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Author Notes:

To whom correspondence should be addressed. Email: andres.garcia@me.gatech.edu

Author contributions: C.T.J., R.E.G., R.M.D., L.F.W., and A.J.G. designed research; C.T.J., J.A.W., R.A., and K.E.M. performed research; R.M.D. contributed new reagents/analytic tools; C.T.J. and A.J.G. analyzed data; and C.T.J., R.E.G., R.M.D., L.F.W., and A.J.G. wrote the paper.

We thank Robin Patel, M.D. for providing S. epidermidis IDRL-8883.

We acknowledge the core facilities at the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology for the use of their shared equipment, services, and expertise.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Centers for Disease Control and Prevention.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services.

Conflict of interest statement: C.T.J. and A.J.G. are inventors on a patent application filed by the Georgia Tech Research Corp. based on the results in this study.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • infection
  • biomaterials
  • orthopedics
  • lysostaphin
  • S. aureus
  • AORTIC-VALVE ENDOCARDITIS
  • IN-VIVO
  • ANTIBIOTIC-RESISTANCE
  • BONE REGENERATION
  • BIOFILMS
  • VASCULARIZATION
  • SUSCEPTIBILITY
  • ANTIBACTERIAL
  • OSTEOMYELITIS
  • BIOMATERIALS

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

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 115, Number 22

Publisher:

, Pages E4960-E4969

Type of Work:

Article | Final Publisher PDF

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.

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© 2018 National Academy of Sciences. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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