Effects of osteogenic ambulatory mechanical stimulation on early stages of BMP-2 mediated bone repair

• Type of Material: Article
• Authors: Brett Klosterhoff, Georgia Institute of Technology; Casey E Vantucci, Georgia Institute of Technology; Jarred Kaiser, Atlanta VA Medical Center; Keat G Ong, University of Oregon; Levi B Wood, Georgia Institute of Technology; Jeffrey A Weiss, University of Utah; Robert Guldberg, Emory University; Nick Willett, Emory University
• Language: English
• Date: 2021-04-07
• Publisher: TAYLOR & FRANCIS INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Rights managed by Taylor & Francis
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1080/03008207.2021.1897582
• Title of Journal or Parent Work: CONNECTIVE TISSUE RESEARCH
• Volume: 63
• Issue: 1
• Start Page: 16
• End Page: 27
• Grant/Funding Information: This work also received support from VA (Merit) Grant RX001985 from the United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development Service. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. B.S.K. received support from the Cell and Tissue Engineering NIH Biotechnology Training Grant (T32-GM008433) and the National Science Foundation Graduate Research Fellowship Program (DGE-1650044).; C.E.V. received support from the National Science Foundation Graduate Research Fellowship Program (DGE-1650044).; Funding for this work was provided by grants from the National Institutes of Health (NIH R21 AR066322; NIH R01 AR069297) and the National Science Foundation (NSF CMMI-1400065). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or National Science Foundation.
• Keywords: Science & Technology; Orthopedics; Cell Biology; Bone repair; angiogenesis word; rehabilitation; Life Sciences & Biomedicine; mechanobiology; immune response

Abstract

Purpose: Mechanical loading of bone defects through rehabilitation is a promising approach to stimulate repair and reduce nonunion risk; however, little is known about how therapeutic mechanical stimuli modulate early-stage repair before mineralized bone formation. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression and angiogenesis during the first 3 weeks of BMP-2 mediated segmental bone defect repair. Materials and Methods: A rat model of BMP-2 mediated bone defect repair was subjected to an osteogenic mechanical loading protocol using ambulatory rehabilitation and a compliant, load-sharing fixator with an integrated implantable strain sensor. The effect of fixator load-sharing on local tissue strain, angiogenesis, and cytokine expression was evaluated. Results: Using sensor readings for local measurements of boundary conditions, finite element simulations showed strain became amplified in remaining soft tissue regions between 1 and 3 weeks (Week 3: load-sharing: −1.89 ± 0.35% and load-shielded: −1.38 ± 0.35% vs. Week 1: load-sharing: −1.54 ± 0.17%; load-shielded: −0.76 ± 0.06%). Multivariate analysis of cytokine arrays revealed that load-sharing significantly altered expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF (p = 0.052) and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects at 3 weeks. Conclusions: Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification.