Biomechanical Approaches and Technologies for Enhancing TAVR Outcomes

项目摘要 经导管主动脉瓣置换术(TAVR)已成为不能手术的患者的救命方案 老年钙化性主动脉瓣病(CAVD)和重度主动脉瓣狭窄(AS)患者。然而，在最近 多年来出现了某些局限性和严重的不良事件：由于主动脉几何形状扭曲而导致分娩失败 严重的瓣膜钙化、瓣膜移位、传导异常和瓣膜旁渗漏(PVL) 血栓栓塞术增加了卒中风险，增加了TAVR后的总体发病率和死亡率。当前 TAVR技术是基于适应于TAVR的组织瓣，但不是专门为TAVR设计的。那些可能 在卷曲和展开过程中受到损坏，导致耐用性有限和功能受损。在……里面 降低PVL的最新一代TAVR设备特别解决方案与更高的发病率相关 心脏传导异常(CCA)，通常导致需要同时安装永久起搏器 植入。这可能会限制TAVR的使用及其在年轻、低风险患者中的预期扩展，包括 BAV(二尖瓣主动脉瓣)患者，其中标签外使用TAVR正在迅速出现。考虑到美国的老龄化 由于预计到本世纪中叶这一数字将翻一番，因此迫切需要 优化手术程序，发展长期TAVR技术--优化以减少并发症 在获得更好的临床结果的同时，提高了患者的治愈率。我们的翻译项目旨在开发下一代TAVR 技术将成像、计算和体外工具结合在一种精细的生物力学分析方法中， 优化方法将指导预先计划和定制TAVR程序，以实现显著更好的效果 改善患者预后，减少随之而来的并发症。我们还致力于提供颠覆性的技术：下一代 阀门专门针对TAVR进行了优化。Polynova聚合阀是使用我们的优化设计开发的。 U01 Quantum项目下的DTE方法和当前的STTR奖。它结合了一种新颖的xSIBS 具有更好的抗卷曲和展开应力的血液相容性聚合物，改善血流动力学 性能和抗血栓性能，以及更长的耐用性。它的TAVR原型将经过严格的测试和 进一步优化。 这些目标将通过使用创新的反向钙化技术(RCT)来预测 CAVD进展。我们将使用大型CAVD患者数据库中特定于患者的重建几何图形 作为改进的数值模拟的输入。我们将扩大我们现有的CAVD患者的大型CT扫描数据库 (目前n=750)，以及利用来自另外两个医疗中心的TAVR数据库(n=293和94， )，对疾病进展进行分类，以进一步为阐明、计划和预测介入提供服务 结果。使用RCT作为预测三尖瓣钙化生长的预测模型的基础 (TAV)和双尖瓣CAVD患者，我们将采用硅内和体外生物力学分析相结合的方法 将包括详细和精细的结构、FSI(流体结构相互作用)和CFD(计算流体 动力学)模拟从CT扫描重建的患者特定的几何结构。异质组织 AVC组件的特性将通过外科CAVD标本的生物力学测试来获得 病人。多尺度组织和钙化建模将利用来自Micro-CT测量的输入来 微调模型。将基于RCT模型用FSI研究CAVD的各个阶段，并进行验证 在体外左心模拟器(LHS)和制作的3D打印模型中进行血流动力学测量 血管模拟Replicator®系统中CAVD患者的复制品，并具有后续血栓形成能力 由柏林左心辅助装置和SynCardia全人工心脏提供动力的流量环中的测量。 我们将使用上述方法微调Polynova聚合物TAVR瓣膜的体外血流动力学和耐用性 方法以及体外高循环系统，并为BAV患者开发专门的设计，以解决 展开和阀门偏心问题。使用活体心脏人体模型(LHHM)进行计算机建模， 我们将评估与TAVR相关的CCAs和房室传导阻滞的预测组织应变 并将成功的TAVR病例与CCA和植入起搏器的病例进行比较。最后， 我们将研究预粘附聚合物生物材料应用于TAVR支架的体外和体内疗效。 减少偏心，密封PVL。

Project Summary Transcatheter Aortic Valve Replacement (TAVR) has emerged as a life-saving solution for inoperable elderly patients with calcific aortic valve disease (CAVD) and severe Aortic Stenosis (AS). However, in recent years certain limitations and serious adverse events emerged: failed delivery due to tortuous aortic geometry and severe valvular calcification, valve migration, conduction abnormalities, and paravalvular leaks (PVL) leading to embolization with increased stroke risk, increasing the overall morbidity and mortality post-TAVR. Current TAVR technology is based on tissue valves adapted to, but not specifically designed for TAVR. Those may sustain damage during crimping and deployment, resulting in limited durability and impaired functionality. In latest-generation TAVR devices ad hoc solutions to reduce PVL have been associated with higher incidence of cardiac conduction abnormalities (CCAs), often leading to the need for concurrent permanent pacemaker implantation. This may limit TAVR utility and its anticipated expansion into younger, lower risk patients, including a BAV (bicuspid aortic valve) patients, in which off-label use of TAVR is rapidly emerging. Given the aging U.S. population segment at high risk for AS that is expected to double by mid-century, there is a critical need for optimizing the procedure and developing long-term TAVR technology – optimized to reduce the complications rates while achieving better clinical outcomes. Our translational project aims to develop next generation TAVR technology. Combining imaging, computational, and in vitro tools in a refined biomechanical analysis methodology, an optimization approach will guide the pre-planning and tailor TAVR procedures for achieving significantly better patient outcomes and reduce ensuing complications. We also aim to offer a disruptive technology: next generation valves specifically optimized for TAVR. The Polynova polymeric valve was developed using our design optimization DTE methodology under a U01 Quantum project and a current STTR award. It incorporates a novel xSIBS hemcompatible polymer with better tolerance to crimping and deployment stresses, improved hemodynamic performance and thromboresistance, and extended durability. Its TAVR prototypes will be rigorously tested and further optimized. These goals will be achieved by employing an innovative Reverse Calcification Technique (RCT) to predict CAVD Progression. We will use patient specific reconstructed geometries from a large CAVD patient’s database as input for refined numerical simulations. We will expand our existing large CT scans database of CAVD patients (currently n=750), as well as utilize TAVR databases from two additional medical centers (n=293 and 94, respectively), to catalog the disease progression to further serve to elucidate, plan and predict interventional outcomes. Using RCT as a base for predictive models of prospective calcification growth – both in tricuspid (TAV) and bicuspid CAVD patients, we will employ a combined in silico and in vitro biomechanical analysis that will include detailed and refined structural, FSI (Fluid Structure Interaction) and CFD (Computational Fluid Dynamics) simulations in the patient specific geometries reconstructed from CT scans. Heterogeneous tissue and AVC components properties will be obtained by biomechanical testing of specimens from surgical CAVD patients. Multiscale tissue and calcification modeling will utilize input derived from micro-CT measurements to fine tune the models. Various CAVD stages will be studied with FSI based on the RCT models, and validated with hemodynamics measurements in a ViVitro left heart simulator (LHS) and in fabricated 3D printed model replicas of CAVD patients in the Vascular Simulations Replicator® system, with follow-up thrombogenicity measurements in flow loops powered by a Berlin left ventricular assist device and SynCardia total artificial heart. We will fine-tune the in vitro hemodynamic and durability of the Polynova polymeric TAVR valve using the above approaches, as well a ViVitro Hi-Cycle system, and develop a dedicated design for BAV patients addressing deployment and valve eccentricity issues. Using in silico modeling with the Living Heart Human Model (LHHM), we will evaluate tissue strains that is predictive of CCAs and atrioventricular blockage associated with TAVR deployment, and compare successful TAVR cases to those with CCAs and pacemaker implantation. Finally, we will study the in vitro and in silico efficacy of pre-adherent polymeric biomaterials applied to TAVR stents in reducing eccentricity and sealing PVL.