钛种植体表面改性对巨噬细胞极化和诱导成骨的影响
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摘要
背景:单纯采用骨形成细胞评价钛种植体材料的生物学性能已不能满足获得早期和长期稳定的骨结合的要求。为实现上述目标,必须深入理解种植体与机体界面相互作用,同时考量包括巨噬细胞在内的体内免疫因素对种植材料的重要影响,指导种植体表面改性。目的:综述近年来钛种植体表面物理、化学性质和生物改性对巨噬细胞极化和诱导成骨影响的研究现状。方法:第一作者应用计算机检索PubM ed、Springerlink、Web of Science、ScienceD irect、CNKI、维普、万方数据库2010年1月至2017年12月发表的文献,选择有关钛种植体、巨噬细胞极化、诱导成骨的文献。结果与结论:巨噬细胞作为固有免疫反应的主要效应细胞,是种植体植入机体后首先到达种植体-组织界面、含量最丰富的一种细胞。种植体表面的不同物理化学和生物改性可通过激活巨噬细胞的M1炎症极化方向或者M2组织愈合方向,进而在种植体骨结合中发挥关键性作用。同时,种植体表面改性还对巨噬细胞诱导成骨有着重要的影响。未来发展方向是从免疫学角度解释种植体-宿主相互作用的愈合机制,研发新型钛种植体,通过巨噬细胞的免疫调节作用诱导骨形成并获得骨偶联的内稳态平衡,实现早期和长期稳定的骨结合。
BACKGROUND: A single use of bone-forming cells to evaluate the biological properties of titanium implant materials cannot meet the demands of early and long-term stable osseointegration. In order to fulfill the objective mentioned above, it is necessary to understand the interaction between implant and body at the interface of implantation. It is also urgent to consider the invaluable function of immunological factors including macrophage, so as to guide the implant surface modification. OBJECTIVE: To review the influence of physical, chemical and biological surface modifications of implants on the macrophage polarization and osteogenesis.METHODS: The first author conducted a computer-based retrieval of Pub Med, Springerlink, Web of Science, Science Direct, CNKI, Cq Vip and Wan Fang databases for relevant articles published from January 2010 to December 2017. The key words were "titanium, implant, macrophage, polarization, osteogenesis" in English and Chinese, respectively. RESULTS AND CONCLUSION: Macrophages represent the first and the most abundant cells in contact with these implant materials and act as main effector cells in the intrinsic immune response. Surface modifications of implants play an important role in osseintegration by a M1 "tissue-inflammatory" polarization or M2 "wound-healing" activation. Furthermore, implant surface modification also affects the osteoinductive ability of macrophage. Future research intends to explain the bone healing mechanism between implant and host tissues from the immunological aspect and develop new-type titanium implants. New surface modification methods of implants, which could induce osteogenesis and acquire bone coupling and homeostasis, will be developed to fulfill early-and long-term stable osseointegration.
BACKGROUND: A single use of bone-forming cells to evaluate the biological properties of titanium implant materials cannot meet the demands of early and long-term stable osseointegration. In order to fulfill the objective mentioned above, it is necessary to understand the interaction between implant and body at the interface of implantation. It is also urgent to consider the invaluable function of immunological factors including macrophage, so as to guide the implant surface modification. OBJECTIVE: To review the influence of physical, chemical and biological surface modifications of implants on the macrophage polarization and osteogenesis.METHODS: The first author conducted a computer-based retrieval of Pub Med, Springerlink, Web of Science, Science Direct, CNKI, Cq Vip and Wan Fang databases for relevant articles published from January 2010 to December 2017. The key words were "titanium, implant, macrophage, polarization, osteogenesis" in English and Chinese, respectively. RESULTS AND CONCLUSION: Macrophages represent the first and the most abundant cells in contact with these implant materials and act as main effector cells in the intrinsic immune response. Surface modifications of implants play an important role in osseintegration by a M1 "tissue-inflammatory" polarization or M2 "wound-healing" activation. Furthermore, implant surface modification also affects the osteoinductive ability of macrophage. Future research intends to explain the bone healing mechanism between implant and host tissues from the immunological aspect and develop new-type titanium implants. New surface modification methods of implants, which could induce osteogenesis and acquire bone coupling and homeostasis, will be developed to fulfill early-and long-term stable osseointegration.
引文
[1]Xing H,Wang X,Xiao S,et al.Osseointegration of layer-by-layer polyelectrolyte multilayers loaded with IGF1 and coated on titanium implant under osteoporotic condition.Int J Nanomedicine.2017;12:7709-7720.
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[3]Sinder BP,Pettit AR,Mc Cauley LK.Macrophages:Their Emerging Roles in Bone.J Bone Miner Res.2015;30(12):2140-2149.
[4]Miron RJ,Bosshardt DD.Osteo Macs:Key players around bone biomaterials.Biomaterials.2016;82:1-19.
[5]Davies LC,Jenkins SJ,Allen JE,et al.Tissue-resident macrophages.Nat Immunol.2013;14(10):986-995.
[6]Mantovani A,Biswas SK,Galdiero MR,et al.Macrophage plasticity and polarization in tissue repair and remodelling.J Pathol.2013;229:176-185.
[7]Anton K,Banerjee D,Glod J.Macrophage-associated mesenchymal stem cells assume an activated,migratory,pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion.Plo S One.2012;7:e35036.
[8]Mosser DM,Edwards JP.Exploring the full spectrum of macrophage activation.Nat Rev Immunol.2008;8:958-969.
[9]Martinez FO,Gordon S.The M1 and M2 paradigm of macrophage activation:time for reassessment.F1000Prime Rep.2014;6:13.
[10]Tugal D,Liao X,Jain MK.Transcriptional control of macrophage polarization.Arterioscler Thromb Vasc Biol.2013;33(6):1135-1144.
[11]Chen Z,Mao X,Tan L,et al.Osteoimmunomodulatory properties of magnesium scaffolds coated withβ-tricalcium phosphate.Biomaterials.2014;35(30):8553-8565.
[12]Murray PJ,Allen JE,Biswas SK,et al.Macrophage activation and polarization:nomenclature and experimental guidelines.Immunity.2014;41:14-20.
[13]Ziegler T,Rausch S,Steinfelder S,et al.A novel regulatory macrophage induced by a helminth molecule instructs IL-10 in CD4+T cells and protects against mucosal inflammation.J Immunol.2015;194(4):1555-1564.
[14]Trindade R,Albrektsson T,Wennerberg A.Current concepts for the biological basis of dental implants:foreign body equilibrium and osseointegration dynamics.Oral Maxillofac Surg Clin North Am.2015;27(2):175-183.
[15]Gibon E,Lu LY,Nathan K,et al.Inflammation,ageing,and bone regeneration.J Orthop Translat.2017;10:28-35.
[16]Cho SW,Soki FN,Koh AJ,et al.Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.Proc Natl Acad Sci U S A.2014;111(4):1545-1550.
[17]Guihard P,Danger Y,Brounais B,et al.Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling.Stem Cells.2012;30(4):762-772.
[18]Karazisis D,Ballo AM,Petronis S,et al.The role of well-defined nanotopography of titanium implants on osseointegration:cellular and molecular events in vivo.Int J Nanomedicine.2016;11:1367-1382.
[19]Karazisis D,Petronis S,Agheli H,et al.The influence of controlled surface nanotopography on the early biological events of osseointegration.Acta Biomater.2017;53:559-571.
[20]LüWL,Wang N,Gao P,et al.Effects of anodic titanium dioxide nanotubes of different diameters on macrophage secretion and expression of cytokines and chemokines.Cell Prolif.2015;48(1):95-104.
[21]Ma QL,Zhao LZ,Liu RR,et al.Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization.Biomaterials.2014;35(37):9853-9867.
[22]樊牮,邹耿森,陈江.钛种植体表面纳米改性及其与机体免疫应答[J].国际口腔医学杂志,2014,41(6):691-693.
[23]He XT,Li X,Yin Y,et al.The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells.J Cell Mol Med.2017.doi:10.1111/jcmm.13431.[Epub ahead of print]
[24]Alfarsi MA,Hamlet SM,Ivanovski S.Titanium surface hydrophilicity modulates the human macrophage inflammatorycytokine response.JBiomed Mater Res A.2014;102(1):60-67.
[25]Hotchkiss KM,Reddy GB,Hyzy SL,et al.Titanium surface characteristics,including topography and wettability,alter macrophage activation.Acta Biomater.2016;31:425-434.
[26]Hotchkiss KM,Ayad NB,Hyzy SL,et al.Dental implant surface chemistry and energy alter macrophage activation in vitro.Clin Oral Implants Res.2017;28(4):414-423.
[27]Lee RS,Hamlet SM,Ivanovski S,et al.The influence of titanium surface characteristics on macrophage phenotype polarization during osseous healing in type I diabetic rats:a pilot study.Clin Oral Implants Res.2017;28(10):e159-e168.
[28]Alfarsi MA,Hamlet SM,Ivanovski S.The Effect of Platelet Proteins Released in Response to Titanium Implant Surfaces on Macrophage Pro-Inflammatory Cytokine Gene Expression.Clin Implant Dent Relat Res.2015;17(6):1036-1047.
[29]Rydén L,Omar O,Johansson A,et al.Inflammatory cell response to ultra-thin amorphous and crystalline hydroxyapatite surfaces.J Mater Sci Mater Med.2017;28(1):9.
[30]Mestres G,Espanol M,Xia W,et al.Inflammatory response to nano-and microstructured hydroxyapatite.PLo S One.2015;10(3):e0120381.
[31]Hamlet S,Ivanovski S.Inflammatory cytokine response to titanium chemical composition and nanoscale calcium phosphate surface modification.Acta Biomater.2011;7(5):234523-234553.
[32]Lee CH,Kim YJ,Jang JH,et al.Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces.Nanotechnology.2016;27(8):085101.
[33]Park JW,Kim YJ,Jang JH,et al.Positive modulation of osteogenesisand osteoclastogenesis-related gene expression with strontium-containing microstructured Ti implants in rabbit cancellous bone.J Biomed Mater Res A.2013;101(1):298-306.
[34]Li K,Shen Q,Xie Y,et al.Incorporation of cerium oxide into hydroxyapatite coating regulates osteogenic activity of mesenchymal stem cell and macrophage polarization.J Biomater Appl.2017;31(7):1062-1076.
[35]Wessely-Szponder J,Szponder T,Bobowiec R.Different activation of monocyte-derived macrophages by antimicrobial peptides at a titanium tibial implantation in rabbits.Res Vet Sci.2017;115:201-210.
[36]Pajarinen J,Kouri VP,J?msen E,et al.The response of macrophages to titanium particles is determined by macrophage polarization.Acta Biomater.2013;9(11):9229-9240.
[37]Nie B,Ao H,Zhou J,et al.Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria,osteogenesis and reduction of macrophage inflammation.Colloids Surf B Biointerfaces.2016;145:728-739.
[38]Cha BH,Shin SR,Leijten J,et al.Integrin-Mediated Interactions Control Macrophage Polarization in 3D Hydrogels.Adv Healthc Mater.2017;6(21).doi:10.1002/adhm.201700289.Epub 2017 Aug 7.
[39]Thalji GN,Nares S,Cooper LF.Early molecular assessment of osseointegration in humans.Clin Oral Implants Res.2014;25(11):1273-1285.
[40]Nagasawa M,Cooper LF,Ogino Y,et al.Topography Influences Adherent Cell Regulation of Osteoclastogenesis.J Dent Res.2016;95(3):319-326.
[41]Ma QL,Fang L,Jiang N,et al.Bone mesenchymal stem cell secretion of s RANKL/OPG/M-CSF in response to macrophage-mediated inflammatory response influences osteogenesis on nanostructured Ti surfaces.Biomaterials.2017;154:234-247.
[42]Hefti T,Frischherz M,Spencer ND,et al.A comparison of osteoclast resorption pits on bone with titanium and zirconia surfaces.Biomaterials.2010;31(28):7321-7331.
[43]Brinkmann J,Hefti T,Schlottig F,et al.Response of osteoclasts to titanium surfaces with increasing surface roughness:an in vitro study.Biointerphases.2012;7(1-4):34.
[44]Milleret V,Tugulu S,Schlottig F,et al.Alkali treatment of microrough titanium surfaces affects macrophage/monocyte adhesion,platelet activation and architecture of blood clot formation.Eur Cell Mater.2011;21:430-444;discussion 444.
[45]Mamalis AA,Markopoulou C,Vrotsos I,et al.Chemical modification of an implant surface increases osteogenesis and simultaneously reduces osteoclastogenesis:an in vitro study.Clin Oral Implants Res.2011;22(6):619-626.
[46]Davison NL,Luo X,Schoenmaker T,et al.Submicron-scale surface architecture of tricalcium phosphate directs osteogenesis in vitro and in vivo.Eur Cell Mater.2014;27:281-297;discussion 296-297.
[47]Wang J,Liu D,Guo B,et al.Role of biphasic calcium phosphate ceramic-mediated secretion of signaling molecules by macrophages in migration and osteoblastic differentiation of MSCs.Acta Biomater.2017;51:447-460.
[48]Sunarso,Toita R,Tsuru K,et al.A superhydrophilic titanium implant functionalized by ozone gas modulates bone marrow cell and macrophage responses.J Mater Sci Mater Med.2016;27(8):127.
[49]F?rster Y,Rentsch C,Schneiders W,et al.Surface modification of implants in long bone.Biomatter.2012;2(3):149-157.
[50]Nayak S,Dey T,Naskar D,et al.The promotion of osseointegration of titanium surfaces by coating with silk protein sericin.Biomaterials.2013;34(12):2855-2864.
[51]Nie B,Ao H,Zhou J,et al.Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria,osteogenesis and reduction of macrophage inflammation.Colloids Surf B Biointerfaces.2016;145:728-739.
[52]Chen Z,Wu C,Gu W,et al.Osteogenic differentiation of bone marrow MSCs byβ-tricalcium phosphate stimulating macrophages via BMP2signalling pathway.Biomaterials.2014;35(5):1507-1518.
[53]Miron R,Bosshardt D.Multi-Nucleated Giant Cells:Good Guys or Bad Guys?Tissue Eng Part B Rev.2017.doi:10.1089/ten.TEB.2017.0242.[Epub ahead of print]
[54]Thalji G,Cooper LF.Molecular assessment of osseointegration in vitro:a review of current literature.Int J Oral Maxillofac Implants.2014;29(2):e171-199.
[55]Wythe SE,Nicolaidou V,Horwood NJ.Cells of the immune system orchestrate changes in bone cell function.Calcif Tissue Int.2014;94(1):98-111.
[56]Takayanagi H.New developments in osteoimmunology.Nat Rev Rheumatol.2012;8(11):684-689.
[57]Trindade R,Albrektsson T,Tengvall P,et al.Foreign Body Reaction to Biomaterials:On Mechanisms for Buildup and Breakdown of Osseointegration.Clin Implant Dent Relat Res.2016;18(1):192-203.
[2]Terheyden H,Lang NP,Bierbaum S,et al.Osseointegration-communication of cells.Clin Oral Implants Res.2012;23(10):1127-1135.
[3]Sinder BP,Pettit AR,Mc Cauley LK.Macrophages:Their Emerging Roles in Bone.J Bone Miner Res.2015;30(12):2140-2149.
[4]Miron RJ,Bosshardt DD.Osteo Macs:Key players around bone biomaterials.Biomaterials.2016;82:1-19.
[5]Davies LC,Jenkins SJ,Allen JE,et al.Tissue-resident macrophages.Nat Immunol.2013;14(10):986-995.
[6]Mantovani A,Biswas SK,Galdiero MR,et al.Macrophage plasticity and polarization in tissue repair and remodelling.J Pathol.2013;229:176-185.
[7]Anton K,Banerjee D,Glod J.Macrophage-associated mesenchymal stem cells assume an activated,migratory,pro-inflammatory phenotype with increased IL-6 and CXCL10 secretion.Plo S One.2012;7:e35036.
[8]Mosser DM,Edwards JP.Exploring the full spectrum of macrophage activation.Nat Rev Immunol.2008;8:958-969.
[9]Martinez FO,Gordon S.The M1 and M2 paradigm of macrophage activation:time for reassessment.F1000Prime Rep.2014;6:13.
[10]Tugal D,Liao X,Jain MK.Transcriptional control of macrophage polarization.Arterioscler Thromb Vasc Biol.2013;33(6):1135-1144.
[11]Chen Z,Mao X,Tan L,et al.Osteoimmunomodulatory properties of magnesium scaffolds coated withβ-tricalcium phosphate.Biomaterials.2014;35(30):8553-8565.
[12]Murray PJ,Allen JE,Biswas SK,et al.Macrophage activation and polarization:nomenclature and experimental guidelines.Immunity.2014;41:14-20.
[13]Ziegler T,Rausch S,Steinfelder S,et al.A novel regulatory macrophage induced by a helminth molecule instructs IL-10 in CD4+T cells and protects against mucosal inflammation.J Immunol.2015;194(4):1555-1564.
[14]Trindade R,Albrektsson T,Wennerberg A.Current concepts for the biological basis of dental implants:foreign body equilibrium and osseointegration dynamics.Oral Maxillofac Surg Clin North Am.2015;27(2):175-183.
[15]Gibon E,Lu LY,Nathan K,et al.Inflammation,ageing,and bone regeneration.J Orthop Translat.2017;10:28-35.
[16]Cho SW,Soki FN,Koh AJ,et al.Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.Proc Natl Acad Sci U S A.2014;111(4):1545-1550.
[17]Guihard P,Danger Y,Brounais B,et al.Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling.Stem Cells.2012;30(4):762-772.
[18]Karazisis D,Ballo AM,Petronis S,et al.The role of well-defined nanotopography of titanium implants on osseointegration:cellular and molecular events in vivo.Int J Nanomedicine.2016;11:1367-1382.
[19]Karazisis D,Petronis S,Agheli H,et al.The influence of controlled surface nanotopography on the early biological events of osseointegration.Acta Biomater.2017;53:559-571.
[20]LüWL,Wang N,Gao P,et al.Effects of anodic titanium dioxide nanotubes of different diameters on macrophage secretion and expression of cytokines and chemokines.Cell Prolif.2015;48(1):95-104.
[21]Ma QL,Zhao LZ,Liu RR,et al.Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization.Biomaterials.2014;35(37):9853-9867.
[22]樊牮,邹耿森,陈江.钛种植体表面纳米改性及其与机体免疫应答[J].国际口腔医学杂志,2014,41(6):691-693.
[23]He XT,Li X,Yin Y,et al.The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells.J Cell Mol Med.2017.doi:10.1111/jcmm.13431.[Epub ahead of print]
[24]Alfarsi MA,Hamlet SM,Ivanovski S.Titanium surface hydrophilicity modulates the human macrophage inflammatorycytokine response.JBiomed Mater Res A.2014;102(1):60-67.
[25]Hotchkiss KM,Reddy GB,Hyzy SL,et al.Titanium surface characteristics,including topography and wettability,alter macrophage activation.Acta Biomater.2016;31:425-434.
[26]Hotchkiss KM,Ayad NB,Hyzy SL,et al.Dental implant surface chemistry and energy alter macrophage activation in vitro.Clin Oral Implants Res.2017;28(4):414-423.
[27]Lee RS,Hamlet SM,Ivanovski S,et al.The influence of titanium surface characteristics on macrophage phenotype polarization during osseous healing in type I diabetic rats:a pilot study.Clin Oral Implants Res.2017;28(10):e159-e168.
[28]Alfarsi MA,Hamlet SM,Ivanovski S.The Effect of Platelet Proteins Released in Response to Titanium Implant Surfaces on Macrophage Pro-Inflammatory Cytokine Gene Expression.Clin Implant Dent Relat Res.2015;17(6):1036-1047.
[29]Rydén L,Omar O,Johansson A,et al.Inflammatory cell response to ultra-thin amorphous and crystalline hydroxyapatite surfaces.J Mater Sci Mater Med.2017;28(1):9.
[30]Mestres G,Espanol M,Xia W,et al.Inflammatory response to nano-and microstructured hydroxyapatite.PLo S One.2015;10(3):e0120381.
[31]Hamlet S,Ivanovski S.Inflammatory cytokine response to titanium chemical composition and nanoscale calcium phosphate surface modification.Acta Biomater.2011;7(5):234523-234553.
[32]Lee CH,Kim YJ,Jang JH,et al.Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces.Nanotechnology.2016;27(8):085101.
[33]Park JW,Kim YJ,Jang JH,et al.Positive modulation of osteogenesisand osteoclastogenesis-related gene expression with strontium-containing microstructured Ti implants in rabbit cancellous bone.J Biomed Mater Res A.2013;101(1):298-306.
[34]Li K,Shen Q,Xie Y,et al.Incorporation of cerium oxide into hydroxyapatite coating regulates osteogenic activity of mesenchymal stem cell and macrophage polarization.J Biomater Appl.2017;31(7):1062-1076.
[35]Wessely-Szponder J,Szponder T,Bobowiec R.Different activation of monocyte-derived macrophages by antimicrobial peptides at a titanium tibial implantation in rabbits.Res Vet Sci.2017;115:201-210.
[36]Pajarinen J,Kouri VP,J?msen E,et al.The response of macrophages to titanium particles is determined by macrophage polarization.Acta Biomater.2013;9(11):9229-9240.
[37]Nie B,Ao H,Zhou J,et al.Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria,osteogenesis and reduction of macrophage inflammation.Colloids Surf B Biointerfaces.2016;145:728-739.
[38]Cha BH,Shin SR,Leijten J,et al.Integrin-Mediated Interactions Control Macrophage Polarization in 3D Hydrogels.Adv Healthc Mater.2017;6(21).doi:10.1002/adhm.201700289.Epub 2017 Aug 7.
[39]Thalji GN,Nares S,Cooper LF.Early molecular assessment of osseointegration in humans.Clin Oral Implants Res.2014;25(11):1273-1285.
[40]Nagasawa M,Cooper LF,Ogino Y,et al.Topography Influences Adherent Cell Regulation of Osteoclastogenesis.J Dent Res.2016;95(3):319-326.
[41]Ma QL,Fang L,Jiang N,et al.Bone mesenchymal stem cell secretion of s RANKL/OPG/M-CSF in response to macrophage-mediated inflammatory response influences osteogenesis on nanostructured Ti surfaces.Biomaterials.2017;154:234-247.
[42]Hefti T,Frischherz M,Spencer ND,et al.A comparison of osteoclast resorption pits on bone with titanium and zirconia surfaces.Biomaterials.2010;31(28):7321-7331.
[43]Brinkmann J,Hefti T,Schlottig F,et al.Response of osteoclasts to titanium surfaces with increasing surface roughness:an in vitro study.Biointerphases.2012;7(1-4):34.
[44]Milleret V,Tugulu S,Schlottig F,et al.Alkali treatment of microrough titanium surfaces affects macrophage/monocyte adhesion,platelet activation and architecture of blood clot formation.Eur Cell Mater.2011;21:430-444;discussion 444.
[45]Mamalis AA,Markopoulou C,Vrotsos I,et al.Chemical modification of an implant surface increases osteogenesis and simultaneously reduces osteoclastogenesis:an in vitro study.Clin Oral Implants Res.2011;22(6):619-626.
[46]Davison NL,Luo X,Schoenmaker T,et al.Submicron-scale surface architecture of tricalcium phosphate directs osteogenesis in vitro and in vivo.Eur Cell Mater.2014;27:281-297;discussion 296-297.
[47]Wang J,Liu D,Guo B,et al.Role of biphasic calcium phosphate ceramic-mediated secretion of signaling molecules by macrophages in migration and osteoblastic differentiation of MSCs.Acta Biomater.2017;51:447-460.
[48]Sunarso,Toita R,Tsuru K,et al.A superhydrophilic titanium implant functionalized by ozone gas modulates bone marrow cell and macrophage responses.J Mater Sci Mater Med.2016;27(8):127.
[49]F?rster Y,Rentsch C,Schneiders W,et al.Surface modification of implants in long bone.Biomatter.2012;2(3):149-157.
[50]Nayak S,Dey T,Naskar D,et al.The promotion of osseointegration of titanium surfaces by coating with silk protein sericin.Biomaterials.2013;34(12):2855-2864.
[51]Nie B,Ao H,Zhou J,et al.Biofunctionalization of titanium with bacitracin immobilization shows potential for anti-bacteria,osteogenesis and reduction of macrophage inflammation.Colloids Surf B Biointerfaces.2016;145:728-739.
[52]Chen Z,Wu C,Gu W,et al.Osteogenic differentiation of bone marrow MSCs byβ-tricalcium phosphate stimulating macrophages via BMP2signalling pathway.Biomaterials.2014;35(5):1507-1518.
[53]Miron R,Bosshardt D.Multi-Nucleated Giant Cells:Good Guys or Bad Guys?Tissue Eng Part B Rev.2017.doi:10.1089/ten.TEB.2017.0242.[Epub ahead of print]
[54]Thalji G,Cooper LF.Molecular assessment of osseointegration in vitro:a review of current literature.Int J Oral Maxillofac Implants.2014;29(2):e171-199.
[55]Wythe SE,Nicolaidou V,Horwood NJ.Cells of the immune system orchestrate changes in bone cell function.Calcif Tissue Int.2014;94(1):98-111.
[56]Takayanagi H.New developments in osteoimmunology.Nat Rev Rheumatol.2012;8(11):684-689.
[57]Trindade R,Albrektsson T,Tengvall P,et al.Foreign Body Reaction to Biomaterials:On Mechanisms for Buildup and Breakdown of Osseointegration.Clin Implant Dent Relat Res.2016;18(1):192-203.