Date of Award
Doctor of Philosophy
Roberto S. Benson, Kevin M.Kit, Bin Zhao
The technology of interfacing neurons with machines through implantable neural electrodes has significant implications. Although there have been studies implanting such electrodes in human to help patients with motor disorders, longevity of these implants remains an unresolved issue. One of the key factors influencing longevity has been adverse tissue response toward the implanted electrodes
The objective of this research is to engineer a comprehensive solution that can manage the response at the cellular level while preserving the electrode functions. Given the complexity of the host response, we hypothesize that a multi-pronged approach would better improve the longevity of the electrodes. Specifically, we emphasize the importance of modulating the inflammatory response from glial cells and directly protecting neurons from oxidative stress induced death. To achieve this goal, a range of polymeric therapeutics (i.e., prodrugs) capable of anti-inflammation and anti-oxidation were designed and synthesized. These polymers were fully characterized for their structural properties and therapeutic effects. Applications of these prodrugs onto the electrodes were achieved using the versatile layer-by-layer (LBL) technique, which enabled the preservation of electrical properties of the electrodes. These in vitro studies laid down the foundations for future in vivo investigations of the efficacy of such a multi-pronged, integrated therapeutic approach for modulating host tissue response. Furthermore, the synthesized prodrugs can be applied for other types of medical implants, where inflammation and oxidative stress are common characteristics of the host response to those implants.
The other approach to achieve therapeutic delivery is the use of stimuli-responsive polymers. Based on the lower critical solution temperature (LCST) behaviors of poly(N-vinyl-2-caprolactam) (PVCL) polymers, its functional derivatives with pH-dependent LCST behaviors were designed via copolymerization with a functional derivative of VCL for smart drug delivery. Sharp and reversible response was observed across a broad range of pH values. PVCL copolymer was demonstrated to be non-cytotoxic at low concentrations. LBL compatibility of the copolymer was also explored. The ultimate goal is to correlate the pH-sensitivity of the PVCL copolymers with the tissue acidosis phenomenon to regulate therapeutic release.
Cao, Yu, "Polymer Mediated Therapeutic Delivery for Neural Interface Applications. " PhD diss., University of Tennessee, 2012.