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

项目总结： 先天性心脏病(CHD)仍然是最常见的出生缺陷类别，也是导致 发达国家的儿童期死亡。构成先心病的结构缺陷的星座， 摘要肺功能不全(PV)是一种常见的畸形，经常需要外科手术治疗。 和替补。心脏直视手术瓣膜置换术有很大的风险 这对患者来说是一种负担，对家庭来说是一个巨大的经济和情感负担。最常用的阀门 用于幼儿的肺瓣膜置换术的瓣膜是生物衍生的(例如人体身体瓣膜)。 这种替代品供不应求，而且还有其他固有的缺点，如长期效果不佳 耐久性和诱导宿主免疫反应的倾向。这些因素的结合导致了一个循环。 重复手术干预，使用几乎不可用且注定会迅速失效的瓣膜。 多血管公司试图通过开发聚合物支架安装式瓣膜(SMV)来解决这些问题， 由安装在金属支架内的聚合物衍生小叶组成，可通过最低限度的 侵入性经导管技术，避免了重复手术的负担，具有改进的潜力 经久耐用。 在目前的SBIR第二阶段应用中，我们试图通过开发更广泛的一系列 尺寸，基于我们现有的平台设计。这建立在我们之前的STTR第一阶段提案中的数据基础上， 证明了一种“超小型”(XS)SMV的可行性，适合在非常小的儿童中使用 右室流出道(RVOT)管道衰竭。通过将本系列扩展到S、M、L和XL， 目前的提案，我们可以解决更广泛的儿科需求，例如最终患者的增长超过 “XS”SMV的可用范围，以及同心支架内支架部署。更大的SMV大小也有明显的用途 对于其他儿科患者，例如有RVOT补片增强的青少年；这一适应症 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，以演示完整的 SMV系列，并向FDA提供数据以供评估。目标1：设计扩大尺寸的SMV支架，以及 仅通过国际标准化组织25539测试评估金属支架的性能。目标2：制造完整的SMV 扩展SMV规模，并通过ISO 5840-3进行必要的测试，以记录SMV性能和 耐用性。目的3：进行生物相容性测试，并将适当大小的SMV移植到GLP绵羊模型中，用于急性 并对瓣膜性能、钙化、血栓形成和局部组织反应进行扩展评估。 这些研究旨在生成数据，以澄清SMV平台的整体性能和潜在用途 病例，并在人体试验中支持第一。

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.