An M2 macrophage-polarized anti-inflammatory hydrogel combined with mild heat stimulation for regulating chronic inflammation and impaired angiogenesis of diabetic wounds

Abstract

At present, approximately 19–34% of diabetic patients (nearly 450 million) may have complications involving diabetic foot ulcers (DFUs). Wound healing of DFUs still faces huge problems, such as long-term chronic inflammation and impaired angiogenesis. Therefore, an M2 macrophage-polarized anti-inflammatory hydrogel (HTHE-M@D) combined with mild heat stimulation is designed for DFUs treatment. The HTHE-M@D hydrogel is prepared by enzymatic cross-linking of epigallocatechin gallate dimer-grafted hyaluronic acid (HA-EGCG) and tyramine-grafted human-like collagen (HLC-TA) and integrating deferoxamine-loaded mesoporous polydopamine nanoparticles (M@D). The hydrogel exhibits prominent enhancement of angiogenesis, which is attributed to the combination of mild heat stimulation via photothermal effects and the angiogenic drugs (deferoxamine) released from the hydrogel. The hydrogel also promotes the transformation of macrophages from the M1 to M2 phenotype and exhibits good anti-inflammatory, antibacterial, antioxidant, hemostatic properties and biocompatibility. Additionally, the hydrogel has desirable mechanical strength, enhanced tissue adhesion and injectability, thus making it more adaptive to DFUs. The results demonstrate that the combination of the hydrogel and mild thermal stimulation promotes skin regeneration of diabetic wounds and shortens the healing time to 13 days. The combined treatment might offer a promising therapeutic strategy for DFUs.