Sustained ROS Scavenging and Pericellular Oxygenation by Lignin Composites Rescue HIF-1α and VEGF Levels to Improve Diabetic Wound Neovascularization and Healing
Authors: Jung Jangwook P. , Olutoye Oluyinka O. , Prajati Tanuj J. , Jung Olivia S. , Yutzy Lane D. , Nguyen Kenny L. , Wheat Stephen W. , Huang JoAnne , Padon Benjamin W. , Faruk Fayiz , Keswani Sonya S. , Kogan Phillip , Kaul Aditya , Yu Ling , Li Hui , Thevasagayampillai Shiyanth , Guerra Mary E. , Short Walker D. , Gunaratne Preethi H. , Balaji Swathi 
Published: June 2022

Although delayed wound healing is an important clinical complication in diabetic patients, few targeted treatments are available, and it remains a challenge 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 lignosulfonate composites with several wound healing properties, including sustained oxygen release through calcium peroxide nanoparticles and reactive oxygen species (ROS) and free radical scavenging by thiolated lignosulfonate nanoparticles. Sustained release of oxygen and ROS-scavenging by these composites promoted endothelial cell branching and characteristic capillary-like network formation under high glucose conditionsin vitro. Gene co-expression network analysis of RNA-sequencing results from ECs cultured on lignin composites showed regulation of inflammatory pathways, alongside the regulation of angiogenic hypoxia-inducible factor-1α (HIF-1a) and vascular endothelial growth factor (VEGF) pathways. In vivo, lignosulfonate composite treatment promoted angiogenic growth factor expression and angiogenesis in full thickness skin wounds in diabetic (db/db) mice, a model of delayed wound healing. Treatment of diabetic wounds with lignosulfonate composites also promoted faster epithelial gap closure and increased granulation tissue deposition by day 7 post-wounding, with a higher presence of pro-healing type macrophages. These effects significantly improved tissue repair outcomes by day 14. Our findings demonstrate that lignosulfonate composites promote diabetic wound healing without requiring additional drugs. This highlights the potential of functionalized lignosulfonate for wound healing applications that requires balanced antioxidation and controlled oxygen release.

Statement of Significance

The lignosulfonate composites developed in this study offer a promising solution for delayed wound healing in diabetic patients. By effectively addressing key factors contributing to the multifaceted pathophysiology of the diabetic wounds, including impaired neovascularization, increased ROS levels, and chronic inflammation and wound proteolysis, these composites demonstrate significant potential for promoting wound repair and reducing the complications associated with diabetic wounds. The unique combination of pro-angiogenic, oxygen-releasing, ECM remodeling and antioxidant properties in these lignosulfonate-based materials highlights their potential as a valuable therapeutic option, providing a novel approach to diabetic wound healing without the need for additional drugs.