impacted by device implantation or usage. Conclusions The completed clinical study demonstrates that the suprachoroidal prosthesis raises no safety concerns and provides improvements in functional vision, activities of daily living, and observer-rated quality of life. Financial Disclosures Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Matthew A Petoe
- Bionics Institute, Melbourne, Victoria, Australia
- Medical Bionics Department, University of Melbourne, Melbourne, Victoria, Australia
| | - Carla J Abbott
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Samuel A Titchener
- Bionics Institute, Melbourne, Victoria, Australia
- Medical Bionics Department, University of Melbourne, Melbourne, Victoria, Australia
| | - Maria Kolic
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
| | - William G Kentler
- Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia
| | - David A X Nayagam
- Bionics Institute, Melbourne, Victoria, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Department of Pathology, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria, Australia
| | - Elizabeth K Baglin
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
| | - Jessica Kvansakul
- Bionics Institute, Melbourne, Victoria, Australia
- Medical Bionics Department, University of Melbourne, Melbourne, Victoria, Australia
| | - Nick Barnes
- Research School of Engineering, Australian National University, Canberra, Australian Capital Territory, Australia
| | - Janine G Walker
- Research School of Engineering, Australian National University, Canberra, Australian Capital Territory, Australia
- Health & Biosecurity, CSIRO, Canberra, Australian Capital Territory, Australia
| | - Lewis Karapanos
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Myra B McGuinness
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Lauren N Ayton
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
- Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, Australia
| | - Chi D Luu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Penelope J Allen
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
- Vitreoretinal Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
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3
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Sorrentino FS, Di Terlizzi P, De Rosa F, Salati C, Spadea L, Gagliano C, Musa M, Zeppieri M. New frontiers in retinal transplantation. World J Transplant 2024; 14:97690. [PMID: 39697450 PMCID: PMC11438945 DOI: 10.5500/wjt.v14.i4.97690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 09/20/2024] Open
Abstract
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells. Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells. Thus, the disruption of photoreceptors takes place. However, even in advanced forms of retinal degeneration, a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact. This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region. The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities. The eyeball's immunological privilege, characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues, is responsible for the low rate of graft rejection in transplant patients. The main discoveries highlight the capacity of embryonic stem cells (ESCs) and induced pluripotent stem cells to regenerate damaged retinal regions. Recent progress has shown significant enhancements in transplant procedures and results. The research also explores the ethical ramifications linked to the utilization of stem cells, emphasizing the ongoing issue surrounding ESCs. The analysis centers on recent breakthroughs, including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation. Moreover, researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation. The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location. Currently, most therapy approaches are in the first phases of development and necessitate further research, including both pre-clinical and clinical trials, to attain favorable visual results for individuals suffering from retinal degenerative illnesses.
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Affiliation(s)
| | - Patrick Di Terlizzi
- Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna 40100, Italy
| | - Francesco De Rosa
- Department of Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”, Meldola 47014, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, "Sapienza" University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Enna 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Centre for Sight Africa, Nkpor, Onitsha 434112, Nigeria
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Vázquez-Domínguez I, Öktem M, Winkelaar FA, Nguyen TH, Hoogendoorn AD, Roschi E, Astuti GD, Timmermans R, Suárez-Herrera N, Bruno I, Ruiz-Llombart A, Brealey J, de Jong OG, Collin RW, Mastrobattista E, Garanto A. Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants in ABCA4. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102345. [PMID: 39494150 PMCID: PMC11531624 DOI: 10.1016/j.omtn.2024.102345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 09/24/2024] [Indexed: 11/05/2024]
Abstract
Deep-intronic (DI) variants represent approximately 10%-12% of disease-causing genetic defects in ABCA4-associated Stargardt disease (STGD1). Although many of these DI variants are amenable to antisense oligonucleotide-based splicing-modulation therapy, no treatment is currently available. These molecules are mostly variant specific, limiting their applicability to a broader patient population. In this study, we investigated the therapeutic potential of the CRISPR-Cas9 system combined with the amphipathic lipopeptide C18:1-LAH5 for intracellular delivery to correct splicing defects caused by different DI variants within the same intron. The combination of these components facilitated efficient editing of two target introns (introns 30 and 36) of ABCA4 in which several recurrent DI variants are found. The partial removal of these introns did not affect ABCA4 splicing or its expression levels when assessed in two different human cellular models: fibroblasts and induced pluripotent stem cell-derived photoreceptor precursor cells (PPCs). Furthermore, the DNA editing in STGD1 patient-derived PPCs led to a ∼50% reduction of the pseudoexon-containing transcripts resulting from the c.4539+2001G>A variant in intron 30. Overall, we provide proof-of-concept evidence of the use of C18:1-LAH5 as a delivery system for therapeutic genome editing for ABCA4-associated DI variants, offering new opportunities for clinical translation.
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Affiliation(s)
- Irene Vázquez-Domínguez
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Mert Öktem
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Florian A. Winkelaar
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Thai Hoang Nguyen
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Anita D.M. Hoogendoorn
- Radboud University Medical Center, Amalia Children’s Hospital, Department of Pediatrics, 6525 GA Nijmegen, the Netherlands
| | - Eleonora Roschi
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Galuh D.N. Astuti
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
- Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang 50275, Indonesia
| | - Raoul Timmermans
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Nuria Suárez-Herrera
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Ilaria Bruno
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Albert Ruiz-Llombart
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Joseph Brealey
- NanoFCM Co Ltd. MediCity, D6 Thane Road, Nottingham NG90 6BH, UK
| | - Olivier G. de Jong
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Rob W.J. Collin
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
| | - Enrico Mastrobattista
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Alejandro Garanto
- Radboud University Medical Center, Department of Human Genetics, 6525 GA Nijmegen, the Netherlands
- Radboud University Medical Center, Amalia Children’s Hospital, Department of Pediatrics, 6525 GA Nijmegen, the Netherlands
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Duncan JL, Bowman A, Laster A, Gelfman C, Birch DG, Boye SE, Daiger SP, Del Priore L, Zack DJ, Handa JT. Inherited Retinal Degenerations and Non-Neovascular Age-Related Macular Degeneration: Progress and Unmet Needs. Transl Vis Sci Technol 2024; 13:28. [PMID: 39688851 DOI: 10.1167/tvst.13.12.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024] Open
Abstract
Inherited retinal degeneration (IRD) disease and age-related macular degeneration (AMD) are leading causes of irreversible vision loss and blindness. Although significant progress has advanced the field in the past 5 years, significant challenges remain. The current article reviews the accomplishments and research advances that have fueled the development of treatments for patients with IRD and AMD, including the first approved gene-augmentation treatment for RPE65-related retinal degeneration and complement inhibition therapies to slow progression of geographic atrophy (GA) in AMD. The article outlines opportunities to address gaps and unmet needs that should lead to additional progress toward the development of treatments for patients with IRDs and non-neovascular AMD in the future.
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Affiliation(s)
- Jacque L Duncan
- Wayne and Gladys Valley Center for Vision, Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA
| | | | - Amy Laster
- Foundation Fighting Blindness, Columbia, MD, USA
| | | | - David G Birch
- Rose-Silverthorne Retinal Degenerations Laboratory, Retina Foundation of the Southwest, Dallas, TX, USA
| | - Shannon E Boye
- Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Stephen P Daiger
- Human Genetics Center, Epidemiology Dept., School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Lucian Del Priore
- Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT, USA
| | - Donald J Zack
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James T Handa
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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6
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Leong A, Li Y, Ruikes TR, Voillot J, Yuan Y, Chen G, Facon A, Chhuon CA, Joffrois C, Tessier G, Cornebois M, Dégardin J, Louise JD, Cheng JX, Yang C, Moulet H, Picaud S. A flexible high-precision photoacoustic retinal prosthesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.03.611068. [PMID: 39282448 PMCID: PMC11398364 DOI: 10.1101/2024.09.03.611068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
Retinal degenerative diseases of photoreceptors are a leading cause of blindness with no effective treatment. Retinal prostheses aim to restore sight by stimulating remaining retinal cells. Here, we present a photoacoustic retinal stimulation technology. We designed a polydimethylsiloxane and carbon-based flexible film that converts near-infrared laser pulses into a localized acoustic field with 56-μm lateral resolution, aiming at high-precision acoustic stimulation of mechanosensitive retinal cells. This photoacoustic stimulation resulted in robust and localized modulation of retinal ganglion cell activity in both wild-type and degenerated ex vivo retinae. When a millimeter-sized photoacoustic film was implanted in the rat subretinal space, pulsed laser stimulation generated neural modulation in vivo along the visual pathway to the superior colliculus, as measured by functional ultrasound imaging. The biosafety of the film was confirmed by the absence of short-term adverse effects under optical coherence tomography retinal imaging, while local thermal increases were measured below 1 °C. These findings demonstrate the potential of photoacoustic stimulation for high-acuity visual restoration over a large field of view in blind patients.
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Hallum LE, Cloherty SL. Harms associated with retinal implantation of a stimulating electrode array to treat outer-retinal degeneration: a systematic review and meta-analysis of safety. PROGRESS IN BIOMEDICAL ENGINEERING (BRISTOL, ENGLAND) 2024; 7:012001. [PMID: 39655855 DOI: 10.1088/2516-1091/ad811e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 09/27/2024] [Indexed: 12/18/2024]
Abstract
Retinal implantation of an electrode array is an emerging treatment for vision loss caused by outer-retinal degeneration. This article collects and analyses harms associated with the treatment reported in the peer-reviewed literature, thus enabling informed decision-making by patients, clinicians, researchers, engineers, and policymakers. We searched MEDLINE, Embase, and clinical trials registries for peer-reviewed journal articles reporting harms outcomes. We extracted data from articles including study design, definitions of 'serious adverse event', and timing of adverse events. We applied the McMaster tool to these articles to assess the risk of bias in harms assessment and reporting. Our searches returned 585 abstracts. We reviewed the full text of 59 articles describing 11 different devices. McMaster scores ranged from 3 to 12 (maximum 15; higher scores indicate less risk). We compiled a comprehensive list of all serious and non-serious adverse events associated with retinal implantation. Several harms were common across devices. Our meta-analysis showed that serious adverse events are log-uniformly distributed throughout follow-up. Improved reporting and further clinical studies are needed to develop a reliable safety profile of retinal implantation. Our findings will help guide the design, conduct, and reporting of future clinical trials of retinal implantation and other emerging treatments for vision loss. (PROSPERO registration: CRD42022308123.).
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Affiliation(s)
- Luke E Hallum
- Faculty of Engineering, University of Auckland, Auckland, New Zealand
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Hinrichs S, Placidet L, Duret A, Authié C, Arleo A, Ghezzi D. Wide-angle simulated artificial vision enhances spatial navigation and object interaction in a naturalistic environment. J Neural Eng 2024; 21:066005. [PMID: 39454585 DOI: 10.1088/1741-2552/ad8b6f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 10/25/2024] [Indexed: 10/28/2024]
Abstract
Objective. Vision restoration approaches, such as prosthetics and optogenetics, provide visual perception to blind individuals in clinical settings. Yet their effectiveness in daily life remains a challenge. Stereotyped quantitative tests used in clinical trials often fail to translate into practical, everyday applications. On the one hand, assessing real-life benefits during clinical trials is complicated by environmental complexity, reproducibility issues, and safety concerns. On the other hand, predicting behavioral benefits of restorative therapies in naturalistic environments may be a crucial step before starting clinical trials to minimize patient discomfort and unmet expectations.Approach. To address this, we leverage advancements in virtual reality technology to conduct a fully immersive and ecologically valid task within a physical artificial street environment. As a case study, we assess the impact of the visual field size in simulated artificial vision for common outdoor tasks.Main results. We show that a wide visual angle (45°) enhances participants' ability to navigate and solve tasks more effectively, safely, and efficiently. Moreover, it promotes their learning and generalization capability. Concurrently, it changes the visual exploration behavior and facilitates a more accurate mental representation of the environment. Further increasing the visual angle beyond this value does not yield significant additional improvements in most metrics.Significance. We present a methodology combining augmented reality with a naturalistic environment, enabling participants to perceive the world as patients with retinal implants would and to interact physically with it. Combining augmented reality in naturalistic environments is a valuable framework for low vision and vision restoration research.
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Affiliation(s)
- Sandrine Hinrichs
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
- Laboratory of Psychophysics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Louise Placidet
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Antonin Duret
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
| | | | - Angelo Arleo
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Diego Ghezzi
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
- Ophthalmic and Neural Technologies Laboratory, Department of Ophthalmology, University of Lausanne, Hôpital ophtalmique Jules-Gonin, Fondation Asile des Aveugles, Lausanne, Switzerland
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9
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Nadolskis L, Turkstra LM, Larnyo E, Beyeler M. Aligning Visual Prosthetic Development With Implantee Needs. Transl Vis Sci Technol 2024; 13:28. [PMID: 39570616 PMCID: PMC11585069 DOI: 10.1167/tvst.13.11.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 10/17/2024] [Indexed: 11/22/2024] Open
Abstract
Purpose Visual prosthetics are a promising assistive technology for vision loss, yet research often overlooks the human aspects of this technology. While previous studies focus on the perceptual experiences or attitudes of implant recipients (implantees), a systematic account of how current implants are being used in everyday life is still lacking. Methods We interviewed six recipients of the most widely used visual implants (Argus II and Orion) and six leading researchers in the field. Through thematic analyses, we explored the daily usage of these implants by implantees and compared their responses to the expectations of researchers. We also sought implantees' input on desired features for future versions, aiming to inform the development of the next generation of implants. Results Although implants are designed to facilitate various daily activities, we found that implantees use them less frequently than researchers expect. This discrepancy primarily stems from issues with usability and reliability, with implantees finding alternative methods to accomplish tasks, reducing the need to rely on the implant. For future implants, implantees emphasized the desire for improved vision, smart integration, and increased independence. Conclusions Our study reveals a significant gap between researcher expectations and implantee experiences with visual prostheses. Although limited by access to a small population of implantees, this study highlights the importance of focusing future research on usability and real-world applications. Translational Relevance This retrospective qualitative study advocates for a better alignment between technology development and implantee needs to enhance clinical relevance and practical utility of visual prosthetics.
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Affiliation(s)
- Lucas Nadolskis
- Interdepartmental Graduate Program in Dynamical Neuroscience, University of California, Santa Barbara, Santa Barbara, CA, USA
| | - Lily M. Turkstra
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, USA
| | - Ebenezer Larnyo
- Center for Black Studies Research, University of California, Santa Barbara, Santa Barbara, CA, USA
| | - Michael Beyeler
- Department of Psychological & Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, USA
- Department of Computer Science, University of California, Santa Barbara, Santa Barbara, CA, USA
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10
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Holiel HA, Fawzi SA, Al-Atabany W. Pre-processing visual scenes for retinal prosthesis systems: A comprehensive review. Artif Organs 2024; 48:1223-1250. [PMID: 39023279 DOI: 10.1111/aor.14824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 05/13/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Retinal prostheses offer hope for individuals with degenerative retinal diseases by stimulating the remaining retinal cells to partially restore their vision. This review delves into the current advancements in retinal prosthesis technology, with a special emphasis on the pivotal role that image processing and machine learning techniques play in this evolution. METHODS We provide a comprehensive analysis of the existing implantable devices and optogenetic strategies, delineating their advantages, limitations, and challenges in addressing complex visual tasks. The review extends to various image processing algorithms and deep learning architectures that have been implemented to enhance the functionality of retinal prosthetic devices. We also illustrate the testing results by demonstrating the clinical trials or using Simulated Prosthetic Vision (SPV) through phosphene simulations, which is a critical aspect of simulating visual perception for retinal prosthesis users. RESULTS Our review highlights the significant progress in retinal prosthesis technology, particularly its capacity to augment visual perception among the visually impaired. It discusses the integration between image processing and deep learning, illustrating their impact on individual interactions and navigations within the environment through applying clinical trials and also illustrating the limitations of some techniques to be used with current devices, as some approaches only use simulation even on sighted-normal individuals or rely on qualitative analysis, where some consider realistic perception models and others do not. CONCLUSION This interdisciplinary field holds promise for the future of retinal prostheses, with the potential to significantly enhance the quality of life for individuals with retinal prostheses. Future research directions should pivot towards optimizing phosphene simulations for SPV approaches, considering the distorted and confusing nature of phosphene perception, thereby enriching the visual perception provided by these prosthetic devices. This endeavor will not only improve navigational independence but also facilitate a more immersive interaction with the environment.
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Affiliation(s)
- Heidi Ahmed Holiel
- Medical Imaging and Image Processing Research Group, Center for Informatics Science, Nile University, Sheikh Zayed City, Egypt
| | - Sahar Ali Fawzi
- Medical Imaging and Image Processing Research Group, Center for Informatics Science, Nile University, Sheikh Zayed City, Egypt
- Systems and Biomedical Engineering Department, Cairo University, Giza, Egypt
| | - Walid Al-Atabany
- Medical Imaging and Image Processing Research Group, Center for Informatics Science, Nile University, Sheikh Zayed City, Egypt
- Biomedical Engineering Department, Helwan University, Helwan, Egypt
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11
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Yang R, Zhao P, Wang L, Feng C, Peng C, Wang Z, Zhang Y, Shen M, Shi K, Weng S, Dong C, Zeng F, Zhang T, Chen X, Wang S, Wang Y, Luo Y, Chen Q, Chen Y, Jiang C, Jia S, Yu Z, Liu J, Wang F, Jiang S, Xu W, Li L, Wang G, Mo X, Zheng G, Chen A, Zhou X, Jiang C, Yuan Y, Yan B, Zhang J. Assessment of visual function in blind mice and monkeys with subretinally implanted nanowire arrays as artificial photoreceptors. Nat Biomed Eng 2024; 8:1018-1039. [PMID: 37996614 DOI: 10.1038/s41551-023-01137-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 10/17/2023] [Indexed: 11/25/2023]
Abstract
Retinal prostheses could restore image-forming vision in conditions of photoreceptor degeneration. However, contrast sensitivity and visual acuity are often insufficient. Here we report the performance, in mice and monkeys with induced photoreceptor degeneration, of subretinally implanted gold-nanoparticle-coated titania nanowire arrays providing a spatial resolution of 77.5 μm and a temporal resolution of 3.92 Hz in ex vivo retinas (as determined by patch-clamp recording of retinal ganglion cells). In blind mice, the arrays allowed for the detection of drifting gratings and flashing objects at light-intensity thresholds of 15.70-18.09 μW mm-2, and offered visual acuities of 0.3-0.4 cycles per degree, as determined by recordings of visually evoked potentials and optomotor-response tests. In monkeys, the arrays were stable for 54 weeks, allowed for the detection of a 10-μW mm-2 beam of light (0.5° in beam angle) in visually guided saccade experiments, and induced plastic changes in the primary visual cortex, as indicated by long-term in vivo calcium imaging. Nanomaterials as artificial photoreceptors may ameliorate visual deficits in patients with photoreceptor degeneration.
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Affiliation(s)
- Ruyi Yang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Peng Zhao
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Liyang Wang
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Chenli Feng
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Chen Peng
- Laboratory of Advanced Materials, Department of Chemistry, Fudan University, Shanghai, P. R. China
| | - Zhexuan Wang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Yingying Zhang
- Key Laboratory of Brain Functional Genomics (Ministry of Education), East China Normal University, Shanghai, P. R. China
| | - Minqian Shen
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Kaiwen Shi
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Shijun Weng
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Chunqiong Dong
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
| | - Fu Zeng
- Key Laboratory of Brain Functional Genomics (Ministry of Education), East China Normal University, Shanghai, P. R. China
| | - Tianyun Zhang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Xingdong Chen
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Shuiyuan Wang
- Shanghai Key Lab for Future Computing Hardware and System, School of Microelectronics, Fudan University, Shanghai, P. R. China
| | - Yiheng Wang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Yuanyuan Luo
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Qingyuan Chen
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Yuqing Chen
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Chengyong Jiang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Shanshan Jia
- School of Computer Science, Institute for Artificial Intelligence, Peking University, Beijing, P.R. China
| | - Zhaofei Yu
- School of Computer Science, Institute for Artificial Intelligence, Peking University, Beijing, P.R. China
| | - Jian Liu
- School of Computer Science, University of Birmingham, Birmingham, UK
| | - Fei Wang
- Department of Hand Surgery, the National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, P. R. China
| | - Su Jiang
- Department of Hand Surgery, the National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, P. R. China
| | - Wendong Xu
- Department of Hand Surgery, the National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, P. R. China
- Department of Hand and Upper Extremity Surgery, Jing'an District Central Hospital, Fudan University, Shanghai, P.R. China
| | - Liang Li
- Center of Brain Sciences, Beijing Institute of Basic Medical Sciences, Beijing, P. R. China
| | - Gang Wang
- Center of Brain Sciences, Beijing Institute of Basic Medical Sciences, Beijing, P. R. China
| | - Xiaofen Mo
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Gengfeng Zheng
- Laboratory of Advanced Materials, Department of Chemistry, Fudan University, Shanghai, P. R. China
| | - Aihua Chen
- Key Laboratory of Brain Functional Genomics (Ministry of Education), East China Normal University, Shanghai, P. R. China
| | - Xingtao Zhou
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Chunhui Jiang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China.
| | - Yuanzhi Yuan
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.
- Zhongshan Hospital (Xiamen), Fudan University, Xiamen, P.R. China.
| | - Biao Yan
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China.
| | - Jiayi Zhang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institute for Medical and Engineering Innovation, Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, P. R. China.
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12
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Fine I, Boynton GM. A virtual patient simulation modeling the neural and perceptual effects of human visual cortical stimulation, from pulse trains to percepts. Sci Rep 2024; 14:17400. [PMID: 39075065 PMCID: PMC11286872 DOI: 10.1038/s41598-024-65337-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/19/2024] [Indexed: 07/31/2024] Open
Abstract
The field of cortical sight restoration prostheses is making rapid progress with three clinical trials of visual cortical prostheses underway. However, as yet, we have only limited insight into the perceptual experiences produced by these implants. Here we describe a computational model or 'virtual patient', based on the neurophysiological architecture of V1, which successfully predicts the perceptual experience of participants across a wide range of previously published human cortical stimulation studies describing the location, size, brightness and spatiotemporal shape of electrically induced percepts in humans. Our simulations suggest that, in the foreseeable future the perceptual quality of cortical prosthetic devices is likely to be limited by the neurophysiological organization of visual cortex, rather than engineering constraints.
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Affiliation(s)
- Ione Fine
- Department of Psychology, University of Washington, Seattle, 98195, USA.
- Faculty of Biological Sciences, University of Leeds, Leeds, UK.
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13
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Oh Y, Hong J, Kim J. Retinal prosthesis edge detection (RPED) algorithm: Low-power and improved visual acuity strategy for artificial retinal implants. PLoS One 2024; 19:e0305132. [PMID: 38889114 PMCID: PMC11185494 DOI: 10.1371/journal.pone.0305132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 05/23/2024] [Indexed: 06/20/2024] Open
Abstract
This paper proposes a retinal prosthesis edge detection (RPED) algorithm that can achieve high visual acuity and low power. Retinal prostheses have been used to stimulate retinal tissue by injecting charge via an electrode array, thereby artificially restoring the vision of visually impaired patients. The retinal prosthetic chip, which generates biphasic current pulses, should be located in the foveal area measuring 5 mm × 5 mm. When a high-density stimulation pixel array is realized in a limited area, the distance between the stimulation pixels narrows, resulting in current dispersion and high-power dissipation related to heat generation. Various edge detection methods have been proposed over the past decade to reduce these deleterious effects and achieve high-resolution pixels. However, conventional methods have the disadvantages of high-power consumption and long data processing times because many pixels are activated to detect edges. In this study, we propose a novel RPED algorithm that has a higher visual acuity and less power consumption despite using fewer active pixels than existing techniques. To verify the performance of the devised RPED algorithm, the peak signal-to-noise ratio and structural similarity index map, which evaluates the quantitative numerical value of the image are employed and compared with the Sobel, Canny, and past edge detection algorithms in MATLAB. Finally, we demonstrate the effectiveness of the proposed RPED algorithm using a 1600-pixel retinal stimulation chip fabricated using a 0.35 μm complementary metal-oxide-semiconductor process.
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Affiliation(s)
- Yeonji Oh
- Department of Medical Science, Korea University, Seoul, South Korea
| | - Jonggi Hong
- Department of Health Sciences & Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon, South Korea
| | - Jungsuk Kim
- Department of Biomedical Engineering, Gachon University, Sungnam, South Korea
- Cellico Research and Development Laboratory, Sungnam, South Korea
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14
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Weinlander E, Erb B, Thiessen C. An Eye for an Eye?: Problematic Risk-Benefit Trade-Offs in Whole Eye Transplantation. THE AMERICAN JOURNAL OF BIOETHICS : AJOB 2024; 24:75-79. [PMID: 38635428 DOI: 10.1080/15265161.2024.2328285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
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15
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Seo HW, Cha S, Jeong Y, Ahn J, Lee KJ, Kim S, Goo YS. Focal stimulation of retinal ganglion cells using subretinal 3D microelectrodes with peripheral electrodes of opposite current. Biomed Eng Lett 2024; 14:355-365. [PMID: 38374901 PMCID: PMC10874361 DOI: 10.1007/s13534-023-00342-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 10/10/2023] [Accepted: 12/07/2023] [Indexed: 02/21/2024] Open
Abstract
Subretinal prostheses have been developed to stimulate survived retinal ganglion cells (RGCs), indirectly following the physiological visual pathways. However, current spreading from the prosthesis electrode causes the activation of unintended RGCs, thereby limiting the spatial resolution of artificial vision. This study proposes a strategy for focal stimulation of RGCs using a subretinal electrode array, in which six hexagonally arranged peripheral electrodes surround a stimulating electrode. RGCs in an in-vitro condition were subretinally stimulated using a fabricated electrode array coated with iridium oxide, following the three different stimulation configurations (with no peripheral, six electrodes of opposite current, and six ground). In-vitro experiments showed that the stimulation with six electrodes of opposite current was most effective in controlling RGC responses with a high spatial resolution. The results suggest that the effective utilization of return electrodes, such as by applying an opposite current to them, could help reduce current spreading beyond the local area targeted for stimulation and elicit RGC responses only in the vicinity of the stimulating electrode. Supplementary Information The online version contains supplementary material available at 10.1007/s13534-023-00342-3.
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Affiliation(s)
- Hee Won Seo
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
| | - Seongkwang Cha
- Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
| | - Yurim Jeong
- Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
| | - Jungryul Ahn
- Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
| | - Kyeong Jae Lee
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
| | - Sohee Kim
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
| | - Yong Sook Goo
- Department of Physiology, Chungbuk National University School of Medicine, Cheongju, Republic of Korea
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16
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Hu M, Liang C, Wang D. Implantable bioelectrodes: challenges, strategies, and future directions. Biomater Sci 2024; 12:270-287. [PMID: 38175154 DOI: 10.1039/d3bm01204b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Implantable bioelectrodes for regulating and monitoring biological behaviors have become indispensable medical devices in modern healthcare, alleviating pathological symptoms such as epilepsy and arrhythmia, and assisting in reversing conditions such as deafness and blindness. In recent years, developments in the fields of materials science and biomedical engineering have contributed to advances in research on implantable bioelectrodes. However, the foreign body reaction (FBR) is still a major constraint for the long-term application of electrodes. In this paper, four types of commonly used implantable bioelectrodes are reviewed, concentrating on their background, development, and a series of complications caused by FBR after long-term implantation. Strategies for resisting FBRs are then devised in terms of physics, chemistry, and nanotechnology. We analyze the major trends in the future development of implantable bioelectrodes and outline some promising research to optimize the long-term operational stability of electrodes. Although current implantable bioelectrodes have been able to achieve good biocompatibility, low impedance, and low mechanical mismatch and trauma, these devices still face the challenge of FBR. Resistance to FBR is still the key for the long-term effectiveness of bioelectrodes, and a better understanding of the mechanisms of FBR, as well as miniaturization, long-term passivation, and coupling with gene therapy may be the way forward for the next generation of implantable bioelectrodes.
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Affiliation(s)
- Mengyuan Hu
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China
| | - Chunyong Liang
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China
| | - Donghui Wang
- Hebei Key Laboratory of Biomaterials and Smart Theranostics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300130, China.
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17
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Brar AS, Parameswarappa DC, Takkar B, Narayanan R, Jalali S, Mandal S, Fujinami K, Padhy SK. Gene Therapy for Inherited Retinal Diseases: From Laboratory Bench to Patient Bedside and Beyond. Ophthalmol Ther 2024; 13:21-50. [PMID: 38113023 PMCID: PMC10776519 DOI: 10.1007/s40123-023-00862-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 11/23/2023] [Indexed: 12/21/2023] Open
Abstract
This comprehensive review provides a thorough examination of inherited retinal diseases (IRDs), encompassing their classification, genetic underpinnings, and the promising landscape of gene therapy trials. IRDs, a diverse group of genetic conditions causing vision loss through photoreceptor cell death, are explored through various angles, including inheritance patterns, gene involvement, and associated systemic disorders. The focal point is gene therapy, which offers hope for halting or even reversing the progression of IRDs. The review highlights ongoing clinical trials spanning retinal cell replacement, neuroprotection, pharmacological interventions, and optogenetics. While these therapies hold tremendous potential, they face challenges like timing optimization, standardized assessment criteria, inflammation management, vector refinement, and raising awareness among vision scientists. Additionally, translating gene therapy success into widespread adoption and addressing cost-effectiveness are crucial challenges to address. Continued research and clinical trials are essential to fully harness gene therapy's potential in treating IRDs and enhancing the lives of affected individuals.
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Affiliation(s)
- Anand Singh Brar
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Mithu Tulsi Chanrai Campus, Bhubaneswar, 751024, India
| | - Deepika C Parameswarappa
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, 500034, India
| | - Brijesh Takkar
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, 500034, India
| | - Raja Narayanan
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, 500034, India
| | - Subhadra Jalali
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, 500034, India
| | - Sohini Mandal
- Dr Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Kaoru Fujinami
- Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, 152-8902, Japan
| | - Srikanta Kumar Padhy
- Anant Bajaj Retina Institute, LV Prasad Eye Institute, Mithu Tulsi Chanrai Campus, Bhubaneswar, 751024, India.
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18
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Mohammadi H, Rafii-Tabar H. Application of Nanoscopic Quantum Systems in Retinal Restoration. J Ophthalmic Vis Res 2024; 19:1-3. [PMID: 38638632 PMCID: PMC11022022 DOI: 10.18502/jovr.v19i1.15415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 12/24/2023] [Indexed: 04/20/2024] Open
Abstract
This is an Editorial and does not have an abstract. Please download the PDF or view the article in HTML.
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Affiliation(s)
- Hadi Mohammadi
- Department of Medical Physics and Biomedical Engineering, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hashem Rafii-Tabar
- Department of Medical Physics and Biomedical Engineering, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- The Physics Branch of the Academy of Sciences of Iran, Tehran, Iran
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19
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Khabou H, Orendorff E, Trapani F, Rucli M, Desrosiers M, Yger P, Dalkara D, Marre O. Optogenetic targeting of AII amacrine cells restores retinal computations performed by the inner retina. Mol Ther Methods Clin Dev 2023; 31:101107. [PMID: 37868206 PMCID: PMC10589896 DOI: 10.1016/j.omtm.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/08/2023] [Indexed: 10/24/2023]
Abstract
Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. Here we used a vector that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. AII amacrine cells simultaneously activate the ON pathway and inhibit the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.
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Affiliation(s)
- Hanen Khabou
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Elaine Orendorff
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Francesco Trapani
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Marco Rucli
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Melissa Desrosiers
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Pierre Yger
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Deniz Dalkara
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
| | - Olivier Marre
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France
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20
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Hirami Y, Mandai M, Sugita S, Maeda A, Maeda T, Yamamoto M, Uyama H, Yokota S, Fujihara M, Igeta M, Daimon T, Fujita K, Ito T, Shibatani N, Morinaga C, Hayama T, Nakamura A, Ueyama K, Ono K, Ohara H, Fujiwara M, Yamasaki S, Watari K, Bando K, Kawabe K, Ikeda A, Kimura T, Kuwahara A, Takahashi M, Kurimoto Y. Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa. Cell Stem Cell 2023; 30:1585-1596.e6. [PMID: 38065067 DOI: 10.1016/j.stem.2023.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 09/03/2023] [Accepted: 11/08/2023] [Indexed: 12/18/2023]
Abstract
Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.
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Affiliation(s)
- Yasuhiko Hirami
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
| | - Michiko Mandai
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan; RIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama 230-0045, Japan
| | - Sunao Sugita
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Akiko Maeda
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Tadao Maeda
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Midori Yamamoto
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Hirofumi Uyama
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan
| | - Satoshi Yokota
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Masashi Fujihara
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Masataka Igeta
- Department of Biostatistics, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Takashi Daimon
- Department of Biostatistics, Hyogo Medical University, Nishinomiya 663-8501, Japan
| | - Kanako Fujita
- Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Tomoko Ito
- Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Naoki Shibatani
- Research Center, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Chikako Morinaga
- RIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama 230-0045, Japan
| | - Tetsuya Hayama
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Aya Nakamura
- Technology Research & Development Division, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Kazuki Ueyama
- Technology Research & Development Division, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Keiichi Ono
- Technology Research & Development Division, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Hidetaka Ohara
- Regenerative & Cellular Medicine Office, Sumitomo Pharma Co. Ltd., Tokyo 103-6012, Japan
| | - Masayo Fujiwara
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Suguru Yamasaki
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Kenji Watari
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Kiyoko Bando
- Regenerative & Cellular Medicine Office, Sumitomo Pharma Co. Ltd., Tokyo 103-6012, Japan
| | - Keigo Kawabe
- Regenerative & Cellular Medicine Office, Sumitomo Pharma Co. Ltd., Tokyo 103-6012, Japan
| | - Atsushi Ikeda
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Toru Kimura
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan; Regenerative & Cellular Medicine Office, Sumitomo Pharma Co. Ltd., Tokyo 103-6012, Japan
| | - Atsushi Kuwahara
- Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co. Ltd., Kobe 650-0047, Japan
| | - Masayo Takahashi
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan
| | - Yasuo Kurimoto
- Department of Ophthalmology, Kobe City Eye Hospital, Kobe 650-0047, Japan; Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
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21
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Aweidah H, Xi Z, Sahel JA, Byrne LC. PRPF31-retinitis pigmentosa: Challenges and opportunities for clinical translation. Vision Res 2023; 213:108315. [PMID: 37714045 PMCID: PMC10872823 DOI: 10.1016/j.visres.2023.108315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/17/2023]
Abstract
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.
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Affiliation(s)
- Hamzah Aweidah
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zhouhuan Xi
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Ophthalmology, Eye Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - José-Alain Sahel
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Leah C Byrne
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
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22
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Bhuckory MB, Wang BY, Chen ZC, Shin A, Huang T, Galambos L, Vounotrypidis E, Mathieson K, Kamins T, Palanker D. Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision. Proc Natl Acad Sci U S A 2023; 120:e2307380120. [PMID: 37831740 PMCID: PMC10589669 DOI: 10.1073/pnas.2307380120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/08/2023] [Indexed: 10/15/2023] Open
Abstract
In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 μm and reaches the 27 μm limit of natural resolution in rats with 20 μm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.
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Affiliation(s)
- Mohajeet B. Bhuckory
- Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA94305
- Department of Ophthalmology, Stanford University, Stanford, CA94305
| | - Bing-Yi Wang
- Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA94305
- Department of Physics, Stanford University, Stanford, CA94305
| | - Zhijie Charles Chen
- Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA94305
- Department of Electrical Engineering, Stanford University, Stanford, CA94305
| | - Andrew Shin
- Department of Material Science, Stanford University, Stanford, CA94305
| | - Tiffany Huang
- Department of Electrical Engineering, Stanford University, Stanford, CA94305
| | - Ludwig Galambos
- Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA94305
| | | | - Keith Mathieson
- Department of Physics, University of Strathclyde, G1 1XQGlasgow, Scotland, United Kingdom
| | - Theodore Kamins
- Department of Electrical Engineering, Stanford University, Stanford, CA94305
| | - Daniel Palanker
- Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA94305
- Department of Ophthalmology, Stanford University, Stanford, CA94305
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23
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Shome I, Thathapudi NC, Aramati BMR, Kowtharapu BS, Jangamreddy JR. Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration. Int Ophthalmol 2023; 43:3891-3909. [PMID: 37347455 DOI: 10.1007/s10792-023-02767-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/08/2023] [Indexed: 06/23/2023]
Abstract
Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease progression can be managed, if not prevented, either by blocking neovascularization ("wet" form of AMD) or by preserving retinal pigment epithelium and photoreceptor cells ("dry" form of AMD). Although current therapeutic modalities are moderately successful in delaying the progression and management of the disease, advances over the past years in regenerative medicine using iPSC, embryonic stem cells, advanced materials (including nanomaterials) and organ bio-printing show great prospects in restoring vision and efficient management of either forms of AMD. This review focuses on the molecular mechanism of the disease, model systems (both cellular and animal) used in studying AMD, the list of various regenerative therapies and the current treatments available. The article also highlights on the recent clinical trials using regenerative therapies and management of the disease.
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Affiliation(s)
- Ishita Shome
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Neethi C Thathapudi
- Centre de Recherche Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
- Department of Ophthalmology and Institute of Biomedical Engineering, Université de Montréal, Montréal, QC, Canada
| | - Bindu Madhav Reddy Aramati
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Bhavani S Kowtharapu
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Jaganmohan R Jangamreddy
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India.
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24
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Sidhu S, Persad PJ, Lam BL, Zann KL, Gregori NZ. Current Assistive Devices Usage and Recommendations for a Future Artificial Vision Prosthesis among Patients with Severe Visual Impairment Due to Inherited Retinal Diseases. J Clin Med 2023; 12:5283. [PMID: 37629325 PMCID: PMC10455651 DOI: 10.3390/jcm12165283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
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.
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Affiliation(s)
- Sophia Sidhu
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (P.J.P.); (B.L.L.)
- UC San Diego School of Medicine, San Diego, CA 92093, USA
| | - Patrice J. Persad
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (P.J.P.); (B.L.L.)
| | - Byron L. Lam
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (P.J.P.); (B.L.L.)
| | - Kasey L. Zann
- Miami Veterans Affairs Medical Center, Miami, FL 33125, USA;
| | - Ninel Z. Gregori
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (S.S.); (P.J.P.); (B.L.L.)
- Miami Veterans Affairs Medical Center, Miami, FL 33125, USA;
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25
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Palanker D. Electronic Retinal Prostheses. Cold Spring Harb Perspect Med 2023; 13:a041525. [PMID: 36781222 PMCID: PMC10411866 DOI: 10.1101/cshperspect.a041525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Retinal prostheses are a promising means for restoring sight to patients blinded by photoreceptor atrophy. They introduce visual information by electrical stimulation of the surviving inner retinal neurons. Subretinal implants target the graded-response secondary neurons, primarily the bipolar cells, which then transfer the information to the ganglion cells via the retinal neural network. Therefore, many features of natural retinal signal processing can be preserved in this approach if the inner retinal network is retained. Epiretinal implants stimulate primarily the ganglion cells, and hence should encode the visual information in spiking patterns, which, ideally, should match the target cell types. Currently, subretinal arrays are being developed primarily for restoration of central vision in patients impaired by age-related macular degeneration (AMD), while epiretinal implants-for patients blinded by retinitis pigmentosa, where the inner retina is less preserved. This review describes the concepts and technologies, preclinical characterization of prosthetic vision and clinical outcomes, and provides a glimpse into future developments.
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Affiliation(s)
- Daniel Palanker
- Department of Ophthalmology and Hansen Experimental Physics Laboratory, Stanford University, Stanford, California 94305, USA
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26
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Wu KY, Mina M, Sahyoun JY, Kalevar A, Tran SD. Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration. SENSORS (BASEL, SWITZERLAND) 2023; 23:5782. [PMID: 37447632 PMCID: PMC10347280 DOI: 10.3390/s23135782] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/04/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023]
Abstract
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.
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Affiliation(s)
- Kevin Y. Wu
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada; (K.Y.W.)
| | - Mina Mina
- Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Jean-Yves Sahyoun
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Ananda Kalevar
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada; (K.Y.W.)
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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27
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Gabriele Sandrian M, Ng E, Nguyen T, Eydelman M. FDA's role in expediting innovation of bioelectronic implants for vision restoration. J Neural Eng 2023; 20:030401. [PMID: 37278453 DOI: 10.1088/1741-2552/acd8f1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/25/2023] [Indexed: 06/07/2023]
Abstract
Bioelectronic implants for vision restoration are medical devices regulated in the United States by the Food and Drug Administration (FDA). This paper provides an overview of regulatory pathways and related FDA programs for bioelectronic implants for vision restoration, and identifies some of the gaps in the regulatory science of these devices. The FDA recognizes that additional discussion regarding development in this space is needed to further develop bioelectronic implants and ensure that safe and effective technologies are made available to patients with profound vision loss. FDA regularly participates in the Eye and the Chip World Research Congress meetings and continues to engage with important external stakeholders, including through public workshops such as the recent co-sponsored Expediting Innovation of Bioelectronic Implants for Vision Restoration. By participating in forums for discussion of these devices with all stakeholders, especially patients, FDA seeks to encourage advancement of these devices.
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Affiliation(s)
- Michelle Gabriele Sandrian
- Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America
| | - Elvin Ng
- Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America
| | - Tieuvi Nguyen
- Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America
| | - Malvina Eydelman
- Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America
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28
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Gong C, Li R, Lu G, Ji J, Zeng Y, Chen J, Chang C, Zhang J, Xia L, Nair DSR, Thomas BB, Song BJ, Humayun MS, Zhou Q. Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo. Bioengineering (Basel) 2023; 10:577. [PMID: 37237647 PMCID: PMC10215307 DOI: 10.3390/bioengineering10050577] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US).
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Affiliation(s)
- Chen Gong
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Runze Li
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Gengxi Lu
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Jie Ji
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
| | - Yushun Zeng
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
| | - Jiawen Chen
- Department of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA
| | - Chifeng Chang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Junhang Zhang
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Lily Xia
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
| | - Deepthi S. Rajendran Nair
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Biju B. Thomas
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Brian J. Song
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Mark S. Humayun
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
| | - Qifa Zhou
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; (C.G.); (R.L.); (G.L.); (J.J.)
- USC Roski Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA
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29
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Fine I, Boynton GM. Pulse trains to percepts: A virtual patient describing the perceptual effects of human visual cortical stimulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.18.532424. [PMID: 36993519 PMCID: PMC10055195 DOI: 10.1101/2023.03.18.532424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The field of cortical sight restoration prostheses is making rapid progress with three clinical trials of visual cortical prostheses underway. However, as yet, we have only limited insight into the perceptual experiences produced by these implants. Here we describe a computational model or 'virtual patient', based on the neurophysiological architecture of V1, which successfully predicts the perceptual experience of participants across a wide range of previously published cortical stimulation studies describing the location, size, brightness and spatiotemporal shape of electrically induced percepts in humans. Our simulations suggest that, in the foreseeable future the perceptual quality of cortical prosthetic devices is likely to be limited by the neurophysiological organization of visual cortex, rather than engineering constraints.
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30
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Cehajic-Kapetanovic J, Singh MS, Zrenner E, MacLaren RE. Bioengineering strategies for restoring vision. Nat Biomed Eng 2023; 7:387-404. [PMID: 35102278 DOI: 10.1038/s41551-021-00836-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 11/30/2021] [Indexed: 12/15/2022]
Abstract
Late-stage retinal degenerative disease involving photoreceptor loss can be treated by optogenetic therapy, cell transplantation and retinal prostheses. These approaches aim to restore light sensitivity to the retina as well as visual perception by integrating neuronal responses for transmission to the cortex. In age-related macular degeneration, some cell-based therapies also aim to restore photoreceptor-supporting tissue to prevent complete photoreceptor loss. In the earlier stages of degeneration, gene-replacement therapy could attenuate retinal-disease progression and reverse loss of function. And gene-editing strategies aim to correct the underlying genetic defects. In this Review, we highlight the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal disease, discuss the benefits and drawbacks of each treatment strategy and the factors influencing whether functional tissue is reconstructed and repaired or replaced with an electronic device, and summarize upcoming technologies for enhancing the restoration of vision.
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Affiliation(s)
- Jasmina Cehajic-Kapetanovic
- Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK.
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
| | | | - Eberhart Zrenner
- Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Robert E MacLaren
- Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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31
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Kim HJ, Sritandi W, Xiong Z, Ho JS. Bioelectronic devices for light-based diagnostics and therapies. BIOPHYSICS REVIEWS 2023; 4:011304. [PMID: 38505817 PMCID: PMC10903427 DOI: 10.1063/5.0102811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 12/28/2022] [Indexed: 03/21/2024]
Abstract
Light has broad applications in medicine as a tool for diagnosis and therapy. Recent advances in optical technology and bioelectronics have opened opportunities for wearable, ingestible, and implantable devices that use light to continuously monitor health and precisely treat diseases. In this review, we discuss recent progress in the development and application of light-based bioelectronic devices. We summarize the key features of the technologies underlying these devices, including light sources, light detectors, energy storage and harvesting, and wireless power and communications. We investigate the current state of bioelectronic devices for the continuous measurement of health and on-demand delivery of therapy. Finally, we highlight major challenges and opportunities associated with light-based bioelectronic devices and discuss their promise for enabling digital forms of health care.
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Affiliation(s)
| | - Weni Sritandi
- Department of Electrical and Computer Engineering, National University of Singapore, Singapore
| | | | - John S. Ho
- Author to whom correspondence should be addressed:
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32
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Nishida K, Morimoto T, Terasawa Y, Sakaguchi H, Kamei M, Miyoshi T, Fujikado T, Nishida K. The influence of stimulating electrode conditions on electrically evoked potentials and resistance in suprachoroidal transretinal stimulation. Jpn J Ophthalmol 2023; 67:182-188. [PMID: 36626079 DOI: 10.1007/s10384-022-00972-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 11/17/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE To determine the influence of stimulating electrode conditions on the amplitudes and latencies of electrically evoked potentials (EEPs) and the resistance at the electrode-tissue interface in the suprachoroidal transretinal stimulation (STS) system. STUDY DESIGN Experimental study. METHODS A scleral pocket (3 × 5 mm) was created just over the visual streak in anesthetized pigmented rabbits (weight, 1.9-2.7 kg), and STS stimulating electrodes were implanted into the pocket. Measurements were obtained with stimulating electrodes of different lengths (0.3 or 0.5 mm) and different surface characteristics (smooth or porous). EEPs elicited with a fixed current under each set of electrode conditions were recorded; three measurement sessions were performed for each rabbit. The resistance at each electrode-tissue interface was measured. RESULTS The latencies and amplitudes of the EEPs did not differ significantly with changes in the height and surface characteristics of the stimulating electrodes, but the resistances at the electrode-tissue interface differed significantly (P = 0.001; the resistance values for the 0.3-mm-long electrode with a porous surface was 5.24 ± 0.67 kΩ and with the 0.3- and 0.5-mm-long electrodes with smooth surfaces were 7.63 ± 0.12 kΩ and 6.77 ± 0.20 kΩ). CONCLUSION Being shorter did not affect the EEPs of the stimulating electrodes with a porous surface while decreasing the resistance at the electrode-tissue interface.
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Affiliation(s)
- Kentaro Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, #E7, Suita, 565-0871, Japan.
| | - Takeshi Morimoto
- Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, #E7, Suita, 565-0871, Japan
| | - Yasuo Terasawa
- R&D Division, Artificial Vision Institute, NIDEK Co., Ltd., Gamagori, Japan
| | - Hirokazu Sakaguchi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, #E7, Suita, 565-0871, Japan.,Department of Ophthalmology, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan
| | - Motohiro Kamei
- Department of Ophthalmology, Aichi Medical University, Nagakute, Japan
| | - Tomomitsu Miyoshi
- Department of Integrative Physiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takashi Fujikado
- Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, #E7, Suita, 565-0871, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, #E7, Suita, 565-0871, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Osaka, Japan
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Güven D, Düzgün E, Kutucu OK, Gül C. Evaluation of the Long-Term Clinical Results of 3 Patients Implanted with the Argus II Retinal Prosthesis. Turk J Ophthalmol 2023; 53:58-66. [PMID: 36847635 PMCID: PMC9973216 DOI: 10.4274/tjo.galenos.2022.53598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
This study presents the long-term clinical results of Argus II retinal prosthesis implantation in eyes with light perception and projection in 3 patients with end-stage retinitis pigmentosa. No conjunctival erosion, hypotony, or implant displacement was observed during postoperative follow-up. The electrical threshold values were lower in the macular region and higher close to the tack fixation region and peripherally. Optical coherence tomography scans showed fibrosis and retinoschisis formation at the retina-implant interface in two cases. This was attributed to mechanical and electrical effects on the tissue due to the active daily use of the system and the electrodes' proximity to the retina. The patients were able to integrate the system into their daily lives and perform activities that they could not do before. Studies on retinal prostheses for the rehabilitation of hereditary retinal diseases are ongoing, so both social and clinical observations and experiences related to the implant are valuable.
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Affiliation(s)
- Dilek Güven
- Acıbadem Maslak Hospital, Clinic of Ophthalmology, İstanbul, Türkiye
| | - Eyüp Düzgün
- University of Health Sciences Türkiye Sultan 2. Abdulhamid Han Training and Research Hospital, Clinic of Ophthalmology, İstanbul, Türkiye
| | - Oğuz Kaan Kutucu
- University of Health Sciences Türkiye Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Ophthalmology, İstanbul, Türkiye
| | - Cengiz Gül
- University of Health Sciences Türkiye Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Ophthalmology, İstanbul, Türkiye
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Wu KY, Kulbay M, Toameh D, Xu AQ, Kalevar A, Tran SD. Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development. Pharmaceutics 2023; 15:685. [PMID: 36840007 PMCID: PMC9963330 DOI: 10.3390/pharmaceutics15020685] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/19/2023] Open
Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.
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Affiliation(s)
- Kevin Y. Wu
- Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Merve Kulbay
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Dana Toameh
- Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
| | - An Qi Xu
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada
| | - Ananda Kalevar
- Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada
| | - Simon D. Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada
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Ghani N, Bansal J, Naidu A, Chaudhary KM. Long term positional stability of the Argus II retinal prosthesis epiretinal implant. BMC Ophthalmol 2023; 23:70. [PMID: 36797684 PMCID: PMC9933348 DOI: 10.1186/s12886-022-02736-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 12/13/2022] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND The Argus II Retinal Prosthesis System (Second Sight Medical Products, Sylmar, California) is an epiretinal prosthesis that serves to provide useful vision to people who are affected by retinal degenerative diseases such as retinitis pigmentosa (RP). The purpose of this study was to analyze postoperative movement of the electrode array. METHODS Five patients diagnosed with profound retinal dystrophy who have undergone implantation of retinal prosthesis at Stony Brook University Hospital. Fundoscopy was performed at postoperative month 1 (M1), month 3 (M3), month 6 (M6), month 12 (M12), and month 24 (M24) visits. Fundoscopy was extracted and analyzed via NIH ImageJ. Data analysis was completed using IBM SPSS. Various lengths and angles were measured each postoperative month using ImageJ. RESULTS There was no significant change in distance between the optic disc and the surgical handle (length AB) over the two-year span (F = 0.196, p = 0.705). There was a significant change in distance of length AB over time between patients between M3 and M6 (p = 0.025). A repeated measures ANOVA revealed that there was statistically significant change of the optic disc-tack-surgical handle angle (𝛾) (M1 to M24) (F = 3.527, p = 0.030). There was no significant change in angle 𝜟 (the angle to the horizontal of the image), angle 𝜶 (tack-optic disc-surgical handle), and angle 𝜷 (optic-disc-surgical handle-tack). CONCLUSION Our results demonstrate that there may be postoperative movement of the retinal prosthesis over time, as a statistically significant downward rotation is reported over the 2 years span. It is important, moving forward, to further study this movement and to take into consideration such movement when designing retinal implants. It is important to note that this study is limited by the small sample size, and therefore, the conclusions drawn are limited.
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Affiliation(s)
- Nimra Ghani
- Department of Ophthalmology, Stony Brook University Hospital, Stony Brook, NY, 11790, USA.
| | - Jahnvi Bansal
- grid.412695.d0000 0004 0437 5731Department of Ophthalmology, Stony Brook University Hospital, Stony Brook, NY 11790 USA
| | - Abhishek Naidu
- grid.412695.d0000 0004 0437 5731Department of Ophthalmology, Stony Brook University Hospital, Stony Brook, NY 11790 USA
| | - Khurram M. Chaudhary
- grid.412695.d0000 0004 0437 5731Department of Ophthalmology, Stony Brook University Hospital, Stony Brook, NY 11790 USA
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36
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Thenappan A. Current Management Options for Patients with Retinitis Pigmentosa. Methods Mol Biol 2022; 2560:353-361. [PMID: 36481910 DOI: 10.1007/978-1-0716-2651-1_32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
With an estimated prevalence of 1 in 4000 worldwide [1], retinitis pigmentosa (RP) comprises a spectrum of progressive inherited retinal disorders that can lead to blindness as early as age 30 [2]. Despite its relatively high prevalence and devastating consequences, RP does not have a definitive cure. Therapeutic attempts have been made with nutritional supplementation, but these strategies only have proven benefit in a limited number of patients with rare forms of RP. Thus, current standards of care involve regular follow-up, management of associated ocular pathology such as macular edema and cataracts, and genetic counseling and low vision rehabilitation. In recent years, gene therapy, visual prostheses, and stem cell therapy have emerged as FDA-approved treatments for RP, but these options are not yet widely used. Herein, this chapter will discuss the therapeutic strategies listed above that comprise the current standards of care and briefly discuss some emerging options.
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Affiliation(s)
- Abinaya Thenappan
- Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA.
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37
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Cojocaru AE, Corna A, Reh M, Zeck G. High spatial resolution artificial vision inferred from the spiking output of retinal ganglion cells stimulated by optogenetic and electrical means. Front Cell Neurosci 2022; 16:1033738. [PMID: 36568888 PMCID: PMC9780279 DOI: 10.3389/fncel.2022.1033738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/10/2022] [Indexed: 12/13/2022] Open
Abstract
With vision impairment affecting millions of people world-wide, various strategies aiming at vision restoration are being undertaken. Thanks to decades of extensive research, electrical stimulation approaches to vision restoration began to undergo clinical trials. Quite recently, another technique employing optogenetic therapy emerged as a possible alternative. Both artificial vision restoration strategies reported poor spatial resolution so far. In this article, we compared the spatial resolution inferred ex vivo under ideal conditions using a computational model analysis of the retinal ganglion cell (RGC) spiking activity. The RGC spiking was stimulated in epiretinal configuration by either optogenetic or electrical means. RGCs activity was recorded from the ex vivo retina of transgenic late-stage photoreceptor-degenerated mice (rd10) using a high-density Complementary Metal Oxide Semiconductor (CMOS) based microelectrode array. The majority of retinal samples were stimulated by both, optogenetic and electrical stimuli using a spatial grating stimulus. A population-level analysis of the spiking activity of identified RGCs was performed and the spatial resolution achieved through electrical and optogenetic photo-stimulation was inferred using a support vector machine classifier. The best f1 score of the classifier for the electrical stimulation in epiretinal configuration was 86% for 32 micron wide gratings and increased to 100% for 128 microns. For optogenetically activated cells, we obtained high f1 scores of 82% for 10 microns grid width for a photo-stimulation frequency of 2.5 Hz and 73% for a photo-stimulation frequency of 10 Hz. A subsequent analysis, considering only the RGCs modulated in both electrical and optogenetic stimulation protocols revealed no significant difference in the prediction accuracy between the two stimulation modalities. The results presented here indicate that a high spatial resolution can be achieved for electrical or optogenetic artificial stimulation using the activated retinal ganglion cell output.
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Affiliation(s)
| | - Andrea Corna
- Institute of Biomedical Electronics, TU Wien, Vienna, Austria
| | - Miriam Reh
- Institute for Ophthalmic Research at the University of Tübingen, Tübingen, Germany
| | - Günther Zeck
- Institute of Biomedical Electronics, TU Wien, Vienna, Austria
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38
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Karamali F, Behtaj S, Babaei-Abraki S, Hadady H, Atefi A, Savoj S, Soroushzadeh S, Najafian S, Nasr Esfahani MH, Klassen H. Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision. J Transl Med 2022; 20:572. [PMID: 36476500 PMCID: PMC9727916 DOI: 10.1186/s12967-022-03738-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/29/2022] [Indexed: 12/12/2022] Open
Abstract
Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina's ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.
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Affiliation(s)
- Fereshteh Karamali
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sanaz Behtaj
- grid.1022.10000 0004 0437 5432Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Queensland, Australia ,grid.1022.10000 0004 0437 5432Menzies Health Institute Queensland, Griffith University, Southport, QLD 4222 Australia
| | - Shahnaz Babaei-Abraki
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hanieh Hadady
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Atefeh Atefi
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Soraya Savoj
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sareh Soroushzadeh
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Samaneh Najafian
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Hossein Nasr Esfahani
- grid.417689.5Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Henry Klassen
- grid.266093.80000 0001 0668 7243Gavin Herbert Eye Institute, Irvine, CA USA
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Jeong H, Kim J, Seo JM, Neviani A. Neurostimulators for high-resolution artificial retina: ASIC design challenges and solutions. J Neural Eng 2022; 19. [PMID: 36374010 DOI: 10.1088/1741-2552/aca262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 11/14/2022] [Indexed: 11/16/2022]
Abstract
Objective.Neurostimulator is one of the most important part in artificial retina design. In this paper, we discuss the main challenges in the design of application-specific integrated circuit for high-resolution artificial retina and suggest corresponding solutions.Approach. Problems in the design of the neurostimulator for the existing artificial retina have not been solved yet are analyzed and solutions are presented. For verification of the solutions, mathematical proof, MATLAB and Ansys simulations are used.Main results. The drawbacks of resorting to a high-voltage complementary metal oxide semiconductor (CMOS) process to deal with the large voltage compliance demanded by the stimulator output stage are pointed out, and an alternative approach based on a circuit that switches the voltage of the common reference electrode is proposed to overcome. The necessity of an active discharge circuit to remove the residual charge of electrodes caused by an unbalanced stimulus is investigated. We present a circuit analysis showing that the use of a passive discharge circuit is sufficient to suppress problematic direct current in most situations. Finally, possible restrictions on input and output (I/O) count are investigated by estimating the resistive-capacitive delay caused by the interconnection between the I/O pad and the microelectrode array.Significance. The results of this paper clarified the problems currently faced by neurostimulator design for the artificial retina. Through the solutions presented in this study, circuits with more competitiveness in power and area consumption can be designed.
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Affiliation(s)
- Hyunbeen Jeong
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea
| | - Jisung Kim
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea
| | - Jong-Mo Seo
- Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Andrea Neviani
- Department of Information Engineering, University of Padova, Padova, Italy
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40
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Nanegrungsunk O, Au A, Sarraf D, Sadda SR. New frontiers of retinal therapeutic intervention: a critical analysis of novel approaches. Ann Med 2022; 54:1067-1080. [PMID: 35467460 PMCID: PMC9045775 DOI: 10.1080/07853890.2022.2066169] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A recent wave of pharmacologic and technologic innovations has revolutionized our management of retinal diseases. Many of these advancements have demonstrated efficacy and can increase the quality of life while potentially reducing complications and decreasing the burden of care for patients. Some advances, such as longer-acting anti-vascular endothelial growth factor agents, port delivery systems, gene therapy, and retinal prosthetics have been approved by the US Food and Drug Administration, and are available for clinical use. Countless other therapeutics are in various stages of development, promising a bright future for further improvements in the management of the retinal disease. Herein, we have highlighted several important novel therapies and therapeutic approaches and examine the opportunities and limitations offered by these innovations at the new frontier. KEY MESSAGESNumerous pharmacologic and technologic advancements have been emerging, providing a higher treatment efficacy while decreasing the burden and associated side effects.Anti-vascular endothelial growth factor (anti-VEGF) and its longer-acting agents have dramatically improved visual outcomes and have become a mainstay treatment in various retinal diseases.Gene therapy and retinal prosthesis implantation in the treatment of congenital retinal dystrophy can accomplish the partial restoration of vision and improved daily function in patients with blindness, an unprecedented success in the field of retina.
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Affiliation(s)
- Onnisa Nanegrungsunk
- Doheny Eye Institute, Pasadena, CA, USA.,Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.,Retina Division, Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Adrian Au
- Stein Eye Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA
| | - David Sarraf
- Stein Eye Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA
| | - Srinivas R Sadda
- Doheny Eye Institute, Pasadena, CA, USA.,Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA
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Lu G, Qian X, Gong C, Ji J, Thomas BB, Humayun MS, Zhou Q. Ultrasound Retinal Stimulation: A Mini-Review of Recent Developments. IEEE TRANSACTIONS ON ULTRASONICS, FERROELECTRICS, AND FREQUENCY CONTROL 2022; 69:3224-3231. [PMID: 36343006 PMCID: PMC10424795 DOI: 10.1109/tuffc.2022.3220568] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Ultrasound neuromodulation is an emerging technology. A significant amount of effort has been devoted to investigating the feasibility of noninvasive ultrasound retinal stimulation. Recent studies have shown that ultrasound can activate neurons in healthy and degenerated retinas. Specifically, high-frequency ultrasound can evoke localized neuron responses and generate patterns in visual circuits. In this review, we recapitulate pilot studies on ultrasound retinal stimulation, compare it with other neuromodulation technologies, and discuss its advantages and limitations. An overview of the opportunities and challenges to develop a noninvasive retinal prosthesis using high-frequency ultrasound is also provided.
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Humayun MS, Lee SY. Advanced Retina Implants. Ophthalmol Retina 2022; 6:899-905. [PMID: 35436597 DOI: 10.1016/j.oret.2022.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 06/14/2023]
Abstract
PURPOSE To discuss the role of advanced retinal implants in retinitis pigmentosa and age-related macular degeneration. DESIGN Presented by Mark S. Humayun as the Charles Schepen's Lecture on the Retina Subspecialty Day of the American Academy of Ophthalmology in 2021. PARTICIPANTS The details of subjects, participants, and controls are provided in the references pertaining to each study. METHODS Review of published literature and clinical trials. MAIN OUTCOME MEASURES Visual and anatomic outcomes from retinal implants. RESULTS Retinal implants have been researched over the past few decades, and some have been advanced into the clinic. Two types of implants-bioelectronic and stem cell-based-have shown promising results in restoring some level of vision in patients with inherited retinal degeneration and geographic atrophy. These implants differ in their constructions, locations of implantation, and safety profiles. The results from some of these retinal implants have shown signs of efficacy, and 1 retinal implant, the Argus II, has been approved by the United States Food and Drug Administration. CONCLUSIONS Careful consideration of the design of the implant and associated surgical techniques are necessary to obtain a stable and effective long-term interface between the implant and the retina.
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Affiliation(s)
- Mark S Humayun
- University of Southern California Roski Eye Institute, University of Southern California Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, California; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Biomedical Engineering, Denney Research Center, University of Southern California, Los Angeles, California.
| | - Sun Young Lee
- University of Southern California Roski Eye Institute, University of Southern California Ginsburg Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, California; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California
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43
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Vu QA, Seo HW, Choi KE, Kim N, Kang YN, Lee J, Park SH, Kim JT, Kim S, Kim SW. Structural changes in the retina after implantation of subretinal three-dimensional implants in mini pigs. Front Neurosci 2022; 16:1010445. [PMID: 36248640 PMCID: PMC9561346 DOI: 10.3389/fnins.2022.1010445] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/16/2022] [Indexed: 11/30/2022] Open
Abstract
The retinal structural changes after subretinal implantation of three-dimensional (3D) microelectrodes were investigated in a mini pig. Three types of electrode were implanted into the subretinal spaces of nine mini pigs: 75-μm-high 3D electrodes on a 200-μm-thick right-angled polydimethylsiloxane (PDMS) substrate (group 1); a 140-μm-thick sloped PDMS substrate without electrodes (group 2); and a 140-μm-thick sloped PDMS substrate with 20-μm-high 3D electrodes (group 3). One mini pig was used as a control. Spectral domain–optical coherence tomography (SD–OCT) images were obtained at baseline and 2, 6, and 12 weeks post-surgery. Retinal specimens were immunostained using a tissue-clearing method 3 months post-implantation. The 75-μm-high 3D electrodes progressively penetrated the inner nuclear layer (INL) and touched the inner plexiform layer (IPL) 2 weeks post-surgery. At 6 weeks post-operatively, the electrodes were in contact with the nerve-fiber layer, accompanied by a severe fibrous reaction. In the other groups, the implants remained in place without subretinal migration. Immunostaining showed that retinal ganglion and bipolar cells were preserved without fibrosis over the retinal implants in groups 2 and 3 during the 12-week implantation period. In summary, SD–OCT and immunohistology results showed differences in the extent of reactions, such as fibrosis over the implants and penetration of the electrodes into the inner retinal layer depending on different types of electrodes. A sloped substrate performed better than a right-angled substrate in terms of retinal preservation over the implanted electrodes. The 20-μm-high electrodes showed better structural compatibility than the 75-μm-high 3D electrodes. There was no significant difference between the results of sloped implants without electrodes and 20-μm-high 3D electrodes, indicating that the latter had no adverse effects on retinal tissue.
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Affiliation(s)
- Que Anh Vu
- Department of Ophthalmology, Korea University School of Medicine, Seoul, South Korea
- Department of Ophthalmology, Hanoi Medical University, Hanoi, Vietnam
| | - Hee Won Seo
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
| | - Kwang-Eon Choi
- Department of Ophthalmology, Korea University School of Medicine, Seoul, South Korea
| | - Namju Kim
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
| | - Yoo Na Kang
- Department of Medical Assistant Robot, Korea Institute of Machinery and Materials (KIMM), Daegu, South Korea
| | - Jaemeun Lee
- R&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, South Korea
| | - Sun-Hyun Park
- R&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, South Korea
| | - Jee Taek Kim
- Department of Ophthalmology, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Sohee Kim
- Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
- *Correspondence: Sohee Kim,
| | - Seong-Woo Kim
- Department of Ophthalmology, Korea University School of Medicine, Seoul, South Korea
- Seong-Woo Kim,
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44
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Abbott CJ, Baglin EK, Kolic M, McGuinness MB, Titchener SA, Young KA, Yeoh J, Luu CD, Ayton LN, Petoe MA, Allen PJ. Interobserver Agreement of Electrode to Retina Distance Measurements in a Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis. Transl Vis Sci Technol 2022; 11:4. [PMID: 36066322 PMCID: PMC9463715 DOI: 10.1167/tvst.11.9.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose The electrode to retina (ER) distance is an important contributory factor to the safety and efficacy of a suprachoroidal retinal prosthesis. Measuring ER distance may be performed by different observers during multisite studies. The aim of this study was to assess the interobserver agreement in measuring ER distance. Methods Three independent, trained observers measured ER distance from the center of each suprachoroidal electrode to the inner retinal pigment epithelium in spectral-domain optical coherence tomography (SD-OCT) B-scans. A total of 121 ER distance measurements from 77 B-scans collected over 5 months from one subject implanted with a second-generation 44-channel suprachoroidal retinal prosthesis (NCT03406416) were made by each observer. Results ER distance ranged from 208 to 509 µm. Pearson's correlation coefficient (ρ) showed agreement of 0.99 (95% confidence interval [CI] = 0.98–0.99) in measuring ER for each pairwise comparison. The mean difference in ER distance between observers ranged from 2.4 to 6.4 µm with pairwise limits of agreement (95% CI) of ±20 µm (5.5% of mean). Intraclass correlation coefficient (ICC) showed agreement of 0.98 (95% CI = 0.97–0.99) between observers. Conclusions There is high agreement in measuring ER distances for suprachoroidal retinal prostheses using our systematic approach between multiple, trained observers, supporting the use of a single observer for each image. Translational Relevance High interobserver agreement outcomes indicate that multiple, trained observers can be used to take ER measurements across different images in suprachoroidal retinal prosthesis studies. This improves multisite study efficiency and gives confidence in interpreting results relating to the safety and efficacy of suprachoroidal retinal prostheses.
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Affiliation(s)
- Carla J Abbott
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Department of Surgery (Ophthalmology), University of Melbourne, Victoria, Australia
| | - Elizabeth K Baglin
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Maria Kolic
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Myra B McGuinness
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia
| | - Samuel A Titchener
- Bionics Institute of Australia, Victoria, Australia.,Medical Bionics Department, University of Melbourne, Victoria, Australia
| | - Kiera A Young
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Jonathan Yeoh
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia
| | - Chi D Luu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Department of Surgery (Ophthalmology), University of Melbourne, Victoria, Australia
| | - Lauren N Ayton
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Department of Surgery (Ophthalmology), University of Melbourne, Victoria, Australia.,Department of Optometry and Vision Sciences, University of Melbourne, Australia
| | - Matthew A Petoe
- Bionics Institute of Australia, Victoria, Australia.,Medical Bionics Department, University of Melbourne, Victoria, Australia
| | - Penelope J Allen
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.,Department of Surgery (Ophthalmology), University of Melbourne, Victoria, Australia
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45
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Yücel EI, Sadeghi R, Kartha A, Montezuma SR, Dagnelie G, Rokem A, Boynton GM, Fine I, Beyeler M. Factors affecting two-point discrimination in Argus II patients. Front Neurosci 2022; 16:901337. [PMID: 36090266 PMCID: PMC9448992 DOI: 10.3389/fnins.2022.901337] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Two of the main obstacles to the development of epiretinal prosthesis technology are electrodes that require current amplitudes above safety limits to reliably elicit percepts, and a failure to consistently elicit pattern vision. Here, we explored the causes of high current amplitude thresholds and poor spatial resolution within the Argus II epiretinal implant. We measured current amplitude thresholds and two-point discrimination (the ability to determine whether one or two electrodes had been stimulated) in 3 blind participants implanted with Argus II devices. Our data and simulations show that axonal stimulation, lift and retinal damage all play a role in reducing performance in the Argus 2, by either limiting sensitivity and/or reducing spatial resolution. Understanding the relative role of these various factors will be critical for developing and surgically implanting devices that can successfully subserve pattern vision.
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Affiliation(s)
- Ezgi I. Yücel
- Department of Psychology, University of Washington, Seattle, WA, United States
| | - Roksana Sadeghi
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Arathy Kartha
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Sandra Rocio Montezuma
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States
| | - Gislin Dagnelie
- Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Ariel Rokem
- Department of Psychology, University of Washington, Seattle, WA, United States,eScience Institute, University of Washington, Seattle, WA, United States
| | - Geoffrey M. Boynton
- Department of Psychology, University of Washington, Seattle, WA, United States
| | - Ione Fine
- Department of Psychology, University of Washington, Seattle, WA, United States,*Correspondence: Ione Fine,
| | - Michael Beyeler
- Department of Computer Science, University of California, Santa Barbara, Santa Barbara, CA, United States,Department of Psychological and Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United States
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46
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Rassia KEK, Moutoussis K, Pezaris JS. Reading text works better than watching videos to improve acuity in a simulation of artificial vision. Sci Rep 2022; 12:12953. [PMID: 35902596 PMCID: PMC9334451 DOI: 10.1038/s41598-022-10719-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/12/2022] [Indexed: 12/03/2022] Open
Abstract
Simulated artificial vision is used in visual prosthesis design to answer questions about device usability. We previously reported a striking increase in equivalent visual acuity with daily use of a simulation of artificial vision in an active task, reading sentences, that required high levels of subject engagement, but passive activities are more likely to dominate post-implant experience. Here, we investigated the longitudinal effects of a passive task, watching videos. Eight subjects used a simulation of a thalamic visual prosthesis with 1000 phosphenes to watch 23 episodes of classic American television in daily, 25-min sessions, for a period of 1 month with interspersed reading tests that quantified reading accuracy and reading speed. For reading accuracy, we found similar dynamics to the early part of the learning process in our previous report, here leading to an improvement in visual acuity of 0.15 ± 0.05 logMAR. For reading speed, however, no change was apparent by the end of training. We found that single reading sessions drove about twice the improvement in acuity of single video sessions despite being only half as long. We conclude that while passive viewing tasks may prove useful for post-implant rehabilitation, active tasks are likely to be preferable.
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Affiliation(s)
- Katerina Eleonora K Rassia
- Cognitive Science Laboratory, Department of History and Philosophy of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Moutoussis
- Cognitive Science Laboratory, Department of History and Philosophy of Science, National and Kapodistrian University of Athens, Athens, Greece
| | - John S Pezaris
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA. .,Department of Neurosurgery, Harvard Medical School, Boston, MA, USA.
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47
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Ito N, Miura G, Shiko Y, Kawasaki Y, Baba T, Yamamoto S. Progression Rate of Visual Function and Affecting Factors at Different Stages of Retinitis Pigmentosa. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7204954. [PMID: 35872870 PMCID: PMC9303139 DOI: 10.1155/2022/7204954] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 06/15/2022] [Accepted: 06/30/2022] [Indexed: 11/17/2022]
Abstract
We reviewed medical records of 121 patients/235 eyes of typical retinitis pigmentosa (RP) patients who could be followed up for at least 5 years with the aim of investigating the long-term course of visual function progression at each RP stage and appropriate assessment methods. Patients were classified into three groups: mild RP (baseline mean deviation (MD) ≥ -5), moderate RP (-25 < baseline MD < -5), and late RP (baseline MD ≤ -25). Linear mixed-effect models were used to follow MD, the average retinal sensitivity of the central four points of the Humphrey field analyzer 10-2 program (S4), and visual acuity (VA) with increasing time. The associations among factors (baseline MD group, sex, hereditary form) and the interaction between each factor and time were also investigated. The mean reduction of the MD, S4, and VA for all patients was -0.37 dB/year, -0.25 dB/year, and 0.018/year, respectively. The moderate RP group had a faster progression than other groups in MD (-0.43 dB/year, p < 0.05). The moderate (-0.31 dB/year, p = 0.01) and late RP groups (-0.25 dB/year, p < 0.01) had faster progression than the mild RP group in S4. The late RP group had faster progression in VA than the other groups (0.03/year, p < 0.05). Females had a slower progression of the S4 (-0.15 dB/year, p = 0.02) and VA (0.01/year, p < 0.001) than males. The autosomal dominant group had a slower progression than the sporadic group in MD (-0.22 dB/year, p = 0.02); the autosomal dominant and autosomal recessive groups had a slower VA decline than the sporadic group (0.01/year, p = 0.03; 0.01/year, p = 0.04). Because the progression rates of VA and visual field test differed as per the RP stage, S4 and VA can also be useful assessment methods depending on the stage. Inheritance form and sex may affect the progression rate.
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Affiliation(s)
- Nana Ito
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Gen Miura
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuki Shiko
- Biostatistics Section, Clinical Research Centre, Chiba University Hospital, Chiba, Japan
| | - Yohei Kawasaki
- Faculty of Nursing, Japanese Red Cross College of Nursing, Tokyo, Japan
| | - Takayuki Baba
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shuichi Yamamoto
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
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48
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Flexible ultrasound-induced retinal stimulating piezo-arrays for biomimetic visual prostheses. Nat Commun 2022; 13:3853. [PMID: 35788594 PMCID: PMC9253314 DOI: 10.1038/s41467-022-31599-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 06/22/2022] [Indexed: 12/29/2022] Open
Abstract
Electronic visual prostheses, or biomimetic eyes, have shown the feasibility of restoring functional vision in the blind through electrical pulses to initiate neural responses artificially. However, existing visual prostheses predominantly use wired connections or electromagnetic waves for powering and data telemetry, which raises safety concerns or couples inefficiently to miniaturized implant units. Here, we present a flexible ultrasound-induced retinal stimulating piezo-array that can offer an alternative wireless artificial retinal prosthesis approach for evoking visual percepts in blind individuals. The device integrates a two-dimensional piezo-array with 32-pixel stimulating electrodes in a flexible printed circuit board. Each piezo-element can be ultrasonically and individually activated, thus, spatially reconfigurable electronic patterns can be dynamically applied via programmable ultrasound beamlines. As a proof of concept, we demonstrate the ultrasound-induced pattern reconstruction in ex vivo murine retinal tissue, showing the potential of this approach to restore functional, life-enhancing vision in people living with blindness.
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49
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Vagni P, Airaghi Leccardi MJI, Vila CH, Zollinger EG, Sherafatipour G, Wolfensberger TJ, Ghezzi D. POLYRETINA restores light responses in vivo in blind Göttingen minipigs. Nat Commun 2022; 13:3678. [PMID: 35760775 PMCID: PMC9237028 DOI: 10.1038/s41467-022-31180-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 06/03/2022] [Indexed: 11/09/2022] Open
Abstract
Retinal prostheses hold the potential for artificial vision in blind people affected by incurable diseases of the outer retinal layer. Available technologies provide only a small field of view: a significant limitation for totally blind people. To overcome this problem, we recently proposed a large and high-density photovoltaic epiretinal device, known as POLYRETINA. Here, we report the in vivo assessment of POLYRETINA. First, we characterise a model of chemically-induced blindness in Göttingen minipigs. Then, we develop and test a minimally invasive injection procedure to insert the large epiretinal implant into the eye. Last, we show that POLYRETINA restores light-evoked cortical responses in blind animals at safe irradiance levels. These results indicate that POLYRETINA holds the potential for artificial vision in totally blind patients affected by retinitis pigmentosa.
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Affiliation(s)
- Paola Vagni
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Marta Jole Ildelfonsa Airaghi Leccardi
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Charles-Henri Vila
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Elodie Geneviève Zollinger
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Golnaz Sherafatipour
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Thomas J Wolfensberger
- Department of Ophthalmology, University of Lausanne, Hôpital Ophtalmique Jules-Gonin, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Diego Ghezzi
- Medtronic Chair in Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland.
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50
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Fauvel T, Chalk M. Human-in-the-loop optimization of visual prosthetic stimulation. J Neural Eng 2022; 19. [PMID: 35667363 DOI: 10.1088/1741-2552/ac7615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/06/2022] [Indexed: 11/12/2022]
Abstract
Retinal prostheses are a promising strategy to restore sight to patients with retinal degenerative diseases. These devices compensate for the loss of photoreceptors by electrically stimulating neurons in the retina. Currently, the visual function that can be recovered with such devices is very limited. This is due, in part, to current spread, unintended axonal activation, and the limited resolution of existing devices. Here we show, using a recent model of prosthetic vision, that optimizing how visual stimuli are encoded by the device can help overcome some of these limitations, leading to dramatic improvements in visual perception. APPROACH We propose a strategy to do this in practice, using patients' feedback in a visual task. The main challenge of our approach comes from the fact that, typically, one only has access to a limited number of noisy responses from patients. We propose two ways to deal with this: first, we use a model of prosthetic vision to constrain and simplify the optimization. We show that, if one knew the parameters of this model for a given patient, it would be possible to greatly improve their perceptual performance. Second we propose a preferential Bayesian optimization to efficiently learn these model parameters for each patient, using minimal trials. MAIN RESULTS To test our approach, we presented healthy subjects with visual stimuli generated by a recent model of prosthetic vision, to replicate the perceptual experience of patients fitted with an implant. Our optimization procedure led to significant and robust improvements in perceived image quality, that transferred to increased performance in other tasks. SIGNIFICANCE Importantly, our strategy is agnostic to the type of prosthesis and thus could readily be implemented in existing implants.
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Affiliation(s)
- Tristan Fauvel
- Institut de la Vision, INSERM, 17 Rue Moreau, Paris, Île-de-France, 75014, FRANCE
| | - Matthew Chalk
- Institut de l a Vision, INSERM, 17 Rue Moreau, Paris, 75014, FRANCE
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