Mackie, Ian Paul; (2004) Development of a novel therapy for the prevention or reduction of cutaneous scarring. Doctoral thesis (M.D.), University College London.

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Abstract

There currently exists no effective therapy for either the prophylaxis or treatment of cutaneous scarring. The myofibroblast has been implicated in the aetiology of pathological scars, and therefore the development of therapies to prevent scarring in man have focussed upon the prevention of the myofibroblast phenotype. The aim of this thesis was to investigate whether insulin could prevent dermal fibroblast - myofibroblast differentiation in vitro and in vivo. Three preparations of insulin that are in common clinical usage were evaluated for their efficacy in reducing fibroblast - myofibroblast differentiation in human dermal fibroblast cell cultures. Using immunohistochemical and western blotting techniques, insulin was shown to be effective in reducing myofibroblast number. The effect of insulin on fibroblast proliferation, total protein and collagen synthesis was also determined. In addition, the effect of insulin on the contraction of 3D collagen gels was evaluated. Using immunohistochemical techniques, the effect of growth factors known to inhibit apoptosis were evaluated for their abilities to reduce fibroblast - myofibroblast differentiation. In addition, prior to commencement of in vivo studies, the effectiveness of insulin in the presence of its physiological antagonists was established. To investigate the effect of insulin in vivo, the compound was tested on healing murine incisional and excisional wounds. Incisional wounds proved to be the most reliable for interpretation. Myofibroblast numbers were assessed using both immunohistochemical and western blotting. Progress towards the development of a novel therapy for the prevention or reduction of cutaneous scarring has been achieved by assessing the effects of insulin both in vitro and in vivo.

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