title: Osteoimmunomodulatory properties of magnesium scaffolds coated with β-tricalcium phosphate.
abstract: The osteoimmunomodulatory property of bone biomaterials is a vital property determining the in vivo fate of the implants. Endowing bone biomaterials with favorable osteoimmunomodulatory properties is of great importance in triggering desired immune response and thus supports the bone healing process. Magnesium (Mg) has been recognized as a revolutionary metal for applications in orthopedics due to it being biodegradable, biocompatible, and having osteoconductive properties. However, Mg's high rate of degradation leads to an excessive inflammatory response and this has restricted its application in bone tissue engineering. In this study, β-tricalcium phosphate (β-TCP) was used to coat Mg scaffolds in an effort to modulate the detrimental osteoimmunomodulatory properties of Mg scaffolds, due to the reported favorable osteoimmunomodulatory properties of β-TCP. It was noted that macrophages switched to the M2 extreme phenotype in response to the Mg-β-TCP scaffolds, which could be due to the inhibition of the toll like receptor (TLR) signaling pathway. VEGF and BMP2 were significantly upregulated in the macrophages exposed to Mg-β-TCP scaffolds, indicating pro-osteogenic properties of macrophages in β-TCP modified Mg scaffolds. This was further demonstrated by the macrophage-mediated osteogenic differentiation of bone marrow stromal cells (BMSCs). When BMSCs were stimulated by conditioned medium from macrophages cultured on Mg-β-TCP scaffolds, osteogenic differentiation of BMSCs was significantly enhanced; whereas osteoclastogenesis was inhibited, as indicated by the downregualtion of MCSF, TRAP and inhibition of the RANKL/RANK system. These findings suggest that β-TCP coating of Mg scaffolds can modulate the scaffold's osteoimmunomodulatory properties, shift the immune microenvironment towards one that favors osteogenesis over osteoclastogenesis. Endowing bone biomaterials with favorable osteoimmunomodulatory properties can be a highly valuable strategy for the development or modification of advanced bone biomaterials.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Zetao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Ling Yuan Road West, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, 74 Zhongshan Second RD, Guangzhou 510080, China. Electronic address: maoxuel@mail.sysu.edu.cn.
authors.forename: Xueli
authors.initials: X
authors.lastname: Mao
authors.affiliation: Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Tan
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Thor
authors.initials: T
authors.lastname: Friis
authors.affiliation: Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 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, China.
authors.forename: Chengtie
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, Brisbane, Queensland 4059, Australia; Australia-China Centre for Tissue Engineering and Regenerative Medicine, Queensland University of Technology, 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: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002130:Calcium Phosphates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D020099:Coated Materials, Biocompatible / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics; D007477:Ions; D008274:Magnesium / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D016062:Porosity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D002130:Calcium Phosphates; D020099:Coated Materials, Biocompatible; D017077:Culture Media, Conditioned; D007477:Ions; D012333:RNA, Messenger; C485817:beta-tricalcium phosphate; D000469:Alkaline Phosphatase; D008274:Magnesium
keywords: Bone substitute; Macrophage; Magnesium; Osteogenesis; Osteoimmunomodulatory property; β-TCP