We engineered implantable small-diameter blood vessels based on ovine smooth muscle and endothelial cells embedded in fibrin gels. Cylindrical tissue constructs remodeled the fibrin matrix and exhibited considerable reactivity in response to receptor- and nonreceptor-mediated vasoconstrictors and dilators. Aprotinin, a protease inhibitor of fibrinolysis, was added at varying concentrations and affected the development and functionality of tissue-engineered blood vessels (TEVs) in a concentration-dependent manner. Interestingly, at moderate concentrations, aprotinin increased mechanical strength but decreased vascular reactivity, indicating a possible relationship between matrix degradation/remodeling, vasoreactivity, and mechanical properties. TEVs developed considerable mechanical strength to withstand interpositional implantation in jugular veins of lambs. Implanted TEVs integrated well with the native vessel and demonstrated patency and similar blood flow rates as the native vessels. At 15 wk postimplantation, TEVs exhibited remarkable matrix remodeling with production of collagen and elastin fibers and orientation of smooth muscle cells perpendicular to the direction of blood flow. Implanted vessels gained significant mechanical strength and reactivity that were comparable to those of native veins. Our work demonstrates that fibrin-based TEVs hold significant promise for treatment of vascular disease and as a biological model for studying vascular development and pathophysiology.
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