Anti-Inflammatory Microgel Coatings for Neural Electrodes

描述（由申请人提供）：神经假体装置具有恢复感觉丧失、脊髓损伤和某些影响脑功能和身体信号的神经系统疾病患者功能的潜力。阻碍有效的长期神经假体装置发展的一个主要问题是缺乏在生物环境中长时间工作的电极。目前，长期植入的电极会引起周围组织的免疫反应，从而促进炎症和疤痕的形成，形成一个屏障，可以阻止神经元和电极之间的电信号传递。这种封锁阻止信号到达电极表面，使器件无用。我们正在为神经电极设计无污染的微凝胶涂层，该涂层含有酶可切割序列（ECS），可以根据周围组织环境的炎症反应按需释放抗炎剂（AIA）。AIAs将有助于减少电极周围区域的炎症和随后的疤痕形成。通过介导疤痕的形成，我们假设神经元和电极之间的电信号通信可以维持，延长装置在体内的使用寿命。这项研究将有利于监测大脑电信号的应用，以及由电极向周围神经元提供刺激的应用。为了开发一种能够长期保持功能的有效电极，我们将把ECS与栓系AIAs结合到微凝胶系统中。这些ECS将包括对凝血酶、MMP-9和MMP-2增加的刺激依赖性反应，这些反应存在于短期、中期和长期炎症中。ECS的按需反应是创新的，因为它允许AIAs根据周围区域存在的炎症量进行控制释放。AIA试验将包括皮质类固醇、蛋白质和小分子。每个ECS将与每个AIA结合，所有迭代将在包括小胶质细胞，星形胶质细胞和神经元的3D共培养系统中进行测试。ECS和AIA的最佳组合将在体内大鼠模型中进行测试，并与未涂覆的电极数据进行比较，使用免疫组织化学分析和神经记录来分析微凝胶涂层在减少长期植入神经电极周围瘢痕形成方面的有效性。

DESCRIPTION (provided by applicant): Neuroprosthetic devices have the potential to restore functionality to patients with sensory loss, spinal cord injuries, and certain neurological diseases that affect brain function and signaling to the body. One major issue preventing the development of effective long-term neuroprosthetic devices is the lack of electrodes that function for long periods of time in the biological environment. Currently, chronically implanted electrodes evoke an immune response from surrounding tissue which promotes inflammation and scar formation, presenting a barrier that can block electrical signal transfer between neurons and the electrode. This blockade prevents signals from reaching the electrode surface, rendering the device useless. We are engineering non-fouling microgel coatings for neural electrodes that contain enzyme-cleavable sequences (ECS) to release anti-inflammatory agents (AIA) in an on-demand fashion in response to inflammation in the surrounding tissue environment. The AIAs will serve to reduce inflammation and subsequent scar formation that occurs in the area surrounding the electrode. By mediating scar formation, we hypothesize that electrical signal communication between neurons and electrode can be maintained, extending the lifetime of the device in vivo. This research will be beneficial for applications involving monitoring of electrical signals in the brain, as well as applications where stimulation is provided by the electrode to surrounding neurons. In order to develop an effective electrode that can maintain functionality for long-term use, we will incorporate ECS with tethered AIAs into the microgel system. These ECS will incorporate a stimulus-dependent response to increases in thrombin, MMP-9, and MMP-2, which are present in short-, mid-, and long-term inflammation. The on-demand response of the ECS is innovative because it allows for controlled release of the AIAs in response to the amount of inflammation that is present in the surrounding area. AIA trials will include corticosteroids, proteins, and small molecules. Each ECS will be combined with each AIA, and all iterations will be tested in a 3D co-culture system that includes microglia, astrocytes, and neurons. The best performing combinations of ECS and AIA will then be tested in an in vivo rat model and compared to uncoated electrode data analyzed using immunohistochemical analysis and neural recordings to demonstrate the increased effectiveness of the microgel coatings for reducing scar formation around chronically implanted neural electrodes. PUBLIC HEALTH RELEVANCE: This project is important for improving public health because the research conducted as part of this proposal will help to improve the functionality of neural electrodes that are implanted in the brain for long periods of time. The new polymer coatings applied to these neural electrodes will utilize an on-demand response to mediate the inflammation that occurs after implantation and allow electrodes to receive electrical (neural) signals for longer periods of time than with standard uncoated electrodes.