Design and Simulation of Valvular Replacement Biomaterials

摘要： 在可预见的未来，由异种生物材料制成的生物瓣膜(BHV)仍将是主要的替代瓣膜设计。然而，BHV的耐久性仍然限于10-15年。失效通常是由疲劳和/或组织矿化引起的小叶结构恶化的结果。因此，与瓣膜设计的特点(如标准支架瓣膜、经皮给药)无关，开发具有更高耐用性的新型异种生物材料仍然是一个重要的临床目标。这是一种独特的心血管工程挑战，由血液接触时产生的极端瓣膜机械需求引起。然而，目前的BHV评估完全依赖于设备水平的评估，这些评估被同时且高度耦合的生物材料力学行为和疲劳、瓣膜设计、血流动力学和钙化所混淆。因此，尽管BHV在临床上已经使用了几十年并日益流行，但在成分生物材料水平上还没有可以接受的方法来评估和模拟BHV的耐久性。这种情况导致了目前BHV生物材料开发的停滞，限制了合理开发的BHV耐久性改进。我们假设可以开发一种生物力学严谨和生理上真实的体内方法来从机制上理解BHV生物材料的内在性能。一旦开发出来，这种方法可以用于合理设计显著提高BHV耐久性的新型生物材料。虽然钙化预防尚未完全解决，但乙醇后处理已被证明可显著减少钙化的发生。此外，其他人和我们已经表明，组织退化是BHV在体外和体内耐受性有限的一个主要独立机制。因此，我们的重点将放在早期组织退化的机制和减少损伤积累的方法上，从而提高BHV的耐久性。

Summary: For the foreseeable future, bioprosthetic heart valves (BHV) fabricated from xenograft biomaterials will remain the dominant replacement prosthetic valve design. However, BHV durability remains limited to 10-15 years. Failure is usually the result of leaflet tructural deterioration mediated by fatigue and/or tissue mineralization. Thus, independent of valve design specifics (e.g. standard stented valve, percutaneous delivery), the development of novel xenograft biomaterials with improved durability remains an important clinical goal. This represents a unique cardiovascular engineering challenge resulting from the extreme valvular mechanical demands that occur with blood contact. Yet, current BHV assessment relies exclusively on device-level evaluations, which are confounded by simultaneous and highly coupled biomaterial mechanical behaviors and fatigue, valve design, hemodynamics, and calcification. Thus, despite decades of clinical BHV usage and growing popularity, there exists no acceptable method for assessing and simulating BHV durability at the component biomaterial level. This situation has contributed to the current stagnation in BHV biomaterial development, limiting rationally developed improvements in BHV durability. We hypothesize that a biomechanically rigorous and physiologically realistic in-vivo approach can be developed for a mechanistic understanding of intrinsic BHV biomaterial performance. Once developed, such an approach can be used to rationally design novel biomaterials that significantly improve BHV durability. While calcification prevention has not been completely solved, ethanol post-treatment has been shown to strongly reduce its onset. Moreover, others and we have shown that tissue degeneration is a major independent mechanism underlying BHV limited durability both in-vitro and in-vivo. Thus, our focus will be on mechanisms of early tissue degeneration and means to reduce damage accumulation, leading to improving BHV durability.