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theses

Spinal cord injury (SCI) is characterized by two phases: the primary phase involves a traumatic event, which can be external or internal injury, and a secondary phase, which entails a number of biochemical processes, eventually resulting in inflammation, neuronal death, and axonal demyelination. Glutamate-induced excitotoxicity (GIE) is the major contributor to this secondary SCI pathway. GIE is mediated by the release of excessive glutamate into synaptic clefts, overstimulating N-methyl-D-aspartate channels, which increases intracellular Ca2+, and results in cell swelling and mitochondrial dysfunction. Furthermore, GIE increases the production of toxic reactive species, leading to DNA and mitochondrial damage, and eventually, cell death. Currently, there is no clinical treatment that specifically targets GIE after SCI, and emergence of a therapeutic target for secondary damage in SCI patients is of utmost need. Uric acid (UA), a product of purine synthesis, acts as an antioxidant by scavenging free radicals and preserves neuronal viability in several in vitro and in vivo SCI models. However, high systemic UA concentrations can be detrimental and lead to hypertension, kidney disease, and gout. Thus, there is need to develop a drug delivery system that can deliver UA locally to the target injured region. Natural polymers show high biocompatibility but lack the ability to be fabricated in such a way that the rate of drug release is controlled. In contrast, use of the synthetic polymer, poly (ɛ-caprolactone; PCL), offers an advantage over natural polymers since it is not only biodegradable and biocompatible, but it also has a controllable degradation rate and is compatible with a vast number of drugs. As such, it has been studied and used extensively in the context of drug delivery applications. Here, using the electrospinning technique, we developed a PCL-UA nanofiber mat containing UA, which has the potential as an implantable drug delivery carrier for UA. We then optimized delivery of UA via this PCL nanofiber mat in short bursts of 2 hours by coating the mats with PEGDA. We then optimized the effective dose of UA released from PCL nanofibers to protect neurons from GIE in organotypic spinal cord slice culture. We show that the mats decrease reactive oxygen species generation and cell death. The long-term goal of this project is to extend these studies in vivo, and ultimately, optimize use for SCI patients. This approach is therapeutically viable since PCL is an FDA approved polymer currently used to deliver multiple drugs and fully excreted from the body upon degradation without any toxic effects.

ETD_10863

M.S.

Includes bibliographical references

doi:10.7282/t3-a4br-e492

ETD graduate

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