**4.1 Development history**

*Prosthesis*

device [56]. The Argus II device has 200 μm electrodes separated by 525 μm, which suggests a theoretical maximum VA of 20/1600. The best result, with grating acuity,

Electrode shape is a factor that may significantly affect the integration of the device by creating an environment where retinal tissue can migrate around the array and create a close interface. Arrays have been designed with sunken chambers or 'wells', into which the inner nuclear layer cells have been shown to migrate. Another approach is the three-dimensional pillar array, with protruding electrodes, designed to produce an intimate apposition between the array and the neuronal cell

Size, shape and contact of the electrode at the tissue interface are all important considerations to improve SR, but also have implications to the charge density per unit area. As the electrode size becomes smaller, there is an exponential increase in concentration of the current, which can result in target tissue damage [59]. Therefore there is an onus on finding materials that can permit the chargeinjection requirements of neural stimulation, while minimizing conduction of heat or inducing tissue degradation. In addition to this, they must be biocompatible, waterproof and remain operational over an extended lifespan. While the precise electrochemical properties of the electrode-electrolyte interface, the capacitance and charge injection limits of different electrode materials is beyond the scope of this chapter, it is worth noting that new technologies, such as nanocoating, nanotubes and conductive polymers are providing promising developments in electrode fabrication, which may offer significant advantages over the more traditional metallic designs, such as iridium, platinum or titanium-based electrodes [60–62]. The emerging field of tissue electronics, which is focused on the use of organic conductive and semi-conductive polymer alternatives to inorganic electronic systems, is rapidly advancing. Recently, long-term *in vivo* studies of a fully organic multi-layer device in rats have shown success in recovery of subcortical and cortical light responses, as well as improvements in visual behaviour [63, 64]. While current electrode devices achieve RGC stimulation by direct current injection to trigger action potentials, it appears that organic coupling occurs in a more physiological manner by modulating local neuronal neurotransmitter release through discretely varying the membrane potentials [65]. It is probable that approaches using conductive polymers, or other chemical photoswitches (e.g. photochromic molecules or photoactive nanoparticles) permit a more natural interaction with the residual neuronal environment, which, in

The Argus II epiretinal device (*Second Sight Medical Products Inc.*) was the first retinal prosthetic system to obtain CE marking (2011) and FDA approval (2013) for commercial use, and is the most widely implanted retinal prosthetic worldwide. Comprising external and implantable components, it utilizes camera-based image capture and VPU processing, with wireless data and power induction, transmitting stimulation commands to an epiretinally located microelectrode array (**Figure 3**). The Argus II system is implanted using standard pars plana vitrectomy and scleral buckling procedures, and usually the surgery includes removal of the native lens. Following removal of the vitreous and posterior hyaloid face, a conjunctival peritomy is performed and the recti muscles are isolated to allow fixation of an encircling band containing the internal coil and in-built application-specific integrated circuit. A 5 mm sclerotomy is created for insertion of the 60-microelectrode

has been reported as 20/1262 (just over 1 cpd) with this system [57].

bodies without requiring excessive remodelling of the retina [58].

theory, could achieve cellular resolution.

**4. Argus II retinal prosthesis system**

**96**

Throughout the 1990s, Humayun demonstrated that low current stimulation of dissected animal retinal tissue could produce localized retinal responses [66]. This was followed by acute epiretinal stimulation experiments of blind human volunteers, with various forms of retinal degeneration. It was shown that stimulation could elicit subjective phosphenes, which in many cases could be accurately

#### **Figure 3.**

*The components of the Argus II retinal prosthesis system (adapted with permission from Second Sight Medical Products).*

**Figure 4.** *Fundus photograph demonstrating an Argus II microelectrode array in situ.*

localized and resolved to an equivalent acuity of up to 4/200 [67, 68]. In a subsequent series of acute stimulation tests using multielectrode arrays, two patients were able to identify crude forms from discrete patterns of electrical stimulation, using 400 μm electrodes arranged in 3 × 3 or 5 × 5 grids.

These promising results led to the development of the Argus I epiretinal prosthesis, which was the first device to undergo chronic testing in 2002 in six patients with end-stage RP. The Argus I device included a 4 × 4 array, comprising 16 alternating 250 and 500 μm diameter electrodes. The initial device design was based closely on that of cochlear implants, with an electronic unit surgically positioned in a postauricular recess of the temporal bone, from where a connecting cable would be passed along a groove in the bone and communicate with the intraocularly placed array. The external camera and VPU components captured the images, which, once encoded, were wirelessly transmitted via an antenna, that was magnetically held in position over the internal electronic unit. Results showed coarse functional performance was better than chance with the device on, with one patient able to detect light, motion and simple shapes [69–71]. In another subject, it was recently shown that the device continued to elicit phosphenes sufficient to permit target localization, orientation and mobility performance better than chance with the device on, 10 years postimplantation [72]. The overall safety and longevity of the device, which demonstrated coarse functional outcomes at a safe charge density limit, led to the development of the Argus II system, with a 6 × 10 microelectrode array and an optimized surgical approach.

#### **4.2 Argus II results**

The phase II multicenter clinical trial for the Argus II retinal prosthesis system began in 2006, enrolling 28 patients with end-stage RP, one with Leber congenital amaurosis and one with choroideremia. The primary endpoints of this study were safety and visual function, while secondary assessments of functionality included activities of daily living, such as orientation and mobility [57, 73, 74].

#### **4.3 Safety outcomes**

Witinn 12 months of the start of the trial, there were 18 reported serious adverse events (SAEs) requiring intervention, occurring in 10 of the 30 implanted patients. These included three cases of presumed endophthalmitis, three cases of conjunctival dehiscence, three cases of conjunctival erosion, two cases of hyptony, two arrays requiring re-tacking and one case each of rhegmatogenous retinal detachment, tractional retinal detachment, a retinal tear, corneal opacification and an inflammatory uveitis. The majority of these SAEs (78%) took place within the first 6 months after implantation and they were clustered among the initial 15 patients (72%). The reduction in SAEs in the second half of the trial was ascribed to refinement of both the device and the implantation procedure during the study, such as inclusion of prophylactic intravitreal antibiotics to the surgical protocol. All SAEs were successfully treated; in the cases of hypotony, the subjects required silicone oil tamponade (in one case for retinal detachment), which led to stabilization of the intraocular pressure [57, 73].

At 36 months, there were five additional reported late SAEs, including two further cases of hypotony and one each of infective keratitis, corneal melt and conjunctival erosion. Within this period, only one device required explantation, due to recurrent conjunctival erosion, and no eyes were enucleated [73]. At 5 years, the latest reported time point, there was only one additional SAE, which was a successfully treated retinal detachment, resulting in a total rate of 24 reported

**99**

**Figure 5.**

*Credit: da Cruz et al. [74].*

*The Argus II Retinal Prosthesis System*

array with the retina [74].

**4.4 Functional outcomes**

*4.4.1 Visual function*

presented in **Figure 5**.

*DOI: http://dx.doi.org/10.5772/intechopen.84947*

SAEs among 12 (40%) of subjects. A total of three devices have been partially or completely removed at the request of the subjects, while a further seven subjects underwent elective repositioning during the trial to improve the contact of the

Overall, this is the largest and longest study of a retinal prosthesis system to date, demonstrating an acceptable safety profile and ongoing functionality and biocompatibility in the majority of subjects. Subsequent case series have shown

There were three objective assessments used to evaluate visual function in the study. Firstly, a 'square localization' task, which involved the subject locating a white square displayed on a black background, indicated by touching the monitor. At 1 year, 94% of subjects could perform the task better with the device on than off. This was maintained at 3 years (89%) and 5 years (80.9%). The second task was 'direction of motion', which was assessed by asking the subject to indicate the direction of a high-contrast white line as it moved across the monitor. Initially 57% of subjects performed better than chance with the device on, which was once again maintained at 3 and 5 years (56 and 50%), respectively. Of note, these two tests of visual function were not performed in all subjects at the 1-year time point, due to their introduction partway through the study. Finally visual function was assessed using, 'grating visual acuity', which consisted of randomly generated widths of black and white gratings in one of four different orientations, displayed for 5 s on a screen. Throughout the study, 27–48% of patients scored better than 2.9 logMAR equivalent (mean 2.5 logMAR), depending on time point, with 38% performing significantly better with the device on than off at year 5. The best result recorded grating acuity was 1.8 logMAR, which approximates to a Snellen acuity of 20/1262 [57, 73–75]. The results from these tests of visual function are

Dorn et al. tested the effect of providing scrambled spatial information to the device compared to one-to-one mapping, to investigate the degree to which the synchronization of multiple electrode stimulation conferred a benefit during motion detection. They found that of the 15 subjects who were able to perform the initial motion detection task better with the device on, 10 (67%) also performed better with one-to-one mapping of spatial information, than with scrambled information [76]. This suggests that the pattern of phosphenes being elicited was important for motion detection, and not that the patient was using the device to detect light, and

*Results for square localization (A), direction of motion (B) and grating visual acuity (C) at yearly time-points.* 

simply scanning with their head to determine direction.

improved safety profiles in parallel with growing surgical familiarity.

#### *The Argus II Retinal Prosthesis System DOI: http://dx.doi.org/10.5772/intechopen.84947*

SAEs among 12 (40%) of subjects. A total of three devices have been partially or completely removed at the request of the subjects, while a further seven subjects underwent elective repositioning during the trial to improve the contact of the array with the retina [74].

Overall, this is the largest and longest study of a retinal prosthesis system to date, demonstrating an acceptable safety profile and ongoing functionality and biocompatibility in the majority of subjects. Subsequent case series have shown improved safety profiles in parallel with growing surgical familiarity.

#### **4.4 Functional outcomes**

### *4.4.1 Visual function*

*Prosthesis*

localized and resolved to an equivalent acuity of up to 4/200 [67, 68]. In a subsequent series of acute stimulation tests using multielectrode arrays, two patients were able to identify crude forms from discrete patterns of electrical stimulation,

These promising results led to the development of the Argus I epiretinal prosthesis, which was the first device to undergo chronic testing in 2002 in six patients with end-stage RP. The Argus I device included a 4 × 4 array, comprising 16 alternating 250 and 500 μm diameter electrodes. The initial device design was based closely on that of cochlear implants, with an electronic unit surgically positioned in a postauricular recess of the temporal bone, from where a connecting cable would be passed along a groove in the bone and communicate with the intraocularly placed array. The external camera and VPU components captured the images, which, once encoded, were wirelessly transmitted via an antenna, that was magnetically held in position over the internal electronic unit. Results showed coarse functional performance was better than chance with the device on, with one patient able to detect light, motion and simple shapes [69–71]. In another subject, it was recently shown that the device continued to elicit phosphenes sufficient to permit target localization, orientation and mobility performance better than chance with the device on, 10 years postimplantation [72]. The overall safety and longevity of the device, which demonstrated coarse functional outcomes at a safe charge density limit, led to the development of the Argus II system, with a 6 × 10 microelectrode array and

The phase II multicenter clinical trial for the Argus II retinal prosthesis system began in 2006, enrolling 28 patients with end-stage RP, one with Leber congenital amaurosis and one with choroideremia. The primary endpoints of this study were safety and visual function, while secondary assessments of functionality included

Witinn 12 months of the start of the trial, there were 18 reported serious adverse events (SAEs) requiring intervention, occurring in 10 of the 30 implanted patients. These included three cases of presumed endophthalmitis, three cases of conjunctival dehiscence, three cases of conjunctival erosion, two cases of hyptony, two arrays requiring re-tacking and one case each of rhegmatogenous retinal detachment, tractional retinal detachment, a retinal tear, corneal opacification and an inflammatory uveitis. The majority of these SAEs (78%) took place within the first 6 months after implantation and they were clustered among the initial 15 patients (72%). The reduction in SAEs in the second half of the trial was ascribed to refinement of both the device and the implantation procedure during the study, such as inclusion of prophylactic intravitreal antibiotics to the surgical protocol. All SAEs were successfully treated; in the cases of hypotony, the subjects required silicone oil tamponade (in one case for retinal detachment), which led to stabilization of the intraocular

At 36 months, there were five additional reported late SAEs, including two further cases of hypotony and one each of infective keratitis, corneal melt and conjunctival erosion. Within this period, only one device required explantation, due to recurrent conjunctival erosion, and no eyes were enucleated [73]. At 5 years, the latest reported time point, there was only one additional SAE, which was a successfully treated retinal detachment, resulting in a total rate of 24 reported

activities of daily living, such as orientation and mobility [57, 73, 74].

using 400 μm electrodes arranged in 3 × 3 or 5 × 5 grids.

an optimized surgical approach.

**4.2 Argus II results**

**4.3 Safety outcomes**

pressure [57, 73].

**98**

There were three objective assessments used to evaluate visual function in the study. Firstly, a 'square localization' task, which involved the subject locating a white square displayed on a black background, indicated by touching the monitor. At 1 year, 94% of subjects could perform the task better with the device on than off. This was maintained at 3 years (89%) and 5 years (80.9%). The second task was 'direction of motion', which was assessed by asking the subject to indicate the direction of a high-contrast white line as it moved across the monitor. Initially 57% of subjects performed better than chance with the device on, which was once again maintained at 3 and 5 years (56 and 50%), respectively. Of note, these two tests of visual function were not performed in all subjects at the 1-year time point, due to their introduction partway through the study. Finally visual function was assessed using, 'grating visual acuity', which consisted of randomly generated widths of black and white gratings in one of four different orientations, displayed for 5 s on a screen. Throughout the study, 27–48% of patients scored better than 2.9 logMAR equivalent (mean 2.5 logMAR), depending on time point, with 38% performing significantly better with the device on than off at year 5. The best result recorded grating acuity was 1.8 logMAR, which approximates to a Snellen acuity of 20/1262 [57, 73–75]. The results from these tests of visual function are presented in **Figure 5**.

Dorn et al. tested the effect of providing scrambled spatial information to the device compared to one-to-one mapping, to investigate the degree to which the synchronization of multiple electrode stimulation conferred a benefit during motion detection. They found that of the 15 subjects who were able to perform the initial motion detection task better with the device on, 10 (67%) also performed better with one-to-one mapping of spatial information, than with scrambled information [76]. This suggests that the pattern of phosphenes being elicited was important for motion detection, and not that the patient was using the device to detect light, and simply scanning with their head to determine direction.

#### **Figure 5.**

*Results for square localization (A), direction of motion (B) and grating visual acuity (C) at yearly time-points. Credit: da Cruz et al. [74].*

### *4.4.2 Orientation and mobility*

In the phase II clinical trial, two tests of orientation and mobility were employed. The first involved locating a simulated black door on a white background across the room. The second consisted of the subject following a 6-inch-wide white line on the floor, either configured as a straight line, or with a 90° turn along its length. Successful performance was maintained at ~50 and 70% in each respective task with the device on, which was significantly better than 15–30% success with the device off [57, 73, 74]. Dagnelie et al. found a similar rate of performance success using a real world 'sidewalk tracking' test in 27 implanted subjects, showing that 67% performed above chance with the device on, compared to 22% with the system off [77]. **Figure 6** illustrates the testing environments for orientation and mobility tasks.

#### *4.4.3 Shape and object recognition*

Arsiero et al. demonstrated, among implanted subjects, recognition of eight simple, solid, white shapes on a black background was significantly better the device on (31%) than off (13%), which improved further to 57% when the shapes were presented as outlines [79]. Luo et al. built upon this, presenting seven implanted subjects with eight high-contrast everyday items, both in the solid and outlined forms. It was found that subjects could identify solid objects to the same degree of accuracy with the device on as they could with the device on in the scrambled mode. Although superior to having the device off, this suggested that subjects were relying on visual cues other than the form presented but the array stimulation pattern. When the shapes were presented in their outlined forms, this significantly improved performance with the device on, above either that of the scrambled mode or with the device off [80].

Another real-world task described by Dagnelie et al., consisted of a 'sock sorting' task, in which subjects were asked to sort a randomly arranged collection of 10 black, 10 white and 10 grey socks into separate piles, according to colour. Each test was performed on a wooden table, or on a background of the subject's choice (i.e. black or white). In both scenarios, the subjects performed significantly better on average with the device on than off [77].

#### *4.4.4 Letter reading*

In a study of 21 implanted subjects, da Cruz et al. studied functional form vision by assessing ability to discriminate high-contrast letters. Letters were grouped according to typographical complexity and randomly displayed on a computer

#### **Figure 6.**

*Photographs of subjects performing door finding (A), line tracking (B) and sidewalk tracking (C) tasks. Credit: Humayun et al. [78], Dagnelie et al. [77].*

**101**

**Figure 7.**

*et al. [82].*

*The Argus II Retinal Prosthesis System*

theoretical limit of the system.

**4.5 Patient-reported outcomes**

*4.4.5 Prehension tasks*

the real-world.

*DOI: http://dx.doi.org/10.5772/intechopen.84947*

screen. Measurements from all subjects revealed a correct identification of 72% of group A (least complex) letters, presented at 30 cm, such that they subtended a visual angle of 41.27°. In the study, 19 and 20 subjects respectively completed the group B and group C letters, correctly identifying 55 and 52% in each instance. In all cases, performance was significantly better with the device turned on than off. A subset of six subjects who identified more than 50% of group A letters in fewer than 60 s went on to complete tests to assess the minimum letter size that could be resolved, while four of these six subjects were also assessed for performance on 2-, 3- and 4-letter word identification. The minimum letter size correctly identified was 0.9 cm, subtending a visual angle of 1.7°. On average, four subjects could identify 6.8 out of 10 words, ranging from 11 to 20 cm in height. In all cases, the performance was significantly better when the device was switched on in standard mode, than when scrambled or off [81]. These results are very promising for the capacity of some patients to achieve good spatial resolution, approaching the

In a series of experiments using a 3D motion-capture system, Luo et al. measured the ability of five subjects to grasp a white block on a black table (**Figure 7**). With the device turned on, subjects would successfully initiate and complete a grasping action 74% of the time, compared to 0% with the device off [82, 83]. Unlike other object recognition tasks, this study suggests a good capacity for the system to permit performance of hand-eye coordination tasks in a 3D environment, similar to that of

An important consideration in visual restoration is the extent to which the recipients judge the system to be beneficial in everyday life. The Functional Lowvision Observer Rated Assessment (FLORA) was developed by Geruschat et al. in order to evaluate the impact of partial restoration of ultra-low vision in subjects undergoing Argus II implantation. Initial results using the FLORA tool demonstrated that it was able to provide useful information about the everyday functional benefit of prosthesis-derived visual restoration, as well as identifying areas in which rehabilitation could be utilized to maximize subjective value. At 1 year, the assessment demonstrated an 80% reported positive effect, which dropped to 65% at 3 years. No patients reported a negative effect using this self-reporting tool [84, 85].

*Subject performing prehension task (a) with live infrared motion capture of subject's hand (b). Credit: Luo* 

#### *The Argus II Retinal Prosthesis System DOI: http://dx.doi.org/10.5772/intechopen.84947*

*Prosthesis*

mobility tasks.

*4.4.2 Orientation and mobility*

*4.4.3 Shape and object recognition*

scrambled mode or with the device off [80].

average with the device on than off [77].

*4.4.4 Letter reading*

In the phase II clinical trial, two tests of orientation and mobility were employed. The first involved locating a simulated black door on a white background across the room. The second consisted of the subject following a 6-inch-wide white line on the floor, either configured as a straight line, or with a 90° turn along its length. Successful performance was maintained at ~50 and 70% in each respective task with the device on, which was significantly better than 15–30% success with the device off [57, 73, 74]. Dagnelie et al. found a similar rate of performance success using a real world 'sidewalk tracking' test in 27 implanted subjects, showing that 67% performed above chance with the device on, compared to 22% with the system off [77]. **Figure 6** illustrates the testing environments for orientation and

Arsiero et al. demonstrated, among implanted subjects, recognition of eight simple, solid, white shapes on a black background was significantly better the device on (31%) than off (13%), which improved further to 57% when the shapes were presented as outlines [79]. Luo et al. built upon this, presenting seven implanted subjects with eight high-contrast everyday items, both in the solid and outlined forms. It was found that subjects could identify solid objects to the same degree of accuracy with the device on as they could with the device on in the scrambled mode. Although superior to having the device off, this suggested that subjects were relying on visual cues other than the form presented but the array stimulation pattern. When the shapes were presented in their outlined forms, this significantly improved performance with the device on, above either that of the

Another real-world task described by Dagnelie et al., consisted of a 'sock sorting' task, in which subjects were asked to sort a randomly arranged collection of 10 black, 10 white and 10 grey socks into separate piles, according to colour. Each test was performed on a wooden table, or on a background of the subject's choice (i.e. black or white). In both scenarios, the subjects performed significantly better on

In a study of 21 implanted subjects, da Cruz et al. studied functional form vision

*Photographs of subjects performing door finding (A), line tracking (B) and sidewalk tracking (C) tasks. Credit:* 

by assessing ability to discriminate high-contrast letters. Letters were grouped according to typographical complexity and randomly displayed on a computer

**100**

**Figure 6.**

*Humayun et al. [78], Dagnelie et al. [77].*

screen. Measurements from all subjects revealed a correct identification of 72% of group A (least complex) letters, presented at 30 cm, such that they subtended a visual angle of 41.27°. In the study, 19 and 20 subjects respectively completed the group B and group C letters, correctly identifying 55 and 52% in each instance. In all cases, performance was significantly better with the device turned on than off. A subset of six subjects who identified more than 50% of group A letters in fewer than 60 s went on to complete tests to assess the minimum letter size that could be resolved, while four of these six subjects were also assessed for performance on 2-, 3- and 4-letter word identification. The minimum letter size correctly identified was 0.9 cm, subtending a visual angle of 1.7°. On average, four subjects could identify 6.8 out of 10 words, ranging from 11 to 20 cm in height. In all cases, the performance was significantly better when the device was switched on in standard mode, than when scrambled or off [81]. These results are very promising for the capacity of some patients to achieve good spatial resolution, approaching the theoretical limit of the system.
