Stimulation of Cardiac Angiogenesis through Growth Factors with a Fibrin Gel Delivery Platform

Purpose Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the micro-environment as it remains localized in the matrix. However, co-delivery of platelet-derived growth factor-BB (PDGF-BB) restores physiological angiogenesis despite high VEGF doses. Recombinant protein delivery of angiogenic factors in clinically attractive due to safety and convenience, but rapid in vivo clearance prevents therapeutic efficacy. Here we use an optimized fibrin platform to enzymatically link recombinant factors to precisely control both in vivo distribution of growth factor dose and duration of stimulus in the myocardium. Methods VEGF and PDGF-BB were fused to the octapeptide sequence α2-PI1-8, which is a substrate for the transglutaminase coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. Optimized gel compositions (Sacchi, PNAS 2014) were loaded with either factor alone or together and injected into 4 locations of the anterior wall of the heart of SD rats. Fibrin alone and phosphate buffered saline (PBS) were used as negative controls. Histology was performed after 1 and 4 weeks. Results Fibrin gels were created with a ratio of 10:1 with doses of 100 μg/mL for VEGF and 10 μg/mL for PDGF-BB based on previous results. Neither emboli during injections nor postoperative neurological complications were observed and mortality remained 0% with all rats completing the experiment. The fibrin gel was entirely degraded already at 1 week, leaving only a scar visible in the injected area at both time points with no difference between experimental groups. Optimized co-delivery of fibrin-α2-PI1-8-VEGF+PDGF-BB was effective in a non-ischemic heart model to significantly improve persistent angiogenesis compared to VEGF alone, despite short duration of treatment ( Conclusion This optimized platform stimulates angiogenesis without introducing genetic material and with a limited duration of treatment. It opens a new strategy to improve safety and efficacy of therapeutic angiogenesis in the heart.