Chitosan, Skeletal Muscle Regeneration And Fibrosis Inhibition
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Treatment of ventral hernias frequently employs use of synthetic and biological meshes, which often results in scar tissue formation and incomplete muscle regeneration, leading to high recurrence rates. A new generation of mesh or scaffold that promotes muscle tissue ingrowth and reduces fibrosis is needed. Chitosan, a co-polymer of N-acetyl glucosamine and N-glucosamine units, has been previously shown to elicit a regenerative response instead of a fibrotic response. In this dissertation, the effects of chitosan on skeletal muscle regeneration, fibrosis formation, and inflammatory response was characterized. The underlying mechanisms were also examined. We found that chitosan coating preferentially promoted murine myoblast adhesion with higher expression of integrin [beta]3 and inhibited murine fibroblast adhesion with reorganization of actin and integrin [beta]1 network. We demonstrated that chitosan may be a promising biomaterial for ventral hernia repair as it reduced mechanisms of fibrosis with increased expression of MMP1 (matrix metalloproteinase 1, a collagenase that also functions as a myokine), reduced expression of vimentin (an intermediate filament that provides mechanical support to cells), and reduced fibroblast adhesion and viability in human fibroblasts, while not affecting human myoblast adhesion and viability in an in-vitro model of acute inflammation. Reduced inflammatory response was observed with chitosan coating on polypropylene meshes at 2 weeks after implantation in a partial thickness defect in rat abdominal wall compared to uncoated polypropylene meshes, with reduced expression of cytokine, TWEAK (tumor necrosis factor-like weak inducer of apoptosis) and its receptor, Fn-14. Chitosan impaired fibroblast adhesion, which was possibly due to reduced expression of integrins, promotion of cell-cell adhesion and reorganization of extracellular matrix and cytoskeletal proteins in human fibroblasts. Human myoblast adhesion was not negatively impacted by chitosan coating. However, myotube formation was impaired with chitosan coating, due to the possible changes in surface bound calcium ions, integrin expression and loss of serum proteins in differentiation media. By characterizing the attachment of myoblasts and fibroblasts to chitosan, and the inflammatory response, I hope to provide insights into developing a new generation of biomaterials for functional wound healing.
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