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    373—Brain-Machine Interface III

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    373.13: A polymer-based interface restores light sensitivity in rat blind retinas

    Location: Halls B-H

    ">*D. GHEZZI1, M. ANTOGNAZZA2, M. METE3, G. PERTILE3, G. LANZANI2, F. BENFENATI1;
    1Dept. of Neurosci. and BrainTechnologies, Fondazione Inst. Italiano Di Tecnologia, Genova, Italy; 2Ctr. for Nano Sci. and Technology@PoliMi, Fondazione Inst. Italiano di Tecnologia, Milano, Italy; 3UO Oculistica, Ospedale S. Cuore-Don Calabria, Negrar, Italy

    Abstract Body: Sight restoration is one of the new frontiers for prosthetic devices that enable the electrical stimulation of neurons. In particular, diseases that affect the retinal pigment epithelium and photoreceptors but preserve the inner retinal layers are preferential targets for implantation of visual prostheses. We discovered that primary neurons can be successfully grown onto a photovoltaic organic polymer and electrically stimulated by light. This result encouraged us to test the efficacy of this method in retinas explanted from albino rats with reproducibly light-induced degeneration of the photoreceptor layer. Acutely dissected retinas were placed on the organic polymer in a sub-retinal configuration (i.e., external layers in contact with the polymer). Light stimulation of the degenerate retina was observed by monitoring multi-unit activity and field potentials with an extracellular electrode positioned in the retinal ganglion cell layer. Multi-unit activity recordings showed that a light stimulus 16-fold lower than the safe limit for pulsed illumination elicited intense spiking activity in degenerate retinas placed on polymer-coated substrates to levels indistinguishable from those recorded in control retinas. Moreover, to evaluate the efficiency of the interface, a dose-response analysis of spiking activity versus light intensity were performed in degenerate retinas. Spiking activity was observed in degenerate retinas over the polymer with a response threshold below 0.3 μW/mm2, a linear increase in a range corresponding to daylight irradiance, and a response saturation above 100 μW/mm2 (considered the safe limit for chronic illumination). A 4-fold increase in the amplitude of the light response at saturation and a significant left shift of the dose-response curves were obtained in retinas placed over the polymer-coated interface respect to degenerate retinas on glass substrates. Our finding indicates that the interface fully mimics functional photoreceptors in activating the processing of the inner retina and is able to rescue normal light sensitivity. These results broaden the possibility of developing a new generation of fully organic prosthetic devices for sub-retinal implants.
    Preliminary results after in-vivo implantation have been already obtained. We demonstrated the long-term tolerability of the organic prosthesis in the eye and its capability to restore light responses monitored by pupillary reflex and visually evoked field potentials in the primary visual cortex.

    Lay Language Summary: Our research indicates that organic materials, in particular photovoltaic semiconducting polymers, are suitable for the generation of a fully organic retinal prosthesis, to restore light sensitivity in blindness caused by photoreceptor degeneration.
    Progressive degeneration of photoreceptors is one of the major causes of adult blindness in “industrialized” countries; as an example, Retinitis pigmentosa defines a set of monogenic hereditary retinal diseases, with a prevalence of 1:4000 worldwide, caused by single mutations in over 150 genes. Moreover, it is thought that a significant number of implicated genes still await identification. This hinders the possibility to effectively cure Retinitis pigmentosa as well as many other retinal genetic diseases by gene therapy. Thus, alternative treatments have been attempted, including drug therapy, optogenetic manipulation, or stem/progenitor cells engrafting. However, despite the enormous efforts and advances in the clinical treatment of eye diseases and some encouraging results in animal models, there is currently no effective cure for the majority of genetic retinal diseases affecting photoreceptors including Retinitis pigmentosa.
    We demonstrated that neurons can be grown onto the semiconductor polymer layer, without affecting the optoelectronic properties of the active material or the physiology of the neuronal network over a long period of time. Moreover, we found that a light pulse is able to depolarize neurons and induce them to fire spikes up to 20 Hz with short peak latencies, negligible latency jitter, and limited number of failures only at illumination frequencies higher than 20 Hz. The spatial resolution of the stimulation paradigm was demonstrated to be in the order of the cell body (20 µm), in spite of the continuous layer of polymer, indicating that the photo-excitation is strictly confined to the illuminated area.
    We then investigated the ability of our polymeric device to restore light sensitivity in retinas explanted from rats bearing a light-induced degeneration of the photoreceptor layer. We documented that a light stimulus failed to induce spiking activity in degenerate retinas on glass substrates, while it elicited intense activity in control retinas. Strikingly, light-induced spiking activity was rescued in degenerate retinas placed onto the prosthesis to levels indistinguishable from those in control retinas.
    Following these promising results, we implanted the prosthesis in the eye of rats bearing photoreceptor degeneration due to mutation in the MERTK gene (RCS). These rats are a recognized animal model of human Retinitis pigmentosa. Preliminary experiments performed in a first cohort of animals show that the retina remains well attached over the entire region of the sub-retinal implant without inflammation or fibrosis. Moreover, the ability of the organic prosthesis to restore light sensitivity was first tested by monitoring the pupillary reflex. Pupil constriction in the implanted blind rat was similar to the response of the non-dystrophic animal and significantly higher than the non-implanted blind animal. Finally, visually evoked field potentials were detected in the visual cortex in implanted blind rats, whereas they were undetectable in the non-implanted animals.
    These results underline the feasibility of our approach, making it possible the realization of an organic prosthesis to restore vision in patients affected by photoreceptor degeneration.
    Since photoreceptor degeneration is associated with the preservation of the inner retina, many groups attempted restoration of vision using electrical stimulation of the remaining retinal network via prosthetic devices implanted either in the epi-retinal or sub-retinal position. However, with respect to traditionally adopted inorganic semiconductors and metals, the use of organic materials for implantation possesses several advantages: (1) an excellent biocompatibility, (2) the simplicity of the fabrication process, and (3) an excellent spatial resolution in stimulating the retina, as a consequence of the properties of the materials that generate a localized capacitive coupling with neurons.