VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits.

Abstract

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 has not yet been demonstrated in clinically relevant studies of aged or large animals. These studies explore, in clinically relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease that overcomes the 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 hind limbs in middle-aged and old mice, and also 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-aged (13 months) and old (20 months) mice. In rabbits, the delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose 2 orders of magnitude lower than the 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 constitute a safe and effective treatment for hind-limb ischemia in clinically relevant animal models, thereby supporting the potential clinical translation of this concept.

• Authors: Erin M Anderson, Eduardo A Silva, Yibai Hao, Kathleen D Martinick, Sarah A Vermillion, Alexander G Stafford, Elisabeth G Doherty, Lin Wang, Edward J Doherty, Paul M Grossman, David J Mooney
• Journal: Journal of vascular research (J Vasc Res) Vol. 54 Issue 5 Pg. 288-298 ( 2017) ISSN: 1423-0135 [Electronic] Switzerland
• PMID: 28930755 (Publication Type: Journal Article)
• Copyright: © 2017 S. Karger AG, Basel.

Chemical References

• Alginates
• Angiogenesis Inducing Agents
• Drug Carriers
• Hexuronic Acids
• Hydrogels
• Vascular Endothelial Growth Factor A
• Insulin-Like Growth Factor I
• Glucuronic Acid

Topics

• Age Factors
• Alginates (chemistry)
• Angiogenesis Inducing Agents (administration & dosage, chemistry)
• Angiography, Digital Subtraction
• Animals
• Disease Models, Animal
• Drug Carriers
• Drug Compounding
• Female
• Glucuronic Acid (chemistry)
• Hexuronic Acids (chemistry)
• Hindlimb
• Hydrogels
• Insulin-Like Growth Factor I (administration & dosage, chemistry)
• Ischemia (diagnostic imaging, drug therapy, physiopathology)
• Mice, Inbred C57BL
• Muscle, Skeletal (blood supply)
• Neovascularization, Physiologic (drug effects)
• Rabbits
• Recovery of Function
• Regional Blood Flow
• Time Factors
• Vascular Endothelial Growth Factor A (administration & dosage, chemistry)