Implantable Three-dimensional Opto-uECoG Interface for Neuroprotection and Restoration of Vision in Glaucoma

主要研究者：Li提案编号：1264772技术描述和知识产权：由于疾病（如青光眼）或创伤造成的视神经损伤通常导致终身残疾，目前大多数是无法治愈的。视神经损伤后神经节细胞的退行性变性被认为主要是由于这些神经元从其视丘脑中的靶神经元获得的神经营养物质的运输减少。目前基于神经营养因子的治疗不足以提供长期的神经保护，并且可以在转导和非转导的神经细胞中产生异常的树突状形态。这项研究的目的是研究一种治疗视神经损伤的创新策略，将眼睛的神经营养治疗与视觉皮层的光学刺激相结合，以促进内源性神经保护和视网膜神经节细胞（RGC）和视网膜功能的保护。据推测，与单独治疗眼睛相比，眼睛和视觉皮层的联合治疗提供了更显著和持续的神经保护水平。具体来说，将通过一种新型的三维（3-D）Opto-µECoG（皮层电图）接口实现对不同层皮层神经元的光学刺激，该接口由多个微型发光二极管（µ-LED）光源、平面外微尺度聚合物波导和单个柔性聚合物平台上的透明µECoG电极组成。将可单独寻址的µ-LED芯片与波导集成将有助于最大限度地减少脑组织内的LED光散射，以实现高空间分辨率和精确的光传递到目标神经元。透明的硬膜外ECoG电极将允许在视觉皮层中的光诱导的神经活动的实时监测。工程Opto-µECoG接口的功能和可靠性将使用体外原代皮质切片和体内大鼠模型进行评估。将评估视觉丘脑的光诱导激活，如通过视觉丘脑中神经元的增强的电活动以及BDN Fandits相关抗凋亡蛋白的上调水平所指示的（ERK 1、2、PI 3 K/Akt和CREB）。还将在具有视神经创伤的大鼠模型中研究联合治疗后增强的神经保护和视力保护，通过比较动物眼的视网膜电图反应和视觉皮层的视觉诱发电位。最终目标是开发基于光遗传学的治疗策略，不仅用于视神经病变，还用于其他脑损伤。PI在生物医学微机电系统（BioMEMS）、神经工程和神经生理学领域建立了合作和互补的研究专长，这使得该项目在执行中可行。更广泛的影响：该研究的科学影响包括：1）研究青光眼患者神经保护和恢复的变革性治疗策略，2）开发基于光遗传学的工程工具，用于与神经元的无缝通信，以及3）深入了解创伤诱导的细胞变性和神经保护的机制。虽然它是专门为青光眼治疗量身定制的，但所提出的治疗策略也可用于治疗创伤引起的视神经损伤和其他脑损伤，如感觉缺陷、帕金森病和抑郁症。这项工作对社会最显著的长期效益包括降低医疗保健费用和改善受上述疾病影响的大量和不断增长的人口的生活质量。除了其科学影响外，这项工作还将为本科生和研究生提供独特的研究经验，以了解不同学科的技术细节，并培养多种转化生物医学技能。为了接触更多的受众，将通过科学博览会与学生分享成果，通过会议介绍和期刊出版物与科学界分享成果，并通过展览与公众分享成果。由于微型设备和系统的视觉吸引力，综合推广计划将非常有效。课程的发展和改进将提供巨大的机会，介绍跨学科的主题和动手实验经验，以学生在多个层次。教育计划的结果将通过内部和外部评估人员进行评估，并通过会议（如ASEE，FIE和MEMS）和内部计划（如科学前沿）进行传播。这些努力将鼓励更多的学生从事研究工作，并最终为生物医学，神经科学和工程培养熟练和知识渊博的劳动力。

PI: Li Proposal No: 1264772 Technical Description and Intellectual Merit: Optic nerve injuries due to diseases (e.g. glaucoma) or trauma often result in lifelong disabilities, and at present most are incurable. Retrograde degeneration of ganglion cells following optic nerve injuries is believed to result primarily from a reduction in the transport of neurotrophic materials these neurons obtain from their target neurons in the visual thalamus. Current neurotrophic factor-based treatments are inadequate to provide long-term neuroprotection and can produce abnormal dendritic morphology in both transduced and non-transduced nerve cells. The objective of this proposed research is to investigate an innovative strategy for treatment of optic nerve injuries, combining neurotrophic therapy of the eye with optical stimulation of the visual cortex to promote endogenous neuroprotection and preservation of retinal ganglion cells (RGC) and retinal function. It is hypothesized that combined treatment of both the eye and visual cortex provides a more significant and sustained level of neuroprotection as compared to treating the eye alone. Specifically, optical stimulation of cortical neurons across different layers will be achieved via a novel three-dimensional (3-D) Opto-µECoG (electrocorticography) interface, which consists of multiple micro light emitting diode (µ-LED) light sources, out-of-plane microscale polymer waveguides, and transparent µECoG electrodes on a single flexible polymer platform. Integration of individually addressable µ-LED chips with waveguides will help minimize the LED light scattering within brain tissue to achieve high-spatial resolution and precise light delivery to the target neurons. The transparent epidural ECoG electrodes will permit real-time monitoring of light-induced neural activity in visual cortex. The functionality and reliability of the engineered Opto-µECoG interface will be evaluated using both in-vitro primary cortical slices and in vivo rat models. Light-induced activation of the visual thalamus will be assessed, as indicated by enhanced electrical activity of neurons in the visual thalamus as well as up-regulated levels of BDN Fandits associated anti-apoptotic proteins (ERK 1,2, PI3K/Akt, and CREB).Enhanced neuroprotection and preservation of vision following the combined treatment will also be investigated ina rat model with optic nerve trauma, by comparing electroretinographic responses from animal eyes and vision-evoked potentials from visual cortex. The ultimate goal is the development of optogenetics-based treatment strategies not only for optic neuropathies, but also for other brain injuries in general. The PIs have established collaborations and complementary research expertise in the areas of biomedical microelectrome chanical systems (BioMEMS), neural engineering, and neurophysiology, which make this project viable in its execution.Broader Impacts: The scientific impacts of this research include: 1) investigation of a transformative treatment strategy for neural protection and restoration in eyes with glaucoma, 2) development of optogenetics-based engineering tools for seamless communication with neurons, and 3) in-depth understanding of the mechanisms of trauma-induced cellular degeneration and neuroprotection. While it is specifically tailored for glaucoma treatment, the proposed treatment strategy can also be used to treat trauma-induced optic nerve injuries and other brain injuries such as sensory deficits, Parkinson's disease, and depression. The most pronounced long-term benefits of this work to society include a reduction of healthcare cost and quality of life improvement for a sizeable, and growing, population affected by the above conditions. In addition to its scientific impacts, this work will offer unique research experiences for undergraduate and graduate students to understand technical details of different disciplines and develop multiple, translational, biomedical skills. To reach larger audiences, the results will be shared with students through science fairs, with scientific communities through conference presentations and journal publications, and with the public through exhibits. The integrated outreach program will be very effective due to the visually appealing nature of microscale devices and systems. The curriculum development and improvement will provide tremendous opportunities to introduce interdisciplinary topics and hands-on experimental experiences to students at multiple levels. The results of the educational programs will be assessed through internal and external evaluators and disseminated through conferences (e.g. ASEE, FIE and MEMS) and in-house programs, such as Frontiers in Science, at MSU. These efforts will encourage more students to pursue careers in research and ultimately produce skilled and knowledgeable workforces for biomedical, neural science, and engineering.