The Optobionics Corporation, a privately held company located in Wheaton, IL, has developed the Artificial Silicon Retina (ASR), which entered into clinical trials of its safety in the summer of 2000. (Optobionics, Artificial Silicon Retina, and ASR are trademarks of the Optobionics Corporation.) This device represents the commercialization of the scientific research of Chow and Chow, two brothers who continue to provide the scientific leadership of the company. Much of their research has centered on the safety and efficacy of a subretinal neuroprosthetic device.
In their early research, Chow and Chow showed that a simple combination of an electrode placed in the subretinal space and a photodiode could become the basis of a visual prosthesis.19 Using a single, very large gold electrode (36 mm2 surface area or about twice the size of the macula in humans) acutely implanted into the subretinal space of an anesthetized rabbit, they observed that illumination of a photodiode connected to the electrode induced cortical activity. The cortical activity, measured by electrodes placed on the scalp of the rabbit, had amplitude and temporal characteristics similar to the visually evoked potential measured in the unoper-ated eye. Further, the magnitude of the cortical-evoked potential could be modulated by adjusting the intensity of the stimulus or the size of the photodiode. With a charge density of 100-nC/cm2, resulting from 12-klux illumination (similar to a bright, sunny day) on a 29-mm2 photodiode, the magnitude of evoked potential was similar to the visually evoked potential measured in the unoperated eye.
Having shown a proof of concept, their research moved into the design and test of an array of photodiodes and electrodes manufactured by standard semiconductor methods. In a series of articles, they have reported on the biological response to an implanted array and the ability to evoke neural activity with the array.20-25 The test ASR has remained relatively unchanged except in its thickness throughout these studies. At the macroscopic scale, the device is a 1- to 3-mm-diameter disk (0.8- to 7-mm2 area), initially being 250 |im thick and reduced to 50 |im thickness in the most recent report. At the microscopic scale, the test ASR is an array of photodiode and electrode elements, each element being approximately 20 x 20 |im by the thickness of the disk. Insulating moats (10-|im width) separate neighboring elements, resulting in a density of approximately 1100 elements/mm2. Each element consists of a photodiode created by variously doped layers of silicon, sandwiched between two layers of gold. On the front side of the array (side closest to the light), the gold electrode is etched to the same dimension of the photodiode. Light reaching the photodiode passes through the gold layer, which is relatively transparent due to its thinness. The gold on the backside of the array forms a single sheet and acts as a return electrode. As gold does not readily adhere to silicon, a chromium adhesion layer is place between the gold and the silicon. The photodiode is responsive to light in the 500- to 1100-nm wavelength range, which covers most of the typical range in humans (360 to 830 nm) plus adding an infrared (IR) response.
In these reports, histological examinations and the electroretinogram (ERG) were used to assay the tissue response to the implant. In chronically implanted cats, they observed a significant loss of cells in the outer nuclear layer but insignificant changes in the cell density for both the inner nuclear layer and retinal ganglion layers.24,25 Additionally, the appearance of giant cells indicated an inflammatory response to the implanted device. As AMD and RP are characterized by the loss of the outer nuclear layer, its loss in these animal experiments is considered inconsequential. Outside the site of implant, the retina had a normal laminar arrangement. The lack of a significant immune response to the implant is not surprising as the device is constructed from well-tolerated materials. Photic stimulation of the implanted eye resulted in an ERG similar to the unimplanted eye. This also is not an unexpected result, as the implant is relatively small and implant materials are well tolerated. If the device led to an out-of-control immune response, it likely would have been apparent in the histology long before affecting the ERG.
The ERG response for IR stimulation was used to verify the implant continued to be functional.24 The ASR is much more sensitive to IR stimulation than the native photoreceptors. These data indicated that the test ASR continued to function as a photodiode array for up to 11 months, the longest time duration reported. However, the magnitude of the ERG took 1 to 2 months to reach its maximum and began to degrade after 4 months. From the data provided, the ERG response had a magnitude of up to 75 |V, and the sign of the response depended on the type of photodiode utilized (negative or positive current generating). The latter finding is a clear indication that this ERG response is simply a stimulus artifact. If the ERG represented neural activity and the two polarities were equally effective at eliciting activity, the two ERGs would be equal and similarly signed. If one polarity were more effective, the more likely case, the ERG would appear when the illumination is initiated for one polarity and when the illumination is terminated for the other polarity. At the end of the study, the arrays were explanted and examined. It was found that the gold electrode material was degraded or absent for active devices, suggesting that the gold electrodes were being dissolved into the tissue by electrical stimulation. Alternative electrode materials, platinum and iridium oxide, have been investigated but no specific recommendations are available at this time.23
In addition to animal experiments, Optobionics has initiated FDA-approved clinic trials to investigate the safety of the ASR in humans. The device currently in clinical trials is a 2-mm-diameter disk of 25 |im thickness. Each photodiode and electrode element has the same 20 x 20-|im dimensions with 10-|im moats separating adjacent elements. Given the approximately 3500 elements on the device, the total photodiode (and electrode) surface area is around 1.4 mm2. In comparison, the devices used in their animal experiments, which had a complete lack of neural response for what should be effective stimulation, had a photodiode area of up to 7 mm2. The only device where a neural response was assuredly observed had a surface area of around 30 mm2 and then under aggressive stimulation.19 The results of these clinical trials are only available in abstract form at this time.26 The implants are reported to be well tolerated and have not resulted in infection, inflammation, or retinal detachment. Additionally, the implants are reported to have improved the recipient's visual function; however, these results are only available as recipient testimonials, not controlled scientific studies. Care must be taken to distinguish the improvement due to the activity of the device and the improvement that occurs simply by the introduction of the device. It has been established that a transient, functional rescue of a dysfunctional retina occurs in animal models as the result of surgical intervention into the subretinal space, even if the intervention does nothing more than expose the subretinal space. Nevertheless, the test of the biocompati-bility of the materials and the development of the implant techniques make the ASR a groundbreaking device.
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