An expandable polymeric valved conduit to repair congenital heart disease

项目概要：超过16，000名美国儿童需要植入带瓣管道来替换右心室。 心室流出道（RVOT）。这些孩子需要一至四次重复的心脏直视手术， 在他们成年之前更换带瓣管道，因为现有的假体不会随着孩子的成长而成长。 我们的多学科合作团队的长期目标是开发一种生物稳定的聚合物带瓣管道 可通过手术植入以重建RVOT，然后扩张（通过连续经导管 避免儿童多次手术。我们的总体目标是设计、验证和演示 器械可扩张性和瓣膜能力的体外和体内概念验证。我们的中央 假设是，使用和控制加工具有足够可塑性的生物稳定聚合物， 阀的优化设计，可以允许连续的受控膨胀，同时保持阀 能力。我们将在以下三个具体目标中检验这一假设：目标1：描述增长 非瓣膜导管的适应性。我们将1.1）表征8 ePTFE的机械性能 1.2）开发了一个计算的材料与不同密度和厚度的单轴拉伸试验机， 基于力学数据的12-24 mm管膨胀模型，以及1.3）验证膨胀 实验性地使用经导管球囊并测量膨胀潜力、单轴拉伸性能 和微架构。目标2：开发适用于所有直径的瓣膜设计。我们假设 具有增加的接合高度和增加的自由边缘长度的瓣膜设计可以从 12-24 mm直径，同时保持瓣膜性能。我们将使用基于流体-结构相互作用的 计算设计、原型制造和实验验证， 迭代地检查设计对带瓣管道的血液动力学性能的影响。目标3： 描述带瓣管道的性能和耐久性。我们将3.1）描述生物相容性 使用主动脉大鼠模型; 3.2）证明在绵羊模型中的急性体内性能; 3.3）评估在 加速磨损试验机中的体外耐久性。预期成果：查明 制造过程中，优化阀门流体动力学的不同阶段的扩张，并进行了在 瓣膜功能的生物相容性、可扩张性和维持的体外和体内概念证明 设备的。拟议研究的创新之处在于，我们将开发一种带阀管道， 特别是在每个扩张阶段都能持久和胜任的增长适应，使用和 开发创新设计、计算模型、制造技术和翻译 方法论。影响和意义：我们的研究结果将有助于进一步发展的证据， 创新的可扩张外科瓣膜装置，有助于避免儿童多次重复心脏直视手术。 未来的研究包括细胞毒性测试和临床前研究，以准备FDA的批准。

Project Summary: More than 16,000 US children need the implantation of a valved conduit to replace the right ventricular outflow tract (RVOT) annually. These children require one to four repeat open-heart surgeries to replace the valved conduit before they reach adulthood because available prostheses do not grow with the child. The long-term goal of our multidisciplinary collaborative team is to develop a biostable polymeric valved conduit that can be implanted surgically to reconstruct the RVOT and then expanded (by successive transcatheter procedures) to avoid multiple surgeries in children. Our overall objective is to design, validate and demonstrate the in vitro and in vivo proof of concept of the expandability and valvar competence of the device. Our central hypothesis is that the use and controlled processing of a biostable polymer with adequate plasticity, associated to an optimized design of the valve, can allow for successive controlled expansions while maintaining valve competence. We will test this hypothesis in the following three specific aims: Aim1: Characterize the growth accommodation of non-valved conduits. We will 1.1) characterize the mechanical properties of 8 ePTFE materials with varying densities and thicknesses using a uniaxial tensile tester, 1.2) develop a computational model of tube expansion from 12-24 mm based on the mechanical data, and 1.3) validate the expansion experimentally using a transcatheter balloon and measuring the expansion potential, uniaxial tensile properties and microarchitecture. Aim 2: Develop a valve design for competence at all diameters. Our hypothesis is that a valve design with increased height of coaptation and increased length of the free edge can be expanded from a 12-24 mm diameter while maintaining valve competence. We will use a fluid-structure interaction based computational design, prototype fabrication, and experimental validation in our heart valve pulse duplicator to iteratively examine the effects of the design on the hemodynamic performance of the valved conduit. Aim 3: Describe the performance and durability of the valved conduit. We will 3.1) characterize the biocompatibility using an aortic rat model; 3.2) demonstrate the acute in vivo performance in a sheep model; 3.3) assess the in vitro durability in an accelerated wear tester. Expected outcomes: to have identified the conditions of the fabrication process, optimized the valve hydrodynamics for different stages of expansion and performed the in vitro and in vivo proof of concept of the biocompatibility, expandability and maintenance of the valvar competence of the device. The innovation of the proposed research is that we will develop a valved conduit designed specifically for growth-accommodation that is durable and competent at every stage of expansion, using and developing innovative designs, computational models, manufacturing techniques and translational methodologies. Impact and significance: our results will contribute to the evidence for further development of an innovative expandable surgical valved device that will help avoid multiple repeat open-heart surgeries in children. Future studies include cytotoxicity testing and a pre-clinical study to prepare FDA approval.