Technology and Innovation, Vol. 19, pp. 605-611, 2018 ISSN 1949-8241 • E-ISSN 1949-825X Printed in the USA. All rights reserved. http://dx.doi.org/10.21300/19.3.2018.605 Copyright © 2018 National Academy of Inventors. www.technologyandinnovation.org RETINAL PROSTHESES: THE ARGUS SYSTEM Tai-Chi Lin1,2,3,4, Lan Yue1,2, and Mark S. Humayun1,2 1Department of Ophthalmology, USC Roski Eye Institute, University of Southern California, Los Angeles, CA, USA 2USC Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, USA 3Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China 4Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China In the late 1990s, Humayun et al. demonstrated intraoperative retinal stimulations from a multi-electrode array in blind volunteers with little or no light perception. The participants reported electrically-elicited visual perception in the visual field that corresponded well to the retinotopic area of stimulation. The subjects exhibited ability to discriminate two separate stimulation sites and to track perception as the electrode moved across the retina. In another proof-of-concept trial, Rizzo et al. demonstrated reproducible visual perception with electrical stimulations of retina in retinitis pigmentosa (RP) patients. With these and other important pilot studies, two generations of the Argus epiretinal prostheses (Argus I and Argus II), which function by stimulating the remaining inner retinal neurons in patients with advanced retinal degeneration, were developed. The basic operations of the Argus series systems are similar, both consisting of a miniature camera, an external video processing unit, extraocular electron- ics, and an intraocular electrode array implant. Visual information gathered by the camera is transformed into controlled patterns of electrical pulses, which are delivered to the surviving retinal neurons by the electrode array. Results from clinical studies showed that Argus systems offer opportunities to restore meaningful vision to the patients. In the review, we will focus on the technical and operational features as well as functional outcomes of the Argus system. Key words: Argus; Retinal prosthesis; Epiretinal prosthesis; Retinitis pigmentosa Artificial sight is restoring sight by electrical stim- complex visual processing that occurs downstream ulation of the visual system. Ancient Greeks were of the retina. As such, the development of cortical aware of the light perception that is elicited, in the visual prosthesis has been slow to gain more momen- absence of visual input, by applying mechanical pres- tum. Rather, recent efforts have been largely focused sure on the eyeball (1). In 1960s, Brindley and Lewin on the development of implants that are placed in implanted an array of radio receivers connected to proximity of the retina for easier accessibility, lower electrodes onto the visual cortex of a blind person and surgical risks, well-preserved retinotopic mapping, showed that short electrical pulses induced sensations and the ability to make use of the remaining retinal of light in the form of points, spots, and bars of light circuitry for signal processing (3). (2). However, surgical implantation in the cortex is Although the idea of retinal stimulation was pat- challenging, and it is difficult to map the visual input ented as early as 1956 (4), it was not until the early directly to electrical output of the visual cortex due to studies (5,6) demonstrating the feasibility of using _____________________ Accepted: October 15, 2017. Address correspondence to Mark S. Humayun, M.D., Ph.D., University of Southern California, 1450 San Pablo Street, Room 6545B, Los Angeles, California 90033, USA. Tel: +1 (323) 865-3092; Fax: +1 (323) 865-0858. Email: [email protected] 605 606 LIN ET AL. a multi-electrode array placed adjacent to the ret- the diffused and/or distorted visual percepts due to ina to elicit visual percepts that the field of retinal undesired activation of the axons of passage (7). As prostheses started to advance rapidly (7). Different an epiretinal implant, both Argus I and II require retinal prostheses products and prototypes have surgical fixation of an electrode array to the retinal since been developed and tested in humans, among surface with a retinal tack. The array is designed which two devices have received regulatory approval to conform to the curvature of the inner retina to for clinical use. Argus II epiretinal implant (Second maintain a consistent distance between the electrodes Sight Medical Products, Sylmar, California) received and the retina for optimized stimulation. both European Union approval (CE mark) and the The Argus systems contain a miniature camera US Food and Drug Administration (FDA) market mounted on a pair of glasses, an external video pro- approval in 2011 and 2013, respectively. Alpha-IMS cessing unit (VPU) worn by the user (Figure1), and (Retina Implant AG, Germany) received CE mark extraocular electronics and an intraocular electrode approval in 2013. array that are interconnected via a transscleral cable Retinal degeneration that involves progressive (Figure 2). The camera captures visual scenes and deterioration and loss of function of photorecep- sends the information to the VPU for advanced pix- tors is a major cause of permanent vision loss (8,9). ilation and processing. The extraocular electronics, Age-related macular degeneration (AMD) and RP are along with the receiver coil, converts the radio fre- two of the more prevalent forms (10). AMD affects quency signals it receives wirelessly from the VPU to 30 to 50 million people globally and more than two the electrical pulses. Stimulation pulses proportional million in the United States (11,12), and RP is esti- to the luminance of the pixelated images are subse- mated to affect 1.5 million people in the world (13). quently delivered to the intraocular electrode array, The etiology of AMD begins by primarily affecting which is attached to the retina. cone photoreceptors in the macula. RP begins with progressive degeneration of rod photoreceptors in the peripheral retina. Preservation of the inner retina in these photoreceptor degenerative diseases has been widely reported (14,15), supporting the possibility of vision restoration by establishing a stimulation mechanism that bypasses the damaged photoreceptor layer and interfaces with the surviving inner retinal neurons that remain capable of neural signaling (7). Retinal implants interface with the retina at dif- ferent positions (16). For example, Argus I and II are Figure 1. External part of the Argus system (Image courtesy of implanted epiretinally and alpha-IMS subretinally. Second Sight Medical Products, Inc.) Epiretinal implantation has the following advantages. First, the prosthesis contacts the retina on the inner surface that is accessible from the vitreous cavity, which reduces the risk of mechanical damage to the retina. Second, besides choroidal perfusion, fluid in the vitreous cavity serves as an additional heat sink that enhances the removal of the heat generated by the implant. Finally, the device directly stimulates ganglion cells, thus being potentially useful in cases of extended retinal degeneration where inner retina circuitry is altered. The disadvantages of the epiretinal prostheses include the difficulty of fixating the elec- Figure 2. Implant part of the Argus system (Image courtesy of trode array uniformly onto the retina and potentially Second Sight Medical Products, Inc.) ARGUS SYSTEM 607 Argus I was the first-generation epiretinal pros- NCT00407602). They ranged from 28 to 77 years old, thesis approved for an investigational clinical trial and all had little to no light perception in both eyes. by the FDA. The Argus I had a microarray of 16 Twenty-nine patients had a diagnosis of RP, and one electrodes in a 4 x 4 arrangement (Figure 3) and was was diagnosed with choroideremia. Among these implanted by one of us (MSH) in six subjects blinded 30 devices, 29 remain implanted and functional to by RP. All subjects perceived light when the device date, while only one was explanted, with the latter was activated, and they could perform visual spatial being due to recurrent conjunctival erosion rather and motion tasks after a short period of training. than device failure. All subjects were able to perceive The long term safety and effectiveness of Argus I light during electrical stimulation. Serious adverse was observed, and ophthalmic images showed a sta- events (SAEs) were reported in 11 patients during ble physical retina-implant interface after long-term the first three years and in only one patient between stimulation up to a decade despite the formation of years three and five. The most common SAEs were some fibrotic tissues around the tack in the early hypotony, conjunctival dehiscence, erosion over the months after the surgery (17). The results of Argus extraocular portion of the implant, and presumable I motivated the development of the more advanced endophthalmitis (culture negative). Most SAEs (61%) Argus II system. occurred within six months of implantation, and three patients accounted for over 55% of SAEs at year three. Two patients needed retacking of the array to the retina one week after implantation (20). Figure 3. Electrode array of the Argus I implant (Image reprinted from Caspi et al.)(18). The Argus II implant consists of an array of 60 Figure 4. Electrode array of the Argus II implant (Image courtesy electrodes arranged in a 6 x 10 grid (Figure 4), cov- of Second Sight Medical Products, Inc.) ering a visual angle of approximately 20o (18,19). The procedure of Argus II implantation requires a Since the camera of Argus II is mounted at the 360o limbal conjunctival peritomy and placement center of the glasses frame, but not in the eye, the of an encircling scleral band, which secures the association between the visual scene and the eye hermetic electronics enclosure and the episcleral movement as in normally sighted people no longer radio frequency antenna. After performing pars exists.