Alan Y. Chow

Subretinal electrical stimulation of the rabbit retina

A number of disorders results in photoreceptor degeneration, yet spare the inner retinal layers. We are investigating the possibility that retinal function may be restored in such a situation by electric current applied from the subretinal space. In the present study, bipolar strip electrodes receiving electric current from external photodiodes were implanted into the subretinal space of adult rabbits. Recordings were made from the scalp overlying the visual cortex in response to photic flash stimulation of one eye before surgery. This was compared to the visual cortex response caused by subretinal electrical stimulation of the same eye from an implanted strip electrode. Electric current to the strip electrode was provided by an externally connected photodiode that was stimulated at a remote location with a photoflash. The electrical stimulus was recordable as a brief electrical implant spike during stimulation. In addition, after the implant spike, cortical responses were obtained in response to subretinal electrical stimulation that resembled closely the normal light induced visual evoked potential produced by the pre-implanted eye. These results indicate that the visual system can be activated by electrical stimulation from the subretinal space and indicate that this approach may provide a means to restore vision to eyes blinded by outer retinal disease.

Implantation of silicon chip microphotodiode arrays into the cat subretinal space

There are currently no therapies to restore vision to patients blinded by photoreceptor degeneration. This project concerns an experimental approach toward a semiconductor-based subretinal prosthetic designed to electrically stimulate the retina. The present study describes surgical techniques for implanting a silicon microphotodiode array in the cat subretinal space and subsequent studies of implant biocompatibility and durability. Using a single-port vitreoretinal approach, implants were placed into the subretinal space of the right eye of normal cats. Implanted retinas were evaluated post-operatively over a 10 to 27 month period using indirect ophthalmoscopy, fundus photography, electroretinography, and histology. Infrared stimulation was used to isolate the electrical response of the implant from that of the normal retina. Although implants continued to generate electrical current in response to light, the amplitude of the implant response decreased gradually due to dissolution of the implants gold electrode. Electroretinograms recorded from implanted eyes had normal waveforms but were typically 10-15% smaller in amplitude than those in unimplanted left eyes. The nonpermeable silicon disks blocked choroidal nourishment to the retina, producing degeneration of the photoreceptors. The laminar structure of the inner retinal layers was preserved. Retinal areas located away from the implantation site appeared normal in all respects. These results demonstrate that silicon-chip microphotodiode-based implants can be successfully placed into the subretinal space. Gold electrode-based subretinal implants, however, appear to he unsuitable fur long-term use due to electrode dissolution and subsequent decreased electrical activity.

Subretinal Semiconductor Microphotodiode Array

BACKGROUND AND OBJECTIVE To examine the function of a semiconductor microphotodiode array (SMA) surgically implanted in the subretinal space. MATERIALS AND METHODS Positive-intrinsic layer-negative (PiN) or negative-intrinsic layer-positive (NiP) SMAs were surgically placed into the subretinal space of rabbits through a pars plana incision and a posterior retinotomy. The implants required no external connections for power and were sensitive to light over the visible and infrared (IR) spectrum; IR stimuli were used to isolate implant-mediated responses from the activity of native photoreceptors. A stimulator ophthalmoscope was used to superimpose IR stimuli on the implant and adjacent retinal areas, and responses were recorded during the postoperative recovery period. SMA responses were also evaluated in vitro. The animals were given lethal anesthetic overdoses, and the retinas were examined histologically. RESULTS The in vitro implant response consisted of an electrical spike, followed by a small-amplitude DC offset that followed the time course of the IR stimulation, and an overshoot at the stimulus offset. The SMAs placed in the subretinal space retained a stable position and continued to function throughout the postoperative period. The SMA responses recorded in vivo included additional slow-wave components that were absent from the in vitro recordings. These responses reverted to the in vitro configuration following the death of the animal. There was a significant loss of retinal cells in areas overlying the implant, and the retina appeared normal away from the implant and surgical site. CONCLUSION SMAs can be successfully implanted into the subretinal space and will generate current in response to light stimulation during an extended period of time.

Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

The Subretinal Microphotodiode Array Retinal Prosthesis

Accessible online at: http://BioMedNet.com/karger We read with interest the letter of Zrenner et al. [1] written in response to our Letter to the Editor [2] regarding a paper that Zrenner et al. [3] had published in Ophthalmic Research. Our letter concerned the matter of Zrenner et al. [3] implying authorship to the concepts and developments of subretinal microphotodiode-based retinal prostheses that we developed and disclosed to them in confidence in prepublication and other materials. We feel that Zrenner et al. [1] in their response have failed to meaningfully address, or perhaps just decided to ignore, the central issue of implied authorship raised in our original letter, instead choosing to address various unrelated matters. We interpret their response as, essentially, a tacit admission of the validity of our original claims. We continue to maintain that for Zrenner et al. [3, p. 271] to have stated, in reference to the development of a microphotodiode retinal prosthesis, that ‘This approach was started in autumn 1995’ is patently untrue and inherently misleading as to the origin of this work. It is impossible to reconcile this statement with the numerous materials that we provided Zrenner et al. in late 1994 and early 1995 detailing our work in this area since 1989, which were listed in our earlier letter [2]. Other statements by Zrenner et al. also leave the reader with a similarly misleading impression. On page 272 of their article Zrenner et al. [3] state: ‘In the second generation, negatively and positively responding MPDs were arranged alternatively in an array so that the adjacent nerve cells can be polarized both negatively and positively ... This further elaboration was brought to successful completion in September 1996 by partners at the IMS’. Neglecting to reveal that this concept and device was shown by us to most of Zrenner et al. (which includes B. Hoefflinger of the IMS) in early 1995 as a patent application [4] is certainly misleading as to authorship in our opinion. In summary, we remain steadfast in our view that it is improper to imply authorship to the ideas and developments of another, whether those ideas are obtained from a patent, a published paper, a personal communication or from unpublished material. Regrettably, it would appear that Zrenner et al. hold a different viewpoint.

Status of the feline retina 5 years after subretinal implantation.

Retinal prosthetics are designed to restore functional vision to patients with photoreceptor degeneration by detecting light and stimulating the retina. Since devices are surgically implanted into the eye, long-term biocompatibility and durability are critical for viable treatment of retinal disease. To extend our previous work, which demonstrated the biocompatibility of a microphotodiode array (MPA) for 10 to 27 months in the normal feline retina, we implanted normal cats with an MPA implant backed with either an iridium oxide or platinum electrode and examined retinal function and biocompatibility for 3 to 5 years. All implants functioned throughout the study period. Retinal function remained steady and normal with a less than 15 percent decrease in electroretinogram response. The retinas had normal laminar structure with no signs of inflammation or rejection in areas adjacent to or distant from the implants. Directly over the implants, a loss of photoreceptor nuclei and remodeling of inner retinal layers existed. These results indicate that the subretinal MPA device is durable and well tolerated by the retina 5 years postimplantation.

Visual evoked potentials to infrared stimulation in normal cats and rats

The absence of effective treatments for retinal degenerative diseases has inspired several laboratories to pursue the development of a retinal prosthetic. In our laboratory, we have focused on the subretinal approach, using an array of photodiodes housed within a silicon chip. These photodiodes generate electrical current in response to wavelengths ranging from 500–1100 nm. Because the native retina is traditionally thought to be insensitive to wavelengths beyond ∼750 nm, we and others have attempted to isolate implant-mediated electrophysiological responses from those of the native retina by using longer wavelength stimuli in the near infrared range. Evoked potentials recorded over the visual cortex in response to infrared stimuli have been reported as evidence of a functional subretinal implant due to the typical physiological characteristics of the waveform: a direct relationship between amplitude and intensity, increased amplitude over the visual cortex, and repeatability of the response. However, these results should be interpreted with caution since here we report an unappreciated sensitivity of the native retina to infrared light under dark-adapted conditions.

Neuroprotective Dose Response in RCS Rats Implanted with Microphotodiode Arrays

Neuropreservation of retinal function and structure in RCS rats following implantation of a microphotodiode array (MPA) has been shown in previous studies (Pardue et al. J Neural Eng 2005;2:S39–47; Pardue et al. Invest Ophthalmol Vis Sci 2005;46:674–682). Since microphotodiodes produce electrical currents in proportion to the intensity of incident light, increased light exposure may result in greater neuroprotective effects. Our previous studies suggested that the frequency of light exposure to electroretinogram (ERG) flash stimuli might provide increased neuroprotection. Thus, in this study, we examined the dose response of subretinal electrical stimulation by exposing RCS rats implanted with MPAs to variable durations and combinations of two different lighting regimens: pulsing incandescent bulbs and xenon stimuli from an ERG Ganzfeld. While incandescent light regimens did not produce any significant differences in ERG function, we found significantly greater dark-adapted ERG b-wave amplitudes in RCS rats that received weekly vs. biweekly ERGs over the course of 8 weeks of follow-up. These results suggest that subretinal electrical stimulation may be optimized to produce greater neuroprotective effects by dosing with periodic higher current.

Subretinal Artificial Silicon Retina Microchip Implantation in Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a progressive condition that causes both central and peripheral vision loss ((1)–(3)). This genetically diverse disease presents with a variable phenotypic onset, but eventually affects both eyes. No treatment is effective in restoring vision once it is lost. Although, a variety of patterns can be observed, vision loss typically occurs first in the midperiphery and progresses to involve the peripheral and finally, the central visual fields creating a funduscopic pattern of pigmented “bone spicules.”

Evaluation of an Artificial Retina in Rodent Models of Photoreceptor Degeneration

In many retinal disorders, the photoreceptor layer degenerates while inner retinal layers are spared (Eisenfeld et al., 1984; Flannery et al., 1989; Stone et al., 1992; Santos et al., 1997). Based on evaluation of patients with photoreceptor degeneration, the inner layers retain some capacity to transmit and process visual information (Humayun et al., 1995,Humayun 1996). Consequently, replacing the photoreceptor layer with healthy retina or an “artificial retina” could restore vision in affected individuals. This objective has been approached by: transplantation of adult photoreceptors (Gouras et al., 1994; Silverman and Hughes, 1989; Huang et al., 1998), embryonic retina (Humayun et al. 2000; Juliusson et al. 1993; Seiler and Aramant, 1998; Seiler et al. 1999), or full thickness retina (Aramant et al., 1999; Ghosh et al. 1998; Seiler et al. 1995) or by implantation of electrodes onto the retinal surface (Eckmiller, 1999; Grumet, et al. 2000; Humayun et al., 1999) or an electronic device into the subretinal space (Peachey and Chow, 1999; Zrenner et al., 1999; Chow et al., 2001a,Chow et al., 2001b).