Plasmonic Retinal Prosthesis

等离子视网膜假体

• 批准号: 10683362
• 负责人: Jonghwan Lee
• 金额: $ 44.18万
• 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/10683362
• 关键词: Action Potentials; Adverse effects; Affect; Age related macular degeneration; Animal Experiments; Animal Model; Biological Models; Biomedical Engineering; Biophysical Process; Blindness; Cells; Chemicals; Chemistry; Clinical; Custom; Development; Devices; Diameter; Disease; Electrodes; Electrophysiology (science); Eye; Eye diseases; Genetic; Heating; Ion Channel; Lasers; Light; Literature; Location; Mathematics; Membrane; Modeling; Modification; Mus; Nature; Nerve; Nervous System; Neural Retina; Neurons; Neurosciences; 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; Surgical complication; System; Technology; Temperature; Testing; Theoretical Studies; Time; Tissues; Toxic effect; Validation; Virus Diseases; Vision; Visual; Visual Cortex; Water; Work; absorption; chemical conjugate; 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; neural stimulation; neuroregulation; new technology; novel; optogenetics; particle; plasmonics; retinal neuron; retinal prosthesis; retinal stimulation; sight restoration; spatiotemporal; stem cell therapy; technology validation; 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，包括光遗传学刺激和干细胞疗法，只有 基于电极的视网膜假体已经验证了其临床前景，但它存在根本性问题。 局限性：装置植入手术复杂，数量有限且固定 刺激部位的位置，最重要的是，由于电流在其中传播，因此空间分辨率较低 十年前，红外光的光热刺激开启了这种可能性。 无需光遗传学的帮助，但红外光的强烈吸水性，“远程”激活神经元 导致大量组织发热和相关的不利影响，以实现细胞分辨率，“远程”神经。 无需大量加热即可激活，我们已经证明，结合使用金纳米颗粒和近 红外光（被水吸收可以忽略不计）可以通过表面等离子体共振产生高度局部化的热量， 这可以通过产生电容膜电流和/或打开温度敏感来激活神经元 我们还表明，纳米颗粒的适当化学结合进一步增强了离子通道。 然而，这种有前途的神经调节方法尚未发挥作用。 在这里，我们建议开发、优化和验证这部小说 技术，称为等离激元视网膜假体，并通过几个重要优势发挥其潜力 与基于电极的视网膜假体相比：（1）它不需要植入任何设备，但 仅涉及玻璃体内注射金纳米棒（AuNRs）；（2）可实现单细胞分辨率； 体内；（3）刺激位置或目标神经节细胞可自由调节；（4）可激活的数量； 每单位时间的神经元可以高达每秒 100,000 个神经元（在我们的试点设置中）；以及 (5) 性能； 随着相关技术的进步，“安装”后还可以进一步升级，因为每个关键部件 我们将通过理论研究、离体优化来开发这项有前景的技术。 首先，因为在任何新型神经接口中都必须有一个体内验证和长期测试。 精确的系统模型为了优化设计，我们将推进我们的数学神经模型 调查目前正在辩论的两个机制并确定以下的初始参数 接下来，使用我们集成扫描激光系统的定制实验装置进行动物实验。 和荧光显微镜，我们将开发和优化视网膜神经节神经元的单细胞刺激 带有基因编码 Ca2+ 指示剂的小鼠视网膜外植体，然后展示了图案化的 多神经元刺激和 AuNR 化学的优化（目标 2）。 实验和理论工作，在体内验证视网膜的图案化近红外刺激 视觉皮层的神经激活类似于自然视觉刺激，参数进一步优化， 并将进行纵向实验来观察和量化其长期功效和毒性（目标3）。

项目成果

Application of M1 macrophage as a live vector in delivering nanoparticles for in vivo photothermal treatment.

• DOI: 10.1016/j.jare.2021.01.010
• 发表时间: 2021-07
• 期刊: Journal of advanced research
• 影响因子: 10.7
• 作者: Im NR;Yang TD;Park K;Lee JH;Lee J;Hyuck Kim Y;Lee JS;Kim B;Jung KY;Choi Y;Baek SK
• 通讯作者: Baek SK

Label-free microendoscopy using a micro-needle imaging probe for in vivo deep tissue imaging.

使用微针成像探针进行体内深层组织成像的无标记显微内窥镜检查。

• DOI: 10.1364/boe.399428
• 发表时间: 2020
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Park,Kwanjun;Kim,JuneHoan;Kong,Taedong;Sun,Woong;Lee,Jonghwan;Yang,TaeseokDaniel;Choi,Youngwoon
• 通讯作者: Choi,Youngwoon

Increasing the antioxidant capacity of ceria nanoparticles with catechol-grafted poly(ethylene glycol).

用儿茶酚接枝聚乙二醇提高二氧化铈纳米颗粒的抗氧化能力。

• DOI: 10.1039/d2tb00779g
• 发表时间: 2022
• 期刊: Journal of materials chemistry. B
• 作者: Hu,Yue;Zhang,Qingbo;Garcia-Rojas,Daniel;Ling,Vivian;Masterson,CaitlinM;Bi,Yidan;Xiao,Zhen;Guo,Xiaoting;Villanova,Jake;Dunn,Joshua;Colvin,VickiL
• 通讯作者: Colvin,VickiL