Biomechanical optimization of TE heart valves

组织工程（TE）提供了创造具有生长和重塑潜力的替代心脏瓣膜的潜力，克服了当前心脏瓣膜装置的局限性。利用自体细胞和可生物降解聚合物，TE心脏瓣膜（TEHV）已经被制造出来，并在生长羔羊的肺循环中发挥了长达四个月的作用。尽管取得了这些令人鼓舞的成果，但仍存在一些重大问题。例如，初始支架结构和力学性能在指导最佳细胞外基质（ECM）结构和强度发展中的作用在很大程度上尚未得到探索。虽然体外培养过程的详细生物力学研究可以为优化TEHV设计提供很多启示，但迄今为止开展的工作很少。最后，我们对作为最终设计范例的天然肺动脉瓣（PV）的结构-强度关系的理解是非常不完整的。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进行严格的定量理解，并利用这些知识开发功能等效的TEHV设计。通过功能等效，我们指的是我们的目标是开发一种工程组织，可以执行等效的生理功能（例如，具有必要的机械性能和耐久性），而不必精确地复制三层尖结构。在进行全面的体内研究之前，我们认为必须首先建立优化体外培养过程中TEHV结构和生物力学所需因素的详细知识。我们假设，精确控制3D支架结构、初始支架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用于优化TEHV设计，以复制天然PV功能。此外，还将严格建立原生肺动脉瓣的结构-强度关系，以确定其设计功能终点。我们将以以下具体目标来探索我们的假设：1)量化羊肺流出道的形状，并确定原生羊PV尖的机制。2)量化如何利用初始支架结构、组成、降解率和机械性能来优化最终的工程心脏瓣膜组织。3)使用新型生物反应器环路成像系统，对采用优化支架设计和3D引导的RV流出道几何形状制造的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.