We developed a surgical method that required only a single slit in the back of the eye to introduce the electrode array. Once in place, it typically retains a tight apposition to the undersurface of the retina without the need for tacks or adhesives (Fig. 5). This stability is achieved in the absence of significant fibrosis around the arrays, which has allowed us to safely and easily remove arrays that had been chronically implanted into the subretinal space of mini pigs (32). Our methods allowed implantation of a 5-mm-diameter electrode array, the largest surface area of an array safely implanted into a living eye (33). Our array should provide vision over roughly 14° of visual angle to assist in navigation through unfamiliar environments.
Biocompatibility includes the biological responses that occur secondary to the surgery, foreign materials, and effects of electrical stimulation. When we began our project, there was no evidence that foreign material could be safely implanted adjacent to the retina for long periods. We surveyed 6 materials as substrates for the electrode array (34). All caused some degree of damage or incited some degree of response to the foreign device, but none were severe enough to produce encapsulation of the implanted device, for instance. Other groups have also shown similarly favorable outcomes with foreign materials placed on the epiretinal surface.
The basic goals of capturing visual information and delivering electrical stimulation to the retina have been achieved by numerous groups. Many different types of implanted devices are well tolerated even after prolonged implantation into the eye. These efforts have provided insights into how neurons respond to electrical stimulation and how these responses differ from those generated by the normal photic stimulation (30,35-44).
These achievements should not be construed to suggest that these areas of investigation are complete or that they will enable success in restoring vision to blind patients. There have been several problems associated with human implants, including multiple cases of extrusion of implanted devices through the conjunctiva, dislodging of retinal tacks, endophthalmitis, hypotony, and failure of hermetic protection of the implanted electronic components, which rendered the devices useless.
Five research groups have been involved in sustained efforts to develop a retinal implant (Table 1). A sixth group, Optobionics, Inc, put in a strong effort but declared bankruptcy after implantation of 20 patients with a subretinal prosthesis (45). The company concluded that its successes were not the result of electrically induced activation of neuronal responses that propagate to the brain. Rather, a “trophic” effect was identified, which although substantiated by careful scientific work (46-48), called into question the value of the device.
The most fundamental outcome of this collective work has been the reporting of the psychophysical threshold for electrical stimulation, that is, the amount of electrical charge required for patients to reliably report a visual sensation. The activation threshold is the most important single parameter to assess the potential safety of the long-term use of these devices and to design the power budget for a prosthetic system (49-51). The thresholds, which have been obtained in patients who were severely blind from RP, were initially found to be relatively high, perhaps too high for safe electrical stimulation with the platinum-type electrodes that were being used given the safety charge limits of these electrodes. More recently, measured thresholds have been substantially lower and more encouraging (in the range of a few microcoulombs per square centimeter or less). However, thresholds have varied considerably across patients, across electrodes within a single patient, and over time (49,52,53). The issue of long-term safety has yet to be reconciled.
Visual acuities have been reported to be as good as 20/1,000, which would provide a significant improvement over the baseline level of “light perception” in implanted patients (54). More recently, obtained with a 16-channel device, visual acuity without the benefits of visual scanning has been reported as equal to the physical spacing of the stimulating electrodes (55). This result has supported a belief that more electrodes would translate into higher quality spatial perception, but this outcome is far from certain. The uncertainty about the potential visual outcome for a given number of electrodes relates to the fact that the electrical fields emanate in complex ways from the electrodes, with patterns of constructive and destructive interference, like the ripples in water caused by the impact of a rock. This phenomenon creates uncertainty about the patterns of activation of neurons that govern the quality of perception.
Studies also demonstrated that implanted patients can localize the quadrant of a large stimulus, identify the direction of moving lines, and identify some common objects like forks and cups (29). The perception of brightness has been shown to correlate with the amount of electrical current used for stimulation, although considerable variability was found in 1 of the 2 subjects (56). Perhaps the most encouraging results have been reported by the Retina Implant AG company (Tubingen, Germany). After 1 week of implantation, a patient was judged to be capable of reading letters and words similar in size to those in newspaper headlines (57,58). If these results, derived by subretinal stimulation, are substantiated by further testing, the retinal prosthetic technology would have the potential to improve the quality of life for severely blind patients.
Several requirements for long-term success have yet to be met. There must be scientifically convincing evidence that the induced vision can improve quality of life for blind patients. There must be solid data on the safety of these devices, which will require surveillance of a large number of implanted patients. There must be further improvements in the engineering of these devices to provide a larger number of stimulating electrodes that can be interfaced more closely to the retinal neurons. Finally, there must be more knowledge of the neuroscience related to more effective stimulus paradigms, encoding of visual information from the retina to the brain, and plasticity of the visual cortex following blindness. There is still relatively little information about the physiology of degenerated retinas, but the need to understand these responses for the application of retinal prostheses has led to a very substantial increase in interest in this question (36,39,40).
Vision is a complex and nuanced sensation compared to hearing, and it will undoubtedly be harder to create useful vision that it was to create useful hearing with cochlear prosthetic devices. There are several impediments to improving vision with such electrical implants. Electrical stimulation tends to activate retinal neuronal pathways indiscriminately, although we and others have discovered strategies to favorably bias the stimulation (30,44,59,60). Indiscriminate stimulation confounds any strategy to create useful vision. Loss of photoreceptors causes significant “reorganization” of the retina that will complicate the attempt to create predictable visual percepts (61,62). Visual cortical changes also occur following loss of retinal input (63,64). The extent to which these cortical changes might help or hinder the interpretation of the percepts generated by artificial electrical stimulation is unknown.
The results of long-term testing of retinal implants in blind humans look promising. To properly consider the risk-to-benefit ratio, one would have to know as much detail about the complications as about the widely reported psychophysical outcomes. Such proper consideration cannot be carried out because the complications that have occurred have not been fully reported in public forums, mostly because the testing has been performed by companies that face the dilemma that reporting of untoward events might compromise the commercial potential of their product. At this stage of the investigation, there is not enough published evidence to offer comprehensive and unbiased advice to patients. Given this reality and the fact that the status of each group in the field is constantly changing, general recommendations of what advice might be given to interested patients are difficult to provide. Any serious consideration of becoming a recipient of a visual prosthesis must be grounded in reflection of the up-to-date outcomes from each group in the field. Representatives from the groups listed in Table 1 can discuss the status of their work and the relative merits of their approach. The interested reader also might access the Web site of each group, which provides descriptions of the current activities and contact information.
Our group decided long ago not to begin chronic human implants until we had developed the technology to expand the number of stimulation channels to above 200, a number that might provide functionally “useful” vision to blind patients, like the ability to navigate safely in an unfamiliar environment. The technology needed to produce such a device includes the means to transmit sufficient power to support stimulation across the larger number of electrodes and the means of providing the hermeticity for the ICs and microwires that course through the ultrathin membrane that enters the eye. Such long-term development efforts are facilitated by the freedom to flexibly pursue technical solutions, the timetable of which is unpredictable. The value of retaining the independence to decide on an appropriate time to begin human implantation is the primary reason that our group has delayed a corporate strategy to develop this technology.
Having implanted wireless devices in laboratory animals for 2 years, we have begun to collect the necessary “preclinical” tests that are required by the Food and Drug Administration to obtain the Investigational Device Exemption that is needed before human testing can begin. Our initial human studies will be conducted with a device that will have more than 200 electrodes, which we anticipate will provide more useful vision for blind patients, although the primary intent of Phase I testing will be “safety.” The BRIP believes that our subretinal approach and that our means to discretely control stimulation across a large number of channels will prove to be advantageous in comparison to other approaches.
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