Mechanical conditioning and the vascular remodeling potential of small intestine submucosa based grafts
Schlaich, Evan M.
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According to the American Heart Association, over seven million cardiovascular operations were performed in 2009. The development of arterial substitutes has been shown to be one promising treatment of vascular disease. Recently, our laboratory has shown that mesenchymal stem cells, derived from hair follicles, can differentiate towards vascular smooth muscle cells (HFSMC) and contract in response to various chemical agonists. After two weeks in 2D culture on the natural biomaterial small intestine submucosa (SIS), the HFSMCs showed ECM secretion, migration, and the potential to generate vasoreactive arterial substitutes. To this end, we hypothesize that 3D HFSMC encapsulated fibrin glued SIS can provide a system for increased cell mitogenicity, alignment, and secretion, thereby generating a more native architecture. Utilization of a chemical cocktail in graft culture medium has been used with moderate success. However, complete mechanisms, synergistic effects, and optimization in conjunction with mechanical forces is still yet to be realized. As such, we propose a two-staged strategy utilizing bioreactor preconditioning and the stimulatory affects of TGFβ-1, ascorbic acid, and insulin. Furthermore, bioreactor fluid flow provides a dynamic culture state, mimetic of the arterial environment. Under strain, HFSMC aligned circumferentially and showed collagen and elastin synthesis, as evidenced by histological examination. The remodeling potential was further explored via transplantation into an ovine arterial system. Grafts remained patent for periods up to 3 months (n=6) and showed an increased cell infiltration. The constructs were well integrated at the anastomosis site and SIS layers became indistinguishable, suggesting no evidence of stenosis or aneurysm formation. Taken together, chemical and mechanical stimulation promotes in vitro cellular remodeling and functionality and suggests a necessary dual approach towards long term in vivo.