Vasculopathy and the associated ischemia is the leading cause of mortality and disability in the United States and other industrialized countries. This disease is often treated by vascular bypass. However, only about one-third of patients have blood vessels suitable for autografts. For these patients, synthetic grafts are an effective alternative when the blood vessel diameter is greater than 6 mm. However, there is tremendous therapeutic need to develop more effective replacements for smaller arteries. To meet this need, numerous groups have endeavored to construct tissue engineered vessel replacements in vitro. Unfortunately, those that have reached clinical trials require 3-6 months to produce and have low compliance. More recently, an alternative approach has been explored in which the vessels are constructed in vivo. Acellular, resorbable vascular grafts are implanted in the circulation of animals, after which the body's natural growth and remodeling (G&R) processes create a new vessel in place of the degrading graft. The material properties of the graft appear to be critical for this process. The Wang group's recent work using this approach in young adult rats has yielded structurally sound, small diameter neoarteries. In addition to arterial collagen, these vessels possess nerves and normal levels of mature elastin, both novel findings for engineered arterial replacements. The objective here, and the next step in pursuit of this goal, is to translate our proven success from young to mature adult rats. Our long-term goal is to improve treatment of cardiovascular disease by providing a vascular graft with off- the-shelf availability that utilizes the human body's own regenerative capabilities to create replacement vessel in situ. Our hypothesis is that older animals will also produce neoarteries with appropriate levels of collagen and elastin when the mechanical and degradation properties of the graft are tailored to compensate for altered collagen and elastin production in older animals. Our hypothesis is supported by numerous studies showing production of collagen and elastin is influenced by mechanical load and by our own in-host remodeling experiments and computational studies. We plan to test this hypothesis, and thereby achieve these objectives, through two specific aims. In the first aim, we will identify differences in the neoartery formatio process in mature rats compared with old. These data will be used to tailor a growth and remodeling computational tool for the neoartery formation process. In the second aim, an optimization algorithm will be used with this tool to design and test a graft for older rats. The expected contribution of the proposed research is the development of a synthetic graft which elicits effective in host neoartery formation in mature animals. These results are expected to have an important positive impact by providing the next critical step towards in situ creation of small diameter neoarteries in humans. Further, we will have introduced an entirely new mechanism driven approach for designing tissue engineered blood vessels. Such an approach will have widespread value for other tissue engineered systems.
The development of a synthetic graft capable of stimulating in host neoartery formation in mature animals is the next vital towards the manufacture replacement vessels for small diameter arteries in humans. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of illness.