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In Vivo Bioluminescence Imaging in a Rabbit Model of Orthopaedic Implant-Associated Infection to Monitor Efficacy of an Antibiotic-Releasing Coating

Miller, Robert J., MS1; Thompson, John M., MD1; Zheng, Jesse, BS2; Marchitto, Mark C., MD1; Archer, Nathan K., PhD1; Pinsker, Bret L., BS1; Ortines, Roger V., MS1; Jiang, Xuesong, PhD2; Martin, Russell A., PhD2; Brown, Isabelle D., BS1; Wang, Yu, PhD1; Sterling, Robert S., MD1; Mao, Hai-Quan, PhD2; Miller, Lloyd S., MD, PhD1,2

doi: 10.2106/JBJS.18.00425
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Background: In vivo bioluminescence imaging (BLI) provides noninvasive monitoring of bacterial burden in animal models of orthopaedic implant-associated infection (OIAI). However, technical limitations have limited its use to mouse and rat models of OIAI. The goal of this study was to develop a larger, rabbit model of OIAI using in vivo BLI to evaluate the efficacy of an antibiotic-releasing implant coating.

Methods: A nanofiber coating loaded with or without linezolid-rifampin was electrospun onto a surgical-grade locking peg. To model OIAI in rabbits, a medial parapatellar arthrotomy was performed to ream the femoral canal, and a bright bioluminescent methicillin-resistant Staphylococcus aureus (MRSA) strain was inoculated into the canal, followed by retrograde insertion of the coated implant flush with the articular surface. In vivo BLI signals were confirmed by ex vivo colony-forming units (CFUs) from tissue, bone, and implant specimens.

Results: In this rabbit model of OIAI (n = 6 rabbits per group), implants coated without antibiotics were associated with significantly increased knee width and in vivo BLI signals compared with implants coated with linezolid-rifampin (p < 0.001 and p < 0.05, respectively). On day 7, the implants without antibiotics were associated with significantly increased CFUs from tissue (mean [and standard error of the mean], 1.4 × 108 ± 2.1 × 107 CFUs; p < 0.001), bone (6.9 × 106 ± 3.1 × 106 CFUs; p < 0.05), and implant (5.1 × 105 ± 2.2 × 105 CFUs; p < 0.05) specimens compared with implants with linezolid-rifampin, which demonstrated no detectable CFUs from any source.

Conclusions: By combining a bright bioluminescent MRSA strain with modified techniques, in vivo BLI in a rabbit model of OIAI demonstrated the efficacy of an antibiotic-releasing coating.

Clinical Relevance: The new capability of in vivo BLI for noninvasive monitoring of bacterial burden in larger-animal models of OIAI may have important preclinical relevance.

1Departments of Dermatology (R.J.M., M.C.M., N.K.A., B.L.P., R.V.O., I.D.B., Y.W., and L.S.M.) and Orthopaedic Surgery (J.M.T., R.S.S., and L.S.M.) and Division of Infectious Diseases, Department of Medicine (L.S.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland

2Departments of Biomedical Engineering (J.Z.) and Materials Science and Engineering (X.J., R.A.M., H.-Q.M., and L.S.M.), Translational Tissue Engineering Center (X.J., R.A.M., H.-Q.M., and L.S.M.), Institute for NanoBioTechnology (X.J., R.A.M., and H.-Q.M.), and Whitaker Biomedical Engineering Institute (H.-Q.M.), Johns Hopkins University, Baltimore, Maryland

E-mail address for L.S. Miller: lloydmiller@jhmi.edu

Investigation performed at the Johns Hopkins University School of Medicine, Baltimore, Maryland

Disclosure: This work was supported by a Johns Hopkins University-Coulter Translational Partnership Award (R.S.S., H-Q.M., and L.S.M.) and T32 AR07708-01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the U.S. National Institutes of Health (J.M.T.). The coating investigated in this work is included in a pending U.S. patent application serial no. 16/076,606: “Compositions and Methods for Preparation of Composite Polymer Coatings on Medical Implants, and Their Use for Co-delivery of Multiple Antimicrobial Agents” (J.Z., H.-Q.M., and L.S.M.). On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work (http://links.lww.com/JBJS/F59).

Copyright © 2019 by The Journal of Bone and Joint Surgery, Incorporated
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