Bacteria-Triggered Hydrogel Delivery of Antibiotics and Probiotics for the Treatment of Chronic Wound Infections

About This Grant

PROJECT SUMMARY Chronic wound infections are increasingly caused by antibiotic resistant bacteria. Biofilm formation in these infections further complicates treatment and leads to increased antibiotic resistance, persistent inflammation, and tissue damage. Probiotics, like Lactobacilli, have been shown to improve wound healing and restore a balanced wound microbiota, while also disrupting and preventing biofilm formation by common wound infection causing bacteria like methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Combination treatment with effective antibiotics and probiotics may greatly enhance healing in infected wounds. Antimicrobial hydrogel wound dressings are used in the treatment of chronic wound infections as they promote tissue hydration and oxygen permeability and locally deliver encapsulated therapeutics. However, existing hydrogel dressings passively release their encapsulated antimicrobial contents leading to unnecessary and prolonged exposure to drugs, often at sub-inhibitory concentrations, which can exacerbate resistance development. In contrast, bacteria-responsive hydrogels can overcome these limitations and provide an on-demand, localized treatment of a wound infection in response to a bacterial stimuli. β-lactamases, which are produced by many pathogenic bacteria that cause wound infections, including MRSA and P. aeruginosa, are a leading cause of antibiotic resistance and represent a promising bacteria-specific enzymatic trigger for drug delivery from bacteria-responsive hydrogels. In this proposal, we will develop β-lactamase-responsive hydrogel wound dressings for on-demand delivery of antibiotics and probiotics aimed at treating chronic wound infections caused by MRSA and P. aeruginosa. The hydrogels will be designed to degrade in the presence of β-lactamases, releasing the encapsulated antibiotic and probiotic treatment at the wound site. We will encapsulate antibiotics commonly used in the treatment of MRSA and P. aeruginosa chronic wound infections in stable liposomal carriers to ensure entrapment within the hydrogel network and protection of probiotics. Lactobacilli will be encapsulated in polymeric coatings or microparticles to maintain viability within the hydrogel and during fabrication. These therapeutics can be integrated either together or individually within the β-lactamase-responsive hydrogels. The specific aims are to: (1) develop β-lactamase-triggered antibiotic releasing hydrogels for the treatment of chronic wound infections, (2) develop β-lactamase-triggered hydrogels for the dual delivery of antibiotics and probiotics for the treatment of chronic wound infections, and (3) evaluate the treatment of porcine full-thickness wound infections with β-lactamase-responsive hydrogels. The long-term objective of this research is to address the clinical challenge of chronic wounds and bacterial resistance by creating a treatment that combines triggered infection control with microbiome modulation.