CNS Response to Implanted Materials

描述（由申请人提供）：植入式硅微电极阵列技术是一种很有前途的高密度、高分辨率神经元活动采样方法，在基础研究和假肢装置中都有应用。当前技术的主要限制之一是长期应用的性能不稳定，这限制了临床发展。虽然脑组织对植入电极的反应被认为是电不稳定的主要原因，但导致记录失败的确切机制尚不清楚。因此，了解硅微电极阵列慢性不稳定性的机制将有助于提高其在慢性基础科学研究和各种神经义肢应用中的实用性。我们观察到在植入硅微电极阵列的成年大鼠运动皮层周围存在持续的ED-1免疫反应性，并且观察到在植入硅微电极阵列周围的组织中神经纤维密度和细胞体显著减少。在微电极刺伤对照组中未观察到ED-1持续上调和神经退行性变，这表明慢性炎症和神经元丢失不是由电极植入的初始机械损伤引起的，而是与脑组织对植入电极的反应有关。我们发现，我们的观察共享具有神经炎症介导的神经毒性成分的疾病的生物学特征。因此，我们假设长期植入硅微电极阵列会导致微电极界面上巨噬细胞的持续激活，导致促炎细胞因子和神经毒性因子的过度产生，从而导致紧邻记录表面的神经元细胞体和纤维的损失。为了验证我们的假设，我们提出了定量方法：a)确定记录失败时微电极脑组织界面的时间组织病理学变化；另外2)我们将使用回收的探针和一种新的系统来确定种植体部位的促炎因子和神经毒性因子的变化，该系统允许随着时间的推移对种植体附近的机构液进行采样；最后，c)我们将验证这样一个假设，即干扰小胶质细胞激活和信号传导的药物可以有效地减弱植入硅微电极阵列周围的神经变性。拟议的研究可能提供深入了解硅微电极阵列慢性不稳定性的生物学机制，并应导致提高其长期应用实用性的策略。

DESCRIPTION (provided by applicant): Implantable silicon microelectrode array technology is a promising approach for high-density, high-resolution sampling of neuronal activity with application in both basic research and prosthetic devices. One of the major limitations of the current technology is inconsistent performance in long-term applications, which limits clinical development. Although the brain tissue response to implanted electrodes is believed to be a major cause of electrical instability, the precise mechanisms that cause failure of recordings are not known. Understanding the mechanisms that underlie chronic instability of silicon microelectrode arrays will, therefore, lead to strategies to improve their usefulness for chronic basic science studies and various neuroprosthetic applications. We have observed persistent ED-1 immunoreactivity around silicon microelectrode arrays implanted in the adult rat motor cortex, and observed significant reductions in nerve fiber density and cell bodies in the tissue immediately surrounding implanted silicon microelectrode arrays. Persistent ED-1 up-regulation and neurodegeneration is not observed in microelectrode stab controls indicating that chronic inflammation and neuronal loss is not caused by the initial mechanical trauma of electrode implantation, but is associated with the brain tissue response to the implanted electrode. We find that our observations share biological features of diseases having a neuroinflammatory mediated neurotoxic component. We, therefore, hypothesize that chronically implanted silicon microelectrode arrays lead to persistent macrophage activation at the microelectrode interface resulting in an over production of proinflammatory cytokines and neurotoxic factors that lead to loss of neuronal cell bodies and fibers immediately adjacent to the recording surface. To test our hypothesis, quantitative methods are proposed: a) to determine the temporal histopathological changes at the microelectrode brain tissue interface that coincide with recording failure; in addition 2) we will determine the changes in proinflammatory and neurotoxic factors at the implant site using retrieved probes and a new system that allows sampling of the institial fluid adjacent to the implant over time; and, finally c) we will test the hypothesis that agents that interfere with microglial activation and signaling are effective in attenuating neurodegeneration around the implanted silicon microelectrode arrays. The proposed research is likely to provide insight into the biological mechanisms that underlie chronic instability of silicon microelectrode arrays, and should lead to strategies to improve their usefulness for chronic applications.