Biologically-engineered Transcatheter Vein Valve: Design Optimization and Preclinical Testing

项目摘要 本研究计划旨在创建一种现成的经导管静脉瓣膜， 重生的机会如果成功的话，它可以治疗成千上万的慢性病患者。 深静脉的静脉功能不全，无法用压缩袜治疗，以及 使人衰弱的腿部溃疡，因为目前没有FDA批准的人工静脉瓣膜。这本小说 静脉瓣膜由直接在镍钛合金支架上的供体真皮成纤维细胞生长的组织形成 然后脱细胞化。我们在最近的一篇文章中表明， 瓣膜符合体外流体动力学性能标准，并可与宿主细胞再生， 包括内皮化，无明显钙化、狭窄或瓣叶增厚 基于初始试验，在绵羊髂静脉模型中进行了输送后试验。 我们建议在此对初始设计和结果进行关键改进， 使用从圆形截面过渡到椭圆形截面的支架， 窦，以改善血流动力学并减轻目前 会随着时间的推移在体内发生。在这一里程碑式的计划中，将首先筛选阀门几何形状 使用阀函数的计算建模，然后流体动力学地表征。 将通过导管将这些窦增强的直径为12 mm的瓣膜输送至 绵羊髂静脉持续长达24周，持续（R61阶段）和不持续（R33阶段） 根据内皮化的速度抗凝。交付将在正常情况下进行 解剖学和通过损害三尖瓣获得的绵羊静脉回流模型 足以确保瓣膜在这些四足动物中循环。纵向评估 将通过超声和静脉造影检查瓣膜功能。采集的瓣叶将 通过以下方式评估尺寸、拉伸机械性能、细胞结构和表型： 免疫组织化学和基质组成通过生物化学测定和组织学。 R33阶段还将举行INTERACT会议以确定GMP FDA对经导管静脉瓣膜的制造和GLP试验预期， 扩展了FDA之前关于我们在体外创建的脱细胞组织的相互作用， 包括根据经导管心脏瓣膜现有ISO标准进行的支架和瓣膜试验。 我们的技术商业化办公室也将参与专利保护 超越PCT申请和商业化机会。

Project Summary This research plan is aimed at creating an off-the-shelf transcatheter vein valve capable of regeneration. If successful, it could treat many thousands of patients who suffer from chronic venous insufficiency in deep veins, untreatable with compression stockings, and the sequelae of debilitating leg ulcers, as there is currently no FDA-approved prosthetic vein valve. This novel vein valve is created from a tissue grown from donor dermal fibroblasts directly on a nitinol stent followed by decellularization. We have shown in a recent publication that the resulting bileaflet valve meets hydrodynamic performance criteria in vitro and regenerates with host cells, including endothelialization, without gross calcification, stenosis, or thickening of the leaflets post-delivery in the ovine iliac vein model based on initial testing. We propose here to make a key improvement upon the initial design and results by using a stent that transitions from a circular section to an oval section, emulating vein valve sinuses to improve hemodynamics and mitigate leaflet fusion to the valve wall that currently occurs in vivo over time. In this milestone-driven plan, valve geometries will first be screened using computational modeling of valve function and then characterized hydrodynamically. Valves of 12 mm diameter enhanced with these sinuses will be delivered via catheter to the ovine iliac vein for up to 24-week duration with (R61 phase) and without (R33 phase) sustained anti-coagulation based on the rate of endothelialization. Delivery will be conducted in the normal anatomy and in a venous reflux model in sheep achieved by compromising the tricuspid valve sufficiently to ensure the valves are cycled in these quadrupeds. Longitudinal assessment of valve function will be made via ultrasound and venogram. Harvested valve leaflets will be assessed for dimensions, tensile mechanical properties, cellularity and phenotype via immunohistochemistry, and matrix composition via biochemical assay and histology. An INTERACT meeting will also be conducted during the R33 phase to ascertain GMP manufacturing and GLP testing expectations of the FDA for a transcatheter vein valve, extending prior FDA interaction regarding the decellularized tissue that we create in vitro to include stent and valve testing in light of ISO standards that exist for transcatheter heart valves. Our Office of Technology Commercialization will also be engaged regarding patent protection beyond the PCT filed and commercialization opportunities.