Lysostaphin-delivering hydrogels to treat orthopaedic device infections

Abstract

Orthopaedic hardware infections are a significant clinical problem with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high anti-staphylococcal activity. We engineered a lysostaphin-delivering injectable poly(ethylene glycol) (PEG) hydrogel to treat Staphylococcus aureus infections in bone fractures and segmental defections. The injectable hydrogel formulation conforms and adheres to the injury and surrounding tissue, ensuring efficient, local delivery of lysostaphin. The objective of this work is to engineer novel lysostaphin-delivering hydrogels to reduce infection and enhance bone repair in murine models of implant-associated orthopaedic infection. The central hypothesis is that controlled delivery of lysostaphin from our osseo-repartive hydrogels will reduce infection and allowing for bone repair to occur. We engineered PEG hydrogels that release active lysostaphin in response to local environmental cues. The hydrogel delivery vehicle enhances lysostaphin stability thereby preserving antimicrobial activity. Lysostaphin-delivering hydrogels eradicate S. aureus infection and support fracture healing of a pin-stabilized fracture infection model. Co-delivery of lysostaphin and BMP-2 to a model of segmental bone defect infection results in the simultaneous elimination of bacteria and bone regeneration. BMP-2 loaded lysostaphin-delivering hydrogels regenerated bone with mechanical integrity. Importantly, these hydrogels restore the local inflammatory environment, as assessed by cytokine and inflammatory cell profiling, to that of a sterile wound by one week. Administration of lysostaphin-delivering hydrogel therapy to established S. aureus infections results in an infection reduction that is potentiated with the addition of systemic antibiotic therapy. These findings support the further development of lysostaphin delivering hydrogels to treat device associated infections. This work is innovative and significant because it establishes a local strategy to effectively reduce bacterial infections while simultaneously supporting bone healing.