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Title: Cellular and gene therapies for the enhancement of peripheral nerve regeneration through bio-engineered nerve conduits
Author: Tohill, Mel Patrick
ISNI:       0000 0004 2669 9243
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Despite optimal surgical management the functional outcome following peripheral nerve injury remains poor. Experimental adjuvant treatments have been developed to enhance peripheral nerve regeneration including the use of bio-engineered conduits, cellular transplantation, the addition of growth factors and modulation of the extra-cellular matrix. Transplantation of cultured Schwann cells (SCs) improves regeneration through bio-engineered conduits. To improve the localisation of transplanted cells in combination with fluorescent immunohistochemical techniques SCs were retrovirally transduced with green fluorescent protein (GFP). GFP-SCs were found to have similar growth and vitality characteristics in comparison with non-transduced cells and following in vivo transplantation were easily identified and enhanced nerve regeneration. Bone marrow stromal cells (MSCs) are capable of unorthodox plasticity. Their abundance, ease of access and culture make them potential substitutes for SC transplantation. Following exposure to glial growth factor, MSCs exhibited phenotypical and morphological characteristics of SCs. Following in vivo transplantation these cells were also found to confer a beneficial effect on nerve regeneration. Neurotrophic factors enhance nerve regeneration however delivery at the site of injury is problematic. The use of gene therapy to provide growth factors at the site of injury may overcome this problem. A splice variant of the IGF-1 gene, Mechano-Growth Factor (MGF) was delivered to the site of peripheral nerve injury and functional and histological measures of regeneration were assessed at 14 weeks. It was found that delivery of the MGF cDNA at the site of injury improved target muscle function and total axon number in regenerating nerves. Extracellular matrix macromolecules are important constituents of the peripheral nerve. The addition of fibronectin, laminin, and collagen substrata were found to enhance SC growth in vitro. Coating nerve guidance fibres with these molecules within a peripheral nerve conduit was also found to enhance nerve regeneration and influence the expression of the cell adhesion molecules NCAM and N-cadherin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available