Visible light cross-linking and bioactive peptides loaded integrated hydrogel with sequential release to accelerate wound healing complicated by bacterial infection

The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge. The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are imperative for the regeneration of the infected wounds. Here, a novel and facile peptide containing injectable hydrogel with sustained antibacterial and angiogenic capabilities is developed. The antibacterial peptide that consists of 11 residues (CM11, WKLFKKILKVL) is loaded onto acrylate-modified gelatin through charge interactions. A vascular endothelial growth factor mimetic peptide KLT (KLTWQELYQLKYKGI) with a GCG (Gly-Cys-Gly) modification at the N-terminal is covalently coupled through a visible light-induced thiol-ene reaction. In this reaction, the acrylate gelatin undergoes cross-linkage within seconds. Based on the physical/chemical double crosslinking strategy, the bioactive peptides achieve sustained and sequential release. The results show that the hydrogel significantly inhibits methicillin-resistant Staphylococcus aureus (MRSA) growth through the rapid release of CM11 peptides at early stage; it forms obvious growth inhibition zones against pathogenic bacterial strains. Moreover, cell counting kit-8 assay and scratch test confirm that the CM11/KLT-functionalized hydrogels promote cell proliferation and migration through the later release of KLT peptides. In a mouse skin wound infected with self-luminous MRSA, the CM11/KLT-functionalized hydrogels enhance wound healing, with rapidly bacterial infection reduction, lower expression of inflammatory factors, and neovascularization promotion. These results suggest that the rationally designed, sustained and sequential release CM11/KLT-functionalized hydrogels have huge potential in promoting the healing of multi-drug resistant bacterial infected wounds.