Improving the Biocompatibility of CNS Devices

 描述(由申请人提供)：尽管植入式记录技术取得了实质性进展，几项证明其治疗潜力的原理实验证明了其治疗潜力，但这项前景光明的技术的使用受到性能不一致和长期时间框架最终失败的限制。到目前为止，用于推进这项技术的设计战略在很大程度上是一种经验性的“建造和测试”方法，没有基于生物信息的压倒一切的理由。虽然人们普遍认为异物反应(FBR)的因素导致单个单位记录性能不一致和失败，但目前使用的设备是在对异物反应(FBR)了解很多之前设计的。到目前为止发现的主要特征与高密度记录阵列植入和持续炎症伴随的组织损伤有关，这一特性与FBR和其他中枢神经系统植入物相同，其中巨噬细胞激活和血脑屏障(BBB)的破坏是一个自我维持的循环，已被观察到复发和缓解，并可能在单个单位记录不稳定和最终失败中发挥关键作用。了解如何减少植入引起的初始损伤和减少FBR的影响将导致改进记录微电极阵列的生物兼容性的策略，并扩大其作为基础科学工具和临床应用的用途。为了解决这一领域，我们的具体目标是：1)了解是否有可能使用止血和免疫调节涂层策略来改善当前FDA批准的技术的记录性能；2)研究设备设计的变化如何影响单个单元记录的一致性和寿命；以及3)使用基于CRISPR的炎症基因的序列特异性调控来减少FBR。该项目的目标是开发一种生物信息策略，以推动可植入神经记录阵列技术作为一种慢性基础科学工具，并走向更多的临床应用。更广泛的目标是了解如何提高所有类型的慢性留置中枢神经系统植入物的生物相容性。

 DESCRIPTION (provided by applicant): Despite substantial advances in implantable recording technology and several proof-of principle experiments demonstrating its therapeutic potential, the use of this promising technology is limited by inconsistent performance and eventual failure over chronic time frames. To date, the design strategy employed to advance the technology has been largely an empirical `build-and-test' approach with no overarching biologically- informed rationale. While it is widely believed that elements of the foreign body response (FBR) contribute to inconsistent single unit recording performance and failure, current devices in use were designed before much was known about the FBR. The major features uncovered thus far are related to the tissue damage that accompanies high-density recording array implantation and persistent inflammation, a property shared with the FBR to other CNS implants, where macrophage activation and disruption of the blood brain barrier (BBB) is a self-sustaining cycle that has been observed to relapse and remit, and likely plays a key role in single unit recording instability and eventual failure. Understanding how to reduce the initial damage caused by implantation and reduce the impact of the FBR will lead to strategies that improve the biocompatibility of recording microelectrode arrays and extend their usefulness as a basic science tool and in clinical applications. To address this area, our specific aims are directed at: 1) understanding whether it is possible to improve the recording performance of a current FDA-approved technology using a hemostatic and immunomodulation coating strategy; 2) studying how changes in device design influence single unit recording consistency and longevity; and, 3) using CRISPR-based sequence-specific regulation of inflammatory genes to reduce the FBR. The objective of this project is to develop a biologically informed strategy that will advance implantable neural recording array technology as a chronic basic science tool and toward increased clinical usage. The broader goal is to understand how to improve the biocompatibility of all types of chronic indwelling CNS implants.