Abstract Body: Introduction: Although regenerative approaches may alter the natural history of abdominal aortic aneurysm (AAA) growth, limitations in delivery, potency, and durability limit their clinical translation. To address these challenges, we are developing a localized delivery platform for mesenchymal stem cell extracellular vesicles (MSC EVs) using click chemistry to enhance EV retention within a fibrin hydrogel, thereby reducing clearance and maximizing therapeutic efficacy.

Hypothesis: We hypothesized that periaortic delivery of MSC EVs in a fibrin matrix would reduce AAA growth in an elastase-perfusion (EP) rat model. We further hypothesized that click mediated EV-fibrin linkage would not adversely impact the potency of the AAA inhibition at four weeks.

Methods: Under IACUC protocol, male rats underwent EP and placement of a catheter with subcutaneous port for delayed periaortic treatment delivery. Animals received BAPN in drinking water and ultrasound measurements of the aortic diameter (AD) until harvest at 26-27 days. All animals surviving beyond 48 hours post-EP were included. On day three post-EP, AD was measured and a fibrinogen/thrombin solution containing azide conjugated (N=6) or no EVs (N=4) was infused through the port. In half of the EV-treated animals, fibrinogen was conjugated with DBCO to enable click-mediated EV binding.

Results and Conclusion: There was no significant difference in AAA dilation between groups, EV treated and control aortas, during the initial three days post-EP. In control animals, continued dilation occurred through harvest (mean ± SD: 1.32 ± 0.06 mm overall; 0.90 ± 0.13 mm from day three), resulting in near doubling of aortic diameter relative to baseline (196 ± 10%). In contrast, EV treated animals demonstrated significantly reduced aneurysm growth (1.00 ± 0.12 mm overall, P<0.01; 0.56 ± 0.21 mm from day three, P<0.02). No significant difference in aortic growth was observed between fibrin-linked and non-linked EV delivery. In conclusion, these findings demonstrate that locally delivered MSC EVs within a fibrin matrix attenuate AAA growth in a small-animal model. Analysis of mechanical properties of the aorta in response to EV therapy is ongoing. Click chemistry represents a promising strategy to enhance EV retention, with ongoing studies evaluating long-term durability.