Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. Although venous grafts are currently the golden standard, the ten-year failure rate is approaching 35%. Bioengineered vascular grafts are capable of remodeling in response to host signals and offer a clear alternative to existing technologies. Recently we showed that fibrin-based small- diameter tissue engineered blood vessels (TEV) exhibited vascular reactivity and considerable mechanical strength to withstand interpositional implantation into the jugular veins of lambs. Implanted TEV remained patent for the duration of the experiment (15 weeks), supported blood flow to the same degree as native veins and exhibited remarkable matrix remodeling. Despite significant progress in design of biomaterials for vascular tissue engineering, the source of cells remains a major problem. Isolation of autologous cells from the patient requires invasive surgery and injures the donor site. Most important, the proliferative capacity and functional properties of vascular smooth muscle cells are limited, especially when they originate from older donors, the population mostly in need for vascular prostheses. To address this challenge, we propose to isolate smooth muscle cells from the bone marrow (BM) of young (6 months to 1year old) and old (aged, >6 years old) animals using a novel methodology that we developed in our laboratory. Tissue engineered vessels from young (yBM-TEV) and aged (aBM-TEV) smooth muscle progenitor cells will be studied with a series of molecular and functional assays. The response of BM-TEV to biochemical and physical stimuli will be evaluated in order to establish optimal culture conditions that improve deposition of extracellular matrix and mechanical strength. Gene expression profiles will be obtained to identify molecules that may be responsible for potential loss of function as a result of aging. In addition, fibrin hydrogels will be decorated with growth factor fusion proteins as a means of improving signaling and enhancing the functional properties of BM-TEV. Finally, we will implant aBM-TEV and yBM-TEV in the venous system of young ovine recipients and assess patency and long-term remodeling up to one year post-implantation. The proposed work will elucidate the effects of aging on the potential of BM-derived smooth muscle cells as a source for vascular tissue engineering and will determine the biochemical and biophysical factors that enhance the functional properties of BM-TEV. ?
Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. To address this health challenge, we will evaluate the potential of bone marrow as an autologous stem cell source for engineering small diameter vascular grafts for treatment of cardiovascular disease. The same cells may also be applied in engineering other cardiac tissues such as heart valves and cardiac patches further increasing the potential clinical impact of this work. ? ? ?
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