Cell Scaffold- and Drug-based Strategies for Improving the Integration of Neural Prostheses into Brain Tissue.

Abstract

Neuroprosthetic devices record extracellular cortical signals which may be used to place exterior devices under a patient’s direct control. Therefore, these systems may restore function to individuals immobilized by paralysis or neurodegenerative disease. For neuroprosthetics to be useful in clinical and research settings, long-term, stable recordings must be achieved. However, these devices are plagued by recording instability, and the reactive tissue response that occurs after insertion into the brain is a likely cause. Specifically, neuronal density is reduced surrounding devices, and encapsulation (composed of microglia and astrocytes) isolates neuroprostheses from their neuronal signal sources.

The research presented describes the development and evaluation of two strategies to improve the tissue response to neuroprostheses: (1) a neural stem cell (NSC)-seeded scaffold and (2) a cell cycle-inhibiting drug. NSCs were hypothesized to secrete factors, such as neurotrophins, which would improve device-tissue integration. The cells were encapsulated in an alginate hydrogel and seeded into a well on the devices. In the first study, in vitro testing identified the optimal alginate composition for NSC encapsulation. The second study characterized the relationship between alginate composition, degradation, and biocompatibility in vivo. The third study evaluated the effects of the NSC scaffold on the tissue response to implanted probes in vivo. The scaffold mitigated the early tissue response, but exacerbated it by six weeks post-implantation. Based on research showing a link between central nervous system injury and cell-cycle re-entry, the final study of the dissertation investigated the role of this phenomenon in the tissue response to neural prostheses. Specifically, the effects of a cell cycle-inhibiting drug (flavopiridol) on electrophysiology and tissue response metrics were explored. Flavopiridol reduced expression of a cell cycle protein in microglia surrounding probes three days after implantation and decreased impedance over the 28 day study period. Additionally, the data revealed novel, significant correlations between recording quality, impedance, and endpoint histology measurements.

In conclusion, the studies demonstrate significant effects of two intervention strategies on tissue response and electrophysiology measurements, characterize alginate stability and its use as a NSC scaffold, and add insight into the relationship between the tissue-device interface and recording quality.