Hyaluronan-based hydrogel achieves in situ administration of protocatechualdehyde to polarize macrophages to M2 phenotype for diabetic wound therapy.

Wound healing destruction brings disability and mortality to patients with diabetes mellitus. Macrophages maintain pro-inflammatory M1 phenotype to halt diabetic wound recovery. Strategies to polarize M1 macrophages into anti-inflammatory and pro-healing M2 phenotype can propel diabetic wound recovery. The fields of wound repair and tissue regeneration have been advanced by developing phytomedicines and their bioactive compounds. Polymeric biomaterials can be used to prepare hydrogels for cutaneous drug administration. In this study, protocatechualdehyde (PCAE), a natural phenolic acid found in herbal medicine namely Salvia miltiorrhiza Bunge, was confirmed to overcome M1-to-M2 macrophage conversion dysfunction. PCAE was covalently conjugated with hyaluronic acid (HA) to form hydrogel (HA-PCAE). When HA-PCAE was placed onto full-thickness wounds of mice with streptozocin-induced diabetes, it resulted in inflammation attenuation, vascular development, granulation tissue generation, and collagen deposition. Pro-healing effects were attributed mainly to PCAE-mediated macrophage remodeling from M1 to M2 phenotype. Notably, HA-PCAE profoundly augmented diabetic wound recovery as compared with PCAE-loaded hydrogel formed using commercially available carboxymethylcellulose (INTRASITE Gel). This study reveals macrophage-modulatory capacity of PCAE, and demonstrates translational potential of HA-PCAE for diabetic wound treatment.