FEATURE

Retinal prosthetics: science fiction or a vision for the future?

BY ADAM YOUNG

“Is it a fact – or have I dreamt it – that, by means of electricity, the world of matter has become a great nerve, vibrating thousands of miles in a breathless point of time?” – Nathaniel Hawthorne, The House of the Seven Gables (1851)

n the 1987 film Predator, the formidable alien has the power of invisibility, to travel between stars and to hunt using Isuperhuman thermal vision. Visual prostheses – or bionic eyes – provide artificial electronic visual sensation to the brain. In most senses, this relates to simulating normal physiological capabilities. But it can also signify surpassing the ordinary function of eye, for example, by acquiring the performance- enhancing qualities of a fictional extraterrestrial species. Although a number of strategies have been trialled for restoring vision, for instance, stem cell transplantation and gene therapy, one of the contemporary approaches has been to artificially replace the dysfunctional neuronal components that generate the optic pathway from the eye to the brain. Surgically implanting electrode arrays into the enables the to convert into electrical Figure 1: The Argus® II Retinal Prosthesis System. © Second Sight. signals. These are then passed to retinal ganglion cells for processing [1]. – where no adequate therapies currently electrode is implanted between the retinal An intact functional visual pathway exist – are thus likely to benefit. Where pigment epithelium and malfunctioning from the retina to the brain is required for the structural integrity of the retina is photoreceptors; an epiretinal approach may traditional retinal prostheses. Patients compromised, however, or in abnormal early equally be used with an implant affixed onto with inherited retinal degenerative disease, visual development, a retinal prosthesis is the retinal surface, at the ganglion cell layer. such as (RP), and dry unlikely to be effective. Animal models of retinal prostheses have age-related (AMD) demonstrated promise in restoring vision. How do bionic eyes work? In a model of retinitis pigmentosa in rats, an Conceptually, a prosthesis could be organic semiconductor retinal prosthesis inserted at any given juncture in the visual successfully underwent implantation in pathway. In one prototype, a small camera vivo leading to a significant and persistent “Further research is is mounted on a pair of glasses to capture recovery of light-sensitivity and needed to identify which images. These signals are transposed [3]. Likewise, in photoreceptor-degenerated initially from a microprocessor, which mouse models, subretinal implants have patients are likely to converts data into electrical signals, and demonstrated spatially and temporally benefit from prosthetics subsequently to a microelectrode array restricted response implanted on the retina. After preliminary patterns [4]. and, importantly, at what processing, the signal is transmitted Alternative techniques depend on an stage the device should be along the optic nerve to the brain to implant which transmits images directly ultimately construct a retinotopic visual to the occipital cortex in patients with introduced” image [2]. In the subretinal method, an acquired visual impairment. Directly

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activating neurons, via a surgical implant in the brain, has the potential to bypass damaged retinal cells in the eye completely [5]. These cortical visual prostheses do not rely on a working optic nerve and could therefore open this technology up to patients with virtually all causes of acquired blindness, regardless of the ocular pathology.

What’s currently available? Worldwide, there are a number of emerging systems. Most devices have focused on patients with degenerative retinopathy, such as RP and AMD. Although a wealth of technology is materialising, many models are at early stages of development and, so far, few have received commercial market approval. The Argus® II Retinal Prosthesis System, developed by Second Sight, is an epiretinal device consisting of a video camera mounted on glasses, a portable visual processing unit, and a wireless 60-electrode Figure 2: The PRIMA photovoltaic subretinal implant. © Pixium Vision. stimulating array [6]. It superseded the first- generation model, Argus I, a 16-electrode with a best measurement of 20/546 on – studied in animal experiments – which modified cochlear implant. In 2011, it was -reversal Landolt-C testing [7], may offer superior biocompatibility [3]. the first retinal prosthesis in Europe to although the manufacturer Retina Implant Risks associated with both the device receive certification mark (CE) approval AG has since ceased trading. Of the 29 and implant surgery can be anticipated and for commercial use. It later received Food participants enrolled in the trial, with the safety profile of retinal prosthetics has & Drug Administration (FDA) regulatory advanced RP or cone-rod dystrophies, been monitored closely over the years. For approval in the US in 2013. Alpha IMS, 25 (86%) could perceive light and six the initial 30 patients in the Argus® II trial, created by Retina Implant AG in Germany, subjects could detect motion. In addition, approximately one third experienced a has also gained European CE marking [7]. 45% of patients reported useful daily serious adverse event in the first three years It is comprised of a wirelessly-powered, life experiences with the implant. There [10]. Complications included conjunctival subretinal microchip with 1500 photodiodes; remains nonetheless large variation in visual erosion (four), hypotony (four), culture- this photosensitive array stimulates the outcomes – including motion detection, negative presumed endophthalmitis (three) bipolar cell layer in the retina. target localisation, form discrimination and and retinal detachment (two). For one Two devices are being developed by orientation / mobility – between patients patient, requiring treatment for recurrent Pixium Vision but are yet to gain commercial with all devices. conjunctival erosion, the implant was approval. The Iris® II Bionic Vision System removed. Most events occurred during is an epiretinal device, incorporating 150 What are the risks and possible the first year and, encouragingly, at five electrodes, which is undergoing initial safety long-term effects? years post-implant, 60% of participants studies in a small number of subjects [8]. Constraints on the hardware and software of experienced no device-related adverse PRIMA is a photovoltaic subretinal implant devices may ultimately limit longevity. Likely events. In addition, 24 of the 30 devices which delivers images to the eye in bursts of as a result of stress on biological tissue, remained implanted and functioning at five near-infrared light. Researchers at Stanford compared to their epiretinal counterparts, years. Beyond this, the longer-term risks University are piloting the device in patients subretinal systems appear to have a shorter are unknown and it is recommended that with geographic atrophy from advanced dry lifespan. The current required for the patients with new devices are followed up at AMD [9]. complex arrangement of inductive coils is least annually. in the region of 50mA [12] and scientists What are the results? are cautious of destructive in vivo heat What obstacles have emerged? Argus® II has allowed patients with RP to see generation. Extrapolating the progress Outputs from artificial visual devices geometric shapes and high-contrast letters in restoring visual function, based on the may contrast significantly from normal in black and white after total loss of central number of electrodes, a higher density array vision. Electrical stimulation typically vision [6]. The best grating visual acuity with upwards of a thousand electrodes elicits discrete light sensations, called achieved with the device to date is logMAR could theoretically restore the patient’s , which are described as images 1.8 (Snellen equivalent of 20/1262). At five ability to recognise faces and read large in a number of different shapes. Measuring years, the benefits of the system have been print. Difficulties arise in obtaining such the success of these devices has thus been a favourable [10] and feasibility trials have fine resolution with the existing hardware contentious issue and employing a battery now been extended to evaluate the device given the dangerous charge density of of tests, including psychophysical tests, in patients with severe dry AMD who are such sophisticated circuit architecture [2]. performance in day-to-day activities and considered legally blind [11]. Electrical engineers are exploring novel subjective patient evaluation, has been Alpha IMS has established the highest heat-resistant materials, such as liquid suggested [14]. These measures differ from single subject visual acuity of any device, crystal polymers [13] and organic conductors conventional visual acuity and field tests,

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in order to detect smaller tangible changes to a discernible reality. Although emulating TAKE HOME MESSAGE associated with ultra-low levels of vision, Predator’s aptitude for interstellar travel and better reflect quality of life. Further seems unlikely, the evolution of bionic eyes • Retinal prosthetics, or bionic research is needed to identify which patients could surely see us ascending further up the eyes, aim to mimic the biological are likely to benefit from prosthetics and, food chain in the near future. function of the eye by converting importantly, at what stage the device should light into electrical signals. be introduced. References • Many devices are at an early The next step in retinal prosthetics is 1. Laha B, Stafford BK, Huberman AD. Regenerating stage of development but exploring the mechanisms that underlie optic pathways from the eye to the brain. Science only a few, including Argus® II following loss of vision 2017;356(6342):1031-4. and Alpha IMS, have received 2. Bloch E, Luo Y, da Cruz L. Advances in retinal prosthesis and subsequently introducing meaningful regulatory approval. systems. Ther Adv Ophthalmol 2019;11:1-16. information to the visually-deprived brain. • Some landmark successes have 3. Maya-Vetencourt JF, Ghezzi D, Antognazza MR, et There is compelling evidence that the al. A fully organic retinal prosthesis restores vision been celebrated in patients with adult brain is malleable. Take taxi drivers in a rat model of degenerative blindness. Nat Mater retinitis pigmentosa, although in London mastering ‘The Knowledge’, for 2017;16(6):681-9. visual outcomes overall have example: after four years of training, those 4. Stutzki H, Helmhold F, Eickenscheidt M, et al. Subretinal been mixed. who qualified experienced increased grey electrical stimulation reveals intact network activity in the blind mouse retina. J Neurophysiol 2016;116(4):1684- • Serious adverse events matter in the hippocampus and displayed 93. associated with retinal improvements on memory tests [15]. In a 5. Brindley GS, Lewin WS. The sensations produced by prosthetics have included similar way, even after many years of little or electrical stimulation of the visual cortex. J Physiol conjunctival erosion and no formed sight, the brain is able to respond 1968;196(2):479-93. endophthalmitis. 6. Luo YH, Fukushige E, da Cruz L. The potential of the to retinal stimulation. Understanding • Trials are now extending the second sight system bionic eye implant for partial sight the structural brain changes driving restoration. Expert Rev Med Devices 2016;13(7):673-81. scope of eligible participants, neurorehabilitation will help design next 7. Stingl K, Bartz-Schmidt KU, Besch D, et al. Subretinal including to patients with generation models of retinal prosthetics. visual implant Alpha IMS – clinical trial interim report. dry age-related macular Vision Res 2015;111:149-60. degeneration. The future of bionic eyes 8. Muqit MMK, Velikay-Parel M, Weber M, et al. Six-month • The objective in prosthetics safety and efficacy of the Intelligent Retinal Implant Future approaches to this technology System II device in retinitis pigmentosa. Ophthalmology technology is now to refine include designing a system able to switch 2019;126(4):637-9. the resolution of devices to to different imaging modes. Human 9. US National Library of Medicine. PRIMA US feasibility ultimately improve quality of vision has evolved to discern the visible study in atrophic dry AMD. 5 January 2018: https:// life for patients. clinicaltrials.gov/ct2/show/NCT03392324 electromagnetic spectrum. Perceptible 10. da Cruz L, Dorn JD, Humayun MS, et al. Five-year wavelengths range from 380-740 safety and performance results from the Argus II nanometres, although there is evidence retinal prosthesis system clinical trial. Ophthalmology that the aphakic eye can perceive ultraviolet 2016;123(10):2248-54. light. One notable illustration is Claude 11. US National Library of Medicine. Argus II retinal Monet, who complained of cyanopsia after prosthesis system dry AMD feasibility study protocol. 28 August 2014: https://clinicaltrials.gov/ct2/show/ removal; many of his paintings NCT02227498 of water lilies after this period diverged 12. Chow AY, Chow VY, Packo KH, et al. The artificial towards bluer hues [16]. At the other end of silicon retina microchip for the treatment of vision the spectrum, infrared radiation – utilised loss from retinitis pigmentosa. Arch Ophthalmol 2004;122(4):460‑9. by snakes and mosquitoes – could allow low 13. Hassler C, Boretius T, Stieglitz T. Polymers for neural vision users to identify potential hazards implants. J Polymer Sci Part B 2011;49(1):18-33. in the environment, for example, a hot 14. Wilke R, Bach M, Wilhelm B, et al. Testing visual drink or an open fire. Second Sight sell functions in patients with visual prostheses. In: thermal imaging devices and it appears Humayun M, Weiland J, Chader G, Greenbaum E, (editors): Artificial Sight: Basic Research, Biomedical they are investing in projects to expand Engineering and Clinical Advances. New York: Springer; this technology into the retinal prosthetics 2007:91-110. market [17]. 15. Woollett K, Maguire EA. Acquiring “the knowledge” of AUTHOR Like all new technology, retinal implants London’s layout drives structural brain changes. Curr Biol are expensive: ‘bionic eye’ treatment, 2011;21:2109-14. including equipment and follow-up, is 16. Gruener A. The effect of and on Claude Monet. Br J Gen Pract 2015;65(634):254-5. estimated to cost £150,000 per patient 17. Second Sight. Second Sight to accelerate development [18]. It is unclear at present whether these of Orion visual cortical prosthesis system. 15 May 2019: new technologies would be funded on the http://investors.secondsight.com/news-releases/news- NHS. However, the decision by National release-details/second-sight-accelerate-development- orionr-visual-cortical Institute of Health & Care Excellence (NICE) 18. Blind NHS patients to be fitted with pioneering ® to recommend Luxturna for patients with bionic eye. The Guardian. 22 Dec 2016: https://www. visual loss due to RPE65 genetic mutations theguardian.com/science/2016/dec/22/blind-nhs- Adam Young, MBBS BSc (Hons) offers hope that commissioning groups will patients-to-be-fitted-with-pioneering-bionic-eye Senior House Officer, London, UK. consider funding retinal prosthetics [19]. 19. National Institute for Health and Care Excellence. Voretigene neparvovec for treating inherited retinal The future of bionic eyes is running hand- dystrophies caused by RPE65 gene mutations. NICE in-hand with our expanding understanding highly specialised technologies guidance [HST11]. Declaration of competing interests: None declared. of the visual system and could soon October 2019. transform from a fantasy of science fiction (All links last accessed November 2019)

Eye News | DECEMBER/JANUARY | VOL 26 NO 4 | www.eyenews.uk.com