Development of a Polymeric Percutaneous Pulmonary Valve for Use in Young Children

 描述（由申请人提供）：先天性心脏缺陷（CHD）是最常见的出生缺陷类型，是发达国家儿童死亡的主要原因。许多形式的CHD需要肺动脉瓣（PV）置换手术，其通常用生物瓣膜（例如人类尸体供体瓣膜）进行，其供应短缺。此外，这种生物衍生的瓣膜由于儿童的攻击性免疫应答而逐渐恶化，导致其整体耐久性差，表现为进行性狭窄和/或功能不全。因此，患有CHD的儿童进入了多次瓣膜置换术的再手术周期。经皮瓣膜输送的出现，沿着支架安装瓣膜（SMV）的发展，可能会改变这种治疗模式，但目前的SMV存在问题，因为它们不能充分卷曲以达到与幼儿血管尺寸兼容的小轮廓，并且不能以应用于幼儿所需的展开直径提供。在本提案中，我们描述了一种采用下一代聚合物的SMV，该聚合物能够可靠地生产薄瓣叶，并在生物相容性和耐久性方面比以前的聚合物选项有显著改善。我们目前的SMV型号具有出色的流体动力学性能，并超过了ISO 5840-3的耐用性指南。在目前的STTR提案中，Polyvascular将与贝勒医学院/德克萨斯儿童医院和赖斯大学的同事合作，将SMV扩展到适合其目标儿科人群的尺寸。在目标1中，我们将调整我们目前的制造方法以制造儿科尺寸的SMV，评估肺动脉压力下的流体动力学性能作为瓣叶厚度的函数，并评估我们制造方法的批次再现性。在目标2中，这些相同瓣膜的补充研究将评估高速循环载荷下的SMV耐久性，目标是达到ISO 5840-3 2亿次循环无失效的目标。在目标3中，我们将模拟SMV压接和再扩张过程，这是产品使用中的必要步骤，但可能会损坏SMV组件。我们将制造具有多种瓣叶厚度的SMV，并在预置后测量其最小可能外径。重新扩张后，将目视评估每个SMV的损坏和/或径向不对称性，并重新测试流体动力学性能。我们假设，在我们的I期STTR中的这些实验将证明在与患有CHD的年轻儿科患者相关的尺寸下产生功能性聚合物SMV的可行性。这些步骤将为第二阶段SMV的最终生产和在动物模型中测试其反应奠定基础。我们预计这种SMV可能为CHD儿童提供新的治疗机会，减少手术次数并带来潜在的长期健康益处。

 DESCRIPTION (provided by applicant): Congenital heart defects (CHD) represent the most common type of birth defect, and are a leading cause of childhood deaths in the developed world. Many forms of CHD require pulmonary valve (PV) replacement surgery, which is typically performed with biologic valves, such as human cadaveric donor valves, which are in short supply. Additionally, such biologically-derived valves deteriorate progressively due to a child's aggressive immune response, leading to their overall poor durability, manifested as progressive stenosis and/or insufficiency. As a result, children with CHD enter a cycle of multiple re-operations for valve replacements. The advent of percutaneous valve delivery, along with the development of stent-mounted valves (SMV), could potentially change this treatment pattern, but current SMVs are problematic because they cannot be crimped sufficiently to reach a small profile that is compatible with vessel sizes in small children, and are not available in deployed diameters that are required for application in small children. In this proposal, we describe an SMV that employs a next-generation polymer that enables the reliable production of thin leaflets, and offers significant improvements in biocompatibility and durability over previous polymeric options. Our current SMV model has excellent hydrodynamic performance and exceeds ISO 5840-3 guidelines for durability. In the present STTR proposal, Polyvascular will team with colleagues at Baylor College of Medicine/Texas Children's Hospital and Rice University to scale the SMV to sizes that are appropriate for its target pediatric population. In Aim 1, we will adapt our current fabrication methods to manufacture pediatric-sized SMVs, assess hydrodynamic performance at pulmonary pressures as a function of leaflet thickness, and assess batch reproducibility of our fabrication method. In Aim 2, complementary studies of these same valves will assess SMV durability under high-speed cyclic loading, with a goal of reaching ISO 5840-3 targets of 200 million cycles without failure. In Aim 3, we will simulate the process of SMV crimping and re-expansion, which are necessary steps in product use, but which may potentially damage SMV components. We will fabricate SMVs with multiple leaflet thicknesses, and measure their minimum possible profile after crimping. After re- expansion, each SMV will be visually assessed for damage and/or radial asymmetry, and will be re-tested for hydrodynamic performance. We hypothesize that these experiments in our Phase I STTR will demonstrate the feasibility of creating functional polymeric SMVs at sizes relevant to young pediatric patients with CHD. These steps will lay the groundwork for final manufacturing of SMVs in Phase II and testing their response in an animal model. We anticipate that this SMV may offer a new therapeutic opportunity for children with CHD, with reduced numbers of surgeries and potential long-term health benefits.