Defense Date

2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Raymond Colello

Abstract

Traumatic spinal cord injury (SCI) is a physically debilitating, emotionally devastating, financially costly, and life-changing condition that afflicts more than 1,000,000 people in the United States alone. Owing to the characteristic neuropathology and low regenerative capacity of the central nervous system, many victims of SCI are left permanently paralyzed. Though the tissue damage caused by the initial insult almost certainly cannot be reversed, intensive research in recent years to elucidate the cellular and molecular events that follows has provided new grounds for optimism. Accordingly, in this dissertation, we present a number of potential treatment strategies aimed to address some of these pathological sequelae seen post-SCI so as to facilitate the regeneration of axons and the recovery of physiological functions. After the initial traumatic insult, a prominent and lasting injury-induced proliferative response occur and results in the development of a gliotic scar that isolates the lesion from the surrounding viable tissue. Although this process aids to prevent the spread of uncontrolled tissue damage, the scar nevertheless acts as a physical barrier to axonal regeneration. Furthermore, cells within the scar are a major source of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPG) and thus the scar acts concomitantly as a biochemical barrier. Concurrent to all this, inflammatory cells infiltrate the lesion and promote cell death through immunologic activation. Neuronal survival is also threatened from the lack of neurotrophic support caused by axonal severance. Finally, the pathology culminates in the formation of a fluid-filled cyst, which represents a gap that further hinders axonal regrowth. Since regeneration cannot physically occur in the presence of a cavity, we, by employing electrospinning techniques, generated a biocompatible matrix implant that can bridge and direct axonal elongation across the fluid-filled cyst. Given the complex array and scope of pathological sequelae post-SCI, it is generally recognized that a multifaceted approach is required to successfully treat SCI. In view of this, we presented novel approaches by which successful tried and true therapeutic strategies are combined to generate an enhanced matrix. An enzyme as well as a growth factor was incorporated into our matrix implants in order to respectively neutralize CSPGs and provide neurotrophic support. Using in vitro assays, we were able to demonstrate excellent protein bioactivity after incorporation. In vivo experimentation of these enhanced matrices is now ongoing. To address the injury-induced proliferative response, which represents an on-ramp off-ramp obstacle that prevents axonal regeneration onto our matrix implant, we showed how X-irradiation can be utilized to moderate this response by killing dividing cells so as to facilitate a more efficient penetration of regrowing axons into and beyond the gliotic scar. Finally, we demonstrate how a novel pharmacologic agent FTY720 can be used to attenuate the inflammatory response by preventing lymphocytic egress from lymphoid tissues. Collectively, these ideas and experimental results represent novel therapeutic strategies that can be combined in order to bring about meaningful functional recovery after SCI.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2009

Share

COinS