Mechanisms of In-Vivo Remodeling in Tissue Engineered Heart Valves

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DESCRIPTION (provided by applicant): Using autologous cells and biodegradable polymers, tissue engineered pulmonary valves (TEPV) have been fabricated and have functioned in the pulmonary circulation of growing lambs for up to 20 weeks, with tissue evolving into a differentiated layered structure resembling that of native valve. More recent studies have demonstrated that use of bone marrow mesenchymal stem cells (BMSC) and PGA/PLLA scaffolds produce functioning implants for up to 8 months in growing lambs which also demonstrated in-vivo structural evolution. These studies have demonstrated the feasibility of engineering pulmonary valve (PV) leaflets and segments of main pulmonary artery (PA) in-vitro. Both structures have functioned well without thrombosis. Moreover, both the gross and microscopic characteristics of the TEPV structures began to approximate those of normal tissues, strongly suggesting that cell phenotypes evolved in a directed fashion to remodel the valvular and vascular tissue. However, while these intriguing studies have yielded insight into TEPV development, our efforts thus far have been largely empirical. There remain significant bioengineering challenges in determining parameters that lead to optimal ECM development and strength. For example, despite the in-vivo evolution of TEPV valve tissue into a tri-layered structure that resembles native valve tissue, we have only very limited information on the extent to which TEPV truly duplicates native PV biomechanical function, nor the mechanisms that regulate the in-vivo remodeling process. The goal of the current research program is to thus quantify and simulate tissue remodeling events that occur post- implantation, and to understand the factors that influence the remodeling rate and the quality and architecture of the ultimate tissue. Specifically, we hypothesize that TEPV implant remodeling is primarily mediated by the level of in-vivo mechanical stimuli to the interstitial cells and developing ECM. Mechanical stimuli will affect the rate of scaffold degradation and the degree of post-implant cellular ingrowth. Relevance to public health includes the develop of valved pulmonary conduits for the pediatric population that can grow with the patient, minimizing the need for continued re-operations to bring the patient to adulthood.