A SYSTEMATIC CHARACTERIZATION OF THE TISSUE RESPONSE IN THE BRAIN TO IMPLANTED ELECTRODE ARRAYS

Neural prosthetics are an emerging technology which has great potential to treat neurological conditions in the clinic and advance neuroscience research at the bench. By stimulating or recording from local neuronal populations using implantable electrode arrays, neural prostheses can interact with the nervous system to treat disease and injury. However, detectable neuronal signals required for the function of neural prostheses can become inconsistent and even progressively decline in chronically implanted devices to the point of failure. The tissue response to implanted electrode arrays is believed to play a significant role in generating the progressive loss of signal fidelity in implanted electrode arrays. The tissue response was initially characterized by the progressive encapsulation of the implant by reactive microglia and astrocytes and the loss of neuronal cell bodies and processes. Further studies suggested that the severity of the tissue response could be attenuated or circumvented by altering the design of electrode arrays by reducing feature size and functional bending stiffness. Many ‘next-generation’ electrode arrays have been fabricated that feature softer biomaterials and smaller feature sizes. In many cases these next-generation devices were successful in reducing gliosis and neuronal death. However, signal fidelity can still become unstable in apparently normal tissue where implanted devices remain undamaged and tissue response is minimal. Therefore, it is essential that we find new understandings into the complexity of the tissue response to inform and guide the design of cortical implanted with greater biocompatibility. The studies in this dissertation present a systematic analysis of the tissue response by (1) reviewing the need for guiding principles in device design, (2) identifying the spatiotemporal patterns of gene expression through RNA-sequencing, (3) exploring protein expression of RNA-seq identified genes, and (4) utilizing novel in-situ methods to evaluate the transcriptional tissue response as the single-cell level in response to implanted devices. The results of these studies expand current understandings of the tissue response and may help guide the design of new generations of biocompatible implanted electrode arrays.