Development of a Biological Stent Graft for Aorta Aneurysm Repair

描述（由申请人提供）：美国每年有超过100，000例患者诊断为腹主动脉瘤（AAA）。大约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方法输送的ePTFE覆膜支架彻底改变了AAA治疗和修复。今天，每年放置超过35，000个AAA支架移植物，仅在美国就使AAA修复设备成为7亿美元的产业。尽管腔内修复术迅速普及，但该器械的失败率很高（1年时超过20%）。这些故障中的大多数是由器械周围或通过器械的泄漏引起的。这种类型的内漏是由覆膜支架与自体主动脉之间的相对运动引起的。这种相对运动由于覆膜支架是静态器械而加剧，其不能随着自体主动脉的动态移动和重塑而重塑。此外，大多数支架移植物包裹在ePTFE（特氟隆）中，其作为血液接触表面工作良好，但不能很好地粘附到周围组织。我们假设，通过用生物片材替换覆膜支架上的ePTFE涂层，我们可能会改善器械在自体主动脉中的固定。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，我们将增加装置和天然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期资助的目的是证明生物颈部固定的初步可行性，以便我们能够更适当地证明II期扩展有效性研究的合理性。具体来说，在第一阶段，我们将：开发一种由犬细胞制成的床单，它与我们以前开发的人类床单的机械性能非常匹配（特定目的1）;通过10 Fr导管在犬模型中植入生物覆膜支架，以评价耐久性、形态学和组织学特性（具体目标2.1）;并在犬模型中比较生物覆膜支架相对于标准治疗的粘附和锚定特性（具体目标2.2）。排除植入后3个月无移位或内漏迹象的AAA，以及与ePTFE覆膜支架相比锚定强度相等或更大，将是证明推进至II期的关键里程碑。该项目的长期目标是将完全生物学的覆膜支架商业化，该覆膜支架可以与宿主主动脉一起重塑，从而降低相对于当前标准治疗的总体失败率。 公共卫生相关性：美国每年有超过100，000名患者被诊断出腹主动脉瘤（AAA），是第13大死亡原因。今天，每年放置超过35，000个AAA血管内支架移植物，使AAA修复器械仅在美国就成为7亿美元的行业。本研究提案描述了一种新的修复器械，可显著降低AAA修复标准治疗相关的相对较高的失败率。

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.