Anti-Inflammatory Microgel Coatings for Neural Electrodes

描述(申请人提供)：神经假体设备有可能恢复感觉丧失、脊髓损伤和某些神经疾病患者的功能，这些疾病会影响大脑功能和对身体的信号。阻碍开发有效的长期神经假体装置的一个主要问题是缺乏在生物环境中长期发挥作用的电极。目前，长期植入的电极会激发周围组织的免疫反应，促进炎症和疤痕的形成，形成一种屏障，可以阻止神经元和电极之间的电信号传输。这种封锁阻止了信号到达电极表面，使设备变得毫无用处。我们正在为神经电极设计无污染微凝胶涂层，该涂层包含酶可裂解序列(ECS)，可按需释放抗炎剂(AIA)，以应对周围组织环境中的炎症。AIAS将有助于减少电极周围区域发生的炎症和随后的疤痕形成。通过调节瘢痕的形成，我们假设神经元和电极之间的电信号通信可以保持，从而延长了装置在体内的寿命。这项研究将有益于涉及监测大脑电信号的应用，以及通过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使用的有效电极，我们将在微凝胶系统中加入ECS和栓系AIAS。这些内皮细胞将结合对凝血酶、基质金属蛋白酶-9和基质金属蛋白酶-2升高的刺激依赖性反应，这些物质存在于短期、中期和长期炎症中。ECS的按需反应是创新的，因为它允许AIAS的受控释放，以回应周围区域存在的炎症数量。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。然后，将在活体大鼠模型中测试ECS和AIA的最佳组合，并与使用免疫组织化学分析和神经记录分析的未涂覆电极数据进行比较，以证明微凝胶涂层在减少长期植入的神经电极周围的疤痕形成方面具有更高的有效性。 公共卫生相关性：该项目对改善公共健康很重要，因为作为该提案的一部分进行的研究将有助于改善长期植入大脑的神经电极的功能。应用于这些神经电极的新型聚合物涂层将利用按需反应来调节植入后发生的炎症，并允许电极比标准未涂层电极接收电(神经)信号的时间更长。

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.