Mechanisms of In-Vivo Remodeling in Tissue Engineered Heart Valves

描述（由申请人提供）：使用自体细胞和可生物降解聚合物，组织工程肺瓣膜（TEPV）已经被制造出来，并在生长羔羊的肺循环中发挥了长达20周的功能，组织进化成与天然瓣膜相似的分化层状结构。最近的研究表明，使用骨髓间充质干细胞（BMSC）和PGA/PLLA支架可以在生长的羔羊体内产生长达8个月的功能植入物，这也证明了体内结构的进化。这些研究证明了体外工程肺动脉瓣（PV）小叶和肺动脉主干（PA）段的可行性。两种结构的功能都很好，没有血栓形成。此外，TEPV结构的大体和微观特征开始接近正常组织，这强烈表明细胞表型以定向方式进化以重塑瓣膜和维管组织。然而，虽然这些有趣的研究已经对TEPV的发展产生了深入的了解，但我们迄今为止的努力主要是经验主义的。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成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体内重塑过程的机制只有非常有限的信息。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，并了解影响重塑速度、最终组织质量和结构的因素。具体来说，我们假设TEPV植入物重塑主要是由对间质细胞的体内机械刺激水平和发生的ECM介导的。机械刺激会影响支架降解的速度和植入后细胞向内生长的程度。与公共卫生相关的包括为儿童人群开发带瓣肺导管，这些导管可以随着患者的成长而增长，最大限度地减少了为使患者成年而继续进行再次手术的需要。

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.