Biomechanical optimization of TE heart valves

组织工程(TE)提供了创造替代心脏瓣膜的潜力，这些瓣膜具有生长和重塑的潜力，克服了目前心脏瓣膜装置的局限性。利用自体细胞和可生物降解的聚合物制造了心脏瓣膜(TEHV)，并在生长中的羔羊的肺循环中发挥了长达4个月的作用。尽管取得了这些令人振奋的成果，但重大问题依然存在。例如，初始支架结构和力学性能对开发最佳细胞外基质(ECM)结构和强度的作用在很大程度上尚未被探索。虽然对体外孵化过程的详细生物力学研究可以为优化TEHV设计提供很多线索，但到目前为止还没有开展什么工作。最后，我们对作为最终设计范例的天然肺动脉瓣(PV)的结构-强度关系的理解是严重不完整的。我们的长期目标是对体内TEHV重塑过程中发生的生物力学事件有一个严格的定量了解，并利用这些知识来开发功能相同的TEHV设计。所谓功能等效性，是指我们的目标是开发一种工程化组织，它可以执行同等的生理功能(例如，具有必要的机械性能和耐用性)，而不必精确地复制三层尖状结构。在进行全面的体内研究之前，我们认为首先必须详细了解在体外孵育过程中优化TEHV结构和生物力学所需的因素。我们假设，精确控制3D支架结构、初始支架的力学性能和生物降解率，以及良好控制的血流动力学加载条件可以用于优化TEHV设计，以复制天然的PV功能。此外，还将严格建立国产肺动脉瓣的结构-强度关系，以确定TEHV设计的功能终点。我们将通过以下具体目标来探索我们的假设：1)量化绵羊肺静脉流出轨迹的形状，并确定本地绵羊肺静脉尖端的机制。2)量化如何利用初始支架的结构、成分、降解率和机械性能来优化合成的工程化心脏瓣膜组织。3)使用新型生物反应器环路成像系统对使用优化支架设计和3D引导房车流出道几何形状构建的TEHV进行体外评估。

Tissue engineering (TE) offers the potential to create replacement heart valves which have the potential for growth and remodeling, overcoming the limitations of current heart valve devices. Using autologous cells and biodegradable polymers, TE heart valves (TEHV) have been fabricated and have functioned in the pulmonary circulation of growing lambs for up to four months. Despite these promising results, significant questions remain. For example, the role of initial scaffold structure and mechanical properties to guide the development of optimal extra- cellular matrix (ECM) structure and strength are largely unexplored. While detailed biomechanical investigations of the in-vitro incubation process could shed much light on optimizing TEHV designs, little work has been conducted to date. Finally, our understanding of the structure-strength relations in native pulmonary valve (PV), which serves as the ultimate design paradigm, is profoundly incomplete. Our long-term goal is to develop a rigorous quantitative understanding of the biomechanical events that occur during in-vivo TEHV remodeling, and to use this knowledge to develop functionally equivalent TEHV designs. By functional equivalent we refer to the fact we aim to develop an engineered tissue that can perform an equivalent physiologic function (e.g. have requisite mechanical properties and durability) without having to precisely reproduce tri-layer cuspal structure. Prior to undertaking comprehensive in-vivo studies, we believe that detailed knowledge of the factors necessary for optimizing TEHV structure and biomechanics during in-vitro incubation must first be established. We hypothesize that precise control of 3D scaffold structure, initial scaffold mechanical properties and biodegradation rates, and well- controlled hemodynamic loading conditions can be used to optimize TEHV designs to duplicate native PV function. In addition, the structure-strength relations of the native pulmonic valve will be rigorously established in order to establish the TEHV design functional endpoint. We will explore our hypotheses with the following specific aims: 1) Quantify the shape of the ovine pulmonary outflow track and determine the mechanics of the native ovine PV cusp. 2) Quantify how initial scaffold structure, composition, degradation rates, and mechanical properties can be exploited to optimize the resultant engineered heart valve tissue. 3) Perform in-vitro evaluation of TEHV fabricated using optimal scaffold designs and 3D guided RV outflow track geometry using novel bioreactor loop imaging system.