Dual-crosslinked mussel-inspired smart hydrogels with enhanced antibacterial and angiogenic properties for chronic infected diabetic wound treatment via pH-responsive quick cargo release

The healing of chronic diabetic wounds remains a key challenge due to its susceptibility to bacterial infection, the inflammatory wound microenvironment, and difficulty in angiogenesis. Herein, a pH-responsive, mussel-inspired, double-crosslinking injectable, and adhesive smart hydrogel formula was exploited to overcome these obstacles simultaneously. The multifunctional double-crosslinking hydrogel was developed through the formation of catechol-catechol adducts and a Schiff-based reaction between amino groups (−NH2) in chitosan quaternary ammonium salt (HTCC) and aldehyde groups (–CHO) in oxidized dextran-dopamine (OD-DA). The double-crosslinking mechanism gave the hydrogels great mechanical properties. Most importantly, via the effective encapsulation of silver nanoparticles (AgNPs) and pro-angiogenic drug deferoxamine (DFO), the hydrogel was given with antibacterial and angiogenic features respectively. At the infected diabetic wound area, the double Schiff base bonds (DA and OD; HTCC and OD-DA) in the hydrogels could quickly achieve pH-response and accomplish a sustained and controlled release of drugs to accelerate wound healing. Through the combination of AgNPs and HTCC, the hydrogel exhibited antimicrobial capacities to gram-positive bacteria (S. aureus) and gram-negative bacteria (E. coli), it did not cause toxic side effects and avoided drug resistance. The DFO released at the infected diabetic wound area promoted angiogenesis by enhancing the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). We elucidated the mechanisms by which the designed hydrogels accelerated the healing of bacterial infected diabetic wounds in vitro and in vivo, and our hydrogels represented a general strategy for the healing of a wide range of tissue injuries.