Objective: Shear-thinning hydrogels are promising vehicles for minimally invasive drug delivery. Continued development of advanced hydrogels is necessary to maximize their therapeutic potential. In this study, we encapsulated an engineered angiogenic cytokine, stromal cell-derived factor 1-α (ESA) in a novel, injectable hydrogel which undergoes a dual crosslinking mechanism. The first crosslinking step occurs ex situ via dynamic covalent bonds. The second step occurs in situ via thermal phase transition at body temperature to enforce the network, extending ESA release. We hypothesized that delivery of ESA via this novel, bioengineered hydrogel would facilitate targeted, sustained intramyocardial release, thereby prolonging endothelial progenitor cell (EPC) homing and improving left ventricular (LV) function in a rat model of myocardial ischemia.
Methods: Cytoprotective and migratory effects of ESA on human EPCs were assessed via WST1 viability and QCM chemotaxis assays. Hydrogel release was monitored using a 4kDa fluorophore. Male Sprague-Dawley rats (n=27) underwent sham surgery or permanent ligation of the LAD followed by injection of 100μL PBS, 25μg of ESA in 100μL PBS, or 25μg ESA encapsulated in 100μL of hydrogel. Left ventricular function, infarct size, and angiogenic response were assessed 4-weeks post-ligation.
Results: Treatment with ESA on serum-starved EPCs increased cell viability by 84% and migration by 114% (Fig. 1A). In vitro release from the hydrogel was sustained for 14 days (Fig. 1B). Finally, in vivo treatment with ESA+hydrogel significantly reduced infarct size, enhanced FAC, and increased arterial density compared to the PBS controls (Figs. 1C-F).
Conclusions: Minimally invasive delivery of ESA via a novel, dual-crosslinking hydrogel facilitates sustained release for a prolonged therapeutic effect. We have demonstrated that encapsulation of ESA limits LV deterioration by enhancing vessel formation and reducing fibrosis.