Development of a TAVI Device with a Reduced Crossing Profile

描述(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，已经产生了快速而深远的临床影响。在人类首次使用TAVI装置不到10年后，每年有近2万名患者接受这些新装置。今天，这一临床人群仅限于不能耐受开放手术的老年、病情较重的患者。虽然商用的TAVI设备显示了极高的存活率，但这些“第一代”设备的大尺寸导致了高比率(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。大部分横断面(直径)来自心尖本身，心尖由来自动物来源的相对较厚的心包组成。因此，牙尖厚度的减少将对患者的预后产生重大影响(减少中风和入路并发症)。此外，随着并发症发生率的降低，很明显，TAVI的应用将扩大到不能手术的患者群体，包括更年轻、更健康的患者，他们将受益于较小的侵入性手术。TAVI设备的扩大使用也将对医疗系统产生积极的经济影响，减少手术时间，缩短住院时间，并降低并发症发生率。我们开发了一种名为“自组装组织工程”(TESA)的技术，这种技术可以从细胞合成的薄片和/或线条中构建出坚固的组织结构，而不需要任何生物材料或可能引发降解、钙化或炎症的化学固定。TESA瓣膜尖端的机械性能也可以通过折叠、分层或嵌入策略进行区域性改变。这项SBIR第一阶段提案的首要目标是证明使用TESA平台制造一种功能齐全的TAVI阀门的可行性，其输送特性比目前的商业设备小约25%。在具体目标#1中，我们将量化机械性能(极限抗拉强度、 杨氏模数、弯曲刚度和缝合保持强度)。这将包括表征不同厚度的薄片和通过不同的折叠或嵌入策略增强的薄片的特性。总而言之，我们将测试 17种不同的配置，包括心包和自然瓣膜控制。然后我们将从这个力学特性的‘库’中来指导组织设计，包括缝合区(优先考虑缝合线的握持强度)和缝合区的组织设计(优先考虑强度，而不是灵活性)。在第二个具体目标中，我们将构建并测试这些 具有基本功能和抗动态疲劳能力的新型TAVI设备。如果不满足成功标准(无穿孔部署，血流动力学测试仪可承受1K周期，加速磨损测试仪可承受5M周期)，我们将根据观察到的故障模式和AIM#1中产生的数据‘库’修改阀门尖端设计。如果满足这些功能里程碑，将在第二阶段应用中进行动物测试。

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.