Development of a TAVI Device with a Reduced Crossing Profile

描述（由申请人提供）：经导管主动脉瓣植入术（TAVI）是一种微创的瓣膜置换术，具有快速而深远的临床影响。在人类首次使用TAVI设备后不到十年，每年有近20,000名患者接受这些新型设备。今天，这种临床人群仅限于不能忍受开放性手术的老年、病情较重的患者。虽然商用TAVI设备显示出良好的存活率，但这些“第一代”设备的大尺寸导致了高发生率（20- 30%）的严重并发症。因此，改进的第二代器件的主要设计目标是减小器件直径。交叉轮廓（直径）的大部分来自于心尖本身，它由来自动物来源的相对较厚的心包组成。因此，减少尖端厚度将对患者的预后产生显著影响（减少中风和通路并发症）。此外，随着并发症发生率的降低，TAVI的应用将从不能手术的患者人群扩大到包括更年轻、更健康的患者，他们将从侵入性更小的手术中受益。扩大TAVI设备的使用也将对医疗保健系统产生积极的经济影响，减少手术室时间，缩短住院时间，减少并发症发生率。我们已经开发了一种名为“组织工程自组装”（TESA）的技术，在这种技术中，细胞合成的薄片和/或线可以构建坚固的组织结构，而不需要任何生物材料或化学固定，从而引发降解、钙化或炎症。TESA阀门尖端的机械性能也可以通过折叠、分层或嵌入策略进行局部改变。SBIR第一阶段提案的总体目标是证明使用TESA平台构建功能TAVI阀的可行性，其输送轮廓比目前的商用设备小25%。在具体目标#1中，我们将量化机械性能(极限抗拉强度，

DESCRIPTION (provided by applicant): Transcatheter aortic valve implantation (TAVI) is a minimally invasive approach to valve replacement that has had a rapid and profound clinical impact. Less than ten years after the first human use of a TAVI device, nearly 20,000 patients annually receive these novel devices. Today, this clinical population is limited to older, sicker patients who cannot tolerate an open surgical procedure. While commercially available TAVI devices demonstrate excellent survival rates, the large size of these 'first generation' devices drives a high rate (20- 30%) of serious complications. Accordingly, the primary design objective for improved second generation devices is a reduction in device diameter. The majority of the crossing profile (diameter) comes from the cusps themselves, which are comprised of relatively thick pericardium derived from animal sources. Thus a reduction in cusp thickness would have a dramatic impact on patient outcomes (decreased stroke and access complications). Moreover, as complication rates are decreased, it is clear that TAVI use will broaden beyond the inoperable patient population to include younger, healthier patients who would benefit from a less invasive procedure. Expanded use of TAVI devices will also have a positive economic impact on the healthcare system, with decreased O.R. times, shorter hospital stays, and reduced complication rates. We have developed a technology called 'Tissue Engineering by Self-Assembly' (TESA), where robust, tissue constructs can be built from cell-synthesized sheets and/or threads, without any biomaterials or chemical fixation that can trigger degradation, calcification, or inflammation. The mechanical properties of TESA valve cusps can also be changed regionally, using folding, layering, or embedding strategies. The overarching goal of this SBIR Phase I proposal is to demonstrate the feasibility of using the TESA platform to build a functional TAVI valve with a delivery profile ~25% smaller than current commercial devices. In Specific Aim #1, we will quantify the mechanical properties (ultimate tensile strength, Young's modulus, bending stiffness and suture holding strength) of several different TESA configurations. This will include characterizing the properties of sheets of various thicknesses and sheets that are reinforced by different folding or embedding strategies. In total, we will test 17 different configurations including pericardium and native valve controls. We will then draw from this 'library' of mechanical properties to guide tissue design in both the suture zone (prioritizing suture holding strength) and the coaptation zone where the individual cusps come together (prioritizing strength then flexibility). In Specific Aim #2, we will build and test these novel TAVI devices for basic functionality and resistance to dynamic fatigue. If success criteria are not met (deploy without perforation, withstand 1k cycles in a hemodynamic tester and 5M cycles in an accelerated wear tester), we will revise the valve cusp design based on the observed failure mode and the data 'library' produced in Aim #1. If these functional milestones are met, animal testing will be pursued in a Phase II application.