Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 78-112).

Injuries to the peripheral nervous system (PNS) are major and common source of disability, impairing the ability to move muscles and/or feel normal sensations, or resulting in painful neuropathies. Annually traumatic nerve injuries resulting from collisions, gunshot wounds, fractures, motor vehicle accidents, lacerations, and other forms of penetrating trauma, affected more than 250,000 patients just in the U.S. The clinical gold standard to bridge long non-healing nerve gaps is to use a nerve autograft- typically the patient’s own sural nerve. However, autografts are not ideal because of the need for secondary surgery to ‘source’ the nerve, loss of function at the donor site, lack of appropriate source nerve in diabetic patients, neuroma formation, and the need for multiple graft segments. Despite our best efforts, finding alternative ‘nerve bridges’ for peripheral nerve repair remains challenging – of the four nerve ‘tubes’ FDA approved for use in the clinic, none is typically used to bridge gaps longer than 10 mm due to poor outcomes. Hence, there is a compelling need to design alternatives that match or exceed the performance of autografts across critically sized nerve gaps. Here we demonstrate that early modulation of innate immune response at the site of peripheral nerve injury inside biomaterials-based conduit can favorably bias the endogenous regenerative potential after injury that obviates the need for the downstream modulation of multiple factors and has significant implications for the treatment of long peripheral nerve gaps. Moreover, our study strongly suggests that more than the extent of macrophage presence, their specific phenotype at the site of injury influence the regenerative outcomes. This research will advance our knowledge regarding peripheral nerve regeneration, and help developing technologies that are likely to improve clinical outcomes after peripheral nerve injury. The significant results presented here are complementary to a growing body of evidence showing the direct correlation between macrophage phenotype and the regeneration outcome of injured tissues.

published_or_final_version / Anatomy / Master / Master of Research in Medicine

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This study was concerned with the ultrastructural changes that occur in axons and glial cells during peripheral nerve regeneration in the cockroach <i>Periplaneta americana</i>. Metathoracic nerve 5 was cut and regeneration of the proximal stump was studied using electron microscopy. Nerve 5 was surrounded by an acellular layer, the neural lamella. Underneath this structure was a layer of glial cells which formed the perineurium. Lanthanum penetration stopped between the perineurial cell processes, revealing them to be the site of the blood-brain barrier (BBB). Underlying the perineurium were the axons, surrounded by the subperineurial glial cells. Extracellular matrix was present between subperineurial glial processes. After cutting nerve 5, the initial changes in the proximal stump were a result of the degeneration of sensory axons. Haemocytes accumulated outside the nerve and morphologically similar granule-containing (g-c) cells appeared inside the nerve. After the first week signs of regeneration were distinguishable. These included axonal sprouting, glial proliferation and extracellular matrix production. Many small axonal sprouts were formed by regrowing axons. These became grouped into bundles, surrounded by glial processes, as the nerve outgrowth elongated. Glial proliferation by cell division began after the first week, and reached a maximum rate between two and three weeks. It is possible that mitosis of glial cells may be triggered by contact with the sprouting axons. Freeze-fracture studies of the tip of the growing nerve showed that formation of gap and septate unctions took place between the glial cells. This junctional assembly was asynchronous. Reinnervation of the coxal muscles occurred 8 weeks after the nerve was cut. At this stage the nerve was composed of several axonal bundles, each containing large and small axons. The nerve did not completely resemble the control even after 16 to 20 weeks of regeneration. Lanthanum incubation showed that the tracer was again excluded by the perineurial cells, indicating that the BBB of the regrown nerve reappeared at 8 weeks. Glial repair was studied following selective glial disruption using localised application of ethidium bromide. This treatment killed the perineurial and subperineurial glial cells. The repair of the glial system involved the transitory appearance of g-c cells in the nerve. 11 days after ethidium bromide treatment, new glial cells were present and lanthanum was excluded by the perineurial cell layer. Preinjection of microspheres into the haemolymph, which were taken up by phagocytic haemocytes, reduced the numbers of g-c cells that appeared in the nerve after ethidium bromide treatment. This lengthened the time required for glial repair. Cell division of neuroglial cells was observed. Cells derived from haemocytes and glial cell division were probably involved in the replacement of the damaged glial cells after ethidium bromide treatment. This study shows that glial cells play an important role in peripheral nerve regeneration in insects, forming the environment through which the regenerating axons grow.

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