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

项目摘要： 先天性心脏病（CHD）仍然是最常见的出生缺陷类别，也是导致先天性心脏病的主要原因。 发达国家的儿童死亡率。在构成冠心病的结构缺陷中， 肺动脉瓣（PV）功能障碍是一种常见的异常，经常需要手术干预 和替换。通过心脏直视手术进行瓣膜置换术， 患者，并代表了家庭的主要经济和情感负担。最常用的阀门 用于幼儿肺动脉瓣置换术的瓣膜是生物衍生的（例如，人尸体瓣膜）。 这种替代品供应短缺，并且具有其他固有的缺点，例如长期性能差。 持久性和诱导宿主免疫应答的倾向。这些因素的结合导致了一个循环 重复的外科手术干预，使用瓣膜，几乎是可用的，注定要迅速失败。 PolyVascular公司试图通过开发聚合物支架安装瓣膜（SMV）来解决这些问题， 包括安装在金属支架内的聚合物衍生的小叶， 侵入性经导管技术，避免了重复手术的负担，有可能改善 耐用性和功能。 在目前的SBIR第二阶段应用中，我们试图通过开发一系列更广泛的 基于我们现有的平台设计。这是基于我们之前的STTR第一阶段提案的数据， 这证明了“超小型”（XS）SMV的可行性，适用于非常小的儿童 右心室流出道（RVOT）导管衰竭。通过将该系列扩展到S、M、L和XL， 目前的提案，我们可以满足更广泛的儿科需求，例如最终的患者增长超出预期 “XS”SMV的可用范围和同心支架中支架展开。更大的SMV尺寸也有明确的用途 对于其他儿科患者，例如既往接受过RVOT补片增强术的青少年;该适应症 需要比“XS”目标范围大得多的直径。 本提案将侧重于必要的设计和表征步骤，以证明完整的 SMV尺寸系列，并向FDA提供数据进行评价。目的1：设计扩张尺寸SMV支架，以及 通过ISO 25539试验仅评估金属支架的性能。目标2：在欧洲制造完整的SMV 扩展SMV尺寸，并通过ISO 5840-3进行必要的测试，以记录SMV性能， 耐久性目的3：生物相容性试验，并将适当大小的SMV转移至GLP绵羊模型，用于急性 以及瓣膜性能、钙化、血栓形成和局部组织反应的扩展评价。 这些研究旨在生成数据，阐明SMV平台的整体性能和潜在用途 案例，并首先在人体试验中提供支持。

Project Summary: Congenital heart disease (CHD) remains the most common category of birth defect and a leading cause of childhood death in the developed world. Of the constellation of structural defects that comprise CHD, dysfunctional pulmonary valves (PV) are a common abnormality, and frequently require surgical intervention and replacement. Valve replacement through open heart surgery carries substantial risk and discomfort for patients, and represents a major financial and emotional burden for families. The most commonly used valves for pulmonary valve replacement in young children are biologically-derived (e.g. human cadaveric valves). Such replacements are in short supply, and have other inherent disadvantages, such as poor long-term durability, and propensity to induce a host immune response. The combination of these factors leads to a cycle of repeat surgical interventions, using valves that are scarcely available and destined for rapid failure. PolyVascular has sought to address these issues by developing a polymeric stent-mounted valve (SMV), comprised of polymer-derived leaflets mounted within a metal stent, that can be delivered via minimally invasive transcatheter techniques, avoiding the burden of repeat surgeries, with potential for improved durability and function. In the present SBIR Phase II application, we seek to expand this model by developing a broader series of sizes, based on our existing platform design. This builds on data from our previous STTR Phase I proposal, which demonstrated the feasibility of an “extra-small” (XS) sized SMV, suitable for use in very small children with failing right ventricular outflow tract (RVOT) conduits. By expanding this series to S, M, L, and XL, in the present proposal, we can address even broader pediatric needs, such as eventual patient growth beyond the usable range of an “XS” SMV, and concentric stent-in-stent deployment. Larger SMV sizes also have clear use for other pediatric patients, such as teenagers with prior patch augmentation of the RVOT; this indication requires a far larger diameters than the “XS” target range. This proposal will focus on the necessary design and characterization steps to demonstrate the utility of the full family of SMV sizes, and provide data to FDA for evaluation. Aim 1: Design expanded size SMV stents, and assess just the metal stents for performance via ISO 25539 testing. Aim 2: Manufacture complete SMVs in the expanded SMV sizes, and conduct necessary tests via ISO 5840-3 to document SMV performance and durability. Aim 3: Biocompatibility testing and transfer a suitably-sized SMV to a GLP sheep model for acute and extended evaluation of valve performance, calcification, thrombosis, and local tissue response. These studies are intended to generate data that clarify overall SMV platform performance, and potential use cases, and support first in human trials.