VEGF and IGF delivered from alginate hydrogels promotes stable perfusion recovery in ischemic hindlimbs of aged mice and rabbits

Biomaterial-based delivery of angiogenic growth factors restores perfusion more effectively than bolus delivery methods in rodent models of peripheral vascular disease, but the same success in clinically relevant aged-animal and large-animal studies has not yet been demonstrated. These studies explore, in clinically-relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease which overcomes challenges encountered in previous clinical trials. Alginate hydrogels providing sustained release of Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor-1 (IGF) were injected into ischemic hindlimbs in middle and old age mice, and in young rabbits as a test of the scalability of this local growth factor treatment. Spontaneous perfusion recovery diminished with increasing age, and only the combination of VEGF and IGF delivery from gels significantly rescued perfusion in middle age (13 month) and old age (20 month) mice. In rabbits, delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose two orders of magnitude lower than typical doses used in past rabbit studies, enhanced perfusion recovery when given immediately after surgery, or as a treatment for chronic ischemia. Capillary density measurements and angiographic analysis demonstrated the benefit of gel delivery. These data together suggest that alginate hydrogels providing local delivery of low doses of VEGF and IGF constitutes a safe and effective treatment for hindlimb ischemia in clinically relevant animal models, supporting the potential clinical translation of this concept.