Flexible Ion-Mediated Artificial Retina

描述（由申请人提供）：提出了一种柔性的、基于蛋白质的、离子介导的视网膜植入物，用于恢复患有视网膜退行性疾病（例如年龄相关性黄斑变性（AMD）和色素性视网膜炎（RP））的患者的视力。正在开发中的植入物使用含视网膜的蛋白质细菌视紫红质（BR）将光转化为pH梯度。这种梯度能够激活视网膜的神经回路，特别是双极细胞和神经节细胞。细菌视紫红质是一种从盐沼古菌中分离出来的光驱动质子泵，这种蛋白质的量子效率几乎与视紫红质相同，视紫红质是眼睛外节的蛋白质。BR的高热和光化学稳定性使其成为蛋白质视网膜植入物中用作光活性介质的优秀候选物。植入物将通过使用局部pH梯度来操作，以通过降低剩余神经细胞周围环境中的pH来激活视网膜的神经回路。正在开发中的柔性植入物可以通过入射光激活以产生视觉反应，并且不需要任何外部设备或电线，这是与基于电极的竞争技术相比的优势。 第一阶段研发计划中提出的实验将确定蛋白质层的最佳数量，以及激活50%双极细胞所需的最低光能阈值。将在切除的P23 H大鼠视网膜（人类常染色体显性RP模型）上探索和测试植入物的视网膜下方向，以收集相对激活效率并评价时空分辨率。将通过与Boston VA医院的Ralph詹森博士合作使用细胞外记录实验来验证视网膜神经节细胞的激活。其次，将在器械上加入额外的基底层，以密封植入物的周边。该第二层将用于从眼内区域包封植入物的生物组分，因此，将增强植入物的生物相容性并降低炎症或免疫反应的风险。最后，基因工程BR将用于产生薄膜，然后在P23 H大鼠视网膜上进行体外测试。将探索由BR的状态突变体组成的薄膜，以允许操纵或消除无关像素，这将有助于视网膜植入物的活性区域的选择性调谐。在本I期研究结束时，将确认最佳视网膜植入物设计用于随后的体内动物实验。

DESCRIPTION (provided by applicant): 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.