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 (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 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 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, ) 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 (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 (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. To compensate, the subjects were trained to plana vitrectomy, including shaving of the vitreous keep the gaze ahead and use head movement to scan base to allow insertion of the electrode array with- the visual scene. All subjects adapted after a short out vitreous traction, the electrode array is inserted period of training (21). Vision restoration of Argus II and fixed onto the inner retinal surface with a single was assessed by the patients’ performance in visually retinal tack. The extraocular portion of the cable is guided tasks when the system was turned on ver- anchored to the sclera with sutures. Between 2007 sus off. The standard clinical visual function tests of and 2009, 30 subjects received the Argus II implant Argus II include high contrast computer-based target in both the U.S. and Europe (www.clinicaltrials.gov- localization, motion detection, and grating visual 608 LIN ET AL. acuity. At year three, with the facilitation of the Argus the visual experience of the patients, enabling faster II system, 25 of 28 patients (89.3%) performed better and more accurate object identification and visual in square localization, 15 of 27 patients performed scene segmentation. Therefore, it is of tremendous better in the detection of the direction of motion, and interest to further understand the electrically-elicited one-third of the patients had the grating visual acuity color perception in Argus II patients in pursuit of the measured at 2.9 LogMAR or better, averaging at 2.5 goal to restore color vision in the blind. LogMAR (21). LogMAR, as a measure of the subject’s In 2015, surgery of Argus II implantation was ability to resolve details as small as one minute of performed for the first time in a dry AMD patient visual angle, can be calculated by taking the base-10 in Manchester, UK. This phase I clinical trial aimed logarithm of the reversal of Snellen acuity; for exam- to evaluate the safety and efficacy of Argus II in ple, a 20/20 vision corresponds to 0 LogMAR and a late-stage AMD. The implant partially restored the 20/200 vision to 1 LogMAR. To put these visual acuity patient’s central vision, enabling him to “see the measurements into perspective, it’s worth noting that outline of people and objects” and “walk around a person able to count fingers at two feet is considered and see things.” This study, despite being at an early to have 20/2000 vision or 2.0 LogMAR. One patient phase, suggests that the central vision restored by achieved a grating acuity of 20/1,262 (1.8 LogMAR), the Argus II and similar prostheses may integrate roughly matching the acuity theoretically achievable with the patient’s remnant peripheral vision and act at the Argus II electrode density (19). Additionally, synergistically to enhance the visual experience of the implant provides functional vision and long-term the advanced AMD patients (7). benefits to the orientation and mobility of the patients Overall, as the first retinal implant with regulatory in more real-life-like settings, such as finding a door approval, Argus II offers exciting opportunities to and following a line on the floor (7). study prosthetic vision in a relatively large cohort of In addition to standard clinical tests, laborato- patients. Results from clinical studies provide strong ry-based exploration of Argus II-produced prosthetic evidence that this epiretinal electronic implant is vision was carried out in subsets of the subjects. In effective in restoring meaningful vision to patients a study, eleven subjects demonstrated the ability to blinded by photoreceptor degeneration. To date, identify high contrast shapes (22). In another study, nearly 300 patients have been implanted with Argus letter recognition was evaluated. The results showed II worldwide. that 70% of the patients were able to recognize letters Despite the encouraging results summarized with horizontal and/or vertical components only. Half above, the Argus II implant, containing only 60 of the subjects could recognize letters that had oblique electrodes (i.e., 60 pixels), is not able to restore high or curved components (23). Luo et al. conducted acuity vision. Further improvement in the spatial studies to evaluate the ability to identify common resolution demands advanced microelectronic and objects from 2D to 3D under high contrast settings hermetic packaging technologies that would allow for in seven subjects (24,25). Overall, subjects with the a higher electrode density on the chip. Furthermore, implant activated exhibited improved performance, improvement in the power and data management is and the improvement is largely dependent on the con- needed to permit sufficient power supply and rapid trast at the edge. Recently, it has been reported that data transmission to the implant while keeping heat up to nine different colors can be elicited depending generation under check. Finally, novel design and on the stimulation parameters. The most prominent implantation techniques that can hold the electrode colors are white, yellow, and blue (26). Perception of array in closer proximity to the retina are desirable different colors could be elicited from the same retinal for increased stimulation efficiency (3). area with different parameters, and the subjects could The past decade has witnessed the rapid growth in simultaneously perceive two distinct colors at two retinal prostheses. It should be noted that, in addition retinal locations (27). Color information, if success- to Argus II and other epiretinal implants, subret- fully integrated into the prosthetic vision by being inal and suprachoroidal implants have also made encoded in electrical pulses, will significantly enhance tremendous progress. Among others, Alpha-IMS, ARGUS SYSTEM 609 a subretinal implant with 1,500 photodiodes in an REFERENCES array (28,29), received CE mark approval in 2013. 1. Grusser OJ, Hagner M. On the history of defor- Implants with photodiodes serving as the visible light mation phosphenes and the idea of internal light sensor often suffer from low photocurrent output. generated in the eye for the purpose of vision. Therefore, Alpha-IMS relies on external power supply Doc Ophthalmol. 1990;74: 57-85. to amplify the photocurrents such that the current 2. Brindley GS, Lewin WS. The sensations pro- pulses delivered by the electrodes are sufficient to duced by electrical stimulation of the visual drive neuronal activation (30). However, the addi- cortex. J Physiol. 1968;196:479-493. tional power amplification circuitry increases the 3. Hossein Nazari PF, Lan Yue, James Weiland, system complexity and surgical difficulty. An alter- Mark S. Humayun. Retinal prostheses: a clinical native approach developed by Palanker et al. adopts perspective. J Vitreoretin Dis. 2017;1:204-213. optical amplification by converting ambient visual 4. Tassicker GE. Preliminary report on a retinal inputs into high intensity near infrared laser pulsing stimulator. Br J Physiol Opt. 1956;13:102-105. that is projected onto the subretinal photodiode array. 5. Humayun MS, de Juan E, Jr., Weiland JD, Dagne- Each pixel consists of a few photodiodes connected in lie G, Katona S, Greenberg R, Suzuki S. Pattern series to further increase the output current (31,32). electrical stimulation of the human retina. Vision This approach avoids complex electrical circuitry, Res. 1999;39:2569-2576. but its safety and efficiency needs to be evaluated 6. Rizzo JF, 3rd, Wyatt J, Loewenstein J, Kelly S, in humans. The clinical evaluation of the Alpha- Shire D. Perceptual efficacy of electrical stim- IMS implant showed that the highest visual acuity ulation of human retina with a microelectrode achieved was 20/546 measured with the Landolt C array during short-term surgical trials. Invest chart, (30) lower than the acuity of 20/200 that would Ophthalmol Vis Sci. 2003;44:5362-5369. be theoretically offered by 1,500 pixels in the array. 7. Yue L, Weiland JD, Roska B, Humayun MS. This observation, along with findings from the animal Retinal stimulation strategies to restore vision: models, suggests that increased electrode density fundamentals and systems. Prog Retin Eye Res. only improves the visual acuity to an extent beyond 2016;53:21-47. which other factors such as electrical properties of the 8. Busskamp V, Duebel J, Balya D, Fradot M, Viney retina will weigh in. A major benefit of Alpha-IMS TJ, Siegert S, Groner AC, Cabuy E, Forster V, and other systems that similarly implant high-density Seeliger M, Biel M, Humphries P, Pagues M, light sensing units intraocularly is that the patients Mohand-Said S, Trono D, Deisseroth K, Sahel can use eye movement, instead of head movement, to JA, Picaud S, Roska B. Genetic reactivation of scan the visual field, which better mimics the natural cone photoreceptors restores visual responses in vision. These advances and the continued excellent retinitis pigmentosa. Science. 2010;329:413-417. work by different groups around the world in visual 9. Curcio CA, Owsley C, Jackson GR. Spare the prostheses will further our understanding of the field rods, save the cones in aging and age-related of artificial sight, leading to improved restored vision maculopathy. Invest Ophthalmol Vis Sci. to otherwise blind patients for whom there is no 2000;41:2015-2018. foreseeable cure. 10. Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Proce H, Jonas JB, Keeffe J, Leasher ACKNOWLEDGMENTS J, Naidoo K, Pesudovs K, Resnikoff S, Taylor HR, Mark S. Humayun has commercial interest and Visions Loss Expert Group. Causes of vision loss holds patents in the development of the epiretinal worldwide, 1990-2010: a systematic analysis. prosthesis with Second Sight Medical Products, Inc., Lancet Glob Health. 2013;1:e339-349. Sylmar, California. 11. Bressler NM. Age-related macular degenera- tion is the leading cause of blindness. JAMA. 2004;291:1900-1901. 12. Friedman DS, O’Colmain BJ, Munoz B, Tomany 610 LIN ET AL.

SC, McCarty C, de Jong PT, Nemesure B, Mitchell G, Handa J, Barale PO< Sahel JA, Stanga PE, P, Kempen J, Eye Diseases Prevalence Research Hafezi F, Safran AB, Salzmann J, Santos A, Birch Group. Prevalence of age-related macular degen- D, Spencer R, Cideciyan AV, de Juan E, Duncan eration in the United States. Arch Ophthalmol. JL, Eliott D, Fawzi A, Olmos de Koo LC, Ho 2004;122:564-572. AC, Brown G, Haller J, Regillo C, Del Priore LV, 13. den Hollander AI, ten Brink JB, de Kok YJ, van ARditi A, Greenberg RJ, Argus II Study Group. Soest S, van den Born LI, van Driel MA, van Five-year safety and performance results from de Pol DJ, Payne AM, Bhattacharya SS, Kell- the Argus II retinal prosthesis system clinical ner U, Hoyng CB, Westerveld A, Brunner HG, trial. Ophthalmology. 2016;123:2248-2254. Bleeker-Wagemakers EM, Deutman AF, Heck- 21. Ho AC, Humayun MS, Dorn JD, da Cruz L, enlively JR, Cremers FP, Bergen AA. Mutations Dagnelie G, Handa J, Barale PO, Sahel JA, Stanga in a human homologue of Drosophila crumbs PE, Hafezi F, Safran AB, Salzmann J, Santos A, cause retinitis pigmentosa (RP12). Nat Genet. Birch D, Spencer R, Cideciyan AV, de Juan E, 1999;23:217-221. Duncan JL, Eliott D, Fawzi A, Olmos de Koo 14. Humayun MS, Prince M, de Juan E, Jr., Barron LC, Brown GC, Haller JA, Regillo CD, Del Pri- Y, Moskowitz M, Klock IB, Milam AH. Mor- ore LV, Arditi A, Geruschat DR, Greenberg RJ, phometric analysis of the extramacular retina Argus II Study Group. Long-term results from from postmortem eyes with retinitis pigmentosa. an epiretinal prosthesis to restore sight to the Invest Ophthalmol Vis Sci. 1999;40:143-148. blind. Ophthalmology. 2015;122:1547-1554. 15. Kim SY, Sadda S, Pearlman J, Humayun MS, de 22. Arsiero M dCL, Merlini F, Sahel JA, Stanga, PE, Juan E Jr, Melia BM, Green WR. Morphometric Hafezi F, Greenberg RJ, Argus II Study Group. analysis of the macula in eyes with disciform Subjects blinded by outer retinal dystrophies age-related macular degeneration. Retina. are able to recognize shapes using the Argus II 2002;22:471-477. retinal prosthesis system. Investig Ophthalmol 16. Lin TC, Chang HM, Hsu CC, Hung KH, Chen Vis Sci. 2011;52:4951. YT, Chen SY, Chen SJ. Retinal prostheses in 23. da Cruz L, Coley BF, Dorn J, Merlini F, Filley degenerative retinal diseases. J Chin Med Assoc. E, Christopher P, Chen FK, Wuyyuru V, Sahel 2015;78:501-505. J, Stanga P, Humayun M, Greenberg RJ, Dag- 17. Yue L, Falabella P, Christopher P, Wuyyuru V, nelie G, Argus II Study Group. The Argus II Dorn J, Schor P, Greenberg RJ, Weiland JD, epiretinal prosthesis system allows letter and Humayun MS. Ten-year follow-up of a blind word reading and long-term function in patients patient chronically implanted with epiret- with profound vision loss. Br J Ophthalmol. inal prosthesis Argus I. Ophthalmology. 2013;97:632-636. 2015;122:2545-2552.e2541. 24. Luo YH-L, Zhong J, Merlini F, Anaflous F, Arsi- 18. Caspi A, Dorn JD, McClure KH, Humayun ero M, Stanga PE, Da Cruz L. The use of Argus® MS, Greenberg RJ, McMahon MJ. Feasibility II retinal prosthesis to identify common objects study of a retinal prosthesis: spatial vision with in blind subjects with outer retinal dystrophies. a 16-electrode implant. Arch Ophthalmol. Investig Ophthalmol Vis Sci. 2014;55:1834. 2009;127:398-401. 25. Luo YH-L, Zhong JJ, da Cruz L. The use of 19. Humayun MS, Dorn JD, da Cruz L, Dagnelie G, Argus® II retinal prosthesis by blind subjects to Sahel JA, Stanga PE, Cideciyan AV, Duncan JL, achieve localisation and prehension of objects Eliott D, Filley E Ho AC, Santos A, Safran AB, in 3-dimensional space. Graefes Arch Clin Exp Arditi A, Del Priore LV, Greenberg RJ, Argus II Ophthalmol. 2015;253(11):1907-14. Study Group. Interim results from the interna- 26. Stanga PE, Hafezi F, Sahel JA, Merlini F, Coley tional trial of Second Sight’s visual prosthesis. B, Greenberg RJ, Argus II Study Group. Patients Ophthalmology. 2012;119:779-788. blinded by outer retinal dystrophies are able to 20. da Cruz L, Dorn JD, Humayun MS, Dagnelie perceive color using the Argus II retinal pros- ARGUS SYSTEM 611

thesis system. Investig Ophthalmol Vis Sci. Peters T, Stingl K, Sachs H, Stett A, Szurman P, 2011;52:4949. Wilhelm B, Wilke R. Subretinal electronic chips 27. Stanga PE, Sahel JA Jr, Hafezi F, Merlini F, Coley allow blind patients to read letters and combine B, Greenberg RJ, Argus II Study Group. Patients them to words. Proc Biol Sci. 2011;278:1489- blinded by outer retinal dystrophies are able to 1497. perceive simultaneous colors using the Argus® II 30. Stingl K, Bartz-Schmidt KU, Gekeler F, Kusnyerik retinal prosthesis system. Investig Ophthalmol A, Sachs H, Zrenner E. Functional outcome Vis Sci. 2012;53:6952. in subretinal electronic implants depends on 28. Kusnyerik A, Greppmaier U, Wilke R, Gekeler F, foveal eccentricity. Invest Ophthalmol Vis Sci. Wilhelm B, Sachs HG, Bartz-Schmidt KU, Klose 2013;54:7658-7665. U, Stingl K, Resch MD, Hekmat A, Bruckmann 31. Mathieson K, Loudin J, Goetz G, Huie P, Wang A, Karacs K, Nemeth J, Suveges I, Zrenner E. Positioning of electronic subretinal implants L, Kamins TI, Galambos L, Smith R, Harris JS, in blind retinitis pigmentosa patients through Sher A, Palanker D. Photovoltaic retinal pros- multimodal assessment of retinal structures. thesis with high pixel density. Nat Photonics. Invest Ophthalmol Vis Sci. 2012;53:3748-3755. 2012;6:391-397. 29. Zrenner E, Bartz-Schmidt KU, Benav H, Besch D, 32. Palanker D, Vankov A, Huie P, Baccus S. Design Bruckmann A, Gabel V-P, Gekeler F, Greppmaier of a high-resolution optoelectronic retinal pros- U, Harscher A, Kibbel S, Koch J, Kusnyerik A, thesis. J Neural Eng. 2005;2:S105-120.