Date of Award

Spring 5-17-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Douglas H Smith, MD

Abstract

Severe trauma to the limbs can often result in the lesioning, or even amputation, of the underlying peripheral nerves. In these cases, endogenous neural repair mechanisms are compromised and a path to the end target may be lost, resulting in the need for surgical intervention. Current repair strategies are incapable of maintaining this regenerative pathway, or providing a bridge to a surrogate end target, often resulting in incomplete repair.

This thesis describes the development and evaluation of a novel method of addressing peripheral nerve lesions and amputations that utilizes living tissue-engineered neural grafts. These grafts are created by the controlled mechanical separation of axons spanning integrated neuron populations in vitro, resulting in axon tracts spanning several centimeters in length. Techniques were developed to encapsulate and transplant these tracts, with the goal of providing structural and nutrient support, while minimizing macrophage infiltration. The efficacy of these constructs in the treatment of lesions and amputations was then assessed using a rat sciatic nerve transection model.

In the first study, the ability of neural constructs to (a) encourage host regeneration from the proximal stump, while also (b) attenuating distal pathway degeneration, was evaluated. At the 4-week time point, the axonal constructs were observed to promote more robust host axonal and tissue regeneration across the graft when compared to unstretched grafts. A measurement of nerve conduction velocities also revealed a statistically significant improvement in the stretch-grown group, correlating with the observed increased fiber regeneration. At the distal pathway, neural constructs were observed to prevent the atrophy of the support cells, and maintain the alignment of the Schwann cell columns for up to 4 months. These results suggest that the use of neural grafts may expand the time window within which successful nerve regeneration can occur.

The axon grafts were then shown to support and maintain regenerating host axon fibers for up to 4 weeks in the absence of a distal end target. Finally, axon grafts pre-attached to an implantable electrode substrate were shown to encourage host ingrowth to the vicinity of the substrate, showing promise for the development of a chronic brain-machine interface.

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