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.