Abstract
The first visual prostheses were conceived approximately 40 years ago, but interest in the field of artificial vision has particularly increased over the last 10–15 years. Recent progress in microtechnology has made it possible to envision extremely small and highly integrated neurostimulators dedicated to restoring some useful vision to blind patients. A number of research groups – essentially multidisciplinary consortia – are presently working on projects aiming at the development of a visual prosthesis stimulating either surviving retinal neurons, fibers of the optic nerve or the visual cortex itself. The annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) is one of the largest ophthalmic research events and provides an excellent update of current work. Approximately 15 years ago, research on visual prostheses was practically unreported at ARVO. Nowadays, there are numerous presentations and several sessions on the topic. At this year’s ARVO meeting, artificial vision was introduced in the ‘Innovations in restoring vision’ paper session on the first day. Over the following days, four sessions (two poster and two paper sessions, totaling 67 presentations) were dedicated to visual prostheses. The aim of this report is to summarize these presentations. The numbers in brackets refer to ARVO program numbers.
Epiretinal implants are electrode arrays implanted on the inner retinal surface. They are fixated by one or several retinal tacks. The surgical approach is relatively straightforward. Both power and visual stimulation data are transmitted to the implanted components through a wireless connection. Several groups are currently enrolling subjects for clinical trials with first- or second-generation prototypes.
The Artificial Retina Project, a consortium led by the Doheny Eye Institute, the Oak Ridge National Laboratory and Second Sight Inc., presented several posters and papers. Retinal morphology following electrical stimulation, stimulation thresholds and spatial properties of multielectrode stimulation were reported in rats (1770, 3015 and 3021). In tiger salamander retinal ganglion cells (RGCs), axonal and somatic stimulation thresholds were similar for those axons crossing the center of the stimulating electrodes (5873). Two studies with the Second Sight Inc. Argus I (16-electrode) prototype demonstrated that this device did not induce optic nerve axon density changes in a retinitis pigmentosa patient (1777) and that spatiotemporal stimulus interaction between neighbouring electrodes (brightness summation) could be minimized using phase-shifted (>3 ms) stimulation (3011). Implantation of the new Argus II (60-electrode) prototype in 33 canine eyes was shown to be both feasible and safe (4050). Second Sight Inc. has obtained US FDA approval for a multicentric clinical trial with this new second-generation device.
The German consortium involving Intelligent Medical Implants (IMI) and the University of Hamburg presented data on four subjects from a clinical trial with their 49-electrode array. On the basis of indocyanine green angiography, fluorescein angiography and ocular coherence tomography imaging, they found only minor changes in implant position and concluded that their device was safe, stable and well-tolerated (1785). Simple stimulation patterns (vertical/horizontal bar or cross) could be recognized, with an average score of 80% (1786).
A second German consortium, the EpiRet Group, presented several studies pertaining to their third-generation prototype. The implant itself, which is entirely intraocular, consists of a receiver coil positioned in the anterior segment (behind the iris), and a highly integrated receiver–stimulator module connected to an array of 25 hat-shaped iridium oxide-covered gold electrodes (1780, 1782 and 3026). Surgical technique was safe and effective. A 1-h stimulation with high-density charges (up to 2 mC/cm2) did not result in tissue alterations (5867). The device was also implanted in six subjects over a 4-week period. Stimulation with biphasic pulse sequences on single and multiple electrodes resulted in thresholds between 2.2 and 73.2 µC/cm2 (2023). The EpiRet group also seems to be ready for a long-term clinical study.
Subretinal implants are electrode arrays placed in the subretinal space (between the retina and the retinal pigment epithelium). The basic concept is that they receive power from external components and that photovoltaic cells are used to transform in situ light into a pattern of stimulation currents, similar to what would have been provided by the degenerated photoreceptor layer. They can also entirely be based on input from external components (power and stimulus information). Surgery is more difficult: most of the groups use an ab externo technique, inserting the array into the subretinal space through a scleral incision with custom-designed instruments.
The Boston Retinal Implant Project consortium is developing an implant with wireless power and data transmission. In two electrophysiological studies, they found that stimulation thresholds for biphasic current pulses were 3.6-times higher for RD1 mice RGCs than in wild-type mice (1771); and that in rabbit RGCs, size and location of the ‘axon initial segments’ (the primary targets for electrical stimulation) were variable (3030). They tested the biocompatibility of block copolymer coatings for electrode arrays (3019) and developed a technology for multilayered high-density interconnections between current sources and electrodes (3035) as well as a 16-channel wireless programmable subretinal microstimulator (3031). The implant design was surgically validated in the minipig (3027). They also implanted inactive polyimide electrode arrays of various shapes and sizes, including pillar electrodes, with a more than 90% success rate (3036). A small 15-electrode array and a large 200-electrode array were simultaneously implanted in the fovea and the peripheral retina (5877).
The German consortium centered around Retina Implant AG and the University of Tübingen presented a procedure to define the most appropriate location for subretinal implantation (3025) and reported transchoroidal/transorbital surgical implantation in eight human volunteers of their subretinal device with an external connector (4049).
Loudin et al. (Stanford University, CA, USA) presented their concept of a single-chip optoelectronic retinal prosthesis with two to three photodiodes per electrode. Power and stimulation data are directly projected onto the photodiodes by a pulsed IR display. Charge injection can reach 1 mC/cm2 (3014). Matsuo et al. (Okayama University, Japan) tested the biocompatibility of photoelectric dye-coupled polyethylene films in rat eyes and found no adverse tissue reactions (1787).
Suprachoroidal implants are placed between the choroid and the sclera. The surgery is less invasive than with subretinal implants.
A Korean consortium from Seoul National University (South Korea) has developed a wireless retinal stimulator for animal models (1774). The fabrication procedure has been improved with in vivo tests on rabbits (1773). Electrically evoked cortical potentials could be elicited with mean thresholds at 29 µC/cm2 (1778). A PET study compared electrical stimulation to light stimulation and showed the overlapping of cerebral areas with increased metabolism for both stimulation methods (1776). In vitro electrophysiological studies compared electrical with light stimulation (3028) as well as stimulation thresholds in degenerated and normal rabbit retinae (3040). In collaboration with an Australian group based at NSW University in Sydney, they reported a surgical technique to introduce a 14-channel electrode array into the suprachoroidal space of rabbit eyes using two polyimide guides (3038). Electrically evoked potentials were measured on the visual cortex during bipolar stimulation (3016).
A Japanese group based at Osaka University presented the architecture of their flexible multichip suprachoroidal implant consisting of nine chip units, each comprising five Pt electrodes (1783). They found that higher charges could be delivered by bullet-shaped electrodes, compared with planar ones (3020). In tests on rabbits with degenerated retinae (no measurable ERG), electrically evoked potentials could be measured during electrical stimulation (3024).
Some other interesting approaches for retinal stimulation have recently emerged. Finlayson and Iezzi (Wayne State University, MI, USA) presented their concept of a neurotransmitter-based retinal prosthesis. Local application of L-glutamate stimulates RGCs with adequate spatiotemporal resolution. ON-type and OFF-type RGCs demonstrated different response latencies (5871). Two groups presented their research on photosensitization of inner retinal neurons. Flannery (University of California, CA, USA) reported a method to confer light sensitivity to inner retinal neurons by genetical engineering. Specific expression of excitatory and inhibitory ‘photoswitches’ in ON and OFF-type RGCs was achieved and neural activity could be modulated by light (8). Grossmann et al. (Imperial College, London, UK) presented a similar approach, leading to good spatiotemporal resolution with photosensitized RGCs; the amount of light necessary to stimulate these RGCs was relatively high (4046). An interesting alternative to electrode stimulation was also presented by George et al. (Los Alamos National Laboratory and NC-State University, NC, USA). With a numerical model for micromagnetic stimulation, they calculated the currents that could be inducted into the retina by magnetic fields generated in a microcoil array (1784).
A group from Shanghai Jiau Tong University presented data from direct optic nerve stimulation. Three penetrating wire electrodes (Pt–iridium or Teflon-coated tungsten) were implanted into the optic nerve of rabbits (3033 and 3037). Best results were obtained with biphasic pulse stimulation. Sakaguchi et al. (Osaka University) implanted three parylene-coated platinum wire electrodes into the optic nerve head of a retinitis pigmentosa patient (4044).
Cortical visual prostheses have few proponents due to the invasive surgery required and the more complex processing of the stimulation patterns. Schiller (MIT Cambridge, MA, USA) presented data on monkeys and simulation experiments on humans aimed at defining optimal coding procedures and array densities (12). In a Russian project, penetrating surface electrodes were used to stimulate the cat visual cortex (3017). Troyk et al. (Illinois Institute of Technology, IL, USA) demonstrated, with the aid of a phosphene simulation system, that an intracortical implant at the dorsolateral surface of the cortex could facilitate visual tasking (5874).
Psychophysical studies – unrelated to specific implantation sites – were also reported. Sommerhalder et al. (Geneva University Hospitals, Switzerland) and Ostrin et al. (Johns Hopkins University, MA, USA) simulated 60 channel implants in normal subjects. Some basic reading abilities could theoretically be restored with such devices (3012); performance on a maze-tracing task was dependent on subject motivation and learning (3029). Yang et al. (Jiau Tong University, Shanghai, China) reported a simulation study on Chinese character reading (3039). Georgi et al. and Ivastinovic et al. (Medical University, Graz, Austria) presented a mobility test (1781) and a modified grating test (3042) suitable for very-low-vision patients. Parikh et al. (University of Southern California) introduced an image processing algorithm, cueing visual prosthesis patients to direct their gaze to important objects in their peripheral visual field (4048). Benav et al. (Tuebingen University, Germany) modeled spatiotemporal characteristics of visual perceptions and particularly stimulus fading due to high-frequency stimulation (3013).
In conclusion, a considerable amount of work is underway in visual prostheses research. An increasing number of groups worldwide have launched clinical trials or are about to do so. There are some new ideas around, but it was impossible for me to extract real highlights from this year’s ARVO meeting. I have briefly mentioned a number of presentations and encourage those interested in retinal implants to have a closer look at the abstracts Citation[1]. Several companies are competing to reach commercialization of visual prostheses. This certainly increases funding in the field, but it also leads to a reporting bias, as some of the most interesting findings are kept confidential. This issue was raised by Josef Rizzo in his introductory talk. To quote an ex-colleague, currently collaborating with a private company in a different field, “I can only tell the boring things, the interesting stuff is confidential”.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Reference
- Association for Research in Vision and Ophthalmology www.arvo.org