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置换心脏瓣膜的可能性，克服了当前心脏瓣膜器械的局限性。 使用自体细胞和可生物降解的聚合物，TE心脏瓣膜（TEHV）已经制造出来，并在生长的羔羊的肺循环中发挥作用长达四个月。尽管取得了这些令人鼓舞的成果，但仍然存在重大问题。例如，初始支架结构和机械性质在引导最佳细胞外基质（ECM）结构和强度的发展中的作用在很大程度上未被探索。 虽然体外培养过程的详细生物力学研究可以为优化TEHV设计提供很多信息，但迄今为止几乎没有进行过任何工作。 最后，作为最终设计范例的天然肺动脉瓣（PV）的结构-强度关系，我们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了解，并利用这些知识开发功能等效的TEHV设计。 通过功能等同，我们指的是我们的目标是开发一种可以执行等同生理功能（例如，具有必要的机械性能和耐久性）而无需精确复制三层瓣尖结构的工程组织。 在进行全面的体内研究之前，我们认为必须首先建立在体外培养过程中优化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、初始支架机械性能和生物降解速率以及良好控制的血液动力学负载条件可用于优化TEHV设计以复制天然PV功能。 此外，将严格建立自体肺动脉瓣的结构-强度关系，以确定TEHV设计功能终点。 我们将探索我们的假设，具体目标如下：1）量化绵羊肺流出道的形状，并确定原生绵羊肺静脉瓣尖的力学。2)量化如何利用初始支架结构、组成、降解速率和机械性能来优化所得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，对采用最佳支架设计和3D引导RV流出道几何结构制造的TEHV进行体外评价。

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.