CNS Response to Implanted Materials

描述(申请人提供)：可植入硅微电极阵列技术是一种很有前途的方法，可用于高密度、高分辨率的神经元活动采样，在基础研究和假体设备中都有应用。目前技术的主要局限性之一是在长期应用中性能不一致，这限制了临床开发。尽管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，了解硅微电极阵列长期不稳定的机制将导致提高其在慢性基础科学研究和各种神经假体应用中的有用性的策略。我们观察到植入成年大鼠运动皮质的硅微电极阵列周围持续的ED-1免疫反应，并观察到植入硅微电极阵列周围组织的神经纤维密度和细胞体显著减少。在微电极刺激组中未观察到持续的ED-1上调和神经变性，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，我们的观察结果与具有神经炎症介导的神经毒性成分的疾病的生物学特征相同。因此，我们假设长期植入的硅微电极阵列导致微电极界面上持续的巨噬细胞激活，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胞体和纤维的丢失。为了验证我们的假设，我们提出了以下定量方法：a)确定与记录失败同时发生的微电极脑组织界面的临时组织病理学变化；2)使用检索到的探针和一个新系统确定种植部位促炎和神经毒性因子的变化，该系统允许随时间推移对种植体附近的组织液进行采样；最后，c)我们将检验以下假设，即干扰小胶质细胞激活和信号传递的制剂在减轻植入的硅微电极阵列周围的神经变性方面有效。这项拟议的研究可能会提供对硅微电极阵列长期不稳定的生物学机制的洞察，并应导致改进其在慢性应用中的有用性的策略。

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.