A flexible, protein-based, ion-mediated retinal implant is proposed for the restoration of vision for patients with retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). The implant under development uses the retinal- containing protein, bacteriorhodopsin (BR), to convert light into a pH gradient. This gradient is capable of activating the neural circuitry of the retina, specificall the bipolar and ganglion cells. Bacteriorhodopsin is a light-driven proton pump isolated from a salt-marsh archaeon and this protein has a quantum efficiency nearly identical to rhodopsin, the protein in the rod outer segments of the eye. The high thermal and photochemical stability of BR make it an excellent candidate for use as the photoactive medium in a protein-based retinal implant. The implant will operate by using a local pH gradient to activate the neural circuitry of the retina by decreasing the pH in the milieu surrounding the remaining neural cells. The flexible implant under development can be activated by incident light to generate a visual response and will not require any external apparatus or wires, an advantage over competing electrode-based technologies. The experiments proposed in this Phase I research and development plan will determine the optimal number of protein layers, in addition to the lowest threshold of light energy required to activate 50% of bipolar cells. A subretinal orientation of the implant will be explored and tested on excised P23H rat retinas (model of human form of autosomal dominant RP) to collect relative activation efficiencies and evaluate spatiotemporal resolution. Activation of retinal ganglion cells will be verified through the use of extracellular recording experiments i collaboration with Dr. Ralph Jensen at the Boston VA Hospital. Secondly, an additional layer of substrate will be incorporated onto the device to seal the perimeter of the implant. This second layer will be used to encapsulate the biological components of the implant from the intraocular domain, and as a result, will enhance the biocompatibility of the implant and reduce the risk of inflammation or an immune response. Lastly, genetically engineered BR will be used to generate thin films that will then be tested on P23H rat retinas ex vivo. Thin films consisting of state mutants of BR will be explored to allow for the manipulation or elimination of extraneous pixels, which will facilitate selective tuning of the active area of the retinal implant. At the conclusion of this Phase I study, the best retinal implant design will be confirmed for use in subsequent in vivo animal experiments.
Public Health Relevance Statement: Public Health Relevance: Approximately 30-50 million humans are blinded due to retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). A light-activated, protein-based retinal implant is proposed to replace the functionality of the impaired photoreceptors and stimulate the neural circuitry of the retina. This protein-based retinal implant has the potential to restore vision to the millions of people affecte by AMD and RP.
Project Terms: Action Potentials; Adhesives; Age related macular degeneration; Animal Experiments; Animals; Archaea; Architecture; Area; Bacteriorhodopsins; base; Biocompatible; Biocompatible Materials; Biological; biomaterial compatibility; Blinded; Boston; Calibration; Cells; Collaborations; dacron; density; design; Development; Development Plans; Devices; Electrodes; Electrophysiology (science); Encapsulated; Evaluation; extracellular; Eye; Film; flexibility; ganglion cell; Genetic Engineering; Goals; Hospitals; Human; human tissue; Immune response; Implant; implantation; improved functioning; in vivo; Inflammation; Inflammatory; Ions; Light; light intensity; Mediating; Mediation; Medical Device; Methods; Modeling; mutant; neural circuit; Neurons; Optics; Patients; pH gradient; Phase; phase 1 study; Photoreceptors; polycation; Polymers; Preparation; Procedures; Process; Production; Property; Proteins; Proton Pump; prototype; public health relevance; quantum; Rattus; Relative (related person); Reproducibility; research and development; research study; Resolution; response; restoration; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; retinal stimulation; Retinitis Pigmentosa; Rhodopsin; Risk; Rod Outer Segments; Running; seal; Silicones; Sodium Chloride; Spatial Distribution; spatiotemporal; Sterilization; Surface; System; Techniques; Technology; Testing; Time; Vision; Visual
