Lignin Composites with Sustained Oxygenation and Reactive Oxygen Species-Scavenging Improve Neovascularization and Healing of Diabetic Wounds

Abstract

ABSTRACTAlthough delayed wound healing is an important clinical complication in diabetic patients, few targeted treatments are available, and it remains challenging to promote diabetic wound healing. Impaired neovascularization is one of the prime characteristics of the diabetic phenotype of delayed wound healing. Additionally, increased levels of reactive oxygen species (ROS) and chronic low-grade inflammation and hypoxia are associated with diabetes, which disrupts mechanisms of wound healing. We developed lignin composites with multiple wound healing-promotive functions, including pro-angiogenesis, sustained oxygenation from calcium peroxide (CaO2)-based oxygen releasing nanoparticles and ROS–scavenging with thiolated lignosulfonate that captures the elevated ROS in diabetic wounds. The sustained release of oxygen and ROS-scavenging by the lignin composites promoted endothelial cell branching and their reorganization into characteristic network formationin vitro, promoted angiogenic growth factor expression and angiogenesis in full thickness skin wounds tested in a diabetic murine model of delayed wound healing, and decreased hypoxia inducible factor-1α (HIF-1α) expression. These effects significantly increased the granulation tissue deposition and tissue repair. Our findings demonstrate that lignin composites promote diabetic wound healing without use of other drugs and show the potential of functionalized lignosulfonate for wound healing applications requiring balanced antioxidation and controlled oxygen release.