Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm

项目总结/摘要 腹主动脉瘤（AAA）是由于动脉中弹性纤维完整性的丧失而引起的主动脉增大。 血管壁随着血管的增长，危及生命的破裂风险增加。一旦直径达到 阈值为5.5 cm，假设破裂风险超过手术干预风险，目前唯一的 批准用于治疗AAA的方法。然而，亚阈值AAA仍然有大约13%的时间破裂， 表明需要阈值前治疗来减缓或停止动脉瘤生长。提供一个再生的 抑制弹性纤维降解并增加弹性生成和胶原合成的治疗可 机械稳定血管并减缓动脉瘤进展。 局部控制输送治疗到动脉瘤部位将是避免全身副作用的理想方法。一 基于细胞但不含细胞的治疗也将提供与含细胞的治疗类似的再生效果。 治疗，但将避免对含细胞疗法施加的强烈监管障碍。在特定 参考脂肪基质细胞（ASC），使用它们的细胞外囊泡（EV）也可以避免植入 和细胞本身的分化，同时仍然发挥其再生作用。也很重要 具有治疗的持续释放，以在更长的时间内对AAA发挥其作用。 该方案旨在开发一种电动汽车磁定位控释系统。该系统将 使用接种在3D纤维蛋白凝胶构建体中的血管平滑肌细胞（VSMC）进行验证，特别关注 递送的EV如何调节基质相关基因表达以及弹性蛋白和胶原蛋白沉积。测试 这些EV如何通过外膜给药到达AAA中的内侧VSMC， 评价其向类淋巴管的猪尿道内的移动。根据这些实验结果， 将开发计算运输模型以预测EV进入血管组织的运动。的 该项目的结果可以作为一种新的再生处理小AAAs的基础，并提供 一种计算工具，用于模拟外部治疗如何到达内侧VSMC。通过这个项目， 申请人将学习研究（包括实验和计算），沟通，教学技能以及 作为科学和临床知识，通过她的学术，研究和临床导师在大学 匹兹堡

Project Summary/Abstract Abdominal aortic aneurysm (AAA) is an enlargement of the aorta caused by loss of elastic fiber integrity in the vascular wall. As the vessel grows, the risk of life-threatening rupture increases. Once the diameter reaches the threshold of 5.5 cm, the risk of rupture is assumed to outweigh the risk of surgical intervention, the only current method approved for treating AAAs. However, sub-threshold AAAs still rupture about 13% of the time, demonstrating the need for a pre-threshold treatment to slow or halt aneurysm growth. Providing a regenerative treatment that inhibits the degradation of elastic fibers and increases elastogenesis and collagen synthesis may stabilize the vessel mechanically and slow aneurysm progression. Local controlled delivery of a treatment to the aneurysm site would be ideal for avoiding systemic side effects. A cell-based yet cell-free treatment would also provide similar regenerative effects to that of a cell-containing treatment but would avoid the intense regulatory hurdles imposed on cell-containing therapies. In specific reference to adipose stromal cells (ASCs), using their extracellular vesicles (EVs) can also avoid engraftment and differentiation of the cells themselves while still exerting their regenerative effects. It is also important to have sustained release of the treatment to exert its effects on the AAA for a longer period of time. This proposal serves to develop a magnet-localizable controlled release system of EVs. This system will be validated using vascular smooth muscle cells (VSMCs) seeded in 3D fibrin gel constructs, specifically looking at how the delivered EVs modulate matrix-related gene expression and elastin and collagen deposition. To test how these EVs could reach the medial VSMCs in an AAA through adventitial administration, EVs will be evaluated for movement into aneurysmal-like porcine aortas. Based on these experimental results, a computational transport model will be developed to predict movements of EVs into aneurysmal tissue. The results of this project could serve as the foundation for a novel regenerative treatment of small AAAs and provide a computational tool to model how external treatments can reach medial VSMCs. Through this project, the applicant will learn research (both experimentally and computationally), communication, teaching skills as well as scientific and clinical knowledge through her academic, research, and clinical mentors at the University of Pittsburgh.