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

PI：Li提案编号：1264772技术描述和智力价值：由于疾病(如青光眼)或创伤造成的视神经损伤通常会导致终生残疾，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觉丘脑的靶神经元获得的神经营养物质的运输减少所致。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形态。本研究的目的是探索一种治疗视神经损伤的创新策略，将眼部神经营养疗法与视觉皮质光刺激相结合，以促进内源性神经保护和视网膜神经节细胞(RGC)和视网膜功能的保存。据推测，与单独治疗眼睛相比，眼睛和视觉皮质的联合治疗提供了更显著和更持久的神经保护水平。具体地说，跨不同层的皮质神经元的光刺激将通过一种新型的三维(3-D)Opto-µECoG(皮层脑电)接口实现，该接口由多个微发光二极管(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。可单独寻址的µ-LED芯片与波导的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输到目标神经元。透明的硬膜外ECoG电极将允许实时监测视觉皮质中光诱导的神经活动。将使用体外原代皮质切片和在体大鼠模型来评估设计的Opto-µECoG接口的功能和可靠性。将评估光诱导的视觉丘脑的激活，如视觉丘脑神经元电活动的增强以及BDNFandits相关抗凋亡蛋白(ERK 1，2，PI3K/Akt，和CREB)水平的上调。在联合治疗后，还将通过比较动物眼睛的视网膜电信号反应和视觉皮质的视觉诱发电位，来研究联合治疗后增强的神经保护和视力保存。最终目标是开发基于光遗传学的治疗策略，不仅适用于视神经疾病，也适用于一般的其他脑损伤。PIS在生物医学微电子机械系统(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业知识，使该项目的实施成为可能。广泛影响：这项研究的科学影响包括：1)研究青光眼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做的，但拟议的治疗策略也可以用于治疗外伤性视神经损伤和其他脑损伤，如感觉障碍、帕金森氏症和抑郁症。这项工作给社会带来的最显著的长期好处包括降低了医疗保健成本，改善了受上述情况影响的相当大且不断增长的人口的生活质量。除了它的科学影响，这项工作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，并发展多种翻译和生物医学技能。为了接触到更多的受众，成果将通过科学博览会与学生分享，通过会议报告和期刊出版物与科学界分享，并通过展品与公众分享。由于微型设备和系统的视觉吸引力，综合外展计划将非常有效。课程的开发和改进将提供巨大的机会，向多个层次的学生介绍跨学科主题和动手实验经验。教育项目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)和内部项目(如密歇根州立大学的科学前沿)进行传播。这些努力将鼓励更多的学生从事研究工作，并最终培养出生物医学、神经科学和工程学方面的熟练和有知识的劳动力。

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.