Artificial Vision

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Chapter 126 Artificial Vision

Mark S. Humayun, Rodrigo A. Brant Fernandes, James D. Weiland

Introduction

More than 1 million Americans are legally blind and 10% have no light perception, from various causes.¹ Certain experimental approaches, such as gene (see Chapter 34, Gene therapy) and drug therapy may be a preventative or therapeutic option.^2,³ However, once photoreceptors are nearly completely lost, such as in end-stage retinitis pigmentosa (RP) (see Chapter 40, Retinitis pigmentosa and allied disorders) or age-related macular degeneration (AMD) (see Chapters 63–66 on epidemiology/risk factors for AMD, pathogenesis, and diagnosis and treatment of dry and wet AMD, respectively), very few approaches⁴ can restore useful vision to blind patients. Retinitis pigmentosa (RP) is the leading inherited cause of blindness with 1.5 million people worldwide affected and an incidence of 1/3500 live births.⁵ Also, AMD is the leading cause of visual loss among adults older than 65, with 700 000 newly diagnosed patients annually in the USA, 10% of whom become legally blind each year.⁶ With an increased mean lifespan, particularly in the developing world, the number of people with age-related eye disease and resulting visual impairment is expected to double during the next three decades.⁷

Few treatment options exist for outer retinal degeneration. The advent of the anti-VEGF therapy has shown effectiveness for neovascular-AMD patients. This therapy is capable of preventing visual loss and even returning vision to patients treated in the initial phases.⁸^–¹⁰ The therapeutic agents inhibit the growth of new blood vessels in the retina. Nevertheless, like most new therapies, it has limitations and drawbacks and there is some evidence that there is disease progression in spite of injections, especially in polypoidal choroidal vasculopathy.¹¹ Moreover, a number of patients seek consultation when the neovascularization is advanced and hence irreversible vision loss has already occurred. Non-neovascular AMD can also become advanced leading to atrophic AMD (e.g., geographic atrophy). Other than the Age Related Eye Disease Study (AREDS) trial showing benefit for non-neovascular AMD patients receiving a formula containing high levels of antioxidants and zinc (500 mg of vitamin C; 400 IU of vitamin E; 15 mg of beta-carotene; 80 mg of zinc as zinc oxide; and 2 mg of copper as cupric oxide),¹² there have been no other approved therapies, albeit many companies are trying to develop a therapy for this slowly progressive variant of AMD. Although gene therapy has not become a proven therapy in AMD, gene therapy has shown some success in Leber’s congenital amaurosis by targeting a specific mutation of the RPE65 gene.¹³^–¹⁶ This is a tremendous scientific breakthrough for this retinal degeneration, despite the fact that the total number of eligible patients is small in number (approximately 1000). Neither anti-VEGF nor many of the proposed pharmacological treatments or gene therapy can address vision lost due to photoreceptor loss, since photoreceptors are not regenerated by these approaches.

This chapter will briefly summarize the history and evolution of electronic visual prostheses, with an emphasis on retinal implants, and will present the current state of the field with remaining challenges that lie ahead.

Background and history of artificial vision

The concept of electrically stimulating the nervous system to create artificial vision was first introduced in 1929, when Foerster, a German neurosurgeon, observed that electrical stimulation of the visual cortex caused his subject to detect a spot of light (phosphene). He further demonstrated that the spatial psychophysical location of this phosphene depended upon the location of the electrical stimulation point over the cortex.¹⁷ The first serious effort (by today’s standards) of establishing an electrical artificial vision system was undertaken less than 50 years ago by Giles Brindley. Brindley’s implantation of an 80-electrode device onto the visual cortex of a blind patient revealed the possibilities of electrical stimulation to restore vision and the barriers to implementation of a suitable device. Brindley’s pioneering work has influenced all subsequent major efforts in the area of electronic visual prostheses. In the past 50 years, exponential advances in our understanding of electronics, physiology, and medicine have enabled the development of implantable microelectronic systems that overcome the shortcomings of Brindley’s large, immobile visual stimulator.¹⁸

Examples of such advances have been noted in the fields of electrical engineering, computer sciences, and micromachining technology. For instance, very large-scale integration (VLSI) circuits and microelectromechanical systems (MEMS) technology have all contributed to the evolution of the field of visual prostheses by allowing for the creation of both smaller electronics and smaller neural interfaces. These technological advancements, coupled with recent scientific investigations, have transformed the focus of the field from that of whether it is possible to create visual sensations through electrical stimulation to the more important question of how to optimize the perceptions for maximum benefit. Current questions being considered are related to the quality of images created by stimulation of many small areas of neuronal tissue as well as the mechanical and electrical biocompatibility of the microelectronic implants.

Whether useful vision can be rendered via artificial visual prostheses depends upon establishing a definition of useful vision that is based on the minimum number of pixels required for human beings to accomplish activities of daily living. Several researchers have completed psychophysical experiments designed to determine the minimum acceptable resolution for useful vision. Brindley originally suggested that 600 points of stimulation (pixels) would be sufficient for reading ordinary print.¹⁸ More recent studies have tested humans with normal visual function by pixelating their vision via a portable phosphene simulator, consisting of a small head-mounted video camera and monitor. Patients then walked through an obstacle course and read pixilated text. In this fashion, it was determined that 625 electrodes implanted in a 1 cm² area near the foveal representation in the visual cortex could produce a phosphene image with a visual acuity of approximately 20/30 and reading rates near 170 words/minute with scrolled text and 100 words/minute with fixed text.¹⁹^–²¹ Further, a degree of learning was noted as walking speeds increased five-fold during 3 weeks of training.²⁰

Studies simulating electrodes placed over the entire macula rather than a foveal pixelization have assessed the ability of subjects to recognize faces through a pixilated square grid. Parameters included grid size (10 × 10 to 32 × 32 dots), dot size, gap width, dot dropout rate, and gray scale resolution. The subjects achieved highly significant facial recognition accuracies in both high- and low-contrast tests with a marked learning effect documented. These results suggest that reliable facial recognition is possible even with crude visual prostheses, and possibly makes the task of engineering the implant easier as it would require fewer data/stimulation channels.²¹ The ability of subjects to read using a pixilated visual simulator has been evaluated in a separate cohort which demonstrated that most subjects are able to read fonts as small as 36 point (with all at 57 point) using a 16 × 16 pixel array.^22,²³

Visual prostheses

Visual prostheses are based on neuronal electrical stimulation at different locations along the visual pathway (i.e., cortical, optic nerve, epiretinal, subretinal). Each of the different approaches will be discussed. In terms of retinal prostheses, advances in microtechnology have allowed for the development of sophisticated implantable stimulators that interface to retina either in the subretinal or epiretinal space. Analogous to the cochlear implants for some forms of deafness, these devices propose to restore useful vision by converting visual information into patterns of electrical stimulation that would excite the remaining inner retinal neurons in diseases such as retinitis pigmentosa and age-related macular degeneration. However, the approach in the visual system is more complex than in the auditory system. In the retina, information processing occurs even at the synapse between photoreceptor and bipolar cells. The pattern of activity in ganglion cells is a non-linear representation of photoreceptor cell excitation. In addition, the retina has 100 million receptors, compared with 15 000 hair cells in the cochlea. While experience from cochlear implants has surely benefited the development of retinal prostheses, the relative complexity of the visual system presents challenges to researchers attempting visual prostheses. In this chapter, the different types of implants, their position in the visual system and recent results are discussed, but special emphasis is given to retinal implants.

Cortical prosthesis

Building upon earlier observations of phosphene perception with cortical stimulation, Brindley and Dobelle began work in the 1960s towards functional, visual cortex prosthesis. They demonstrated the ability to evoke phosphenes and patterned perceptions by electrically stimulating the occipital cortex via permanently implanted electrodes.^18,²⁴^–³⁰ Both researchers implanted arrays with over 50 electrodes subdurally over the occipital pole, thus providing evidence of the ability to return the sensation of vision to individuals who had severed visual pathway anterior to the visual cortex. Dobelle’s 64-channel platinum electrode surface stimulation prosthesis allowed blind patients to recognize 6-inch characters at 5 feet (approximately 20/1200 visual acuity).^28,^29,³¹ Difficulties encountered in these experiments included the following: (1) controlling the number of phosphenes induced by each electrode; (2) interactions between phosphenes; (3) use of high currents and large electrodes that induced pain from meningeal stimulation; and (4) occasional focal epileptic activity following electrical stimulation.^28,^32,³³ Patients in these initial experiments complained of not being able to appreciate distinct phosphenes, but rather reported seeing “halos” surrounding each phosphene.³⁴

Since most of the visual cortex is deep within the calcarine fissure and inaccessible to cortical surface electrodes, intracortical stimulation was introduced in hopes of remedying the shortcomings of surface cortical stimulation via a lower-current, higher-fidelity system. The intracortical devices employed smaller electrodes closer to the target neurons, thus requiring less current and resulting in a more localized stimulation. The stimulus threshold is 10–100 times lower for intracortical prosthesis as compared to surface stimulation. Further, this approach allows for closer spacing of electrodes at 500 µm apart and thus possibly higher resolution. Initial studies, during which the intracortical prosthesis was implanted in humans for a period of 4 months, demonstrated the ability to produce phosphenes which usually had color.³⁵ Documented advantages of the intracortical versus surface cortical implants include: (1) predictable forms of elicited phosphenes; (2) absence of flicker phenomenon; (3) reduction in phosphene interactions: (4) increased number of electrodes; (5) reduced overall power requirement.^33,³⁵^–³⁷

Current models of the intracortical prosthesis include the Utah electrode array. This device consists of multiple silicon spikes organized in a square grid measuring 4.2 mm by 4.2 mm.³⁶ A platinum electrode is at the tip of each spike. A pneumatic system, which inserts 100 electrode devices into the cortex in about 200 ms, is required for minimal trauma during insertion of this array.³⁸ The cortical visual prosthesis is advantageous over other approaches because it bypasses all diseased visual pathway neurons rostral to the primary visual cortex. As such, this approach has the potential to restore vision to the largest number of blind patients.

There are some limitations to the cortical visual prostheses. First, histologic changes for chronically implanted prostheses need to be further investigated.³⁹^–⁴¹ In the case of silicon-doped penetrating electrodes, tissue reaction has ranged from none to a thin capsule around each electrode track to gliosis and buildup of fibrotic tissue between the array and meninges.⁴² Second, the organization of the visual field is markedly more complex at the level of the primary cortex than at the retina or optic nerve and is not easily reproducible between various patients.³⁴ Next, there is a high level of specialization of every area of cortex for various parameters including color, motion, and eye movement, making it unlikely to garner simple phosphenes from stimulation.⁴³ Finally, surgical complications of this approach carry significant morbidity and mortality for the patient. The future success of the intracortical prosthesis requires further investigation of these areas.

Optic nerve prosthesis

Investigators have targeted the optic nerve as a potential site for the implementation of a visual prosthesis.^44,⁴⁵ Veraart et al. was the most recent of such groups attempting this method, employing the concept of a spiral nerve cuff electrode.⁴⁶^–⁴⁹ Essentially, an electrode cuff is surgically implanted circumferentially on the external surface of the optic nerve. As this device does not penetrate the optic nerve sheath, it relies on the principle of retinotopic organization within the optic nerve. One group has recently implanted a chronic, self-sizing cuff with four electrodes into a human patient.⁵⁰ Preliminary reports have demonstrated that electrical stimulation of the optic nerve produces colored phosphenes broadly distributed throughout the visual field.^46,⁵¹

The optic nerve is an appealing site for the implementation of a visual prosthesis, as the entire visual field is represented in a small area. This area can be reached surgically and presents a viable anatomic location for an implant; however, there are several hurdles to overcome regarding this approach. First, the optic nerve is a densely consolidated neural structure with approximately 1.2 million axons in a 2-mm-diameter cylinder. While this allows for the entire visual field to be represented in a relatively small area, it is difficult to achieve focal stimulation of neurons, and to garner the exact retinotopy of the optic nerve. The dense packing of neurons requires a large number of electrode contacts from the prosthesis in a small area, increasing the risk of damage to the nerve.⁵² Surgical manipulation of this area requires dissection of the dura mater, creating possible harmful CNS effects including infection and possible interruption of blood flow to the optic nerve. Fourth, intervention at this point within the optic pathway requires intact retinal ganglion cells (RGC) and therefore is limited to the treatment of outer retinal (photoreceptor) degenerations. The optic nerve and RGC represent higher-order structures than the bipolar cells targeted by the retinal prosthesis. As such, the processing power of the bipolar, horizontal, and amacrine cells is lost and therefore much more image processing must be achieved by the implant rather than relying on intact human physiologic pathways. Last, the nerve fibers from the macula lie most centrally within the optic nerve. Cuff electrodes, thus, are farthest away from macular fibers and this will dramatically limit the use of this approach especially for AMD as the peripheral fibers will get stimulated along with the central macular fibers. Future development of this technology must address the above issues. Investigators have also proposed intraneuronal stimulation devices in order to more accurately target individual neurons within the optic nerve.⁵³

Veraart et al. published results of an optic nerve prosthesis implanted in a patient. A volunteer with retinitis pigmentosa and no residual vision was chronically implanted with an optic nerve electrode connected to an implanted neurostimulator and antenna. An external controller with telemetry was used for electrical activation of the nerve that resulted in phosphene perception. Open-loop stimulation allowed the collection of phosphene attributes and the ability to elicit perception of simple geometrical patterns. Low perception thresholds allowed for large current intensity range within safety limits. In a closed-loop paradigm, the volunteer was using a head-worn video camera to explore a projection screen. The volunteer underwent performance evaluation during the course of a training program with 45 simple patterns. Multiple bars (each 320 × 22 mm when projected on a screen) were combined to form letters on a 1 × 1 m screen, with the patient at 0.5 m from the screen. After learning, the volunteer reached a recognition score of 63% with a processing time of 60 seconds. The results were encouraging in that the blind volunteer was able to adequately interact with the environment while demonstrating pattern recognition and a learning effect for processing time and orientation discrimination.⁵⁴

Retinal prostheses

Pathology of retinitis pigmentosa and selected macular disorders

Whereas the above prostheses are potentially useful for patients who have compromised visual pathways posterior to the retina, a microelectronic retinal implant is suitable for cases in which the patient is affected by an outer retinopathy as with RP or AMD. Potts and Inoue, some 40 years ago, demonstrated the ability to evoke an electrically elicited response (EER) via ocular stimulation using a contact lens as a stimulating electrode.⁵⁵^–⁵⁷ This discovery was expounded upon by Knighton, who demonstrated that inner retinal layers could be electrically stimulated and would elicit an EER.^58,⁵⁹

For a retinal prosthesis to function properly, the retina must not be affected by disease to the point where not enough viable cells remain to initiate a neural signal. Postmortem morphometric analysis of the retina of patients with end-stage RP has revealed that 78.4% of inner nuclear and 29.7% of ganglion layer cells were retained compared to only 4.9% of photoreceptors.^6,⁶⁰^–⁶³ Also, 93% of RGC were spared and an increase in inner nuclear layer cells (by 10%) were noted in legally blind neovascular AMD patients.^64,⁶⁵ Furthermore, no statistical significance was noted between non-neovascular eyes with geographic atrophy and age-matched controls.^64,⁶⁵ This demonstrates limited transsynaptic neuronal degeneration in the aforementioned retinopathies, and as such, it is theoretically possible to electrically stimulate the remaining retinal neurons to elicit useful visual perceptions. It is important to understand the stages of outer retinal degeneration and the associated anatomical and physiological changes that occur. A comprehensive study has been done by Marc, in which three phases of degeneration and remodeling are classified.⁶⁶ In the first two phases, photoreceptor stress and death and associated loss of tropic transport are observed. Both bipolar and horizontal cells can actually retract dendrites, while the latter can sprout axonal and dendritic processes that can reach the inner plexiform layer. Müller cells can form a dense fibrotic layer and seal off the subretinal space, electrically isolating implants placed there via the choroid. In phase 3, the number of viable cells of all classes is depleted. Bipolar and amacrine cells can migrate up to the ganglion cell layer and undergo neural rewiring.

Such anatomical changes manifest physiologically. Using a patch clamp technique in a degenerate mouse model, it has been shown that rod bipolar cells lose their sensitivity to the excitatory neurotransmitter glutamate while they increase their response to the inhibitory horizontal cell neurotransmitter GABA.⁶⁷ Thus, the retinal circuitry is altered both anatomically and physiologically by degeneration.

In spite of these well-documented changes in the inner retina after photoreceptor loss, numerous studies have established the safety and efficacy of electrical stimulation of the retina. Early studies by Humayun and colleagues ⁶¹^–⁶⁴ established the feasibility of electrical stimulation of the retina. In an operating room setting, hand-held electrodes were inserted into the eye of blind test subjects. The test subjects reported the appearance of small spots of light when the electrodes were activated. The apparent location of the spot of light in general corresponded with the retinal area stimulated. Similar experiments were repeated by other groups.^68,⁶⁹ While these experiments only allowed a few hours of testing in each subject, the critical findings led to the development of chronic implant system.

Epiretinal prostheses

Epiretinal implants rely on imaging devices such as a camera and then transform this visual information to patterns of electrical stimulation to excite remaining retinal neurons. Designs tend to vary in terms of how much required electronic circuitry is contained in an intraocular device versus extraocular elements. Power sources and signal transmission may be accomplished by induction coils, penetrating wires, or lasers.

The advantages of the epiretinal approach include the following: (1) the epiretinal placement allows for the vitreous to act as a sink for heat-dissipation from the microelectronic device; (2) a minimal number of microelectronics are incorporated into the implantable portion of the device; (3) the wearable portion of electronics allows for easy upgrades without requiring subsequent surgery, and (4) the electronics allow the user and the doctor full control over every electrode and image processing parameters, allowing the implant to be customized for each patient. The disadvantages to this approach include: (1) requirement of techniques that will provide prolonged adhesion of the device to the inner retina, and (2) further distance of the epiretinal device to the target bipolar cells than the subretinal device requires increased current.

ARGUS I

The ARGUS I System consists of a 16-channel stimulator, similar in size to Advanced Bionics Clarion, positioned behind the ear, and attached to a cable that terminates at an electrode array on the epiretinal surface. The electrode array is a 4 × 4 grid of platinum disk electrodes, either 260 µm or 520 µm in diameter. The overall size of the ARGUS I array is 3 × 3 mm. An inductive coil link is used to transmit power and data to the internal portion of the implant from an external video processing unit (VPU) and a miniature camera is mounted on a pair of glasses. The video camera captures a portion of the visual field and relays the information to the VPU. The VPU digitizes the signal in real-time, applies a series of image processing filters, down samples the image to a 4 × 4 pixilated grid, and creates a series of stimulus pulses based on pixel grayscale values and lookup tables customized for each subject. The data are delivered via an inductive RF coil link and the application-specific circuitry to the pulse generator.

The surgical procedure for the ARGUS I system requires a botulinum toxin injection 2 weeks prior to the surgery, in the superior, inferior, medial, and lateral rectus muscles of the test subject, due to the concern that the subject’s eye movement might break the cable connecting the intraocular electrode array to the extraocular electronic case.

At 2 weeks later, under general anesthesia, the implant is placed in a recess well created in the temporal skull, the same way it is done for the cochlear implants.⁷⁰

To secure and protect the cable, a shallow groove is created along the temporal skull. The cable is then placed in the groove and delivered through a lateral canthotomy into the periocular space. Next, the cable and electrode array are implanted under the four rectus muscles. A complete pars plana vitrectomy is performed and the array introduced to the eye through a 5-mm circumferential scleral incision placed 3 mm posterior to the limbus. The array is placed temporal to the fovea and a single retinal tack inserted to secure the array in place.⁷¹ A clinical trial of the ARGUS I device began in 2002 and enrolled six RP patients.

Subjects were able to discriminate between different percepts, identify everyday objects such as a knife, a plate or a cup, and detect the direction of motion. Perceptual thresholds were within safe limits and were stable over time.^72,⁷³ Perceptual thresholds correlated with separation (i.e., lift-off) between the electrode array and the retina.^73,⁷⁴ In addition, increasing frequency of pulses lowered the charge per pulse in a predictable way.⁷⁵

The best visual acuity using the ARGUS I was the maximum allowable by the spacing of electrodes on the array (i.e., 20/4000), but this was only demonstrated in one test subject.⁷⁶ Adverse events included erosion of the conjunctiva over the cable at the sclerotomy and detachment of one array after one subject incurred blunt ocular trauma (subsequent re-tacking was successful).

ARGUS II

The ARGUS II System (Fig. 126.1) uses an external camera system very similar to ARGUS I, but the implanted part of the device is completely different. The ARGUS II System comprises an encircling band (sclera buckle), an inductive coil and a case containing the electronic components attached to the band, and an integrated ribbon cable and electrode array. The electrode array spans 20° of visual field corner-to-corner. All components fit inside the orbit. The dimensions of the ARGUS II are as follows: electronics case: height, 3.2 mm, diameter, 10.29 mm; receiving coil: height, 16.33 mm, width, 9.7 mm; wire diameter, 0.25 mm; two layers of winding; electrode array 5.5 mm wide and 6 mm long; electrode cable: length, 53.1 mm; width, 1.9 mm.

Fig. 126.1 ARGUS II System. (A) Schematics of the ARGUS II system and the eye. (B) ARGUS II 60 electrode array placed in the surface of the retina with tack in place.

The implantation procedure is similar to a pars plana vitrectomy with encircling buckle. The device is placed under the four rectus muscles, with the implanted electronic components sutured on the superior temporal quadrant, with the anterior edge of the case 7 mm posterior from the limbus, and sutures around the encircling band on the other four quadrants. The cable and array are then inserted through a 5-mm incision at 3.5 mm posterior to the limbus. After the incision is sutured watertight, the array is them tacked to the retinal surface. The optimal placement of the array is over the macular area. External components of the system are similar to ARGUS I and the basis of operation is the same.

The ARGUS II is being evaluated in a single-arm, prospective, multicenter clinical trial. A total of 30 subjects were enrolled between June 2007 and August 2009 at 10 clinical centers.⁷⁷ The electrode array extends across 20° of visual field, measured from corner to corner. All subjects were able to perceive light during electrical stimulation. Experiments documented improvement in object localization. Using a target of a 7 cm white square on a black LCD screen at 30 cm distance, 27 out of 28 subjects (96%) performed better in localizing the object with System ON versus OFF, and no subjects performed significantly better with the System OFF.⁷⁵ Motion detection was also improved, but to a lesser extent as this is a more difficult task. Using a target of a white bar moving across a black LCD screen, 16 out of 28 subjects (57%) performed this test better with the System ON versus OFF.⁷⁷ Some subjects report the perception of color, which can be reliably produced under certain conditions.

All subjects’ acuity was measured at worse than 2.9 logMAR in both eyes before implantation. To date, none of the subjects have been able to reliably score on the visual acuity scale in either eye with the System OFF. Seven subjects have been able to reliably score on the scale with the System ON in at least one follow-up time point. The best result to date is 1.8 logMAR (equivalent to Snellen 20/1262).⁷⁷

Letter reading was tested in 22/30 subjects. Six of these subjects were able to identify any letter of the alphabet at a 63.5% success rate (versus 9.5% with the system off). In all 22 subjects, a small set of eight letters was identified 72.5% correctly, versus 16.8% with the system off. Subjects were free to take as much time as needed to make a judgment. Subjects provided answers after 100 seconds in the full alphabet and 44 seconds in the limited letter set.⁷⁸ Some subjects were able to put the letters together into words and read sentences.⁷⁹

Most subjects had no serious adverse events (SAE) and none had any unanticipated adverse events. Of the 30 subjects, 21 subjects (70%) had no SAEs. Three subjects experienced conjunctival erosion due to the extraocular device, this being the most common SAE. All but one was successfully repaired. One device needed to be explanted and this was accomplished without any complications. Other SAEs included three cases of endophthalmitis; each was treated with intravitreal antibiotics and the devices were not explanted and remain functional. There were three cases of hypotony that were resolved with surgical intervention. There was one intraoperative tear treated successfully during surgery with laser retinopexy and two retinal detachments that required subsequent surgery to reattach the retina.⁸⁰

Based on these results, and manufacturing details provided by Second Sight Medical Products Inc., the ARGUS II received a CE Mark in March 2011, making it the first retinal implant to be sold as a medical device in Europe. This is a major milestone in the field of artificial vision and will allow many more patients to be implanted and allow further post-market studies.

Intelligent Medical Implants (IMI, Bonn) is developing an active epiretinal prosthesis. The electronics are located in the same location as the ARGUS II implant.⁸¹ The device has 49 electrodes and fits entirely inside the orbit. Inductive coupling is used for power and an optical link is used for data. The IMI group has published its surgical approach in animals as well as acute testing procedures and results.

The acute testing surgery was performed under subconjunctival anesthesia. The four eye muscles were fixed, and a pars plana vitrectomy with complete removal of the vitreous and posterior hyaloid were performed. Afterwards, the electrodes were introduced into the eye using one of the sclerotomies with the MESE 12 system (Fig. 126.2). The MESE 12 system is a hand-held surgical instrument for controlled positioning of a microcontact film (BSA) on the surface of the retina. The system must be held by the surgeon during the entire procedure.

Fig. 126.2 MESE 12 hand-held system.

The main findings of the chronic implant clinical trial are low thresholds to elicit visual perceptions including form vision and that the implant is reasonably well tolerated by the eye. The device was only activated in the clinic and directly controlled by computer (i.e., no camera). Most implants were removed after a few months, but some have stayed in place for several years. Thresholds in one subject were measured for an extended period and ranged from 8.0 and 35.9 nC (i.e., single µA of current) and were reported as stable over an extended period of testing.⁸² The subjects report that the phosphenes have different appearances, point-to-point relative location is possible, and simple shapes such as a horizontal bar are recognized when presented.⁸³

Epi-Ret is the third group developing an active epiretinal prosthesis and the group has implanted six test subjects with implants in 2006. This unique implant is designed to fit entirely inside the eye yet has a provision for external power via an inductive wireless link. The electrode array has 25 electrodes that are slightly protruding from the substrate (Fig. 126.3).

Fig. 126.3 Fundus photos of all 6 chronic implants to date. (A) White arrow shows Artificial Silicon Retina (courtesy from Optobionics/ASR. Dr John Pollack), (B) ARGUS I (courtesy from Second Sight Medical Products, Inc.), (C) Active Subretinal Device (courtesy from Retina Implant, GmbH, Prof. Eberhart Zrenner), (D) Epi-ret 25 electrode device (courtesy from Prof. Peter Walter), (E) 49 electrode epiretinal device (courtesy from Intelligent Medical Implants, Prof. Gisbert Richard), (F) ARGUS II (courtesy from Second Sight Medical Products, Inc.).

The implantation surgical procedure requires a pars plana vitrectomy and the removal of the lens or in the case of pseudophakic patients, the removal of the intraocular lens (IOL) and the capsular remnants. An 11-mm corneoscleral incision is performed for the insertion of the device, and transscleral 10.0 sutures are utilized for the stabilization and placement of the inductive coil and electronics module right behind the iris, resembling an IOL scleral fixation. A micro cable acts as a substrate for microelectronic components, but its flexibility allows it to bend, following the eye curvature. After the corneoscleral incision is closed the stimulation electrodes are fixed on the surface of the retina with two retinal tacks.

The explantation procedure leaves the tacks in place, only considering removal when the tacks are already loose, and utilizes SF₆ gas at 20% for tamponade. At 6 months after explantation, some adverse effects were observed, as gliosis around tacks and epiretinal membranes.⁸⁴ These investigational implants were only in place for 28 days, which did not allow extensive testing. Consistent with the other epiretinal implant studies, low perceptual thresholds (i.e., single µA of current) were reported.⁸⁵ The implantation and explantation of the device were successful. Exams during implantation showed that the device remained in position for the entire implant period. Exams 6 months after explantation showed only some proliferation around the retinal tacks, which were left in place.⁸⁶

Subretinal prosthesis

The subretinal approach to the retinal prosthesis involves implanting a microphotodiode array between the bipolar cell layer and retinal pigment epithelium. This is accomplished surgically either via an intraocular approach through a retinotomy site (ab interno) or a transscleral approach (ab externo).

The subretinal prosthesis, using microphotodiodes (solar cells) alone as a powering mechanism, offers an attractive solution to enhance the vision of patients affected by RP and AMD.⁸⁷ However, several limitations currently hinder this technology from realizing its goal of being a visual prosthesis. Of primary concern is the inefficiency of current photodiode technology.⁸⁸ The illumination levels required in order to achieve adequate electrical current generation are not realistically attainable as the solar cells will need to generate electrical energy many orders of magnitude greater than that which is currently viable.⁸⁹^–⁹²

This limitation jeopardizes the passive, all-inclusive nature of the subretinal prosthesis, which more than likely will require active power supplementation from an external source in order to achieve threshold current levels. Because a device based solely on microphotodiodes (solar cells) is very unlikely to be a prosthetic in the sense that it directly produces phosphenes via electrical stimulation, this section will only focus on subretinal prostheses that have enough power to function as such. A clinical trial of passive subretinal devices is discussed in the section on electrotherapeutics (below).

There are distinct advantages and disadvantages to the subretinal prosthesis approach. Advantages include closer proximity to the next surviving neuron in the visual pathway (i.e. bipolar cell) and therefore less current requirement, and the lack of mechanical means of fixation. The disadvantages include the limited subretinal space to place electronics as well as the close proximity of the retina to the electronics which would increase the likelihood of thermal injury to the neurons. If the subretinal implant is comprised as an electrode array with the electronics outside the eye (ab externo approach), then the implant will have a cable piercing the sclera. Issues related to such a surgical approach include long-term tethering effects because of the cable and a transchoroidal incision resulting in a greater likelihood of subretinal hemorrhage as well as possible retinal detachment either total or localized. In the latter case, the subretinal fluid would increase the distance between the underlying electrode and the retinal neurons and therefore increase the current requirements.

In 2009, Retina Implant AG (RI) started a clinical trial on a new subretinal prosthesis. The new implant has an intraocular part, comprising the array and cable (Fig. 126.4A,B). The microphotodiode array has 1500 pixels elements, with an additional 16 electrodes for direct stimulation tests (Fig. 126.4A). The electrode is placed subretinally, and the cable exits the eye through the pars plana and follows an intraorbital, subcutaneous path to exit behind the earlobe (Fig. 126.4B).

Fig. 126.4 Subretinal implant and cable.

(From Zrenner E, Bartz-Schmidt KU, Benav H, et al. Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc Biol Sci 2011;278:1489–97, with permission from Proc R Soc B, published online November 3, 2010.)

The direct stimulation electrodes are shown magnified, with their respective patterns of stimulation (see Fig. 126.4C–F). Also the microphotodiode array is shown magnified, with its rectangular photodiodes above each squared electrode (Fig. 126.4G). The implantation can be theoretically performed intraocularly, through either a pars plana vitrectomy (PPV) and retinotomy (ab interno), or PPV and a transscleral approach (ab externo)^87,^93,⁹⁴; however, to-date, only the ab externo approach has been used in the patients. A 2008 publication detailed the implantation and explantation of the device in humans.⁹⁵ Hypotensive anesthesia is used to prevent the risk of excessive choroidal bleeding when a 5-mm incision is made in the choroid to introduce the array into the subretinal space. A guide is used to help slide the electrode array under the retina but the procedure is done without direct visualization which can result in multiple attempts to achieve the proper placement of the array under the macula. A silicone oil tamponade is used to prevent retinal detachment. The device remains in position during the time of implantation, and can be explanted by opening and removing the electrode array through the initial choroidal incision. A fundus photo and the placement of the device on the skull are shown in Fig. 126.5.

Fig. 126.5 Subretinal implant in a retinitis pigmentosa patient. (A) Electrode placed on the subretinal space. (From Zrenner E, Bartz-Schmidt KU, Benav H, et al. Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc Biol Sci 2011;278:1489–97, with permission from Proc R Soc B, published online, November 3, 2010.) (B) Traject of the cable from the eye to the external connector.

The RI device has been implanted in 12 subjects, with planned explantation several weeks to 3 months later. Of the first seven subjects, four had electronic hardware problems that precluded further testing of the implanted active chip. By study design, implants were removed after 1 month (first eight implants) and 3 months (last three implants), except for one subject who refused to have the implant removed. Functional testing of the active subretinal implant has demonstrated the ability to see lines and determine the correct orientation of these lines. A scanning laser ophthalmoscope was used to directly activate the subretinal chip and a laser area as small as 100 µm produced a visual perception.⁸⁷

This group published in 2010 detailed results from the last three (of 12) implant subjects.⁸⁷ Having gained experience from the first nine subjects, hardware problems were largely avoided in the last three. Also, placement of the subretinal array was more consistent in the macula. Results from these three subjects showed that one patient could identify the direction of the letter “U” when presented in one of four orientations (20/24 times correct), when using the DS electrodes. Patient two of this group could identify letters and combine these into words. All three patients could detect the orientation of gratings, with patient two achieving a visual acuity of logMAR 1.74. This study was the first to report letter reading, providing strong support for functional vision via electrical stimulation. The short duration of implantation (1 or 3 months) limited the amount of data available from these tests. The robustness of this system needs to be improved. The device experienced technical failures at a rate unacceptable for a clinical implant, although fewer problems were noted in later implants.

This group recently announced a second trial with a device that eliminates the percutaneous connector by adding a power module, which is implanted behind the ear.⁹⁶ A power control module is implanted behind the ear, essentially replacing the percutaneous connector. An external system to provide wireless power is worn around the waist. The rest of the device is as described above. This study found that five subjects were able to identify various objects in their vicinity (plates, fruit, and desk items). Additionally, the subjects recognized borders of cars and sidewalks and were able to utilize shadows in an outdoor environment.

The Boston Retina Implant Project (BRIP) has developed a 15-channel implantable stimulator. It uses a configuration similar to the IMI and ARGUS II implants, but has a subretinal electrode array. The first-generation device comprised a flexible substrate attached to the sclera, and had three drawbacks according to the authors: (1) the receiver coils were smaller, which made power and data telemetry difficult; (2) the silicone coating was not feasible for long-term implantation; and (3) the surgical procedure was technically difficult, due to the different sites of placement of the electronics and of insertion of the cable and array.

The new-generation implants have the power and data receiver coils in the anterior part of the eye, surrounding the cornea, just behind the conjunctiva. The case is now made of titanium, and since the electrode implantation is in the same quadrant as the electronics, the surgical access to create a scleral flap and insert the array has been made easier.⁹⁷

Palanker et al. suggested a new design for a retinal prosthesis. It consists of a system with 2500 electrodes/mm² (corresponding to a maximum visual acuity of 20/80), with two basic geometries providing optimal proximity to retinal neural cells: perforated membranes and protruding electrode arrays.⁹⁸ In an in vitro experiment placing retinas with the photoreceptor side down in contact with a 13 µm implant with 40 µm apertures, retinal tissue migration was observed in all samples of rat, chicken, and rabbit retina (Fig. 126.6). Migration occurred through pores >5 µm.⁹⁹

Fig. 126.6 (A) Three-layered membrane with channels on top, inner chambers and a fenestrated membrane at the bottom. Voltage can be applied across the two electrodes (horizontal blue lines). Current flow between the two electrodes is indicated by the red lines with arrows. 2′ indicates electrode interface with inner retina. (B) Rat retina grown on the structure after 7 days in vitro, with migration of retinal cells through the 20 and 35 µm holes into the middle chambers, but not through the 3 µm holes in the lower membrane. GC, Ganglion cells; IN, inner nuclear layer; ON, outer nuclear layer.

(Reproduced with permission from Palanker et al. Attracting retinal cells to electrodes for high-resolution stimulation, Vol. 5314. San Jose, CA: SPIE; 2004.)

The in vivo model was studied in RCS rats with subretinal Mylar films with pores of 15–40 µm, showing robust migration of the inner retinal layer after 5–9 days.⁹⁹ Some questions arise from this approach, mainly if the retinal tissue will remain viable after migrating through the pores, if the circuitry will be kept functional, and lastly if the migrated tissue will differentiate into fibrous tissue. Another approach consists of subretinal implants with protruding electrodes, so that cells can migrate to the spaces between the electrodes, similar to the migration observed in the perforated membrane. In vivo implantation on RCS rats of 70 µm in height with 10 µm in diameter arrays showed after 15 days penetration of the pillars into the inner plexiform layer and the retina well preserved (Fig. 126.7).¹⁰⁰

Fig. 126.7 (A) Protruding electrodes (labeled 1) on the subretinal array penetrating the retina after migration of retinal cells into the empty spaces between the pillars. (B) 10 µm pillars protruding into the inner plexiform layer of a Royal College of Surgeons rat after 15 days of implantation.

(Reproduced with permission from Palanker et al. Attracting retinal cells to electrodes for high-resolution stimulation, Vol. 5314. San Jose, CA: SPIE; 2004.)

Recent alternative approaches

Investigators from Japan have recently collaborated on a relatively new approach to artificial vision they term suprachoroidal transretinal stimulation (STS) (Fig. 126.8). They have hypothesized that placing a stimulating electrode in the suprachoroidal space or in the fenestrated sclera along with a ground electrode in the vitreous cavity, may allow for a less-invasive method to achieve functional percepts. The advantages to such an approach are several. First of all, the surgery is less complicated. Second, the electrodes are less invasive to the retina. Third, the electrodes are relatively easy to remove or replace if damaged.^101,¹⁰²

Fig. 126.8 Suprachoroidal-transretinal stimulation (STS) prosthesis. (A) Internal part of the STS system. (B) Electrode array (6 × 6 × 0.5 mm) with 49 platinum electrodes in a 7 × 7 arrangement. (C) Return electrode and extraocular microelectronic simulator. (D) External transmitter and processor of the STS system. (E) Microstimulator.

(Reproduced with permission from Morimoto T, Kamei M, Nishida K, et al. Chronic implantation of newly developed suprachoroidal-transretinal stimulation prosthesis in dogs. Invest Ophthalmol Vis Sci 2011;52:6785–92.)

However, this approach remains to be proven over long-term implantation. Specifically, because the electrodes are further from the target neurons, they should need to deliver higher currents and the current spread should be greater, therefore limiting the resolution.^101,¹⁰²

Initially, STS has been investigated in the Royal College of Surgeons (RCS) rats and rabbits. In the RCS rats, the investigators studied threshold intensities of electrically evoked potentials (EEPs) from the superior colliculus (SC). It was found that the response to the STS was recorded in the localized retinotopically corresponding SC areas, suggesting that the focal stimulation to the degenerated retina effectively elicits artificial vision in the RCS rats. Similar findings were noted in rabbits as well. The threshold intensity of the EEPs was 5–10 nC of electrical charge, suggesting that stimulation via STS may be attained with relatively low stimulating current.^101,¹⁰² However, we should note that rabbit sclera and retina are thinner than in humans, thus partially accounting for the relatively low stimulating current in this study.

Recently, the results from the last long-term implantation in dogs were published.¹⁰³ STS microelectrode arrays were implanted into a scleral pocket of beagle dogs and were kept in place for 3 months. The electrode array and the return electrode were connected to the extraocular stimulator by a multiwire cable, connected wirelessly to an extra corporeal processor and transmitter. The electrode array measured 6 × 6 × 0.5 mm, with 49 platinum electrodes in a 7 × 7 arrangement fixed in a clear silicone rubber platform coated with Parylene. The stimulating electrode was 0.5 mm in diameter and 0.5 mm in length and the distances between the centers of electrodes were 0.75 mm and the return platinum electrode placed in the vitreous cavity were 6.5 mm in length and 0.5 mm in diameter. Nine of the electrodes on the array were electrically active for this experiment. After 3 months all three prostheses were safely implanted with no intraoperative complications, the position of the eyes was maintained orthophoric without proptosis during the follow-up period and all the wounds healed properly with no sign of infections or wound dehiscence. The notch of the array could be seen on the fundus examination on dogs two and three. The ERGs had the normal a-wave and b-waves, and the shape did not differ from the ERGs recorded from the unoperated fellow eye 3 months after the implantation in all three animals. Histologic sections from two implanted and control eyes showed no obvious changes in the structure of retina and choroid beneath the electrode array in dogs one and three; however, pathologic changes were detected in the retina of dog two (Fig. 126.9). The retinal and choroidal architecture was destroyed due to the mechanical pressure, according to the authors.¹⁰³

Fig. 126.9 Light microscopic photographs of the retina and sclera from the implanted eyes of two dogs. (A,C) Photographs of the retina and sclera around the electrode array from dog one. No damage of the retina is visualized. (B,D) Photographs of the retina and sclera around the array from dog two. Local damage of the retina and choroid at the site of the implanted electrode array can be seen (arrowheads), however the other area of retina on the array is intact (arrows).

In a 2011 paper, Fujikado et al. reported results of semi-chronic, suprachoroidal implantation of two patients with RP. The visual acuity of the patients before implantation was light perception. The 49-electrode array (5.7 × 4.6 × 0.5 mm) was placed in the suprachoroidal space without causing retinal detachment or vitreous hemorrhage, and the internal devices of the implant were implanted under the skin on the temporal side of the head. The implants remained functional for the 4 weeks of the study. After 5–7 weeks the implants were surgically removed (first and second patient, respectively).¹⁰⁴

Phosphenes were elicited by currents delivered through six electrodes in patient one and through four electrodes in patient two. The success of discriminating 2 bars was better than the chance level in both patients. In patient two, the success of a grasping task was better than the chance level, and the success rate of identifying a white bar on a touch panel increased with repeated testing.¹⁰⁴

An Australian group is also investigating the feasibility of a suprachoroidal placement of the electrode array.¹⁰⁵ The surgical procedure consists of lateral canthotomy followed by a full-thickness sclerotomy, exposing the choroid. A “pocket” is created in the suprachoroidal space, for the insertion of a flexible electrode array 15–17 mm into the eye, beneath the area centralis. The array is then sutured in place, and platinum ball electrodes (1.5 mm diameter) were placed in the vitreous cavity and in the suprachoroidal space, next to the electrode, to act as return electrodes for electrical stimulation. The animal was then placed in a stereotaxic frame and kept in a dark, electrically shielded Faraday room.

A platinum electrode was implanted in the skin of the back of the neck, to serve as reference, and a craniotomy was them performed to expose the primary visual cortex, and placement of the platinum macroelectrode, in the region corresponding to the macular region of the retina. The cortical electrode was used for all evoked potential recordings due to the full-field flashes and electrical stimulation of the electrode.¹⁰⁵ The authors report that charge thresholds depended only upon the number of sites stimulated in parallel. Electrode size, pulse width, and position of the return electrode did not affect charge threshold.

The transchoroidal systems described above represent a new approach that has some advantages compared with the subretinal and epiretinal approaches. For example the ab externo approach through the sclera, potentially less complicated than the ab interno approach, along with a more stable positioning of the electrode on the suprachoroidal space decreases the risk of retinal detachment. However, given the distance between the retina and sclera (250–300 µm in cats ¹⁰⁶; 204–490 µm in humans¹⁰⁷), it is suggested that such prosthesis will not achieve the same resolution as the epiretinal or subretinal prostheses.¹⁰⁸ Also, higher currents will be required for stimulation, due to all the layers interposed between the array and the ganglion/bipolar cells. However, animal studies already showed the ability to evoke cortical potentials using suprachoroidal of the outer nuclear layer, outer plexiform layer and inner nuclear layer stimulation.¹⁰⁹^–¹¹³

The Microfluidic Retinal Prosthesis is an alternative approach that will mimic normal chemical signaling between neurons in the retina and brain.¹⁰⁴^–¹⁰⁹

The overall hypothesis is that digital images may be transposed into neurochemical signals through a microfluidic chip, chronically implanted in the subretinal space. The design of their neurotransmitter-based visual prosthesis utilizes a multitude of microfluidic orifices that create a two-dimensional array of “chemical pixels”, arranged to create an image analogous to an inkjet printer, delivering neurotransmitter to the retina or brain. The device design eliminates the need for mechanical valves by using an inactive or “caged” form of neurotransmitter that is photoactivated by ultraviolet light.^114,¹¹⁵

This approach may be used to stimulate the retina alone or function in concert with electrical stimulation techniques to reduce the amount of current required for electrophosphene thresholds, thus reducing the potential toxicity associated with heat and electrode breakdown that currently limit the function of electrical stimulating devices.

Furthermore, a microfluidic retinal prosthesis chip may allow for a number of unique features, including the ability to bundle electrical stimulation with neurotransmitter stimulation and the simultaneous, or independent, delivery of therapeutic drugs. In this way, deoxyribonucleic and ribonucleic acids (DNA and RNA), peptides, neurotransmitters, and hormones can all be packaged as phototriggered caged pro-drugs. Then these photoactivated molecules can be delivered via an “uncage-and-release” microfluidic retinal implant technology allowing for in vivo photoactivation and release of drugs upon the retinal surface.¹¹⁶^–¹³⁰

Consequently, this type of retinal prosthesis potentially allows for greater flexibility in replacing the lost photoreceptor inputs to degenerative outer retinopathies. In addition, certain growth factors and peptides or other drugs which may have a therapeutic effect may be delivered efficiently from the chip itself. Thus, there is the potential for both electrical stimulation with sensory excitation and the added potential regenerative role that drug delivery may allow.

Major concerns about excess glutamate in retinal neurons exist as glutamate is well-known to kill neurons through excitotoxicity, and therefore the release and scavenging of this neurotransmitter will have to be extremely well regulated. To have functional microfluidics with proteins in them over the long term, as is required in a retinal prosthesis, is a difficult technological problem. Similarly, the ability to draw neurons from existing retinal tissue close to electrodes and yet not totally disrupting their natural connections in the retina might also be difficult to titrate.

Electrotherapeutics

The Optobionics Artificial Silicon Retina (ASR) has shown some efficacy in improving vision, not through direct action of the device, but instead through a neurotrophic effect.

Initially developed as a retinal prosthesis, the ASR was implanted (subretinal and extramacular) in ten patients in a single-center study and then 20 subjects in a multicenter study. The 3-mm-diameter implants had 3500 microphotodiodes that generated stimulating current in response to incident light (Fig. 126.3). Results from the first six subjects were published in 2004, reporting that all six described subjective improvements in vision. Three of the six had improved early treatment diabetic retinopathy study (ETDRS) scores, while one in six had an enlarged visual field postoperatively. However, the improved vision included areas of the visual field far from the implant location. The authors concluded that the subretinal ASR implant was not directly mediating artificial vision (i.e., electrical stimulation via the ASR did not directly affect visual perception). Instead, the ASR’s presence in the subretinal space was acting via an indirect effect, possibly through release of growth factors, and improving the health of the retina.¹³¹

The theoretical current output of a subretinal microphotodiode in a sunny environment is <1 nA (nano Ampere) (10⁻⁹),¹³² far below what is required for electrical activation of nerves. Thus, the ASR cannot be considered a retinal prosthesis.

The multicenter study provided additional results from visual task performance and more detail on the surgical procedure. Adverse events included three cases of ASR migration; two incidences of fracture of the device during implantation (the damaged device was easily removed), and six visually significant cataracts (versus three in the fellow eyes).¹³³ The most recent report from the group states that visual improvements are maintained in the original six implant subjects from the single-center trial.¹³⁴

Optogenetics

A quickly emerging alternative to an implanted bioelectronic device is the “optogenetic” approach. Pioneered by Deisseroth,¹³⁵^–¹³⁷ the optogenetic technique modifies individual neurons to include light-sensitive ion channels, the most common being channel rhodopsin 2 (ChR2). When light of a specific wavelength is shone on to the cell, ChR2 opens resulting in depolarization of the cell. Viral vectors such as adeno associated virus are used to get the ChR2 DNA into the cell. Bi et al. first demonstrated that this could be used to modify retinal ganglion cells, showing that light-evoked neural responses were present in a mouse model of retinal degeneration when the mouse RGCs contained ChR2.¹³⁸ Others have extended this initial work to show that behavioral responses were preserved in rd1 mice¹³⁹ and that photoreceptor nuclei cell bodies could be modified and initiate a neural response even in the absence of outer segments.¹⁴⁰ Incorporating a second light-sensitive channel (Halorhodopsin) into the dendrites of a retinal ganglion cell and ChR2 in the soma, to enable a center-surround response dependent on the wavelength of light, the optogenetic approach has some significant advantages over the bioelectronic approach. By making each cell light sensitive, vision can potentially be restored to near normal acuity. Also, using light as the activating signal allows the optics of the eye to be used to focus the image on the retina. In other words, the optogenetic approach can come much closer to restoring natural vision, versus artificial vision provided by bioelectronic approaches. However, many potential challenges must be overcome before optogenetic approaches can be clinically viable. The main issue relates to sensitivity. Currently, modified cells require bright, blue light (460 nm) to be activated, roughly four orders of magnitude above cone light sensitivity threshold in normally sighted people. It is not clear how such intense light would interact with a diseased retina, with remnant light sensitivity. Given that photophobia is sometimes a symptom of RP, then directing a bright light into the photophobic patient’s eye is unlikely to provide a benefit. In addition, it is unclear if the modified cells permanently maintain this light sensitivity, or if reinjection is required.