Dr Jong Min Ong, Vitreo-Retinal Department, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK. Email: firstname.lastname@example.org
Visual prostheses including artificial retinal devices are a novel and revolutionary approach to the treatment of profound visual loss. The development of the field of visual prosthesis began with cortical prosthetic devices but since then, a variety of devices which target different sites along the visual pathway have been developed with the retinal prosthesis being the most advanced. We present a review of the history of these devices, an update on the current state of play and future prospects of this field.
Visual prostheses including artificial retinal devices are a novel and revolutionary approach to the treatment of profound visual loss. These devices have evolved to a level where in current clinical trials they are beginning to restore basic visual function to blind individuals. The defining feature of visual prostheses is the eliciting of visual sensations or phosphenes by electrically stimulating residual neurons at some point along the visual pathway.
Historically, the earliest reports of artificially induced phosphenes were associated with direct cortical stimulation. Since then devices have been developed that target many different sites along the visual pathway. These devices can be categorized according to the site of action along the visual pathway into cortical, subcortical, optic nerve and retinal prostheses. Although the earliest reports involved cortical stimulation, with the advancement in surgical techniques and bioengineering, the retinal prosthesis or artificial retina has become the most advanced visual prosthesis. It is also the form accounting for the greatest number of completed and ongoing clinical trials.
Retinal prosthetic devices function by producing small, localized currents that alter the membrane potential of adjacent retinal neurons. The energy required by retinal prosthetic devices can be derived either directly from incident light acting through a photoelectric cell or from an external power source, usually a rechargeable battery or a combination of both. Retinal prosthetic devices can also be categorized according to the site of implantation into epiretinal and subretinal prosthesis.
Assessing and recording the efficiency of these devices with standard tests of visual acuity and visual field presents various challenges as subjects entering these trials have little or no vision. Tests that more accurately assess improvements in visual function and quality of life have had to be devised. With the current generation of retinal prostheses, subjects have been subjected to tests of and demonstrated improvements in mobility, motion detection, object localization, grating identification and object recognition.
There are alternative approaches to artificial retinal systems currently in development. These alternative designs target the optic nerve, the lateral geniculate body and the visual cortex. However, they are at an earlier stage of development relative to the retinal prostheses and few have reached the stage of widespread clinical trial. Nonetheless, their development is critical for the treatment of cases where the retina is destroyed or the optic nerve is severely damaged as in glaucoma and trauma associated blindness.
The progress made in development of visual prosthetic devices offers some hope to blind individuals. Plans for more sophisticated designs and increasing the number of electrodes offer the possibility of further improvements in function. Although the visual prostheses available at present are far from restoring normal vision, restoration of some stable functional vision to these blind individuals has been a major milestone in the treatment of severe and irreversible vision loss.
Rationale for a visual prosthesis
Blindness affects over 40 million people around the world.1 It is estimated that there are over 50 000 people registered blind (visual acuity < 6/60) in Australia and around half of this is due to age-related macular degeneration.1,2 Visual loss in age-related macular degeneration and retinal dystrophies such as retinitis pigmentosa (RP) results in loss of photoreceptors and retinal pigment epithelial cells. The role of an artificial retina is mainly to replace photoreceptor properties – visual transduction and stimulation of bipolar and subsequent ganglion cells. Glaucoma is estimated to account for up to 13% blind registration.2 In this disease there are no functioning ganglion cells and the optic nerve is functionally absent. In this case, cortical and subcortical prostheses would be required. This is also the case for severe trauma involving both eyes where there is no residual functioning retina.
In 1929, Foerster, a German neurologist and neurosurgeon, discovered that by electrically stimulating the occipital pole, his subject would describe the sensation of a small spot of light (phosphene).3 In 1931, Krause and Schum electrically stimulated the left occipital pole of a patient that had been completely hemianopic for 8 years, from a gunshot wound of the left optic radiation, and produced similar localized phosphenes confirming that the visual cortex does not wholly lose its functional capacity despite years of deprivation of visual imput.4
The idea of an electronic prosthetic device can be traced to a patent awarded to an Australian, Graham Tassicker, who in 1956 described how a photo-sensitive selenium cell placed behind the retina of a blind patient resulted in phosphenes.5 In the 1960s and 1970s, Brindley6,7 and Dobelle8,9 pioneered the field of artificial vision by implanting electrodes into the visual cortex and demonstrating that they were able to induce consistent phosphenes. Around that time, Uematsu also investigated the feasibility of a visual prosthesis and managed to evoke phosphenes which blinked or fluttered and some which remained stable in position. Evoked phosphenes also varied from simple white to multicoloured complex patterned.10
Further development in the field was limited until the 1990s when advances in biomaterials, microfabrication, electronics and retinal surgery led to a cascade of developments in the field centred mainly on the artificial retina but also in the miniaturization of cortical stimulating devices.11,12 The preclinical investigations carried out in this decade would lead to the large number of clinical experiments and trials in the decade from 2000 to 2010 that will be discussed later. Currently two retinal prosthetic devices are in large-scale clinical trials with evidence of well-demonstrated functional vision.13,14 These are the most advanced prostheses to date and details of them, one epiretinal and the other subretinal will be discussed.
All visual prostheses including artificial retinal devices need to perform several basic functions. They must firstly detect and capture the ‘light-based’ image. This image must then be transduced into an electrical stimulus. As described previously, this transduction step can be intrinsic to the device in the form a photoelectric cell or it can be achieved by a visual processing device. In the case of the photoelectric cell the current can be amplified secondarily to create a larger stimulus. The current is then delivered to the adjacent remaining retinal cells.
The residual cells that may be present in outer retinal dystrophies include ganglion, bipolar, amacrine, horizontal and, in cases that retain perception of light, some photoreceptor cells. Regardless of which cells are stimulated initially, the signal must ultimately evoke an active response in ganglion cells. Ganglion cells via their axons activate subcortical and cortical visual areas via the optic nerve and tracts to induce a phosphene. The retinal prosthesis has several distinct advantages with regards to ease of surgical access and implantation over cortical and subcortical devices. The receptive field properties of the retina are well known and electrical stimulation of an area of the retina produces the perception of light in a predictable location. However, for a retinal prosthesis to function, the retinal ganglion cells and visual pathways distal to the retina need to be viable. The use of the first generation of retinal prostheses has been limited to inherited outer retinal diseases such as RP that affect the outer retina but leaves the inner retina relatively spared.15–18
Retinal prostheses can be categorized based on its location into epiretinal and subretinal prosthesis.
The current group of epiretinal prostheses consist of three main components. The first component captures light images using a camera. The second component transforms this image into patterns of electrical stimulation. The third component, which lies on the inner surface of the retina, then stimulates the remaining cells in the inner retina.19 There are a variety of epiretinal devices being developed.20–25 Only three devices that are in the most advanced stages of development will be described.
The most advanced retinal prosthesis project at present is the Argus II epiretinal implant developed by Second Sight Medical Products Inc, based in California. The first generation model of the device, Argus I, consisted of an intraocular epiretinal multi-electrode array measuring 250–500 µm with 16 platinum micro-electrodes (Fig. 1). The array was positioned temporal to the fovea and fixed in place with a single spring-tensioned retinal tack that was inserted through the electrode array. The extraocular component consisted of an external spectacle mounted camera, which was used to capture images which were translated into pixilated images by a visual processing unit. This processed information as well as the power required was transmitted by an inductive link telemetry system to magnetic coils implanted in the temporal skull. The electrical signal was then delivered via trans-scleral cables connected to the multi-electrode array. The source of the units power was an externally worn battery pack. In animal models, chronic electrical stimulation of the retina by the epiretinal prosthesis did not elicit any inflammatory reaction, neovascularization or encapsulation. The presence and mechanical effect of the tack also showed minimal effect on the retinal layers.26
Clinical trials of the Argus I were commenced in 2002 at the Doheny Retina Institute and the Argus I device was implanted into six subjects with RP where the vision was reduced to bare light perception. Subjects described visual perceptions that were retinotopically consistent when the retina was stimulated by the implanted electrodes.
When subjects with the Argus I device were tested, they demonstrated improvements in object detection, object counting, object discrimination and direction of movement with the device turned on relative to off.27,28 An improvement in subject performance during tasks was also observed with increased use of the device demonstrating that sight restoration is also a learning process.27 The Argus I prosthesis also produced patterned visual perception in patients with spatial resolution at an acuity level that reached the limit determined by the distance between the electrodes when tested with computer generated gratings.29,30
In 2007, the US Food and Drug Administration approved the second generation Argus II retinal prosthesis system using an epiretinal implant for clinical study in humans (Figure 2). The Argus II implant component consists of 60 independently controllable electrodes (Fig. 3). The current trial is registered at http://clinicaltrials.gov/show/NCT00407602. In the trial the system has been implanted in 30 subjects at 11 centres worldwide. Subjects are reported to have demonstrated improved motion detection, mobility and were also able to distinguish common household objects.20,21 In orientation and motion tasks, subjects successfully navigated to a door 58% of the time with the system on compared with 32% with the system off. In 22 subjects, using the system enabled them to correctly identify letters in a closed set test 73% of the time as compared with 17% with the system off (Fig. 4).31,32 Subjects also demonstrated improved spatial-motor tasks including improvements seen in square localization tasks.33 It should be highlighted that these tasks were all performed under controlled conditions, for example, letter reading was done with a external liquid crystal display screen in a darkened room and white letters were displayed on a black background. Although there is growing evidence of useful spatial resolution there is a limitation in field of vision afforded by the device. The visual field in subjects with a prosthetic device is directly related to the size of the stimulated area of the retina and hence, the diameter of the electrode array. One option to increase the field of vision is to increase the size of the implant which presents further bioengineering challenges. Assessments are being undertaken to determine if the current device has resulted in an improvement in daily function in the subjects. The Argus II device received commercial approval in Europe in March 2011.
The second epiretinal prosthesis is the Learning Retinal Implant developed by Intelligent Medical Implants AG. The Learning Retina Implant system consists of an extraocular and intraocular portion. The extraocular portion consists of a retinal encoder (RE) which is situated on the frame of a pair of glasses. The RE approximates the typical receptive field properties of retinal ganglion cells and replaces the visual processing capabilities of the retina by means of 100 to 1000 individually tunable spatiotemporal filters. This processing capability of the RE simulates the filtering operations performed by the ganglion cell. The RE output is then encoded and transmitted via wireless signal and energy transmission system to the implanted retina stimulator which is implanted on the surface of the retina and held in place with retinal tacks.19,21 The main feature of Learning Retinal Implant is the RE which can be used to assist with the adjustment of the stimulation parameters for the individual patient.19 Acute trials commenced in 2003 when 20 patients with RP underwent electrical stimulation lasting 45 min. In this study, 19 patients described sensation of phosphenes during stimulation.34 Chronic studies in human subjects commenced in 2005 but results are not available as yet. A multicentre clinical trial is currently proposed in Europe and registered at http://clinicaltrials.gov/ct2/results?term=NCT00427180.
The EpiRET GmbH group consisting of researchers at Aachen University Clinic and the Fraunhofer Institute for Microelectronic Circuits in Germany, have developed a device similar to the Second Sight Vision implant. The EPI-RET3 implant consists also of an extraocular and intraocular component (Fig. 5). The Extraocular component utilizes a complimentary metal-oxide semiconductor camera in glasses frames to capture images. This image is then transferred wirelessly to a receiver placed in the anterior vitreous similar to an intraocular lens. This receiver in turn stimulates the epiretinal implant via a connecting micro-cable. The implant consists of an array of 25 electrodes (5 × 5) apposed to the ganglion cells. The main difference of the EPI-RET3 implant from the Argus II is that the former has all of the ocular devices within the globe – there is no wire passing through a sclerostomy. The EPI-RET3 implant underwent human trials in 2007 when it was implanted in six patients for 4 weeks. The implant was tolerated with moderate postoperative inflammation, and the position of the implants remained stable until removal.22,35 Currently, a second generation wireless implant system is being developed with considerably higher number of electrodes and more signal processing power.22
There are other epiretinal prosthesis designs23–25 being developed globally but they still remain in the early stages of development.
Subretinal prostheses involve implantation of the prosthetic device between the retina – most likely the bipolar cell layer, and the Retinal Pigment Epithelium. Access to the subretinal space can be either ab externo (scleral incision) or ab interno (through the vitreous cavity and retina). Two subretinal implants have been developed to a very good level and these will be described in detail.
The earliest retinal prosthesis was a subretinal prosthesis, Artificial Silicon Retina (ASR), developed by Optobionics Corporation.36–38 The ASR is 2 mm in diameter and 25 µm in thickness. It is an optobionic device, meaning that the energy required by retinal prosthetic devices is derived from incident light, and is composed of approximately 5000 independently functioning electrode tipped microphotodiodes. The electrical charge produced by the ASR was designed to alter the membrane potential of contacting retinal neurons and to simulate how light would normally activate these cells to form retinotopic visual images. It was found to be safe in animal models36,37 and following approval by the Food and Drug Administration in late 1999, it was implanted in six patients with RP.38 The ASR was well tolerated by all six patients after 6 to 18 months of follow up. Visual function improvements occurred in all patients and included unexpected vision improvements in retinal areas distant from the implant.38 This suggested that the ASR could have some neurotrophic effect on the retina. They hypothesized that chronic low-level electrical stimulation induces an upregulation of protective neurotrophic survival factors that improve the function of remaining photoreceptors.39 It has been demonstrated, however, that the energy provided by an optobionic device would be insufficient to electrically activate remaining retinal neurons.40 After Phase II trials, in 2007 an involuntary petition to liquidate under Chapter 7 was filed and approved against Optobionics Corporation.
Retina Implant AG, founded early in 2003 in Tübingen, Germany, initially developed an optobionic implant consisting of a microphotodiode array with 7000 microelectrodes in a checker-board pattern configuration.41,42 The implant was used in animal models but they discovered that the energy generated from the microphotodiode array was insufficient43–45 and additional power source would be needed. A compound visual prosthesis device was developed.46 This consisted of three parts: a subretinal, extraocular and subdermal (Figs 6,7). The subretinal part consists of a 4 × 4 array of titanium-nitride electrodes (diameter 50 mm, spacing 280 mm) and a microphotodiode array with 1550 photodiodes and electrodes which lies parafoveally. The extraocular portion is a foil strip carrying 22 golden connection lanes to the external connection and the reference electrode. The subdermal portion consists of a silicone cable that leads subperiosteally to the retro-auricular space where it penetrates the skin and ends in a plug. This prosthesis was implanted for 4 weeks in 12 subjects with RP without complications.46–49 Improved object localization and differentiation of individual letters were described in some subjects.48,49 A multicentre clinical trial has been registered at http://clinicaltrials.gov/ct2/results?term=NCT01024803. Second stage of clinical trials is planned for later this year with the aim of implanting a newer version of the device over the next few years.
Boston Retinal Implant Project co-founded by Rizzo and Wyatt developed an epiretinal prosthesis which underwent acute clinical trials.50,51 However, because of inability to obtain consistent results, Boston Retinal Implant Project have abandoned the epiretinal implant and are now developing a subretinal implant instead.19 Their subretinal prosthesis consists of a miniaturized, hermetically encased, wirelessly operated device (Fig. 8). This array is implanted in the subretinal space using a specially designed ab externo surgical technique that affixes the bulk of the prosthesis to the surface of the sclera. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete power supply components. Feedthroughs from the case connect to secondary power- and data-receiving coils. The device is currently undergoing animal studies.52,53 There are other optobionic retinal prosthesis designs being investigated32,54,55 but at present none as yet have undergone animal studies.
There are distinct advantages and disadvantages for both the epiretinal and subretinal prosthetic devices. The advantage of an epiretinal implant is that surgical approach in the vitreous cavity is well understood and routine. Also, the entire vitreous cavity can be used to house the prosthesis with minimal disruption to the retina. Epiretinal placement also allows for the vitreous to act as a sink for heat dissipation from the prosthesis. The micro-electronics for the epiretinal devices are incorporated into the extraocular component of the device allowing for easy upgrades without requiring further surgery. The disadvantage however is that the prosthesis is thought to stimulate ganglion cells and hence bypasses the processing function of the bipolar and amacrine cells. The information captured has to be processed prior to stimulation of the ganglion cells by the epiretinal device requiring more sophisticated processing to account for retinal algorithms.56
The subretinal devices have the advantage of using the processing capabilities of the bipolar and amacrine cells to some extent. Stimulating at the bipolar cell level will allow significant retinal processing to shape the neural response. Placing the prosthesis in the subretinal space will also use the retina to hold the electrodes in close proximity to the viable retinal cells. The disadvantage is that the subretinal space is confined and hence limits the size of the prosthesis. The close proximity of the device also increases the likelihood of thermal injury to the neurons and consequently limits the thermal budget of the implant.56
Optic nerve/tract prosthesis
In blind patients with functional retinal ganglion cells, the optic nerve is an alternative for electrical stimulation. However, achieving focal stimulation and unravelling the exact retinotopic distribution within it is challenging.19
Veraart57,58 chronically implanted a self-sizing spiral cuff electrode around the optic nerve in two subjects. These subjects were able to recognize simple patterns projected onto a screen,26 localize and discriminate objects.55,59–61 An alternative to the cuff-electrode is the insertion of multiple penetrating electrodes onto the optic nerve and optic disc.62–68 Stimulation of these electrodes in the acute setting have produced the sensation of phosphenes.66
The lateral geniculate nucleus is attractive stimulation target for a visual prosthesis as it is physically adjacent to areas targeted for deep brain stimulation therapy for movement disorders such as Parkinson's disease and hence surgical access will only require minor modification of these techniques.69–71 There are currently early experiments being conducted on non-human primates on the feasibility of lateral geniculate nucleus prostheses.72–74
As mentioned earlier, early work on a visual prosthesis first started with the idea of developing a cortical prosthesis. In the 1960s and 1970s, Brindley6,7 and Dobelle8,9 started by implanting electrodes into the visual cortex, electrical stimulation of which resulted in phosphenes.6–9 However, because the electrodes arrays were situated on the cortex above the pia, the currents needed to evoke phosphenes were in the milliampere (mA) range resulted in poor spatial resolution, discomfort from dural stimulation and, in some cases, focal epileptic activity.6,9,19,75 Schmidt11 then developed intracortical electrodes which resulted in average thresholds of below 25 micro-ampere (µA) with closer two-point resolution compared with surface stimulation.11
Current models of the intracortical prosthesis includes the IIlinois Intracortical Visual Prosthesis Project and the Utah Electrode Array (UEA).12,18,76,77 Following the Food and Drug Administration approval, the Utah Electrode Array has been recently undergone short-term implantation in human subjects.77 The main advantage of intracortical implants is that it is the only therapeutic approach for individuals with non-functioning retinae or optic nerves.
The development of artificial vision in australia
In 2009, the Australian Research Council funded a new collaborative research initiative to develop a functional bionic eye through funding to be administered under the Australian Research Council's Special Research Initiatives scheme. Through its response to the 2020 Summit, the Australian Government committed funding of AUD$50 million over 4 years. The two research teams chosen to share this award are Bionic Vision Australia (BVA) and Monash Vision.78
Bionic Vision Australia is a national consortium of researches from Bionic Ear Institute, Centre for Eye Research Australia, National Information and Communications Technology Australia (NICTA), University of Melbourne and the University of New South Wales with Australian National University and University of Western Australia as project partners. BVA is currently developing a supra-choroidal device. This consists of a two systems with a cochlear implant behind the ear with the stimulation being transmitted to a 98-channel electrode array located in the supra-choroidal space.79 BVA is planning to develop two devices. The first is a wide-view device and the second is a high-acuity device. The purpose of the wide-view device, which consists of 98 electrodes, is to allow subjects to manoeuvre around large objects to enable them to lead more independent lives. BVA aims to have this device tested in the first patient in 2013. The development of the high-acuity device will build on the prototype of the wide-view system and will consists of over 1000 electrodes with the aim of enabling subjects to recognize faces and read large print. This device should be ready for testing around 2014.80 At present, BVA is performing animal studies using its device.79
Monash Vision Group is a consortium which includes Monash University and Alfred Hospital in Melbourne. In contrast to BVA's approach, Monash Vision Group aims to develop a cortical implant which would directly stimulate V1 visual cortex. The advantage of a cortical prosthesis, as mentioned previously, is this approach will be beneficial in patients in whom the optic nerve and tract disease. This project commenced recently in 2010 and is currently in the product development phase. Monash Vision Group aims to undertake human trials by 2014.81
Outcome measurement of prosthetic vision
Standard tests such as visual acuity, visual fields and electro-retinography are insufficient measures when used in subjects with the visual prosthesis as they have very low baseline vision, for example, bare light perception. Testing in these subjects can be complex and must be individualized depending on the initial level of impairment and level of sight restoration. Bach82 proposed a battery of tests to assess vision in subjects with very low vision. These tests include light perception, temporal resolution with single versus double flash discrimination, localization of light and motion. Other test used in the assessment in subjects with prosthetic visual devices include standardized psyco-physical tests, tests related to day-to-day activities and also tests that solicit subjects own evaluation and impressions as to the usefulness of the device. Taken together, these tests give the best evaluation of even marginal improvement in vision with the use of the device.
There have been many advances in the treatment of diseases which result in visual impairment. These treatments prevent or limit the extent of visual impairment.83,84 The options, however, are limited once an individual has lost vision. The visual prosthesis is a radical and innovative approach in restoring vision to these individuals.
Early work towards this goal started with the cortical prosthesis.6–9 Now, there are a variety of designs which target various sites on the visual pathway. The most advanced prosthesis, however, is the retinal prosthesis.19 The retinal prosthesis that is closest to becoming commercially available is the Argus II by Second Sight. The Retina Implant AG prosthesis is entering multicentre trials and may produce an alternative concept with a subretinal and photodiode-based device.
At present, chronic implantation of these devices has demonstrated improvements in mobility, motion detection, object recognition, letter and word reading during testing under specific conditions. Assessments are being done to determine if this translates to an improvement in activities of daily living. Further development will be necessary for these devices to allow an improvement in the quality of life for blind individuals. The quest remains for the ability to restore useful vision in blind individuals and with advances in biomechanical engineering this may become a possibility in the not too distant future.
The authors acknowledge financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London (UCL) Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.