Delayed delivery of endothelial progenitor cell derived extracellular vesicles via shear-thinning gel improves post-infarct hemodynamics

Abstract Background EVs are promising therapeutics for cardiovascular disease, but poorly-timed delivery may hinder efficacy. We characterized the time-dependent response to EPC-EVs within an injectable shear-thinning hydrogel (STG+EV) post-MI to identify when an optimal response is achieved. Methods The angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in vitro . A rat model of acute MI via LAD ligation was created and STG+EV was delivered via intramyocardial injections into the infarct borderzone at timepoints corresponding to phases of post-MI inflammation – 0h (immediate), 3h (acute inflammation), 4d (proliferative), and 2wk (fibrosis). Hemodynamics 4 weeks post-treatment were compared across treatments and controls (PBS, STG). Scar thickness and ventricular diameter were assessed histologically. Primary hemodynamic endpoint was end systolic elastance. The secondary endpoint was scar thickness. Results EPC-EVs incubated with chronically vs. acutely hypoxic HUVECS resulted in a 2.56±0.53 vs 1.65±0.15 -fold increase (p=0.05) in number of vascular meshes and higher uptake of EVs over 14 hours. Ees improved with STG+EV therapy at 4d (0.54±0.08) vs PBS or STG (0.26±0.03, p=0.02; 0.23±0.02, p=0.008). Preservation of ventricular diameter (6.20mm±0.73 vs. 8.58mm±0.38, p=0.04; 9.13mm±0.25, p=0.01) and scar thickness (0.885mm±0.046 vs. 0.615mm±0.029, p Conclusions Delivery of STG+EV 4 days post-MI improves LV contractility and preserves global ventricular geometry, compared to controls and immediate therapy post-MI. These findings suggest other cell-derived therapies can be optimized by strategic timing of therapeutic intervention.