title: Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis.
abstract: The application of mesoporous silica nanospheres (MSNs) loaded with drugs/growth factors to induce osteogenic differentiation of stem cells has been trialed by a number of researchers recently. However, limitations such as high cost, complex fabrication and unintended side effects from supraphysiological concentrations of the drugs/growth factors represent major obstacles to any potential clinical application in the near term. In this study we reported an in situ one-pot synthesis strategy of MSNs doped with hypoxia-inducing copper ions and systematically evaluated the nanospheres by in vitro biological assessments. The Cu-containing mesoporous silica nanospheres (Cu-MSNs) had uniform spherical morphology (∼100nm), ordered mesoporous channels (∼2nm) and homogeneous Cu distribution. Cu-MSNs demonstrated sustained release of both silicon (Si) and Cu ions and controlled degradability. The Cu-MSNs were phagocytized by immune cells and appeared to modulate a favorable immune environment by initiating proper pro-inflammatory cytokines, inducing osteogenic/angiogenic factors and suppressing osteoclastogenic factors by the immune cells. The immune microenvironment induced by the Cu-MSNs led to robust osteogenic differentiation of bone mesenchymal stem cells (BMSCs) via the activation of Oncostation M (OSM) pathway. These results suggest that the novel Cu-MSNs could be used as an immunomodulatory agent with osteostimulatory capacity for bone regeneration/therapy application.
  
  
  CONCLUSIONS
  In order to stimulate both osteogenesis and angiogenesis of stem cells for further bone regeneration, a new kind of hypoxia-inducing copper doped mesoporous silica nanospheres (Cu-MSNs) were prepared via one-pot synthesis. Biological assessments under immune environment which better reflect the in vivo response revealed that the nanospheres possessed osteostimulatory capacity and had potential as immunomodulatory agent for bone regeneration/therapy application. The strategy of introducing controllable amount of therapeutic ions instead of loading expensive drugs/growth factors in mesoporous silica nanosphere provides new options for bioactive nanomaterial functionalization.
authors.affiliation: State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People's Republic of China; 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: Mengchao
authors.initials: M
authors.lastname: Shi
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; 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: Saba
authors.initials: S
authors.lastname: Farnaghi
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: Thor
authors.initials: T
authors.lastname: Friis
authors.affiliation: Guangdong Provincial Key Laboratory of Stomatology & Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Ling Yuan Road West, Guangzhou 510055, People's Republic of China; 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: Xueli
authors.initials: X
authors.lastname: Mao
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
authors.affiliation: State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People's Republic of China; 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: chengtiewu@mail.sic.ac.cn.
authors.forename: Chengtie
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D054118:Nanospheres / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects*; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007155:Immunologic Factors; D012822:Silicon Dioxide; D003300:Copper
keywords: BMSC; Bone repair; Copper; Macrophage; Mesoporous silica nanoparticles