Plasmonic Retinal Prosthesis

等离子视网膜假体

• 批准号: 10237893
• 负责人: Jonghwan Lee
• 金额: $ 47.67万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237893
• 关键词: Action Potentials; Adverse effects; Affect; Age related macular degeneration; Animal Experiments; Animal Model; Biological Models; Biomedical Engineering; Biophysical Process; Blindness; Caliber; Cells; Chemicals; Chemistry; Clinical; Custom; Development; Devices; Disease; Electrodes; Electrophysiology (science); Eye; Eye diseases; Genetic; Gold; Heating; Ion Channel; Lasers; Light; Literature; Location; Mathematics; Membrane; Modeling; Modification; Mus; Nature; Nerve; Nervous system structure; Neural Retina; Neurons; Neurosciences; Operative Surgical Procedures; Ophthalmology; Patients; Pattern; Penetration; Performance; Physiologic pulse; Resistance; Resolution; Retina; Retinal Degeneration; Retinal Ganglion Cells; Retinitis Pigmentosa; Safety; Scanning; Site; Spottings; Stargardt' s disease; Surface Plasmon Resonance; System; Technology; Temperature; Testing; Theoretical Studies; Time; Tissues; Toxic effect; Validation; Virus Diseases; Vision; Visual; Visual Cortex; Water; Work; absorption; base; clinical application; clinical development; design; efficacy validation; experimental study; fluorescence imaging; fluorescence microscope; ganglion cell; implantation; improved; in vivo; instrument; intravitreal injection; minimally invasive; multidisciplinary; nanoGold; nanoparticle; nanorod; nanotoxicology; neural stimulation; neuroregulation; new technology; novel; optogenetics; particle; plasmonics; relating to nervous system; retinal neuron; retinal prosthesis; retinal stimulation; sight restoration; spatiotemporal; stem cell therapy; visual stimulus

SUMMARY Among various approaches to restore vision, including optogenetic stimulation and stem cell therapy, only the electrode-based retinal prosthesis has validated its clinical promises. However, it suffers from fundamental limitations: it requires a complicated surgery for device implantation, has both the limited number and fixed location of stimulation sites, and above all, has a low spatial resolution since electric currents spread in conductive media like the retina. A decade ago, photothermal stimulation with infrared light opened the possibility of ‘remotely’ activating neurons without the aid of optogenetics, but the strong water absorption of infrared light leads to bulk tissue heating and associated adverse effects. To enable cellular-resolution, ‘remote’ neural activation without the bulk heating, we have demonstrated that a combined use of gold nanoparticles and near- infrared light (negligibly absorbed by water) can produce highly-localized heat via surface plasmon resonance, and this can activate neurons by generating capacitive membrane currents and/or opening temperature-sensitive ion channels. We also have shown that appropriate chemical conjugation of nanoparticles further enhances the efficacy of near-infrared stimulation. This promising neuromodulation approach, however, has yet not demonstrated its potential as a retinal prosthesis. Here, we propose to develop, optimize, and validate this novel technology, termed plasmonic retinal prosthesis, and compose its potential with several important advantages when compared to the electrode-based retinal prostheses: (1) it does not require any device implantation but only involves intravitreal injection of gold nanorods (AuNRs); (2) the single-cell resolution can be achieved in vivo; (3) stimulation locations or targeted ganglion cells are freely adjustable; (4) the number of activatable neurons per unit time can be as high as 100,000 neurons per second (in our pilot setup); and (5) the performance is further upgradable after ‘installation’ as the relevant technologies advance because every key component locates outside the eye. We will develop this promising technology through theoretical study, ex vivo optimization, in vivo validation, and long-term testing. First, since it is essential in any novel neural interface to have an accurate model of the system in order to optimize the design, we will advance our mathematical neuron model to investigate two mechanisms currently under debate and determine the initial parameters for the following animal experiments (Aim 1). Next, using our custom experimental setup that integrates a scanning laser system and fluorescence microscope, we will develop and optimize single-cell stimulation of retinal ganglion neurons in retina explants of mice with genetically-encoded Ca2+ indicators, followed by both the demonstration of patterned multi-neuron stimulation and the optimization of AuNR chemistry (Aim 2). Finally, we will integrate our experimental and theoretical work to validate in vivo that patterned near-infrared stimulation of the retina induces neural activation in the visual cortex similar to natural visual stimuli, with the parameters being further optimized, and will perform a longitudinal experiment to observe and quantify its long-term efficacy and toxicity (Aim 3).

概括 在恢复视力的各种方法中，包括光遗传学模拟和干细胞疗法，仅 基于电极的视网膜假体已验证其临床承诺。但是，它遭受了基本的影响 局限性：需要进行复杂的设备植入手术，同时具有有限的数量和固定 刺激位点的位置，最重要的是，由于电流扩散，因此具有低空间分辨率 像视网膜这样的导电媒体。十年前，红外光的光热刺激打开了可能性 无需光遗传学的“远程”激活神经元，但强烈的红外水滥用 导致散装组织加热和相关的不良反应。为了启用细胞分辨率，“远程”神经元 激活没有大量加热，我们已经证明了金纳米颗粒和接近 - 红外光（用水吸收的可忽略）可以通过表面等离子体共振产生高度定位的热量， 这可以通过产生电容膜电流和/或开放温度敏感来激活神经元 离子通道。我们还表明，适当的纳米颗粒化学结合进一步增强了 近红外刺激的功效。然而，这种承诺的神经调节方法尚未 证明了其作为视网膜假体的潜力。在这里，我们建议开发，优化和验证这部小说 技术称为血浆式视网膜假体，并具有几个重要优势的潜力 与基于电子的视网膜假体相比：（1）它不需要任何设备植入 仅涉及玻璃体内注射金纳米棒（Aunrs）； （2）可以在 体内（3）刺激位置或靶向神经节细胞可自由调节； （4）可激活的数量 每单位时间神经元每秒的神经元高达100,000个神经元（在我们的飞行员设置中）； （5）表演 随着相关技术的推进，“安装”后可以进一步升级，因为每个关键组件 位于眼外。我们将通过理论研究，实体优化开发这项有前途的技术， 体内验证和长期测试。首先，因为在任何新型神经界面中都必须具有 系统的准确模型为了优化设计，我们将推进数学神经元模型 调查当前正在争论的两种机制，并确定以下的初始参数 动物实验（目标1）。接下来，使用我们集成扫描激光系统的自定义实验设置 和荧光显微镜，我们将开发并优化残留神经神经元中的单细胞刺激 带有一般编码的Ca2+指标的小鼠的视网膜外植体，然后是图案的演示 多神经元刺激和Aunr化学的优化（AIM 2）。最后，我们将整合我们的 实验和理论工作以验证体内构成视网膜近红外刺激的体内 视觉皮质中的神经激活类似于天然的视觉刺激，参数进一步优化， 并将进行纵向实验，以观察和量化其长期效率和毒性（AIM 3）。