Sulfated chitosan rescues dysfunctional macrophages and accelerates wound healing in diabetic mice

Emerging evidence suggests that dysfunctional macrophages can cause chronic inflammation and impair tissue regeneration in diabetic wounds. Therefore, improving macrophage behaviors and functions may improve therapeutic outcomes of current treatments in diabetic wounds. Herein, we present a sulfated chitosan (SCS)-doped Collagen type I (Col I/SCS) hydrogel as a candidate for diabetic wound treatments, and assess its efficacy using streptozocin (STZ)-induced diabetic wound model. Results showed that Col I/SCS hydrogel significantly improved wound closure rate, collagen deposition, and revascularization in diabetic wounds. Flow cytometry analysis and immunofluorescent staining analysis showed that the Col I/SCS hydrogel accelerated the resolution of excessive inflammation by reducing the polarization of M1-like macrophages in chronic diabetic wounds. In addition, ELISA analysis revealed that the Col I/SCS hydrogel reduced the production of pro-inflammatory interleukin (IL)-6 and increased the production of anti-inflammatory cytokines including IL-4 and transforming growth factor-beta 1 (TGF-β1) during wound healing. Moreover, the Col I/SCS hydrogel enhanced the transdifferentiation of macrophages into fibroblasts, which enhanced the formation of collagen and the extracellular matrix (ECM) in wound tissue. We highlight a potential application of manipulating macrophages behaviors in the pathological microenvironment via materials strategy. STATEMENT OF SIGNIFICANCE: Improving the chronic inflammatory microenvironment of diabetic wounds by regulating macrophage behaviors has been of wide concern in recent years. We designed a Col I/SCS hydrogel based on Collagen type I and sulfated chitosan (SCS) without exogenous cells or cytokines, which could significantly improve angiogenesis and resolve chronic inflammation in diabetic wounds, and hence accelerate diabetic wound healing. The Col I/SCS hydrogel could facilitate the polarization of M1-to-M2 macrophages and activate the transdifferentiation of macrophages to fibroblasts. Additionally, the Col I/SCS hydrogel also equilibrated the content of pro-inflammatory and anti-inflammatory cytokines. This strategy may afford a new avenue to improve macrophage functions and accelerate diabetic chronic wound healing.