Efficiency and Safety of Microstimulation Via Different Electrode Materials

摘要 我们实验室的长期目标是了解和表征微电极植入的效果， 神经性和非神经性脑组织的生理记录和刺激 细胞，以及提高神经植入物的生物兼容性、装置稳定性和性能 通过使用先进的材料和组织工程方法。父母的大脑的目标是 第一个R01项目是为了了解电荷转移、电化学和生物相容性 电极对微刺激的疗效和安全性。研究人员使用微刺激来推断 大脑结构之间的功能联系或结构和行为之间的因果联系。目前， 微刺激疗法对恢复视觉、听觉和躯体感觉功能越来越有兴趣 除了在生物电子医学中的应用之外。目前的神经刺激参数和安全限度是 初步建立在使用尸检组织学的宏观电极的基础上。它们应针对以下方面进行修订 使用捕捉神经组织健康和功能动态变化的技术的微电极。另一个 微刺激的挑战在于它对宿主组织反应的敏感性。电极植入引起 电极污垢、进行性神经元丢失和炎性胶质细胞增生症，导致刺激减少 长期植入后的疗效和阻抗增加。为了应对这些挑战，具体的 该项目的目标是评估神经刺激的急性有效性和安全限度，通过不同的 体内电极材料(目标1)，检测刺激对电极材料和培养细胞的影响 体外(目标2)，并表征不同来源的体内微刺激的慢性安全性和稳定性。 电极材料(目标3)。要求提供多样性补充资金，以支持研究和培训 安娜·凯利女士是匹兹堡大学生物工程系的应届毕业生。女士。 凯利将以毕业后研究助理的身份参与这项拟议的研究至少一年， 等待拨款批准。凯利女士将进行针对小鼠急性和慢性研究的研究 在家长奖的第一个和第三个具体目标中详细说明。在急性研究中，将植入微电极 进入表达基因编码的钙指示剂和/或基因标记的小胶质细胞的小鼠皮质 表达一种荧光蛋白。通过使用双光子显微镜，刺激阈值和疗效 将对电极材料和刺激参数进行评估。通过参与全面培训后 在这些实验中，凯利女士将进行她的独立项目，专门关注 血脑屏障和血管系统对微刺激的影响。特别是，这些研究将集中在潜在的 微刺激对细胞和/或血浆和蛋白质从血管系统及其后续的渗漏的影响 脑实质的反应，包括对周细胞形态和行为的潜在变化 血管相关的小胶质细胞，参与炎症反应中的血脑屏障渗漏。

Summary Our laboratory’s long-term goal is to understand and characterize the effects of microelectrode implantation, recording, and stimulation on brain tissue from a physiological perspective in both neuronal and non-neuronal cells, as well as to improve the biological compatibility, device stability, and performance of neural implants through the use of advanced materials and tissue engineering approaches. The goal of the parent BRAIN initiative R01 project is to understand the charge transfer, electrochemical, and biocompatibility properties of electrodes on the efficacy and safety of microstimulation. Researchers have used Microstimulation to infer functional connections between brain structures or causal links between structure and behavior. Currently, microstimulation therapy is gaining interest for the restoration of visual, auditory, and somatosensory functions in addition to applications in bioelectronic medicine. Current neural stimulation parameters and safety limits were primarily established based on macro electrodes using postmortem histology. They should be revised for microelectrodes using technologies that capture dynamic changes to neural tissue health and function. Another challenge with micro-stimulation is its susceptibility to host tissue responses. Implantation of electrodes causes electrode fouling, progressive neuronal loss, and inflammatory gliosis, leading to decreased stimulation efficacy and increased impedance over long-term implantation. To address these challenges, the specific objectives of this project are to assess the acute efficiency and safety limit of neural stimulation via different electrode materials in vivo (Aim 1), examine the effects of stimulation on electrode materials and cultured cells in vitro (Aim 2), and to characterize the chronic safety and stability of microstimulation in vivo from different electrode materials (Aim 3). Diversity supplement funding is requested to support the research and training of Ms. Anna Kelly, who is a recent graduate of the Bioengineering Department at the University of Pittsburgh. Ms. Kelly will participate in the proposed research as a post-baccalaureate research assistant for at least one year, pending grant approval. Ms. Kelly will conduct research directed toward both acute and chronic mouse studies detailed in the parent award's first and third specific aims. In the acute studies, microelectrodes will be implanted into the cortices of mice expressing genetically encoded calcium indicators and/or genetically labeled microglia expressing a fluorescent protein. Through the use of 2-photon microscopy, the stimulation threshold and efficacy of electrode materials and stimulation parameters will be assessed. After comprehensive training via participating in these experiments, Ms. Kelly will conduct her independent project focusing specifically on the response of the blood-brain barrier and vasculature to microstimulation. In particular, these studies will focus on the potential effect of microstimulation on the leakage of cells and/or plasma and protein from the vasculature and the ensuing response in the brain parenchyma, including potential changes to the morphology and behavior of pericytes and vascular-associated microglia, which have been implicated in BBB leakage in response to inflammation.