Retinal neuroprosthesis: science fact or science fiction?

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Retinal neuroprosthesis: science fact or science fiction? ‘…vision impairment results in momentous personal and economic burdens to both individuals and society.’ Expert Rev. Ophthalmol. 2(2), 145–148 (2007)

Nigel H Lovell† and Gregg J Suaning † Author for correspondence University of New South Wales, and National Information and Communications Technology Australia (NICTA), Graduate School of Biomedical Engineering, Sydney, 2052, Australia Tel.: +61 293 853 922 Fax: +61 296 632 108 [email protected]

10.1586/17469899.2.2.145

For an epiretinal implant, electrodes are When, over a quarter of a century ago, Steve Austin was equipped with prosthetic legs and bionic introduced into the vitreous space in intimate vision (and attendant sound effects) for a mere contact with the inner retinal layer. This $6 million, there was no doubt that we were in approach is typically embodied as a two-unit the realm of ‘science fiction’. Cue the early 21st device, wherein extraocular and intraocular Century with advances in microelectronics, her- devices communicate by way of transcutanemetic encapsulation, biomaterials suitable for ous radio-frequency (RF) telemetry or, in some long-term implantation and associated surgical proposals, a transcorneal laser [1–3]. The techniques, and we have crossed the divide from extraocular device comprises a camera and ‘science fiction’ to the possibility of ‘science fact’, electronics for encoding and transmitting a albeit with capabilities somewhat less impressive stimulation paradigm. The intraocular device than the clinicians from Universal Studios, USA. receives and decodes the transmission, usually With vision being the by way of a micromost feature-rich and com- ‘…one obvious advantage electronic package plex of the senses and visual of an epiretinal implant is the known as an applicacues being critical to tasks of intewell-defined topographic tion-specific everyday living, vision grated circuit (ASIC). mapping of the impairment results in The ASIC connects to visual space…’ momentous personal and the electrode array, economic burdens to both individuals and soci- which is positioned at the vitreoretinal interety. In this editorial we will examine a number of face, providing controllable charge injection to technical, scientific and clinical barriers to turn- the inner retina at each of several electrode ing laboratory testing and clinical trialling of a sites (16 or 49, respectively, from the aforeretinal neuroprosthesis into a successful thera- mentioned teams). The stimulation paradigm peutic device that provides patterned vision to is used to determine which of a select number the profoundly vision impaired. of electrodes are actively delivering electrical The scope of this discussion will not extend to stimuli at any given time. all visual prostheses, but will focus on the devices In an epiretinal device, the tissue targeted for that, to date, have shown the most promise in stimulation is the inner retinal layer, which conchronic clinical trials in humans, namely those tains the retinal ganglion cells (RGCs) that have of the epiretinal neurostimulators from Ameri- survived the progression of diseases, such as can and German teams. In other approaches, retinitis pigmentosa and age-related macular researchers have placed devices directly on the degeneration. However, it is likely, with elecvisual cortex, employed nerve cuffs surrounding trodes in close apposition to the inner retina, the optic nerve and implanted unencapsulated that bipolar cells, as well as the axons of the microelectronic devices intimately contacting RGCs, will also be depolarized under certain the subretinal surface. conditions. This concern aside, one obvious

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To strike the balance described previously, is it ethical to go to advantage of an epiretinal implant is the well-defined topographic mapping of the visual space and established surgical market with a device with low numbers of electrodes and invest profits from those devices towards research and innovation of techniques for introducing the electrode array [4]. The disadvantage of such an implantation approach is that it better devices? Conversely, is it ethical to wait for a magic can only be used to treat diseases where there is a viable optic number of electrodes that may be decades away and deprive nerve. In response to such diseases, there can be large-scale reor- today’s blind community of a chance at even rudimentary ganization of the retina with substantial gliosis. Despite this, vision? If the latter is true, should the vision impaired be made studies have shown that human RGCs maintain their viability to wait for 10, 100, 1000, 10,000 or 100,000 electrodes? To after the onset of these degenerative diseases [5], that the surviving draw upon the cochlear implant analogy, recipients are able to retinal neurons are capable of being electrically stimulated [6] and hear – remarkably well in many cases – with just 22 electrodes. that rudimentary phosphene vision is achievable in humans with This, it is safe to say, has surprised many researchers in the field, not only because 22 electrodes have provided such remarkable advanced retinal degeneration. Effectively replacing vision with the same resolution as that of benefits, but also because these benefits have, for the better part normally sighted humans would require an image-capturing of two decades, continued to substantially improve in isolation from the electrode numbers [9]. device to replace the function of the photoreceptor cells, of which there are ‘Effectively replacing vision with the This is due, in large part, to more than 100 million in each eye, same resolution as that of normally improved speech-processing stratconverging to some one million egies, that is, the way in which sighted humans would require an RGCs. Current epiretinal implant the electrodes are used. Will the technology is capable of supporting, at image-capturing device to replace same be true for visual prostheses? the function of the photoreceptor best, up to 100 electrodes. The discord Will cortical plasticity, as it is cells, of which there are more than known, allow the vision system to between these two numbers is where intense research is being conducted reorganize such that extra100 million in each eye…’ and where the divide between ‘science ordinary sense can be made of the fiction’ and ‘science fact’ lies. The transition from tens to hundreds world through low numbers of electrodes? Will this vision conor even thousands of electrodes will require the resolution of major tinue to improve in unison with continued improvements in outstanding technical, scientific and clinical issues. These are dis- stimulation strategies? cussed in the following sections. The list is by no means exhaustive; however, if significant advances are made in the following Parallelization of stimulus encoding & delivery areas, then the path to successful long-term implantation of a In the field of neurostimulation to date, no end organ has device of ‘hundreds-order’ will be considerably clearer. required stimulation rates that would necessitate stimulus strategies and data throughput rates that would require a deviA question of numbers: psychophysics ation from a serial mode of stimulation whereby a single curEarly studies in Utah, USA, by Cha and coworkers aimed to rent source is switched between multiple electrodes in a timequantify the number of phosphenes – spots of visual percepts, pat- division multiplexed manner. Initial research in the area of terned within the visual space, analogous to pixels on a television epiretinal vision prosthetics has adopted the traditional serial screen – necessary to read and navigate, and to achieve various lev- approach. More recently, our group [10,11] and others [12] have els of visual acuity. To a first-order approximation and, indeed, as been investigating alternate simulation paradigms that could logic would predict, the case of ‘more is better’ was found – but, be incorporated into an intraocular implant for epiretinal stimsignificantly for the present discussion, low numbers of electrodes ulation. One approach is to use multiple concurrent sources to were found to be not without merit. Indeed, the ability to read activate electrodes in a parallel fashion. The need for paralleltext characters was arguably ‘useful’ at 100 phosphenes, with read- ization has been driven by the increasing recognition that a ing speeds of up to 70 words per minute [7]. Navigation was possi- device capable of effectively simulating prosthetic vision will ble with a few hundred phosphenes with no marked improvement require electrode numbers and transcutaneous communicaobserved beyond 625 phosphenes. Once the 100-phosphene level tions protocols that exceed what is possible with a serial mode was reached, visual acuity was affected to a greater extent by phos- of electrode stimulation, in which an image is built up by phene density than by phosphene quantity. Mobility was most sig- sequentially activating electrodes in a rasterized approach, nificantly influenced by the size of the visual field [8]. So, if a one- much like the electron beam in a cathode-ray tube television to-one correspondence of phosphenes to electrodes can be set draws an image. The difficulty with the rasterized approach is that there is a minimum amount of time (typically 100 µs to assumed, how many electrodes are enough? To address this question, a rather complex balance must be 1 ms) needed to inject charge in order to activate the neural struck – a balance that considers not only patient benefit and tissue and to recover that charge to avoid damage to the same safety, but also the limitations of our engineering and surgical tissue, thus making the number of electrodes capable of being expertise, and the commercial forces that bring such things to ‘serviced’ by a single stimulation source not only finite, but quite small indeed. the patients for whom benefit may be derived.

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Retinal neuroprosthesis: science fact or science fiction?

There are complex design issues associated with these revised stimulation strategies. The microelectronic design needed for providing multiple sites of charge injection and recovery at safe levels to ensure long-term viability of the tissue is one technological challenge. A major unknown is the interaction between multiple current sources in terms of current leakage between adjacent electrodes producing unpredicted or unwanted neural activation [13] and charge imbalances, which can affect electrode longevity and tissue health. Neural–electrode interface

Possibly one of the most crucial yet least researched and understood areas of the retinal neuroprosthesis is the electrode–tissue interface. A suboptimal interface will probably cause electrode or tissue damage by exceeding predefined charge density limits. A concomitant factor is that the stimulus thresholds for visual perception are closely linked to the separation distance between electrode and tissue, as well as the amount of gliosis and retinal remodeling that occurs as part of the pathological process. To date, both these factors have limited implant designs to low electrode counts. With new materials and better methods to create a more intimate electrode–tissue contact, it should be possible to lower stimulation thresholds and also reduce electrode size without exceeding the safe limit for charge injection. However, many questions are yet to be answered. Will a chronically implanted neurostimulation device have a rescue effect on the neural retina and possibly arrest further degeneration? Will it be possible to create a biostable electrode through polymeric coating that is capable of high levels of charge injection but will also have drug-eluting capabilities – for example, to release neurotrophic factors to encourage RGC neurite ingrowth and reduce the electrode tissue impedance? Device biocompatibility

The inherent attraction of creating a device with hundreds, if not thousands, of electrodes has provided impetus for the movement away from commonly used biomaterials, such as alumina-based ceramics, silicone elastomer and platinum. Hermetically encapsulated devices using these materials do not currently exist for such high electrode counts. Current auditory neuroprosthesis with, at most, a few tens of electrodes are probably at the limit of the current technological approaches. Our group and collaborators have been developing new microtechnologies and manufacturing processes to use materials with substantial histories in biostability and compatibility to create hermetic feedthroughs with the potential of interfacing References 1

Majji B, Humayun MS, Weiland JD, Suzuki S, D’Anna SA, de Juan Jr E. Long-term histological and electrophysiological results of an inactive epiretinal electrode array implantation in dogs. Invest. Ophthalmol. Vis. Sci. 40, 2073–2081 (1999).

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hundreds of electrodes, constructed from silicone and platinum, to neurostimulator microelectronics, which are hermetically encapsulated in a ceramic [14]. Other groups have been exploring new materials for potential lifetime implantation within the ocular anatomy [15,16]. Such materials, in the absence of historical record in chronic implantations, will likely require protracted and detailed clinical trials and evaluation before they find widespread adoption in any therapeutic device. This said, once the benefit can be demonstrated to outweigh the risk, such devices and their materials may quickly find their place in therapeutic devices. Summary

If future success for a clinically useful therapeutic device is linked to the research activity within a field, then there is great promise for a retinal neuroprosthesis. The number of research groups contributing in important ways to the vision prosthesis knowledge base is growing at an exponential rate. However, as detailed previously, there are many technological challenges and biological unknowns that stand in the way of creating such a device. In this editorial, we have touched on a number of critical issues, including parallelization of stimulus encoding and delivery, the neural–electrode interface, device biocompatibility and the plasticity at the visual system in relation to the psychophysics of visual perception. This is by no means a comprehensive list. The research push is for more densely packed electrode grids with larger quantities of electrodes. If we are attempting to restore vision to the profoundly visually impaired in a manner analogous to normal vision, then this remains ‘science fiction’. However, the ‘science fact’ is that sufficient evidence exists to suggest that the provision of some degree of visual perception will occur in the near to medium future. The research, development and commercial effort will cost orders of magnitude more than the $6 million it took Steve Austin to run and see. But it is hard to put a monetary value on restoring some form of patterned vision to a person – giving them independence and mobility and providing them with some of the visual cues that most of us take for granted. The vexing question remains how many electrodes is sufficient for a ‘useful’ therapeutic device? As the scientific jury is still out on this issue, a look into the distant past may provide some wisdom. The 15th Century philosopher, Desiderius Erasmus, claimed, “In the kingdom of the blind, the one-eyed man is king”. In the vision prosthesis landscape, perhaps the equivalent question is, “In the kingdom of the blind, will the man/woman with 100 electrodes be king/queen?”

2

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Humayun MS, Weiland JD, Fujii GY et al. Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res. 43, 2573–2581 (2003).

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Suaning GJ, Lovell NH. CMOS neurostimulation ASIC with 100 channels, scaleable output and bi-directional radio frequency telemetry. IEEE Trans. Biomed. Eng. 48, 248–260 (2001).

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Stone JL, Barlow WE, Humayun MS, de Juan Jr E, Milam AH. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa Arch. Ophthalmol. 110, 1634–1639 (1992).

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Humayun MS, de Juan E, Dagnelie G, Greenberg RJ, Propst RH, Phillips DH. Visual perception elicited by electrical stimulation of the retina in blind humans. Arch. Opthalmol. 1141, 40–46 (1996).

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Cha K, Horch KW, Normann RA, Boman DK. Reading speed with a pixelized vision system. Op. Soc. Am. J. 9, 673–677 (1992).

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Cha K, Horch KW, Normann RA, Mobility performance with a pixelized vision system. Vision Res. 32, 1367–1372 (1992).

Liu W, Sivaprakasam M, Singh PR, Bashirullah R, Wang G. Electronic visual prosthesis. Artificial Organs 27, 986–995 (2003).

13

Dokos S, Suaning GJ, Lovell NH. A bidomain model of epiretinal stimulation. IEEE Trans. Neural Syst. Rehab. Eng. 13, 137–146 (2005).

14

Schuettler M, Stiess S, King, Suaning GJ. Fabrication of implantable microelectrode arrays by laser-cutting of silicone rubber and platinum foil. J. Neural Engineering 2(1), S121–S128 (2005).

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Hallum LE, Dagnelie G, Suaning GJ, Lovell NH. Simulating auditory and visual sensorineural prostheses: a comparative review. J. Neural Engineering 4, S58–S71 (2007). Lovell NH, Hallum LE, Chen S et al. Advances in retinal neuroprosthetics. In: Neural Engineering. Akay M (Ed.). Wiley Press, NY, USA (2007).

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Suaning GJ, Hallum LE, Preston PJ, Lovell NH. An efficient multiplexing method for addressing large numbers of electrodes in a visual neuroprosthesis. Presented at: 26th Annual International Conference of the IEEE-EMBS. San Francisco, CA, USA, September 1–5, 2004.

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Seo M-J, Kim SJ, Chung H, Kim ET, Yu HG, Yu YS. Biocompatibility of polyimide microelectrode array for retinal stimulation, Materials Sci. Engineering: C. 24, 185–189 (2004).

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Xiao X, Wang J, Liu C et al. In vitro and in vivo evaluation of ultrananocrystalline diamond for coating of implantable retinal microchips. J. Biomed Materials Res. Part B: Applied Biomaterials 77B, 273–281 (2006).

Affiliations •

Nigel H Lovell Professor, University of New South Wales, and National Information and Communications Technology Australia (NICTA), Graduate School of Biomedical Engineering, Sydney, 2052, Australia Tel.: +61 293 853 922 Fax: +61 296 632 108 [email protected]

•

Gregg J Suaning University of Newcastle, School of Engineering, Building ES, Room 402, University Drive, Callaghan 2308, Australia Tel.: + 61 249 216 196 Fax: + 61 249 216 946 [email protected]

Expert Rev. Ophthalmol. 2(2), (2007)