Abstract Microelectrode arrays (MEAs) have great potential for therapeutic use in direct brain-computer interface (BCI) control of robotic prostheses to improve the lives of patients suffering from debilitating conditions related to loss of limbs or limb function. MEAs also have the potential to restore loss of sensory perception in vision, hearing, and tactile sensation by applying patterned current stimulation to sensory neurons. As promising as these therapies are, there is a major shortcoming to the current state of the art in implanted MEAs in that their recording and stimulation quality degrades over time, and the implants eventually become non-functional. Their use as therapeutic devices to treat chronic conditions that persist for the patient's life requires MEAs that are stable over decades rather than months to years. The underlying mechanisms leading to failure for chronically implanted MEAs have yet to be fully elucidated. One candidate is degradation of the electrode or insulation material leading to mechanical device failure. Another important factor is the host foreign body response. Inflammation due to activation of microglia and astrocytes can lead to gliosis and the formation of a “glial scar” encapsulating the device and preventing efficient recording and stimulation of neurons. Recently, gene therapy-based interventions using CRISPR/Cas systems for gene knockout have shown great promise in modifying the immune response. Recent work in the Cui lab has shown the efficacy of using functionalized silica nanoparticles (SNPs) as a versatile surface modification for microelectrodes. MEAs coated with polyethylenedioxythiophene (PEDOT)/SNP have improved electrochemical properties over standard bare metal electrodes and the capacity to be loaded with therapeutic compounds due to their porous structure with a high surface area. These properties make MEAs coated with PEDOT/SNP an ideal platform for highly targeted gene delivery, as the silica nanoparticles can be efficiently loaded with DNA. This proposal aims to develop this technology to efficiently gene modify microglia locally around implanted MEAs to reduce inflammation and to measure the effect of inflammation on recording quality and stimulation efficiency, as well as long-term device stability. In addition, I will investigate how changes in the foreign body response affect the remodeling of tissue surrounding the implant. I will take the approach of loading SNP coated MEAs with DNA encoding CRISPR gene therapy vectors targeting inflammatory pathways in microglia. The CRISPR vectors will be electrochemically delivered to cells directly interfacing with the implanted devices. The development of this technology has great potential to enhance the therapeutic value of implanted devices by increasing their performance and longevity by reducing inflammation and gliosis and to increase our fundamental understanding of how the brain responds to implanted devices. Once established, this technology will be a versatile platform for highly targeted gene delivery, having both spatiotemporal and cell-type specificity.

Project Narrative Microelectrode arrays have great promise clinically for bioelectronic medicine, especially for neural recording and stimulation, but currently, they have a high failure rate after months to years post-implant, thought to be due in part to inflammation. To assess the role of the inflammatory response in device failure and potentially overcome this limitation, this proposal aims to develop silica nanoparticles as an electrode coating material that can be loaded with DNA vectors for efficient and spatiotemporally targeted gene editing at the electrode interface to reduce the host immune response and improve device performance as well as study the immune response through loss of function experiments.