title: The effect of osteoimmunomodulation on the osteogenic effects of cobalt incorporated β-tricalcium phosphate.
abstract: Osteoblast lineage cells are direct effectors of osteogenesis and are, therefore, commonly used to evaluate the in vitro osteogenic capacity of bone substitute materials. This method has served its purposes when testing novel bone biomaterials; however, inconsistent results between in vitro and in vivo studies suggest the mechanisms that govern a material's capacity to mediate osteogenesis are not well understood. The emerging field of osteoimmunology and immunomodulation has informed a paradigm shift in our view of bone biomaterials-from one of an inert to an osteoimmunomodulatory material-highlighting the importance of immune cells in materials-mediated osteogenesis. Neglecting the importance of the immune response during this process is a major shortcoming of the current evaluation protocol. In this study we evaluated a potential angiogenic bone substitute material cobalt incorporated with β-tricalcium phosphate (CCP), comparing the traditional "one cell type" approach with a "multiple cell types" approach to assess osteogenesis, the latter including the use of immune cells. We found that CCP extract by itself was sufficient to enhance osteogenic differentiation of bone marrow stem cells (BMSCs), whereas this effect was cancelled out when macrophages were involved. In response to CCP, the macrophage phenotype switched to the M1 extreme, releasing pro-inflammatory cytokines and bone catabolic factors. When the CCP materials were implanted into a rat femur condyle defect model, there was a significant increase of inflammatory markers and bone destruction, coupled with fibrous encapsulation rather than new bone formation. These findings demonstrated that the inclusion of immune cells (macrophages) in the in vitro assessment matched the in vivo tissue response, and that this method provides a more accurate indication of the essential role of immune cells when assessing materials-stimulated osteogenesis in vitro.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Zetao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Jones
authors.initials: J
authors.lastname: Yuen
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.affiliation: Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, People's Republic of China. Electronic address: chengtiewu@mail.sic.ac.cn.
authors.forename: Chengtie
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, Brisbane, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia. Electronic address: yin.xiao@qut.edu.au.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002130:Calcium Phosphates / Q000008:administration & dosage*; D003035:Cobalt / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000737:chemistry; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects / Q000276:immunology*; D000067996:RAW 264.7 Cells; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002130:Calcium Phosphates; D007155:Immunologic Factors; C485817:beta-tricalcium phosphate; D003035:Cobalt
keywords: Bone substitute materials; Cobalt; Immunomodulation; Macrophage; Osteogenesis