Aldehyde-modified sodium alginate/gelatin-based bacteriophage-loaded multifunctional hydrogel for promoting the healing of multidrug-resistant bacterial-infected wounds

Multidrug-resistant bacterial infections in skin injuries are hard to repair. There is an urgent need to develop new antibacterials, antibiofilm formation, and immunomodulatory wound dressing. In this study, we produced a bacteriophage-loaded multifunctional hydrogel consisting of aldehyde-modified sodium alginate (ADA), gelatin (GEL), and carboxymethyl chitosan (CMCS) through a Schiff base reaction and borax complexation. These post-reactive ADA/GEL/CMCS/Phage (AGCP) hydrogels, particularly the AGCP3 hydrogel, boast a porous structure, high swelling rate, effective hemostasis, controlled degradation, good rheological properties, and strong antibacterial activity. Furthermore, the hydrogel developed in this study can sustainably release various bacteriophages targeting the bacteria responsible for major skin infections, thereby enhancing antibacterial activity and preventing bacterial biofilm formation. Besides, cytotoxicity and cell proliferation demonstrated that the hydrogel, comprising three polysaccharides, ADA, GEL, and CMCS, facilitates skin tissue regeneration by enhancing cellular proliferation and migration. The AGCP hydrogel enhanced healing and controlled inflammation in bacterial-infected wounds, as evidenced by wound closure, collagen deposition, and quantitative reverse transcription polymerase chain reaction results. In conclusion, the AGCP3 hydrogel exhibits strong antibacterial properties, excellent expands, biocompatibility, hemostatic properties, and a controlled release of bacteriophages, making it ideal for universal bacteriophage delivery systems and wound dressings for skin wounds infected with multidrug-resistant bacteria.