Tunable antibiotic delivery from gellan hydrogels

Abstract

Hydrogels are used extensively in wound management. Many wounds are highly susceptible to infection and hydrogels can provide localized antibacterial delivery to treat and prevent this infection. There are several key considerations in designing antibacterial hydrogels for wound therapy, including preserving activity of encapsulated antibacterial agents, controlling drug release timescales and concentrations, and having the ability to conform to various wound configurations. In this work, we have used gellan, a U.S. Food and Drug Administration approved food additive, to develop antibiotic loaded hydrogels focusing on these criteria. These hydrogels were formed to exhibit a range of mechanical properties, which were investigated using oscillatory rheology. We denoted hydrogels formed using 1% w/v gellan and 1 mM CaCl₂ “ointment” hydrogels and those formed using 4% w/v gellan and 7 mM CaCl₂ “sheet” hydrogels. Vancomycin, a broad-spectrum antibiotic against Gram-positive bacteria, was encapsulated in these hydrogels both directly and/or in graphitized carbon black nanoparticles (CNPs). We found that vancomycin released from both sheet and ointment hydrogels at therapeutically effective concentrations over 9 days with CNPs and 6 days without CNPs. Applying the Ritger–Peppas and Peppas–Sahlin semi-empirical drug release models to sheet hydrogels, we determined that Fickian diffusion dominates release while case II relaxation also has a small contribution. The sheet hydrogels exhibited a larger overall release of the drug (83.6 ± 1.6% compared to 67.0 ± 2.6% for ointments), which was attributed to the larger swelling resulting from osmotic pressure differences between the hydrogel formulations and the release buffer. We also suggest that final drug release amounts are influenced by intermolecular interactions between vancomycin and gellan, which were observed via quartz crystal microbalance with dissipation monitoring. Lastly, we examined the potential for future in vivo translation. We demonstrated in vitro growth inhibition of Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus in the presence of these hydrogels, demonstrating that vancomycin activity is preserved upon encapsulation. We also showed that these hydrogels are non-toxic to important wound healing cells including fibroblasts and mesenchymal stem cells.