Biocompatible hyaluronic acid-divinyl sulfone injectable hydrogels for sustained drug release with enhanced antibacterial properties against Staphylococcus aureus

Highlights: • Biocompatible HA-DVS injectable hydrogels were obtained after hydrogel formulations optimization. • A sustained release of CFX, TCN and AMX antibiotics, and AAS anti-inflammatory agent, from different HA-DVS formulations was achieved. • Hydrogels loaded with a combination of antibiotics and AAS demonstrated a synergic enhanced antibacterial activity against S. aureus. Hyaluronic acid (HA) solutions were crosslinked with divinyl sulfone (DVS) and subsequently loaded with antibiotic molecules to obtain biocompatible and antibacterial injectable hydrogels. The crosslinking degree of the hydrogels was modulated by varying the reaction time and the HA:DVS weight ratio. Synthesized HA-DVS hydrogels were characterized by their rheological properties, pore size, swelling capacity and hydrolytic and thermal degradation. Biocompatibility was assessed by measuring pH, osmolality and by in vitro cytotoxic assay. Acetyl salicylic (AAS) loaded hydrogels display anti-inflammatory properties in vitro, whereas cefuroxime (CFX), tetracycline (TCN) and amoxicillin (AMX) loaded hydrogels show in vitro antibacterial activity against Staphylococcus aureus. The combine use of antibiotics and AAS produces a synergic effect that reduces the S. aureus population up to a log10 reduction (R) of 5.55. Overall results show that antibiotic/AAS loaded HA-DVS hydrogels could be effectively used to combat S. aureus infections and to increase the antibacterial activity of antibiotics commonly used against S. aureus.