THE ARGUS® II RETINAL PROSTHESIS SYSTEM: AN OVERVIEW

David D. Zhou, Ph.D., Jessy D. Dorn, Ph.D., Robert J. Greenberg, M.D., Ph.D., Argus II Study Group Second Sight Medical Products, Inc. Sylmar, CA

ABSTRACT The Argus II Retinal Prosthesis System is the only commercially-approved treatment for severe to profound Retinitis Pigmentosa in the world. Over 10 years of research and development have gone into this device; it is now commercially available in the European Economic Area, Saudi Arabia, and in the United States. The Argus II System consists of an implant (including an epiretinal electrode array, an electronics case, and a receiver antenna), as well as a body-worn computer and a pair of glasses with a miniature video camera. It converts video images from the camera into stimulation patterns that are transmitted to the implant in real time, allowing users to perceive patterns of light. All aspects of the System have been extensively bench tested and found to provide long-term reliability. These findings have been borne out in a clinical trial; in over 120 subject-years of testing, there has been only one device failure. Clinical trial results have established the safety and probable benefit of the Argus II System.

Index Terms— Retinal prosthesis, epiretinal array, Retinitis Pigmentosa

1. INTRODUCTION

Retinitis Pigmentosa (RP) is a genetic disease that slowly robs fully-sighted people of their vision. Photoreceptors, the light-sensing cells of the retina, degenerate, causing irreparable vision loss. While the photoreceptors are lost in RP, most other parts of the visual pathway remain largely intact and functional, including bipolar cells and ganglion cells (the output cells of the retina) as well as the optic nerve and visual structures in the brain.

Retinal prostheses (also called retinal implants or bionic eyes) work by electrically stimulating the remaining retinal cells, bypassing the degenerated photoreceptors. The electrical signals move up the visual pathway into the visual cortex, where they are perceived as visual percepts. Many different groups worldwide are investigating retinal prostheses; some approaches involve inserting an electrode or photodiode array subretinally, near the photoreceptors [1], [2], some insert an array epiretinally, near the ganglion cells [3], while others involve placing an array in the suprachoroidal space [4], [5].

Until recently, all of these efforts were investigational. After over 10 years of research and development, The Argus II Retinal Prosthesis System is the first commercially-available device approved for the treatment of RP. It is CE Marked and has been available in the European Economic Area since 2011. Recently, the FDA has approved it for sale in the United States under a Humanitarian Device Exemption.

This article provides an overview of the Argus II System, including design, principle of operation, bench testing, and clinical trial testing.

2. THE ARGUS II SYSTEM

The Argus II System consists of implanted and external components. 2.1 Implant The implant is an epiretinal prosthesis that includes a receiver coil (antenna), electronics, and an electrode array. These are implanted in and around the eye (Figure 1A). The array has 60 platinum based electrodes arranged in a 6x10 grid. Each electrode is 200 µm in diameter; horizontal and vertical pitch is 525 µm. The array covers about 20° of visual field (diagonally). The flexible polymer thin-film electrode array, which follows the curvature of the retina, is attached to the retina over the macula with a retinal tack (Figure 1B). The extra-ocular portion of the Argus II Implant is secured to the eye by means of a scleral band.

Figure 1A. Internal components of the Argus II System.

Electronics case

Electrode array

Receiver coil

Figure 1B. A thin-film polymer 60 electrodeof a RP subject. 2.2 Externals The external equipment consists of gprocessing unit (VPU), and a cable (Figureinclude a miniature video camera and a tranArgus II Clinician Fitting System softwconfigure the Argus II system stimulationvideo processing strategies for each subjeprovides modules for electrode control,clinicians to interactively construct test stimover amplitude, pulse-width, and freqstimulation waveform of each electrode.

Figure 2. External components of the Argus 2.3 Principle of Operation The Argus II System provides real-time vito blind patients. During use, the miniatuhoused in the patient’s glasses captures a scsent to the small patient-worn VPU wherand transformed into instructions that are glasses via a cable. These instructions wirelessly to the receiver coil in the implantthen sent to the electrode array, which emitelectricity. These pulses are intended to byp

Transmitter coilCamera

Video Proces

e array in the eye

lasses, a video e 2). The glasses nsmitter coil. The ware is used to n parameters and ect. The software , permitting the muli with control quency of the

s II System.

isual information ure video camera ene. The video is e it is processed sent back to the are transmitted

t. The signals are ts small pulses of pass the damaged

photoreceptors and stimulate the rwhich transmit the visual informatito the brain. This process is perception of patterns of light whiinterpret as visual patterns (Figure 3

Figure 3. The patient perceives patelectrical stimulation.

3. BENCH TEST

The Argus II Retinal Implant has bcomponent, sub-assembly, and systreliability. The hermetic electrdemonstrated to prevent moisture device, extending the functional lFinished implants have reached mlifetime in accelerated testing and s4 years in real time testing. Thinarray insulation so far has reachetesting and an equivalent lifetimaccelerated testing. 3.1 Electrode Material Electrode arrays withstood aggstimulation and provided long-termcorrosion or material degradation. developed by Second Sight, Platinuverified with soak tests for over 10 sufficient chronic charge density mC/cm2 for retinal stimulation. Platinum Gray is similar to the moblack except it has significantly m(Figure 4) [6].

sing Unit (VPU)

retina’s remaining cells, ion along the optic nerve intended to create the ich patients can learn to 3).

tterns of light created by

TING

been tested in-vitro at the tem levels for long-term ronics case has been accumulation inside the lifetime of the implant. more than 10 years of so far reached more than

n-film polymer electrode ed 7 years in real-time

me of over 26 years in

gressive constant pulse m safe stimulation without

The electrode material um Gray, has been fully years and has more than capacity – up to 1.0

The high surface area ore familiar soft platinum more mechanical stability

Figure 4. SEM micrographs of Second SighGray electrode material (top) showing the msurface area and Platinum Gray coated thin-(bottom). 3.2 Electrical Stimulation and Waveform

Electrical stimulation of Argus II Retinbiphasic cathodic first, charge balanced pulses. Electrode voltage excursion impedance are monitored during active pulassess device stability. The electrode v(Figure 5A) remains low during the long-and is far below the water window potenelectrode material. Electrode impedancestable during the long-term stimulation. 3.3 Magnetic Resonance Imaging (MRcompatibility

The System has also been tested for Mag

Imaging (MRI) safety and compatibilitindicated that the exposure of the AProsthesis System to various conditions MHz and 3.0-T/128-MHz systems will device, alter its functionality, or have safefor the patient [7].

ht Platinum material’s high -film electrodes

ms

nal implant uses constant current and electrode

lse stimulation to voltage excursion -term stimulation ntial of platinum e (Figure 5B) is

RI) safety and

gnetic Resonance ty. Test results

Argus II Retinal using 1.5-T/64-not damage the

ety consequences

Figure 5. The voltage excursion wabiphasic, cathodic first pulse stimulaimpedance curves (B. bottom) recorstimulation.

4. CLINICAL TRIAL

The Argus II System is being studiesubjects in the U.S. and Europe, whstill ongoing. These subjects will bAs of December 2012, there were othe clinical trial. The average time (SD 1.1 years), with a range of 1.2 –

At the time of implant, all subjdeteriorated to bare light perceptiononly able to detect very bright lifunctional vision). Most (29) had re 4.1 Reliability As of December 2012, there was ondevice, suspected to be due to ddevice during implantation. Theimplanted but is non-functional. Alto function.

aveforms (A. top) by ation and electrode rded during long-term

L TESTING

ed in a clinical trial of 30 hich began in 2007 and is e followed for ten years. over 120 subject-years in implanted was 4.1 years

– 5.6 years. ects’ residual vision had

n or worse (i.e., they were ight, and had no useful tinitis pigmentosa.

ne failure of an implanted amage sustained by the

e device has remained ll other devices continue

4.2 Safety Safety was monitored by recording and investigating adverse events due to the device or surgery. There were no unexpected device- or procedure-related adverse events (i.e., all events that occurred were part of a pre-defined list of the events that could be expected from this type of ophthalmic surgery). All adverse events that did occur were treated with standard ophthalmic techniques. 4.2 Probable Benefit All subjects perceived light with their Argus II Systems, and all subjects used their Systems at home. Probable Benefit was measured in the clinical trial with a battery of visual function and functional vision assessments to determine whether subjects showed better visual performance with the System turned ON vs. turned OFF. Assessments were administered at regular time points throughout the clinical trial (e.g., baseline, 3 months, 6 months, 12 months, 2 years, etc.). 4.2.1 Visual Function The visual function assessments were computer-based tests with high-contrast stimuli presented on a touch screen. The most basic assessment was Square Localization [8]; it tested subjects’ ability to locate and touch a white square at a random location on a black touch screen monitor (Figure 6A). Each target square (40 trials total) remained on the screen until the subject touched the monitor where he or she believed the square was located. The distance from the center of the target square to the subject’s response was calculated for each trial.

The second visual function test, Direction of Motion, assessed subjects’ ability to determine the direction of a white bar as it crossed the black touch screen at a random angle (0-360°) [9]. After each bar moved across the screen (80 trials total), the subject drew the direction he or she perceived on the monitor (Figure 6B). The unsigned angle difference between the target and response was calculated. A successful performance on this test required spatial vision ability: subjects must be able to perceive spatial information from their electrode array (i.e., distinguish between electrodes on different areas of the array) in order to successfully determine the direction of motion.

Grating Visual Acuity, the final visual function test used in the clinical trial, was designed to measure subjects’ visual acuity using principles similar to the standard Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart. In this test, subjects were required to determine the orientation (horizontal, vertical, diagonal right, diagonal left) of black and white gratings of differing spatial frequencies (Figure 6C). The test measured acuity in units of log of the Minimum Angle of Resolution (logMAR), from

2.9 logMAR (or about 20/16000 on the Snellen acuity scale) to 1.6 logMAR (~ 20/800).

Figure 6A. A subject performing the Square Localization assessment.

Figure 6B. The Direction of Motion task.

Figure 6C. The Grating Visual Acuity assessment.

All visual function tests were performed with the subjects’ Systems turned ON and with it OFF (using only their residual vision) as a control.

As a group, subjects performed Square Localization and Direction of Motion better with the System ON compared to OFF at each time point (Figure 7). Grating Visual Acuity was the most difficult of the visual function tests. Only one subject was able to score on this test with the implanted eye when the System was OFF, and that was achieved at only one time point. With the System ON, between 31% and 50% of subjects scored between 2.9 – 1.6 logMAR depending on

the time point (up to 24 months post-implant). The best score to date was 1.8 logMAR (or 20/1262 on the Snellen acuity scale).

Figure 7A. Square Localization results averaged across subjects at yearly time points.

Figure 7B. Direction of Motion results (mean response error ± mean standard error) averaged across subjects at yearly time points.

4.2.2 Functional Vision The functional vision assessments were developed to test subjects’ visual performance on more real-world tasks in less controlled environments. They included Orientation and Mobility tasks such as finding a door and following a line (Figure 8), as well as questionnaires and observer-rated assessments intended to measure subjects’ functional vision in everyday life and their general well-being.

On the Orientation and Mobility (O&M) tasks, the subjects as a group performed better with the System ON than OFF at each time point (Figure 9).

The Functional Low-vision Observer Rated Assessment (FLORA) involved interviews (self-report) and observation of subjects performing real daily life and O&M tasks. It was administered by trained independent blind and low-vision rehabilitation therapists. The results were categorized according to the effect the Argus II System had on the subjects’ lives (both their functional vision and their well-being). Results showed that the Argus II System had a generally positive effect on a majority of subjects assessed (20 of 26, or 76%) and a neutral effect on 23% of subjects. No subjects had been negatively affected.

Two questionnaires, the Massof Activity Inventory and the Visual Quality of Life (VisQoL), did not find clear effects of the Argus II System on the daily life (Massof) or quality of life (VisQoL), primarily because these instruments have been designed and validated for patients with significantly better vision.

Figure 8. A blind subject walks along the line in an Orientation & Mobility Task trial.

Figure 9A. Average success rate across subjects (± standard error) on the “Find the Door” O&M task at yearly time points.

Figure 9B. Average success rate across subjects (± standard error) on the “Follow the Line” O&M task at yearly time points.

5. COMMERCIALIZATION In 2011, the Argus II Retinal Prosthesis System was granted CE Mark, thus becoming the first commercially-available treatment for Retinitis Pigmentosa in the world. There are currently six implanting centers in Europe and one in Saudi Arabia. Over 20 patients have been implanted with the commercial device. Several more countries and centers are being added to the program in 2013.

In February 2013, the FDA granted approval to market the Argus II System in the U.S. under the Humanitarian Use Device exemption. It is expected to be available in the U.S. to patients later in 2013. Roughly a dozen implanting centers in the US are expected to be open by the end of 2013.

6. CONCLUSIONS

Recent years have seen major advances in retinal prostheses, which are bringing hope to people with previously-untreatable disorders such as Retinitis Pigmentosa. The Argus II Retinal Prosthesis System, which has been shown to be reliable, safe, and to provide probable benefit, is currently available in the European Economic Area, Saudi Arabia, and will soon be available for commercial sale in the Unites States.

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