Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression

• Type of Material: Article
• Authors: Albert Cheng, Georgia Institute of Technology; Laxminarayanan Krishnan, Georgia Institute of Technology; Pallab Pradhan, Georgia Institute of Technology; Laura D. Weinstock, Georgia Institute of Technology; Levi B. Wood, Georgia Institute of Technology; Krishnendu Roy, Emory University; Robert Guldberg, Emory University
• Language: English
• Date: 2019-02-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/jor.24186
• Title of Journal or Parent Work: JOURNAL OF ORTHOPAEDIC RESEARCH
• Volume: 37
• Issue: 2
• Start Page: 299
• End Page: 307
• Grant/Funding Information: This work was supported under the AFIRM II (U.S. Armed Forces Institute of Regenerative Medicine) effort, Award No. W81XWH-14-2-0003. The U.S. Army Medical Research Acquisition Activity was the awarding and administering acquisition office. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. L.D.W. was supported in part by the Cell and Tissue Engineering NIH Biotechnology Training Grant (T32-GM008433).
• Keywords: DELIVERY; Life Sciences & Biomedicine; Science & Technology; PERSISTENT INFLAMMATION; FRACTURE NONUNION; BMP-INHIBITORS; nonunion; INDUCED MEMBRANE; OSTEOBLAST DIFFERENTIATION; RISK-FACTORS; delayed treatment; BMP-2; MARROW; Orthopedics; chronic immune dysregulation; FUNCTIONAL REPAIR; IMMUNOSUPPRESSION

Abstract

Delayed union and nonunion are a significant concern in long bone fractures and spinal fusions. Treatment of nonunion often entails multiple revision surgeries that further increase the financial, physical, and emotional burden on patients. The optimal treatment strategy for nonunions remains unclear in many cases, and the risk of complications after revision procedures remains high. This is in part due to our limited understanding of the biological mechanisms that inhibit proper bone healing and lead to nonunion. And yet, few preclinical models directly investigate how healing is impacted after establishment of nonunion, with most instead primarily focusing on treatment immediately after a fresh bone injury. Here, we utilized a critical size femoral defect model in rats where treatment was delayed 8 weeks post-injury, at which time nonunion was established. In this study, acute and delayed treatments with bone morphogenetic protein-2 (BMP-2) were assessed. We found that delayed treatment resulted in decreased bone formation and reduced mechanical strength compared to acute treatment, even when BMP-2 dose was increased by 2.5 times the acute treatment dose. Interestingly, serum cytokine analysis at 12 weeks post-treatment revealed signs of chronic immune dysregulation after delayed treatment. In particular, non-responders (rats that did not exhibit defect bridging) demonstrated higher overall expression of inflammatory cytokines, including TNFα and IL-1β, compared to responders. These findings suggest that re-establishing long-term immune homeostasis may be critical for successful bone healing, particularly after nonunion. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:299–307, 2019.