Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing

• Type of Material: Article
• Authors: Christopher T. Johnson, Georgia Institute of Technology; James A. Wroe, Georgia Institute of Technology; Rachit Agarwal, Georgia Institute of Technology; Karen E. Martin, Georgia Institute of Technology; Robert E. Guldberg, Emory University; Rodney M. Donlan, Centers for Disease Control and Prevention; Lars Westblade, Emory University; Andres J. Garcia, Georgia Institute of Technology
• Language: English
• Date: 2018-05-29
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2018 National Academy of Sciences. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1801013115
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 115
• Issue: 22
• Start Page: E4960
• End Page: E4969
• Grant/Funding Information: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health Grants R01AR062920 (to A.J.G.) and F30AR069472 (to C.T.J.).
• Keywords: AORTIC-VALVE ENDOCARDITIS; ANTIBACTERIAL; BIOFILMS; IN-VIVO; S. aureus; Multidisciplinary Sciences; OSTEOMYELITIS; VASCULARIZATION; BONE REGENERATION; Science & Technology - Other Topics; BIOMATERIALS; lysostaphin; orthopedics; Science & Technology; SUSCEPTIBILITY; biomaterials; infection; ANTIBIOTIC-RESISTANCE
• Research Categories: Engineering, Mechanical; Engineering, Biomedical

Abstract

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.