Artificial Vision: Testing of a Novel Electrical Stimulation Electrode Array and Optimization of Electrical Stimulation Parameters for Biomimetic Retinal Stimulation

Abstract

Electrical retinal implants aim to restore some artificial vision to patients, e.g., suffering from Retinitis Pigmentosa (RP), by electrically stimulating (e-stim) the remaining retinal network. Although implanted patients have demonstrated improvements in daily life activities, the implants face significant limitations in both temporal and spatial resolution. Over the last decade, optimizing stim paradigms has been the subject of several studies. However, many underlying mechanisms of retinal e-stim still remain unclear. Therefore, this project seeks to understand the effects of e-stim on the retina and to identify optimized stim strategies. By systematically investigating different stim paradigms in an appropriate RP mouse model, profound new insights were found. A newly methodical protocol was established. Degenerated mouse retinal explants were stimulated subretinally, and the evoked ganglion cell (GC) responses were recorded using Ca2+-imaging and MEA. This allowed a precise spatiotemporal analysis of the stim dependent GC activity and the investigation of the role of the neuromodulator Ca2+ in shaping GC responses. First, applying e-stim using the advanced chip layout of the RetinaSensor (dense electrode array; macro-electrodes are replaced by 6 circular arranged micro-electrodes) and activating the electrodes biomimetically could confine the GC activation spread to ~60 µm. Regarding optimized stim parameters, the systematic investigation of e-stim parameters showed the advantage of a biphasic cathodic-first pulse with the target- (stimulating) and counter- (opposite polarity as target) electrode being nearby in evoking GC responses. The significance of the target and counter-electrode positioning for future implants was further validated, as it was demonstrated that the cathode (negative electrode) elicited stronger GC responses compared to the anode (positive electrode). Moreover, applying different stim frequencies revealed a correlation between frequency, response strength and stim depth. Combined Ca2+-imaging with MEA spike recordings revealed that high-frequent stim (>5 Hz) clamped the intracellular Ca2+ electrogenically at elevated levels and lead to an outage of action potentials throughout sustained e-stim. Finally, the disintegration of the conventional 1 ms pulse into several 100 µs pulses lead to an increase in response variation within a voltage range of 0.4 V compared to e-implants, yielding higher variety in translating light intensities into e-stim. Overall, the stim strategies elaborated in this thesis combined with advanced implant design like RetinaSensor with biomimetic electrode activation will guide future studies in enhancing retinal responses spatiotemporally and be the next step to enhanced e-mediated artificial vision.

Dissertation ist gesperrt bis 22. Oktober 2027 !