ABSTRACT
Implanted orthopedic devices become infected more frequently than any other implanted surgical device. These infections can be extremely costly and result in significant patient morbidity. Current treatment options typically involve the long term, systemic administration of a combination of antibiotics, often followed by implant removal. Here we engineered an injectable hydrogel capable of encapsulating Pseudomonas aeruginosa bacteriophage and delivering active phage to the site of bone infections. Bacteriophage retain their bacteriolytic activity after encapsulation and release from the hydrogel, and their rate of release from the hydrogel can be controlled by gel formulation. Bacteriophage-encapsulating hydrogels effectively kill their host bacteria in both planktonic and biofilm phenotypes in vitro without influencing the metabolic activity of human mesenchymal stromal cells. Bacteriophage-encapsulating hydrogels were used to treat murine radial segmental defects infected with P. aeruginosa. The hydrogels achieved a 4.7-fold reduction in live P. aeruginosa counts at the infection site compared to bacteriophage-free hydrogels at 7 days postimplantation. These results support the development of bacteriophage-delivering hydrogels to treat local bone infections.
Subject(s)
Bacteriophages/physiology , Biofilms/drug effects , Hydrogels/pharmacology , Animals , Bacteriophages/drug effects , Biofilms/growth & development , Bone and Bones/microbiology , Bone and Bones/pathology , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Polyethylene Glycols/chemistry , Pseudomonas Infections/microbiology , Pseudomonas Infections/pathology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/virologyABSTRACT
Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair.
