Antioxidative and Angiogenic Hyaluronic Acid-Based Hydrogel for the Treatment of Peripheral Artery Disease

Abstract

Peripheral arterial disease (PAD) is a progressive atherosclerotic disorder characterized by blockages of the arteries supplying the lower extremities. Ischemia initiates oxidative damage and mitochondrial dysfunction in the legs of PAD patients, causing injury to the tissues of the leg, significant decline in walking performance, leg pain while walking, and in the most severe cases, nonhealing ulcers and gangrene. Current clinical trials based on cells/stem cells, the trophic factor, or gene therapy systems have shown some promising results for the treatment of PAD. Biomaterial matrices have been explored in animal models of PAD to enhance these therapies. However, current biomaterial approaches have not fully met the essential requirements for minimally invasive intramuscular delivery to the leg. Ideally, a biomaterial should present properties to ameliorate oxidative stress/damage and failure of angiogenesis. Recently, we have created a thermosensitive hyaluronic acid (HA) hydrogel with antioxidant capacity and skeletal muscle-matching stiffness. Here, we further optimized HA hydrogels with the cell adhesion peptide RGD to facilitate the development of vascular-like structures <i>in vitro</i>. The optimized HA hydrogel reduced intracellular reactive oxygen species levels and preserved vascular-like structures against H₂O₂-induced damage <i>in vitro</i>. HA hydrogels also provided prolonged release of the vascular endothelial growth factor (VEGF). After injection into rat ischemic hindlimb muscles, this VEGF-releasing hydrogel reduced lipid oxidation, regulated oxidative-related genes, enhanced local blood flow in the muscle, and improved running capacity of the treated rats. Our HA hydrogel system holds great potential for the treatment of the ischemic legs of patients with PAD.