UBC Theses and Dissertations
Development and application of non-rejectable skin substitute to improve wound healing Forouzandeh, Farshad
Skin substitutes consist of dermal and epidermal components are very beneficial to improve the current strategies of wound healing. However, these substitutes are not yet a routine treatment for burns or non-healing wounds mainly due to the difficulty of timely obtaining autologous skin cells. The aim of this study is to investigate the immunoprotective role of IDO in bilayer skin substitutes made out of non-autologous cells. To address this aim, first we asked the question of whether tryptophan deficient environment caused by IDO expression is safe for the survival of nonimmune cells, mainly primary skin cells. The results of our study showed a significant activation of apoptotic pathway as well as GCN2 kinase pathway in T cells, but not in skin cells, in response to the tryptophan deficient environment mediated by IDO expression. We then studied whether there is any differences between the main T cell populations in response to IDO mediated low tryptophan environment. Our results showed a marked immunosuppressive effect of IDO expression on human T cells with more suppressive effect on proliferation of CD8⁺ compared to that of CD4⁺ T cells which is, at least in part, due to differences in the level of GCN2 kinase pathway activation between these two sets of immune cells. Thereafter, we developed a bilayer skin substitute equipped with IDO expression ability. We found that IDO expressed by treated fibroblasts of this skin substitute suppress the proliferation of bystander lymphocytes in vitro considerably. Further, in our in vivo experiments, we found that the expression of IDO by cells of skin substitute significantly improved the wound healing rate, reduce the number of infiltrating T cells, and induced more revascularization in the wounds received IDO expressing skin substitutes compared to the non-IDO expressing ones. In conclusion, the results of this thesis research revealed that IDO expression can improve the efficacy of non-autologous bilayer skin substitutes to be used not oniy as a wound coverage, but also as a source of wound healing process improvement. A better revascularization seen in IDO grafted skin substitute further improved the graft take and survival.
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