Development of a Biological Stent Graft for Aorta Aneurysm Repair

描述（由申请人提供）：在美国，每年有超过10万名患者被诊断为腹主动脉动脉瘤（AAA）。其中约70%的患者需要手术干预以防止动脉瘤进展。近20年前，Parodi通过使用可通过血管内入路输送的ePTFE支架，彻底改变了AAA的治疗和修复。如今，每年有超过35000例AAA支架移植，仅在美国，AAA修复设备就成为了一个价值7亿美元的产业。尽管血管内修复技术被迅速采用，但该设备仍存在显著的故障率（一年内超过20%）。这些故障大多是由设备周围或通过设备的泄漏引起的。这种类型的内漏是由支架移植装置和原生主动脉之间的相对运动引起的。这种相对运动由于支架移植物是静态装置，不能随着原生主动脉的动态移动和重塑而重塑而加剧。此外，大多数支架都包裹在ePTFE（聚四氟乙烯）中，它可以很好地作为血液接触面，但不能很好地粘附周围组织。我们假设，通过用生物薄片代替支架上的ePTFE覆盖物，我们可能会改善装置在原生主动脉中的固定。也就是说，通过提供支持细胞向内生长和组织粘附的天然胶原基质，我们将增加设备与原生主动脉之间的结合强度。我们称这种方法为生物颈部固定。该I期授权的目的是证明生物颈部固定的初步可行性，以便我们可以更适当地证明II期扩大疗效研究的合理性。具体来说，在第一阶段，我们将：开发一个由犬细胞构建的薄片，该薄片与我们之前开发的人类薄片的机械性能密切匹配（具体目标1）；通过10 French导管在犬模型中植入生物支架，以评估耐久性、形态学和组织学特性（Specific Aim 2.1）；并在犬模型中比较生物支架相对于标准护理的粘附性和锚定性（Specific Aim 2.2）。在植入后3个月排除无移位或内漏迹象的AAA，以及相对于ePTFE支架移植物相同或更高的锚定强度将是证明进入II期的关键里程碑。该项目的长期目标是将一种完全生物支架商业化，这种支架可以与宿主主动脉一起重塑，从而相对于目前的护理标准降低总体失败率。

DESCRIPTION (provided by applicant): Abdominal aorta aneurysms (AAA) are diagnosed in more than 100,000 patients in the U.S. each year. About 70% of these patients require surgical intervention to prevent aneurysm progression. Nearly 20 years ago, Parodi revolutionized AAA treatment and repair by using an ePTFE stent graft that could be delivered via an endovascular approach. Today, more than 35,000 AAA stent grafts are placed annually, making AAA repair devices a $700 million industry in the U.S. alone. Despite the rapid adoption of endovascular repair, the devices are associated with a significant failure rate (more than 20% at one year). The majority of these failures are caused by leakage around or through the device. This type of endoleakage is caused by relative motion between the stent graft device and the native aorta. This relative motion is aggravated by the fact that the stent grafts are static devices that cannot remodel as the native aorta moves and remodels dynamically. Moreover, most stent grafts are wrapped in ePTFE (Teflon), which works well as a blood contacting surface, but does not adhere well to the surrounding tissue. We hypothesized that by replacing the ePTFE covering on a stent graft with a biological sheet, we might improve upon the fixation of the device into the native aorta. That is, by providing a natural collagen substrate which would support cell ingrowth and tissue adhesion, we would increase the bonding strength between the device and the native aorta. We termed this approach biological neck fixation. The objective of this Phase I grant is to demonstrate the initial feasibility of biological neck fixation such that we can more appropriately justify expanded efficacy studies in Phase II. Specifically, in Phase I, we will: develop a sheet built from canine cells that closely matches the mechanical properties of human sheets that we have developed previously (Specific Aim 1); implant the biological stent graft via a 10 French catheter in a canine model to evaluate durability, morphology, and histological properties (Specific Aim 2.1); and compare the adhesion and anchoring properties of biological stent grafts relative to the standard of care in a canine model (Specific Aim 2.2). Exclusion of the AAA without signs of migration or endoleakage at 3 months post-implant, and equal or greater anchoring strength relative to ePTFE stent grafts will be the key milestones to justify advancing to Phase II. The long-term objective of this project will be to commercialize a completely biological stent graft that can remodel with the host aorta, thereby reducing the overall failure rate relative to the current standard of care. PUBLIC HEALTH RELEVANCE: Abdominal aorta aneurysms (AAA) are diagnosed in more than 100,000 patients in the U.S. each year, and are the 13th leading cause of death. Today, more than 35,000 AAA endovascular stent grafts are placed annually, making AAA repair devices a $700 million industry in the U.S. alone. This Research Proposal describes a new repair device which may significantly reduce the relatively high failure rates associated with the standard of care in AAA repair.