Mechanisms of In-Vivo Remodeling in Tissue Engineered Heart Valves

描述（由申请人提供）：使用自体细胞和生物可降解聚合物，制造了组织工程肺动脉瓣（TEPV），并在生长羔羊的肺循环中发挥作用长达20周，组织演变成类似于天然瓣膜的分化分层结构。最近的研究表明，使用骨髓间充质干细胞（BMSC）和PGA/PLLA支架在生长中的羔羊中产生长达8个月的功能植入物，这也证明了体内结构进化。这些研究已经证明了体外工程化肺动脉瓣（PV）小叶和主肺动脉（PA）段的可行性。两种结构功能良好，无血栓形成。此外，TEPV结构的总体和微观特征开始接近正常组织，强烈表明细胞表型以定向方式进化以重塑瓣膜和血管组织。然而，尽管这些有趣的研究已经深入了解了TEPV的发展，但我们迄今为止的努力主要是经验性的。在确定导致最佳ECM发展和强度的参数方面仍然存在重大的生物工程挑战。例如，尽管TEPV瓣膜组织在体内进化为类似于天然瓣膜组织的三层结构，但我们对TEPV真正复制天然PV生物力学功能的程度以及调节机制的信息非常有限。体内重塑过程。因此，当前研究计划的目标是量化和模拟植入后发生的组织重塑事件，并了解影响重塑速率以及最终组织的质量和结构的因素。具体而言，我们假设TEPV植入物重塑主要是由间质细胞和发育中的ECM的体内机械刺激水平介导的。机械刺激将影响支架降解的速率和植入后细胞向内生长的程度。与公共卫生的相关性包括为儿科人群开发带瓣肺管道，该管道可以与患者一起生长，最大限度地减少继续再次手术以使患者成年的需要。

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.