Photovoltaic stimulation of retinal ganglion cells with wide-field epiretinal prosthesis

Retinal prostheses have become in the past decade a promising and realistic technology to restore vision. Nonetheless, sight restoration with retinal prostheses in a clinically relevant perspective requires resolution and implantation challenges not yet achieved. Our goal is the development of a foldable and wide field-retinal prosthesis capable of achieving a wireless photovoltaic stimulation of retinal ganglion cells and restore at least 40° of visual field, though being injectable trough minimal incision. The 2345 organic photovoltaic stimulating pixels of our retina prosthesis are distributed into biomimetic pattern within an active area of 13 mm (44° of visual field) and the light-triggered current profile generated by those pixels shows a reproducible ability to elicit activity in explanted rodents’ retinas mimicking human retina dystrophies. Extracellular recordings of prosthetic-evoked spiking activity of retinal ganglion cells reveal both direct and network-mediated stimulation when the degenerating retina circuit is explanted on top of the stimulating device, while when retinas are layered on bare PDMS substrates, any light-evoked pattern of response can be detected among retina spontaneous activity. Screening of different conditions of illumination (pulse duration and intensity) with Rd10 retinas explanted on our prosthesis shows a direct activation from the minimal radiant exposure tested - that is 7 times smaller than the maximum permissible retinal irradiance allowed for ophthalmic applications in this case- while network-mediated activation requires higher light exposure and can be supressed using synaptic blockers. The clinical compliance of the so-designed prosthesis and those preliminary results on explanted retinas represent a step forward in building wide-field photovoltaic retinal prostheses.

Photovoltaic stimulation of retinal microcircuit for vision restoration

Naïg Aurelia Ludmilla Chenais

Sight restoration through retinal prostheses was still a mere dream a century ago. Current challenges are even greater: providing a quantitatively and qualitatively useful artificial vision to late blind patients. Existing approaches all face engineering and biological questions which directly threaten the quality of the restored vision. Compromises made on stiff materials or external powering restrain the restored visual field and the stimulation resolution. Epiretinal implants are large but offer limited resolution, and stimulate retinal ganglion cell non-specifically through multiple compartments, including distal axons. Subretinal and suprachoroidal implants are limited in size but rely on inner retina activation: it allows to preserve most of spatial and temporal properties of the sighted response, but neurons' responsivity rapidly wanes. Axonal activation and desensitization hamper the spatiotemporal properties of the perceived phosphenes. High-level perceptual mechanisms can resolve the missing piece of information, but require a high cognitive load: a too high price to pay for implants recipients to adapt and use artificial vision on day to day life. Current visual prostheses do not rescue vision as a primary sense in implanted patients. A 20/200 visual acuity, together with a 30 to 40° visual field and qualitative properties as close as possible to patients' early visual experience are the minimal requirements for a useful prosthetic approach. The introduction of light-powered electronics represents a step forward in biomimetic retinal activation, but it is not fully emancipated from power supply and limited coverage concerns. The use of organic semiconductors allows to fabricate flexible p-n junctions that can be embedded into a large hemispherical epiretinal implant. Such a photovoltaic array can cover 45° of visual angle, and total up to 10'498 pixels. Complementary to this high-density and wide-field implant engineering, investigations on retinal network activation allow to design network-oriented photovoltaic stimulation paradigms. Strategies that factor the intrinsic connectivity and properties of retinal neurons - convergence, lateral inhibition and adaptation mechanisms - permit to take advantage of the retinal microcircuit organization. A wide-field photovoltaic epiretinal approach could restore peripheric vision with native visual acuity in Retinitis Pigmentosa patients, as well as a theoretical 20/480 foveal visual acuity. The high resolution of the stimulation has been electrophysiologically evaluated in-vitro; photovoltaic stimulation of degenerating mouse retinas revealed that the non-rectangular photovoltage delivered under 560 nm illumination was prone to recruit inner excitatory and inhibitory circuits from the epiretinal side. This allows first to avoid uncontrolled axonal stimulation of retinal ganglion cells, second to preserve the intrinsic processing, and third to benefit from natural lateral response segregation. In addition, delivering light stimuli in a non-stationary manner that micmics fixational saccades allows to reduce neurons' desensitization. The proposed approach, that combines withstanding organic photovoltaic prosthesis, and naturalistic epiretinal stimulation paradigm, could allow to stimulate human parasol cells with a natural spatial resolution and limit the need of head scanning. Both points are critical for motion perception, self-orientation and ambulation in late blind patients.

EPFL2021

A comprehensive study of neural retina stimulation towards better visual prosthesis resolution

Marta Jole Ildelfonsa Airaghi Leccardi, Naïg Aurelia Ludmilla Chenais, Laura Ferlauto, Diego Ghezzi

A major obstacle to make retinal prostheses a realistic technology to restore a functional form of vision allowing normal mobility is the low resolution achieved by current devices. Aims. Using photovoltaic pixels based on organic materials, we aimed at building a wireless high-density epiretinal prosthesis able to restore a theoretical visual acuity of 20/600. Our high-resolution stimulation device also makes it possible to dissect the retinal circuitry activation under spatially confined stimulus to further investigate the mechanisms of neural response clustering. Methods. Extracellular recordings of photovoltaic prosthetic-evoked spiking activity were conducted on explanted Rd10 mice retinas upon increasing exposure conditions. A quantitative analysis of RGCs’ direct and indirect activation thresholds was performed using a custom-made MEA. Both square pulses and continuous photovoltage profiles, measured on top of photovoltaic pixels, were used as stimulation waveforms. Results. Direct and network-mediated light-evoked responses were both detected in retinas explanted on the photovoltaic pixels. Moreover, significant differences in the activation thresholds were observed between photovoltage pulses and square pulses injection. Conclusions. Both photovoltaic stimulation and electrical injection of light-triggered voltage profiles elicited a reproducible activity in explanted dystrophic retinas. Besides, the use of capacitive voltage profiles generated by the photovoltaic device enabled to lower the threshold for INL-mediated RGCs activation. Our results provide interesting insights for the use of non-diraquien pulses in neural tissues stimulation. They also suggest that the promotion of epiretinal indirect RGCs’ excitation could have a beneficial effect on the spatial confinement of the neural retina’s response to prosthetic stimulation.

2018

Injectable, Self-opening, and Freestanding Retinal Prosthesis for Fighting Blindness

Marta Jole Ildelfonsa Airaghi Leccardi, Laura Ferlauto, Diego Ghezzi, Kevin Sivula

Purpose:In the past decade, retinal prostheses emerged as promising technology to restore a primitive, although clinically useful, form of vision. However, fighting blindness with retinal prostheses require challenges not yet achieved. From a clinical perspective, sight restoration requires to reach two main goals: enlarging the visual field of the patient and improving its visual acuity. From the engineering point of view, these needs demand the overcoming of two major issues: implanting a prosthesis (i) large enough to cover the retinal surface and (ii) embedding a high number of highly dense stimulatory elements. Our goal is the development of an injectable, self-opening, and freestanding retinal prosthesis restoring at least 40° of visual field, therefore covering at least a retinal surface of 12 mm in diameter. Moreover, the prosthesis must have a hemispherical shape in order to minimize the distance from the targeted cells over its entire surface, it should operate according to a photovoltaic stimulation principle and it must be injected trough a minimal scleral incision. Methods:Using solution processes and micro-fabrication techniques, we designed a retinal prosthesis based on polydimethylsiloxane (PDMS) as shell material, embedding photovoltaic pixels made of conjugated polymers. The prosthesis is shaped with a molding technique. Results:The prosthesis consists in a photovoltaic PDMS-interface, embedding 2345 organic stimulating pixels (100 µm and 150 µm in diameter, density 54.34 px/mm2) with a biomimetic distribution in an active area of 13 mm (44° of visual field). Our results indicate that those photovoltaic pixels can deliver up to 54.22±10.55 mA/cm2 and generate an electrode potential of 182.22±6.72 mV when illuminated with a pulse light of 10 ms, 32.47 µW/mm2, at 530 nm. Sample tested n = 20. Accelerated aging tests and experiments with explanted retinas are currently under evaluation. Conclusions:These preliminary results show the potential of organic photovoltaic technology in the fabrication of a retinal prosthesis with large surface area and high stimulation efficiency. The biocompatibility and mechanical compliance of the materials represent an additional step forward in building advanced photovoltaic retinal prostheses.

2017