Project Summary/Abstract Retinal degeneration leads to blindness due to loss of photoreceptors. However, a significant number of the inner retinal neurons survive to a large extent, providing an opportunity for a restoration of vision by electrical stimulation of these cells. We developed a photovoltaic substitute of the photoreceptors, which directly converts light into pulsed electric current in each pixel, stimulating the nearby second-order neurons. Clinical trial in patients blinded by atrophic Age-related Macular Degeneration confirmed the safety, stability of such implants and spatial resolution closely matching the 100µm pixel size. However, the current geometry of the flat bipolar pixels does not allow significant decrease of the pixel size due to rapid increase of the stimulation threshold with smaller pixels. We will develop three complimentary approaches to this challenge, which should enable decreasing the pixel size down to 20µm and thereby enable highly functional restoration of sight. Instead of using local return electrodes in each pixel of a bipolar design, we will use monopolar pixels whose active electrodes can serve as both, anodes and cathodes. In this design, the return current flows via dark pixels using integrated shunt resistors, which enables deeper penetration of electric field into the retina. In addition, we will use optically-controlled current steering for enhanced field confinement. It enables adjustment of the lateral and axial confinement of electric field in tissue by spatiotemporal optical modulation of the photovoltaic array. We will also use pillar electrodes: utilizing the migration of the inner retinal neurons into the voids in the subretinal implant, the stimulating electrode on top of a pillar gets closer to the target cells. This way, the stimulation threshold is decreased and selectivity of the bipolar cells stimulation increased. All three approaches can be combined, each already demonstrated very encouraging preliminary results, and now they will be developed to the full extent for eventual transition into clinical testing.