Transfer characteristics of subretinal visual implants: corneally recorded implant responses.

PURPOSE: The subretinal Alpha IMS visual implant is a CE-approved medical device for restoration of visual functions in blind patients with end-stage outer retina degeneration. We present a method to test the function of the implant objectively in vivo using standard electroretinographic equipment and to assess the devices' parameter range for an optimal perception. METHODS: Subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) consists of 1500 photodiode-amplifier-electrode units and is implanted surgically into the subretinal space in blind retinitis pigmentosa patients. The voltages that regulate the amplifiers' sensitivity (V gl) and gain (V bias), related to the perception of contrast and brightness, respectively, are adjusted manually on a handheld power supply device. Corneally recorded implant responses (CRIR) to full-field illumination with long duration flashes in various implant settings for brightness gain (V bias) and amplifiers' sensitivity (V gl) are measured using electroretinographic setup with a Ganzfeld bowl in a protocol of increasing stimulus luminances up to 1000 cd/m2. RESULTS: CRIRs are a meaningful tool for assessing the transfer characteristic curves of the electronic implant in vivo monitoring the implants' voltage output as a function of log luminance in a sigmoidal shape. Changing the amplifiers' sensitivity (V gl) shifts the curve left or right along the log luminance axis. Adjustment of the gain (V bias) changes the maximal output. Contrast perception is only possible within the luminance range of the increasing slope of the function. CONCLUSIONS: The technical function of subretinal visual implants can be measured objectively using a standard electroretinographic setup. CRIRs help the patient to optimise the perception by adjusting the gain and luminance range of the device and are a useful tool for clinicians to objectively assess the function of subretinal visual implants in vivo.

[Retinal and Cortical Activation by Electrical Stimulation with Retina Implants]. / Retinale und kortikale Aktivierung durch elektrische Stimulation mit Netzhautimplantaten.

In Germany, about 30,000 to 40,000 people suffer from retinitis pigmentosa (RP), which ultimately results in blindness. The only aid to blind RP patients are retinal implants: These have been under development for several years and have now been approved as a medical product. Retinal implants produce visual perceptions in response to electrical stimulation of the degenerated retina and are useful in the everyday life of blind people. However, the currently achievable quality of vision is such that people with a retinal implant are still legally blind. The visual quality that can be achieved with epi- and subretinal implants depends not only on patient-specific factors such as individual history and status of retinal degeneration, but especially on the interface between implant and retina and the quality of the achievable neuronal activation. Biophysical approaches to functional improvements of the implants are founded on the physiology of the retina (cell density, intraretinal interconnections), are based on technical optimisation of the interface (electrode materials, size and density), and exploit the stimulation protocols with which visual information is fed into the degenerated retina (time courses of electrical stimuli, spatiotemporal stimulation pattern). Optimisation of stimulation parameters can be supported by a detailed analysis of cortical responses, with appropriate electrophysiological and optical methods. This article looks at both the physiological and biophysical fundamentals of electrical retinal stimulation, as well as the resulting retinal and cortical activation.

Electrical multisite stimulation of the isolated chicken retina.

Visual prostheses such as subretinal implants are intended for electrical multisite excitation of the retinal network. To investigate relevant issues like spatial resolution and operational range, we have developed an in vitro method using microelectrode arrays to stimulate isolated retinae. Ganglion cell activity in the chicken retina evoked by distally applied spatial voltage patterns consisted of fast bursts, transient inhibition and delayed discharges, and depended on the amount, location and spatial pattern of the injected charge. The response was altered or disappeared when synaptic transmission was blocked. Our results indicate that shape perception and object location can be partially achieved with subretinal electrical multisite stimulation.

Can subretinal microphotodiodes successfully replace degenerated photoreceptors?

The idea of implanting microphotodiode arrays as visual prostheses has aroused controversy on its feasibility from the moment it appeared in print. We now present results which basically support the concept of replacing damaged photoreceptors with subretinally implanted stimulation devices. Network activity in degenerated rat retinae could be modulated through local electrical stimulation in vitro. We also investigated the long term stability and biocompatibility of the subretinal implants and their impact on retinal physiology in rats. Ganzfeld electroretinograms and histology showed no significant side effect of subretinal implants on retinal function or the architecture of the inner retina.

Patch-clamping of primary cardiac cells with micro-openings in polyimide films.

Patch-clamping is a powerful method for investigating the function and regulation of ionic channels. Currently, great efforts are being made to automate this method. As a step towards this goal, the feasibility of patch-clamping primary cells with a microscopic opening in a planar substrate was tested. Using standard microfabrication and ion beam technology, small-diameter openings (2 and 4 microm) were formed in polyimide films (thickness 6.5 microm). Single cells (sheep Purkinje heart cells, Chinese hamster ovary cells) in a suspension were positioned on top of the opening and sucked towards the opening to improve adhesion of the cell to the planar substrate, hence increasing the seal resistance. Voltage/current measurements yielded a median seal resistance of 1.3 Mohms with 4 microm openings (n=24) and 26.0 Mohms with 2 microm openings (n = 75), respectively. With 2 microm openings, successful loose-patch recordings of TTX-sensitive inward currents and action potentials in sheep Purkinje heart cells (n = 18) were made. In rare cases, gigaseals (n = 4) were also measured, and a whole-cell configuration (n = 1) could be established. It was concluded that the simple planar patch approach is suitable for automated loose-patch recordings from cells in suspension but will hardly be suitable for high-throughput whole-cell patch-clamping with high-resistance seals.

[Physiological functional evaluation of retinal implants in animal models]. / Physiologische Funktionsprüfungen von Retinaimplantaten an Tiermodellen.

Retinal implants can--by electrical stimulation--create visual impressions in people with certain kinds of degenerative retinal diseases (e.g. Retinitis Pigmentosa). Electrically evoked potentials in the retina must be transferred into the visual cortex in an orderly manner, a prerequisite for any kind of form- and movement-perception. In the current developmental stage the difficult investigations are performed in various animal models: isolated retinae of intact chicken and of RCS-rats (a model for Retinitis Pigmentosa), as well as in anesthetised rabbits, pigs and cats with intact retinae. Our investigations show that spatially selective ganglion-cell responses can be recorded following focal electrical stimulation, in healthy and as well in degenerated retinae. Registration of activities in area 17 of the visual cortex demonstrate that electrical retinal stimulation can indeed activate it.

[Subretinal microphotodiode array as replacement for degenerated photoreceptors?]. / Subretinales Mikrophotodioden-Array als Ersatz für degenerierte Photorezeptoren?

A survey is given on the status of developments, concerning a subretinal electronic microphotodiode array that aims at replacing degenerated photoreceptors. Various prototypes have been developed, tested, and implanted in various experimental animals up to 18 months. The fact that electrical responses were recorded from the visual cortex of pigs after electrical stimulation by subretinal electrodes and the fact that responses are also recorded in-vitro in degenerated rat retinae, shows the feasibility of this approach. However, there are a number of open questions concerning the biocompatibility, the long-time stability, and the type of transmitted image to be solved before application in patients can be considered.

The development of subretinal microphotodiodes for replacement of degenerated photoreceptors.

There are presently several concepts to restore vision in blind or highly visually handicapped persons by implanting electronic devices into the eye in order to partially restore vision. Here, the approach to replace retinal photoreceptors by a subretinally implanted microphotodiode array (MPDA) is summarized. A survey is given on the present state of the development of MPDAs, the possibility of in vitro and in vivo tests as well as first results on biocompatibility and histology. Additionally, electrophysiological recordings in rabbits and rats are presented which have received such subretinal implants.