Extracellular Vesicle Delivery System for Treatment of Abdominal Aortic Aneurysm

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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.