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

项目摘要 这项研究计划旨在创造一种现成的经导管静脉瓣膜 重生的力量。如果成功，它可以治疗成千上万患有慢性阻塞性肺疾病的患者。 深静脉的静脉功能不全，不能用加压袜子治疗，以及 衰弱的腿部溃疡，因为目前没有FDA批准的人工静脉瓣膜。这部小说 静脉瓣膜是由供体真皮成纤维细胞直接生长在镍钛合金支架上的组织制成的。 然后是去细胞。我们在最近的一份出版物中表明，由此产生的双叶纸 瓣膜在体外符合流体力学性能标准，并与宿主细胞一起再生， 包括内皮化，无明显钙化、狭窄或小叶增厚 基于初步测试的产后绵羊髂静脉模型。 我们在此建议对最初的设计和结果进行关键改进，具体如下 使用从圆形部分过渡到椭圆形部分的支架，模拟静脉瓣膜 改善血流动力学和减轻瓣叶融合到瓣膜壁上的鼻窦目前 随着时间的推移在体内发生。在这个里程碑式的计划中，阀门的几何形状将首先进行筛选 利用计算模型对阀门的功能进行了建模，并对其进行了流体力学表征。 直径12毫米的瓣膜将通过导管输送到 绵羊髂静脉持续时间长达24周(R61期)和不持续(R33期) 根据血管内皮化率进行抗凝。交货将在正常情况下进行 绵羊三尖瓣病变静脉反流模型的解剖学研究 足以确保阀门在这些四足动物中循环。纵向评估 瓣膜功能将通过超声波和静脉造影来实现。收获的瓣叶将被 通过以下方式评估尺寸、拉伸机械性能、细胞密度和表型 免疫组织化学，生化分析和组织学检测基质成分。 在R33阶段还将举行一次InterAct会议，以确定GMP FDA对经导管静脉瓣膜的制造和GLP测试预期， 将FDA之前关于我们在体外创建的脱细胞组织的交互作用扩展到 包括根据现有的经导管心脏瓣膜ISO标准进行支架和瓣膜测试。 我们的技术商业化办公室也将致力于专利保护 超越PCT备案和商业化的机会。

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.