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Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression
Author(s) -
Cheng Albert,
Krishnan Laxminarayanan,
Pradhan Pallab,
Weinstock Laura D.,
Wood Levi B.,
Roy Krishnendu,
Guldberg Robert E.
Publication year - 2019
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.24186
Subject(s) - nonunion , medicine , bone healing , cytokine , homeostasis , immune system , surgery , immunology
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.