A Local Release Of Microtubule-Stabilizing Agents From An Aligned Microfiber Platform To Promote Spinal Cord Tissue Repair
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In the field of tissue engineering, some of the most promising therapeutic applications to promote spinal cord tissue repair have involved biomaterials. Electrospun microfibers provide an optimum platform to both promote directional guidance and release a therapeutic treatment for a long-duration. Paclitaxel administration has been shown to promote nerve tissue repair, but translation has been limited due to its incorporation in a neuropathic pain-inducing solvent. This thesis describes our work in establishing a platform that releases microtubule-stabilizing agents (paclitaxel and sunitinib) from aligned, electrospun fibers to promote tissue repair after a traumatic central nervous system injury. Approximately 282,000 patients in the United States have a traumatic spinal cord injury (SCI), resulting in a loss of function below the site of injury, and yet there remains no clinically approved treatment for patients after an injury. Traumatic spinal cord injuries ultimately result in an inhibitory environment that prevents axonal regeneration from occurring. Previously, a low concentration administration of paclitaxel has been shown to promote axonal extension and attenuate the upregulation of inhibitory molecules after a spinal cord injury, yet requires a new incorporation method due to toxicity and potency issues with a high concentration administration. Previously, aligned, electrospun poly-lactic acid (PLA) microfibers have promoted spinal cord tissue regeneration, but had a limited effect on the inhibitory components present after a spinal cord injury. In this study we effectively incorporated paclitaxel, and other microtubule-stabilizing agents, into electrospun PLA microfibers and sustained their release for up to twelve weeks in vitro. Additionally, we established that a local release of these molecules from electrospun microfibers promotes dorsal root ganglion neurite extension in a growth-conducive and inhibitory environment, as well as inhibits astrocytic activity such as proliferation and chondroitin-sulfate proteoglycan upregulation. Finally, this study tested this platform in a rat model of spinal cord injury and determined that it inhibits reactive gliosis and does not exacerbate neuropathic pain. Our findings provide a targeted approach to improve overall spinal cord tissue repair after a traumatic injury in the spinal cord.