Drug Delivery Systems Based on Titania Nanotubes and Active Agents for Enhanced Osseointegration of Bone Implants

doi:10.2174/0929867326666190726123229
摘要

TiO2纳米管（TNT）是用于局部药物输送的有吸引力的纳米结构。由于其优异的生物相容性和理化性质，已尝试将TNT进行多种功能化以用作治疗剂递送平台。在这篇综述中，我们讨论了基于TNT的递送系统应用的当前进展，重点是TNT的各种功能性，以增强骨-植入物界面处的成骨作用并防止植入物相关的感染。用于增强成骨作用的疗法的创新仍然代表着骨缺损再生中的关键挑战。总体概念集中在结合使用骨诱导材料和骨诱导因子或骨促进因子的使用上。在这种情况下，我们重点介绍了使用五类生物活性剂改善TNT功能的策略：生长因子（GFs），他汀类药物，植物衍生的分子，无机治疗性离子/纳米颗粒（NPs）和抗菌化合物。
关键词: TiO2纳米管，药物输送，生长因子，他汀类药物，类黄酮，无机离子，纳米颗粒，抗生素，骨整合。
« Previous Next »
[1] 
Brunette, D.M.; Tengvall, P.; Textor, M.; Thomsen, P. Titanium in Medicine, 1st ed; Springer: Berlin, Heidelberg, 2001. 
[http://dx.doi.org/10.1007/978-3-642-56486-4] 
[2] 
Bishop, J.A.; Palanca, A.A.; Bellino, M.J.; Lowenberg, D.W. Assessment of compromised fracture healing. J. Am. Acad. Orthop. Surg.,  2012, 20(5), 273-282.
[http://dx.doi.org/10.5435/JAAOS-20-05-273] [PMID: 22553099] 
[3] 
Wang, X.; Xu, S.; Zhou, S.; Xu, W.; Leary, M.; Choong, P.; Qian, M.; Brandt, M.; Xie, Y.M. Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review. Biomaterials,  2016, 83, 127-141.
[http://dx.doi.org/10.1016/j.biomaterials.2016.01.012] [PMID: 26773669] 
[4] 
Le Guéhennec, L.; Soueidan, A.; Layrolle, P.; Amouriq, Y. Surface treatments of titanium dental implants for rapid osseointegration. Dent. Mater.,  2007, 23(7), 844-854.
[http://dx.doi.org/10.1016/j.dental.2006.06.025] [PMID: 16904738] 
[5] 
Aksakal, B.; Yildirim, Ö.S.; Gul, H. Metallurgical failure analysis of various implant materials used in orthopedic applications. J. Fail. Anal. Prev.,  2004, 4(3), 17-23.
[http://dx.doi.org/10.1007/s11668-996-0007-9] 
[6] 
Kulkarni, M.; Mazare, A.; Gongadze, E.; Perutkova, Š.; Kralj-Iglič, V.; Milošev, I.; Schmuki, P.; Iglič, A.; Mozetič, M. Titanium nanostructures for biomedical applications. Nanotechnology,  2015, 26(6) 062002
[http://dx.doi.org/10.1088/0957-4484/26/6/062002] [PMID: 25611515] 
[7] 
Kulkarni, M.; Mazare, A.; Schmuki, P.; Iglic, A. Influence of anodization parameters on morphology of TiO2 nanostructured surfaces. Adv. Mat. Lett.,  2016, 7(1), 23-28.
[http://dx.doi.org/10.5185/amlett.2016.6156] 
[8] 
Awad, N.K.; Edwards, S.L.; Morsi, Y.S. A review of TiO2 NTs on Ti metal: Electrochemical synthesis, functionalization and potential use as bone implants. Mater. Sci. Eng. C,  2017, 76, 1401-1412.
[http://dx.doi.org/10.1016/j.msec.2017.02.150] [PMID: 28482507] 
[9] 
Gulati, K.; Maher, S.; Findlay, D.M.; Losic, D. Titania nanotubes for orchestrating osteogenesis at the bone-implant interface. Nanomedicine (Lond.),  2016, 11(14), 1847-1864.
[http://dx.doi.org/10.2217/nnm-2016-0169] [PMID: 27389393] 
[10] 
Nguyen, S.; Hiorth, M. Advanced drug delivery systems for local treatment of the oral cavity. Ther. Deliv.,  2015, 6(5), 595-608.
[http://dx.doi.org/10.4155/tde.15.5] [PMID: 26001175] 
[11] 
Park, J.; Bauer, S.; von der Mark, K.; Schmuki, P. Nanosize and vitality: TiO2 nanotube diameter directs cell fate. Nano Lett.,  2007, 7(6), 1686-1691.
[http://dx.doi.org/10.1021/nl070678d] [PMID: 17503870] 
[12] 
Oh, S.; Brammer, K.S.; Li, Y.S.; Teng, D.; Engler, A.J.; Chien, S.; Jin, S. Stem cell fate dictated solely by altered nanotube dimension. Proc. Natl. Acad. Sci. USA,  2009, 106(7), 2130-2135.
[http://dx.doi.org/10.1073/pnas.0813200106] [PMID: 19179282] 
[13] 
Brammer, K.S.; Oh, S.; Cobb, C.J.; Bjursten, L.M.; van der Heyde, H.; Jin, S. Improved bone-forming functionality on diameter-controlled TiO(2) nanotube surface. Acta Biomater.,  2009, 5(8), 3215-3223.
[http://dx.doi.org/10.1016/j.actbio.2009.05.008] [PMID: 19447210] 
[14] 
Yu, W.Q.; Jiang, X.Q.; Zhang, F.Q.; Xu, L. The effect of anatase TiO2 nanotube layers on MC3T3-E1 preosteoblast adhesion, proliferation, and differentiation. J. Biomed. Mater. Res. A,  2010, 94(4), 1012-1022.
[http://dx.doi.org/10.1002/jbm.a.32687] [PMID: 20694968] 
[15] 
Wang, N.; Li, H.; Lü, W.; Li, J.; Wang, J.; Zhang, Z.; Liu, Y. Effects of TiO2 nanotubes with different diameters on gene expression and osseointegration of implants in minipigs. Biomaterials,  2011, 32(29), 6900-6911.
[http://dx.doi.org/10.1016/j.biomaterials.2011.06.023] [PMID: 21733571] 
[16] 
Lv, L.; Liu, Y.; Zhang, P.; Zhang, X.; Liu, J.; Chen, T.; Su, P.; Li, H.; Zhou, Y. The nanoscale geometry of TiO2 nanotubes influences the osteogenic differentiation of human adipose-derived stem cells by modulating H3K4 trimethylation. Biomaterials,  2015, 39, 193-205.
[http://dx.doi.org/10.1016/j.biomaterials.2014.11.002] [PMID: 25468371] 
[17] 
Zhang, R.; Wu, H.; Ni, J.; Zhao, C.; Chen, Y.; Zheng, C.; Zhang, X. Guided proliferation and bone-forming functionality on highly ordered large diameter TiO2 nanotube arrays. Mater. Sci. Eng. C,  2015, 53, 272-279.
[http://dx.doi.org/10.1016/j.msec.2015.04.046] [PMID: 26042715] 
[18] 
Zhang, Y.; Luo, R.; Tan, J.; Wang, J.; Lu, X.; Qu, S.; Weng, J.; Feng, B. Osteoblast behaviors on titania nanotube and mesopore layers. Regen. Biomater.,  2017, 4(2), 81-87.
[PMID: 30792885] 
[19] 
Li, Y.; Li, F.; Zhang, C.; Gao, B.; Tan, P.; Mi, B.; Zhang, Y.; Cheng, H.; Liao, H.; Huo, K.; Xiong, W. The dimension of titania nanotubes influences implant success for osteoclastogenesis and osteogenesis patients. J. Nanosci. Nanotechnol.,  2015, 15(6), 4136-4142.
[http://dx.doi.org/10.1166/jnn.2015.9602] [PMID: 26369022] 
[20] 
Ainslie, K.M.; Tao, S.L.; Popat, K.C.; Daniels, H.; Hardev, V.; Grimes, C.A.; Desai, T.A. In vitro inflammatory response of nanostructured titania, silicon oxide, and polycaprolactone. J. Biomed. Mater. Res. A,  2009, 91(3), 647-655.
[http://dx.doi.org/10.1002/jbm.a.32262] [PMID: 18988278] 
[21] 
Chamberlain, L.M.; Brammer, K.S.; Johnston, G.W.; Chien, S.; Jin, S. Macrophage inflammatory response to TiO2 nanotube surfaces. J. Biomater. Nanobiotechnol.,  2011, 2(3), 293-300.
[http://dx.doi.org/10.4236/jbnb.2011.23036] 
[22] 
Rajyalakshmi, A.; Ercan, B.; Balasubramanian, K.; Webster, T.J. Reduced adhesion of macrophages on anodized titanium with select nanotube surface features. Int. J. Nanomedicine,  2011, 6, 1765-1771.
[PMID: 21980239] 
[23] 
Smith, B.S.; Capellato, P.; Kelley, S.; Gonzalez-Juarrero, M.; Popat, K.C. Reduced in vitro immune response on titania nanotube arrays compared to titanium surface. Biomater. Sci.,  2013, 1(3), 322-322.
[http://dx.doi.org/10.1039/C2BM00079B] 
[24] 
Neacsu, P.; Mazare, A.; Cimpean, A.; Park, J.; Costache, M.; Schmuki, P.; Demetrescu, I. Reduced inflammatory activity of RAW 264.7 macrophages on titania nanotube modified Ti surface. Int. J. Biochem. Cell Biol.,  2014, 55, 187-195.
[http://dx.doi.org/10.1016/j.biocel.2014.09.006] [PMID: 25220343] 
[25] 
Lü, W.L.; Wang, N.; Gao, P.; Li, C.Y.; Zhao, H.S.; Zhang, Z.T. 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.
[http://dx.doi.org/10.1111/cpr.12149] [PMID: 25521217] 
[26] 
Neacsu, P.; Mazare, A.; Schmuki, P.; Cimpean, A. Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways. Int. J. Nanomedicine,  2015, 10, 6455-6467.
[PMID: 26491301] 
[27] 
Anderson, J.M. Biological responses to materials. Annu. Rev. Mater.,  2001, 31(1), 81-110.
[http://dx.doi.org/10.1146/annurev.matsci.31.1.81] 
[28] 
Anderson, J.M. Inflammation, wound healing, and the foreign-body response In:  Biomaterials Science: An Introduction to Materials; 3rd ed; Ratner, B.; Hoffman, A.; Schoen, F.; Lemons, J., Eds.; Academic Press: San Diego, USA,, 2013; pp. 296-304.
[http://dx.doi.org/10.1016/B978-0-08-087780-8.00044-9] 
[29] 
Franz, S.; Rammelt, S.; Scharnweber, D.; Simon, J.C. Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. Biomaterials,  2011, 32(28), 6692-6709.
[http://dx.doi.org/10.1016/j.biomaterials.2011.05.078] [PMID: 21715002] 
[30] 
Brown, B.N.; Ratner, B.D.; Goodman, S.B.; Amar, S.; Badylak, S.F. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials,  2012, 33(15), 3792-3802.
[http://dx.doi.org/10.1016/j.biomaterials.2012.02.034] [PMID: 22386919] 
[31] 
Cimpean, A.; Ion, R.; Gordin, D-M.; Neacsu, P.; Mitran, V.; Gloriant, T. Biomaterials as modulators of the macrophage inflammatory response In: Nanotechnology; 1th ed. Navani, N.K.; Sinha, S., Eds.; Studium Press LLC: India, 2013; Vol.11, pp. 376-412.
[32] 
Novak, M.L.; Koh, T.J. Macrophage phenotypes during tissue repair. J. Leukoc. Biol.,  2013, 93(6), 875-881.
[http://dx.doi.org/10.1189/jlb.1012512] [PMID: 23505314] 
[33] 
Spiller, K.L.; Nassiri, S.; Witherel, C.E.; Anfang, R.R.; Ng, J.; Nakazawa, K.R.; Yu, T.; Vunjak-Novakovic, G. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials,  2015, 37, 194-207.
[http://dx.doi.org/10.1016/j.biomaterials.2014.10.017] [PMID: 25453950] 
[34] 
Alvarez, M.M.; Liu, J.C.; Trujillo-de Santiago, G.; Cha, B.H.; Vishwakarma, A.; Ghaemmaghami, A.M.; Khademhosseini, A. Delivery strategies to control inflammatory response: Modulating M1-M2 polarization in tissue engineering applications. J. Control. Release,  2016, 240, 349-363.
[http://dx.doi.org/10.1016/j.jconrel.2016.01.026] [PMID: 26778695] 
[35] 
Ma, Q.L.; Zhao, L.Z.; Liu, R.R.; Jin, B.Q.; Song, W.; Wang, Y.; Zhang, Y.S.; Chen, L.H.; Zhang, Y.M. Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization. Biomaterials,  2014, 35(37), 9853-9867.
[http://dx.doi.org/10.1016/j.biomaterials.2014.08.025] [PMID: 25201737] 
[36] 
Del Curto, B.; Brunella, M.F.; Giordano, C.; Pedeferri, M.P.; Valtulina, V.; Visai, L.; Cigada, A. Decreased bacterial adhesion to surface-treated titanium. Int. J. Artif. Organs,  2005, 28(7), 718-730.
[http://dx.doi.org/10.1177/039139880502800711] [PMID: 16049906] 
[37] 
Puckett, S.D.; Taylor, E.; Raimondo, T.; Webster, T.J. The relationship between the nanostructure of titanium surfaces and bacterial attachment. Biomaterials,  2010, 31(4), 706-713.
[http://dx.doi.org/10.1016/j.biomaterials.2009.09.081] [PMID: 19879645] 
[38] 
Kummer, K.M.; Taylor, E.N.; Durmas, N.G.; Tarquinio, K.M.; Ercan, B.; Webster, T.J. Effects of different sterilization techniques and varying anodized TiO2 nanotube dimensions on bacteria growth. J. Biomed. Mater. Res. B Appl. Biomater.,  2013, 101(5), 677-688.
[http://dx.doi.org/10.1002/jbm.b.32870] [PMID: 23359494] 
[39] 
Ercan, B.; Taylor, E.; Alpaslan, E.; Webster, T.J. Diameter of titanium nanotubes influences anti-bacterial efficacy. Nanotechnology,  2011, 22(29)295102
[http://dx.doi.org/10.1088/0957-4484/22/29/295102] [PMID: 21673387] 
[40] 
Anitha, V.C.; Lee, J.H.; Lee, J.; Banerjee, A.N.; Joo, S.W.; Min, B.K. Biofilm formation on a TiO2 nanotube with controlled pore diameter and surface wettability. Nanotechnology,  2015, 26(6) 065102
[http://dx.doi.org/10.1088/0957-4484/26/6/065102] [PMID: 25604920] 
[41] 
Valdez-Salas, B.; Beltrán-Partida, E.; Castillo-Uribe, S.; Curiel-Álvarez, M.; Zlatev, R.; Stoytcheva, M.; Montero-Alpírez, G.; Vargas-Osuna, L. In vitro assessment of early bacterial activity on micro/nanostructured Ti6Al4V surfaces. Molecules,  2017, 22(5), 832.
[http://dx.doi.org/10.3390/molecules22050832] [PMID: 28524087] 
[42] 
von Wilmowsky, C.; Bauer, S.; Roedl, S.; Neukam, F.W.; Schmuki, P.; Schlegel, K.A. The diameter of anodic TiO2 nanotubes affects bone formation and correlates with the bone morphogenetic protein-2 expression in vivo. Clin. Oral Implants Res.,  2012, 23(3), 359-366.
[http://dx.doi.org/10.1111/j.1600-0501.2010.02139.x] [PMID: 21443609] 
[43] 
von Wilmowsky, C.; Bauer, S.; Lutz, R.; Meisel, M.; Neukam, F.W.; Toyoshima, T.; Schmuki, P.; Nkenke, E.; Schlegel, K.A. In vivo evaluation of anodic TiO2 nanotubes: an experimental study in the pig. J. Biomed. Mater. Res. B Appl. Biomater.,  2009, 89(1), 165-171.
[http://dx.doi.org/10.1002/jbm.b.31201] [PMID: 18780361] 
[44] 
Kang, C-G.; Park, Y-B.; Choi, H.; Oh, S.; Lee, K-W.; Choi, S-H.; Shim, J-S. Osseointegration of implants surface-treated with various diameters of TiO2 nanotubes in rabbit. J. Nanomater.,  2015, 2015 634650
[http://dx.doi.org/10.1155/2015/634650] 
[45] 
Lavenus, S.; Trichet, V.; Le Chevalier, S.; Hoornaert, A.; Louarn, G.; Layrolle, P. Cell differentiation and osseointegration influenced by nanoscale anodized titanium surfaces. Nanomedicine (Lond.),  2012, 7(7), 967-980.
[http://dx.doi.org/10.2217/nnm.11.181] [PMID: 22394187] 
[46] 
Jang, I.; Shim, S.C.; Choi, D.S.; Cha, B.K.; Lee, J.K.; Choe, B.H.; Choi, W.Y. Effect of TiO2 nanotubes arrays on osseointegration of orthodontic miniscrew. Biomed. Microdevices,  2015, 17(4), 76.
[http://dx.doi.org/10.1007/s10544-015-9986-1] [PMID: 26149697] 
[47] 
Bjursten, L.M.; Rasmusson, L.; Oh, S.; Smith, G.C.; Brammer, K.S.; Jin, S. Titanium dioxide nanotubes enhance bone bonding in vivo. J. Biomed. Mater. Res. A,  2010, 92(3), 1218-1224.
[PMID: 19343780] 
[48] 
Fan, X.; Feng, B.; Liu, Z.; Tan, J.; Zhi, W.; Lu, X.; Wang, J.; Weng, J. Fabrication of TiO2 nanotubes on porous titanium scaffold and biocompatibility evaluation in vitro and in vivo. J. Biomed. Mater. Res. A,  2012, 100(12), 3422-3427.
[http://dx.doi.org/10.1002/jbm.a.34268] [PMID: 22791689] 
[49] 
Liang, B.; Fujibayashi, S.; Neo, M.; Tamura, J.; Kim, H.M.; Uchida, M.; Kokubo, T.; Nakamura, T. Histological and mechanical investigation of the bone-bonding ability of anodically oxidized titanium in rabbits. Biomaterials,  2003, 24(27), 4959-4966.
[http://dx.doi.org/10.1016/S0142-9612(03)00421-6] [PMID: 14559009] 
[50] 
Salou, L.; Hoornaert, A.; Louarn, G.; Layrolle, P. Enhanced osseointegration of titanium implants with nanostructured surfaces: an experimental study in rabbits. Acta Biomater.,  2015, 11(1), 494-502.
[http://dx.doi.org/10.1016/j.actbio.2014.10.017] [PMID: 25449926] 
[51] 
Ding, X.; Zhou, L.; Wang, J.; Zhao, Q.; Lin, X.; Gao, Y.; Li, S.; Wu, J.; Rong, M.; Guo, Z.; Lai, C.; Lu, H.; Jia, F. The effects of hierarchical micro/nanosurfaces decorated with TiO2 nanotubes on the bioactivity of titanium implants in vitro and in vivo. Int. J. Nanomedicine,  2015, 10, 6955-6973.
[PMID: 26635472] 
[52] 
Sul, Y.T. Electrochemical growth behavior, surface properties, and enhanced in vivo bone response of TiO2 nanotubes on microstructured surfaces of blasted, screw-shaped titanium implants. Int. J. Nanomedicine,  2010, 5(5), 87-100.
[http://dx.doi.org/10.2147/IJN.S8012] [PMID: 20463928] 
[53] 
Lieberman, J.R.R.; Daluiski, A.; Einhorn, T.A.A. The role of growth factors in the repair of bone. Biology and clinical applications. J. Bone Joint Surg. Am.,  2002, 84(6), 1032-1044.
[http://dx.doi.org/10.2106/00004623-200206000-00022] [PMID: 12063342] 
[54] 
Lee, K.; Silva, E.A.; Mooney, D.J. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J. R. Soc. Interface,  2011, 8(55), 153-170.
[http://dx.doi.org/10.1098/rsif.2010.0223] [PMID: 20719768] 
[55] 
Leof, E.B. Growth factor receptor signalling: location, location, location. Trends Cell Biol.,  2000, 10(8), 343-348.
[http://dx.doi.org/10.1016/S0962-8924(00)01795-5] [PMID: 10884687] 
[56] 
Reddi, A.H. BMPs: from bone morphogenetic proteins to body morphogenetic proteins. Cytokine Growth Factor Rev.,  2005, 16(3), 249-250.
[http://dx.doi.org/10.1016/j.cytogfr.2005.04.003] [PMID: 15949967] 
[57] 
Radomsky, M.L.; Aufdemorte, T.B.; Swain, L.D.; Fox, W.C.; Spiro, R.C.; Poser, J.W. Novel formulation of fibroblast growth factor-2 in a hyaluronan gel accelerates fracture healing in nonhuman primates. J. Orthop. Res.,  1999, 17(4), 607-614.
[http://dx.doi.org/10.1002/jor.1100170422] [PMID: 10459770] 
[58] 
Osathanon, T.; Nowwarote, N.; Manokawinchoke, J.; Pavasant, P. bFGF and JAGGED1 regulate alkaline phosphatase expression and mineralization in dental tissue-derived mesenchymal stem cells. J. Cell. Biochem.,  2013, 114(11), 2551-2561.
[http://dx.doi.org/10.1002/jcb.24602] [PMID: 23749297] 
[59] 
Del Angel-Mosqueda, C.; Gutiérrez-Puente, Y.; López-Lozano, A.P.; Romero-Zavaleta, R.E.; Mendiola-Jiménez, A.; Medina-De la Garza, C.E.; Márquez-M, M.; De la Garza-Ramos, M.A. Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro. Head Face Med.,  2015, 11(1), 29.
[http://dx.doi.org/10.1186/s13005-015-0086-5] [PMID: 26334535] 
[60] 
Graham, S.; Leonidou, A.; Lester, M.; Heliotis, M.; Mantalaris, A.; Tsiridis, E. Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing. Expert Opin. Investig. Drugs,  2009, 18(11), 1633-1654.
[http://dx.doi.org/10.1517/13543780903241607] [PMID: 19747084] 
[61] 
Caplan, A.I.; Correa, D. PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J. Orthop. Res.,  2011, 29(12), 1795-1803.
[http://dx.doi.org/10.1002/jor.21462] [PMID: 21618276] 
[62] 
Schmidmaier, G.; Wildemann, B.; Ostapowicz, D.; Kandziora, F.; Stange, R.; Haas, N.P.; Raschke, M. Long-term effects of local growth factor (IGF-I and TGF-β 1) treatment on fracture healing. A safety study for using growth factors. J. Orthop. Res.,  2004, 22(3), 514-519.
[http://dx.doi.org/10.1016/j.orthres.2003.09.009] [PMID: 15099629] 
[63] 
Rosier, R.N.; O’Keefe, R.J.; Hicks, D.G. The potential role of transforming growth factor beta in fracture healing. Clin. Orthop. Relat. Res.,  1998(Suppl. 335), S294-S300.
[http://dx.doi.org/10.1097/00003086-199810001-00030] [PMID: 9917649] 
[64] 
He, H.; Yu, J.; Liu, Y.; Lu, S.; Liu, H.; Shi, J.; Jin, Y. Effects of FGF2 and TGFbeta1 on the differentiation of human dental pulp stem cells in vitro. Cell Biol. Int.,  2008, 32(7), 827-834.
[http://dx.doi.org/10.1016/j.cellbi.2008.03.013] [PMID: 18442933] 
[65] 
Street, J.; Bao, M.; deGuzman, L.; Bunting, S.; Peale, F.V. Jr.; Ferrara, N.; Steinmetz, H.; Hoeffel, J.; Cleland, J.L.; Daugherty, A.; van Bruggen, N.; Redmond, H.P.; Carano, R.A.D.; Filvaroff, E.H. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA,  2002, 99(15), 9656-9661.
[http://dx.doi.org/10.1073/pnas.152324099] [PMID: 12118119] 
[66] 
Vo, T.N.; Kasper, F.K.; Mikos, A.G.A. Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv. Drug Deliv. Rev.,  2012, 64(12), 1292-1309.
[http://dx.doi.org/10.1016/j.addr.2012.01.016] [PMID: 22342771] 
[67] 
Newman, M.R.; Benoit, D.S. Local and targeted drug delivery for bone regeneration. Curr. Opin. Biotechnol.,  2016, 40, 125-132.
[http://dx.doi.org/10.1016/j.copbio.2016.02.029] [PMID: 27064433] 
[68] 
Popat, K.C.; Eltgroth, M.; LaTempa, T.J.; Grimes, C.A.; Desai, T.A. Titania nanotubes: a novel platform for drug-eluting coatings for medical implants? Small,  2007, 3(11), 1878-1881.
[http://dx.doi.org/10.1002/smll.200700412] [PMID: 17935080] 
[69] 
Gulati, K.; Aw, M.S.; Findlay, D.; Losic, D. Local drug delivery to the bone by drug-releasing implants: perspectives of nano-engineered titania nanotube arrays. Ther. Deliv.,  2012, 3(7), 857-873.
[http://dx.doi.org/10.4155/tde.12.66] [PMID: 22900467] 
[70] 
Oliveira, W.F.; Arruda, I.R.S.; Silva, G.M.M.; Machado, G.; Coelho, L.C.B.B.; Correia, M.T.S. Functionalization of titanium dioxide nanotubes with biomolecules for biomedical applications. Mater. Sci. Eng. C,  2017, 81, 597-606.
[http://dx.doi.org/10.1016/j.msec.2017.08.017] [PMID: 28888015] 
[71] 
Ducy, P.; Karsenty, G. The family of bone morphogenetic proteins. Kidney Int.,  2000, 57(6), 2207-2214.
[http://dx.doi.org/10.1046/j.1523-1755.2000.00081.x] [PMID: 10844590] 
[72] 
Açil, Y.; Springer, I.N.G.; Broek, V.; Terheyden, H.; Jepsen, S. Effects of bone morphogenetic protein-7 stimulation on osteoblasts cultured on different biomaterials. J. Cell. Biochem.,  2002, 86(1), 90-98.
[http://dx.doi.org/10.1002/jcb.10197] [PMID: 12112019] 
[73] 
Patel, Z.S.; Young, S.; Tabata, Y.; Jansen, J.A.; Wong, M.E.K.; Mikos, A.G. Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model. Bone,  2008, 43(5), 931-940.
[http://dx.doi.org/10.1016/j.bone.2008.06.019] [PMID: 18675385] 
[74] 
Govender, S.; Csimma, C.; Genant, H.K.; Valentin-Opran, A.; Amit, Y.; Arbel, R.; Aro, H.; Atar, D.; Bishay, M.; Börner, M.G.; Chiron, P.; Choong, P.; Cinats, J.; Courtenay, B.; Feibel, R.; Geulette, B.; Gravel, C.; Haas, N.; Raschke, M.; Hammacher, E.; van der Velde, D.; Hardy, P.; Holt, M.; Josten, C.; Ketterl, R.L.; Lindeque, B.; Lob, G.; Mathevon, H.; McCoy, G.; Marsh, D.; Miller, R.; Munting, E.; Oevre, S.; Nordsletten, L.; Patel, A.; Pohl, A.; Rennie, W.; Reynders, P.; Rommens, P.M.; Rondia, J.; Rossouw, W.C.; Daneel, P.J.; Ruff, S.; Rüter, A.; Santavirta, S.; Schildhauer, T.A.; Gekle, C.; Schnettler, R.; Segal, D.; Seiler, H.; Snowdowne, R.B.; Stapert, J.; Taglang, G.; Verdonk, R.; Vogels, L.; Weckbach, A.; Wentzensen, A.; Wisniewski, T.; Wisriewsk, T. BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J. Bone Joint Surg. Am.,  2002, 84(12), 2123-2134.
[http://dx.doi.org/10.2106/00004623-200212000-00001] [PMID: 12473698] 
[75] 
Mbalaviele, G.; Sheikh, S.; Stains, J.P.; Salazar, V.S.; Cheng, S.L.; Chen, D.; Civitelli, R. Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J. Cell. Biochem.,  2005, 94(2), 403-418.
[http://dx.doi.org/10.1002/jcb.20253] [PMID: 15526274] 
[76] 
Axelrad, T.W.; Einhorn, T.A. Bone morphogenetic proteins in orthopaedic surgery. Cytokine Growth Factor Rev.,  2009, 20(5-6), 481-488.
[http://dx.doi.org/10.1016/j.cytogfr.2009.10.003] [PMID: 19892584] 
[77] 
Termaat, M.F.; Den Boer, F.C.; Bakker, F.C.; Patka, P.; Haarman, H.J. Bone morphogenetic proteins. Development and clinical efficacy in the treatment of fractures and bone defects. J. Bone Joint Surg. Am.,  2005, 87(6), 1367-1378.
[http://dx.doi.org/10.2106/JBJS.D.02585] [PMID: 15930551] 
[78] 
Kanakaris, N.K.; Giannoudis, P.V. Clinical applications of bone morphogenetic proteins: current evidence. J. Surg. Orthop. Adv.,  2008, 17(3), 133-146.
[PMID: 18851797] 
[79] 
Daluiski, A.; Engstrand, T.; Bahamonde, M.E.; Gamer, L.W.; Agius, E.; Stevenson, S.L.; Cox, K.; Rosen, V.; Lyons, K.M. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat. Genet.,  2001, 27(1), 84-88.
[http://dx.doi.org/10.1038/83810] [PMID: 11138004] 
[80] 
Shen, B.; Bhargav, D.; Wei, A.; Williams, L.A.; Tao, H.; Ma, D.D.F.; Diwan, A.D. BMP-13 emerges as a potential inhibitor of bone formation. Int. J. Biol. Sci.,  2009, 5(2), 192-200.
[http://dx.doi.org/10.7150/ijbs.5.192] [PMID: 19240811] 
[81] 
Miyazono, K.; Kamiya, Y.; Morikawa, M. Bone morphogenetic protein receptors and signal transduction. J. Biochem.,  2010, 147(1), 35-51.
[http://dx.doi.org/10.1093/jb/mvp148] [PMID: 19762341] 
[82] 
Derynck, R.; Zhang, Y.E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature,  2003, 425(6958), 577-584.
[http://dx.doi.org/10.1038/nature02006] [PMID: 14534577] 
[83] 
Heldin, C.H.; Landström, M.; Moustakas, A. Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr. Opin. Cell Biol.,  2009, 21(2), 166-176.
[http://dx.doi.org/10.1016/j.ceb.2009.01.021] [PMID: 19237272] 
[84] 
Nakahiro, T.; Kurooka, H.; Mori, K.; Sano, K.; Yokota, Y. Identification of BMP-responsive elements in the mouse Id2 gene. Biochem. Biophys. Res. Commun.,  2010, 399(3), 416-421.
[http://dx.doi.org/10.1016/j.bbrc.2010.07.090] [PMID: 20674548] 
[85] 
Chen, G.; Deng, C.; Li, Y.P. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci.,  2012, 8(2), 272-288.
[http://dx.doi.org/10.7150/ijbs.2929] [PMID: 22298955] 
[86] 
Xiao, G.; Gopalakrishnan, R.; Jiang, D.; Reith, E.; Benson, M.D.; Franceschi, R.T. Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J. Bone Miner. Res.,  2002, 17(1), 101-110.
[http://dx.doi.org/10.1359/jbmr.2002.17.1.101] [PMID: 11771655] 
[87] 
Pecina, M.; Giltaij, L.R.; Vukicevic, S. Orthopaedic applications of osteogenic protein-1 (BMP-7). Int. Orthop.,  2001, 25(4), 203-208.
[http://dx.doi.org/10.1007/s002640100262] [PMID: 11561491] 
[88] 
Pountos, I.; Georgouli, T.; Henshaw, K.; Bird, H.; Jones, E.; Giannoudis, P.V. The effect of bone morphogenetic protein-2, bone morphogenetic protein-7, parathyroid hormone, and platelet-derived growth factor on the proliferation and osteogenic differentiation of mesenchymal stem cells derived from osteoporotic bone. J. Orthop. Trauma,  2010, 24(9), 552-556.
[http://dx.doi.org/10.1097/BOT.0b013e3181efa8fe] [PMID: 20736793] 
[89] 
Kyllönen, L.; D’Este, M.; Alini, M.; Eglin, D. Local drug delivery for enhancing fracture healing in osteoporotic bone. Acta Biomater.,  2015, 11(1), 412-434.
[http://dx.doi.org/10.1016/j.actbio.2014.09.006] [PMID: 25218339] 
[90] 
Zheng, Y.; Wu, G.; Zhao, J.; Wang, L.; Sun, P.; Gu, Z. rhBMP2/7 heterodimer: an osteoblastogenesis inducer of not higher potency but lower effective concentration compared with rhBMP2 and rhBMP7 homodimers. Tissue Eng. Part A,  2010, 16(3), 879-887.
[http://dx.doi.org/10.1089/ten.tea.2009.0312] [PMID: 19814588] 
[91] 
Guo, J.; Wu, G. The signaling and functions of heterodimeric bone morphogenetic proteins. Cytokine Growth Factor Rev.,  2012, 23(1-2), 61-67.
[http://dx.doi.org/10.1016/j.cytogfr.2012.02.001] [PMID: 22421241] 
[92] 
Wang, J.; Zheng, Y.; Zhao, J.; Liu, T.; Gao, L.; Gu, Z.; Wu, G. Low-dose rhBMP2/7 heterodimer to reconstruct peri-implant bone defects: a micro-CT evaluation. J. Clin. Periodontol.,  2012, 39(1), 98-105.
[http://dx.doi.org/10.1111/j.1600-051X.2011.01807.x] [PMID: 22092868] 
[93] 
Gautschi, O.P.; Frey, S.P.; Zellweger, R. Bone morphogenetic proteins in clinical applications. ANZ J. Surg.,  2007, 77(8), 626-631.
[http://dx.doi.org/10.1111/j.1445-2197.2007.04175.x] [PMID: 17635273] 
[94] 
McKay, W.F.; Peckham, S.M.; Badura, J.M. A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE Bone Graft). Int. Orthop.,  2007, 31(6), 729-734.
[http://dx.doi.org/10.1007/s00264-007-0418-6] [PMID: 17639384] 
[95] 
Vaccaro, A.R.; Patel, T.; Fischgrund, J.; Anderson, D.G.; Truumees, E.; Herkowitz, H.; Phillips, F.; Hilibrand, A.; Albert, T.J. A pilot safety and efficacy study of OP-1 putty (rhBMP-7) as an adjunct to iliac crest autograft in posterolateral lumbar fusions. Eur. Spine J.,  2003, 12(5), 495-500.
[http://dx.doi.org/10.1007/s00586-003-0561-8] [PMID: 12908103] 
[96] 
Vaccaro, A.R.; Patel, T.; Fischgrund, J.; Anderson, D.G.; Truumees, E.; Herkowitz, H.N.; Phillips, F.; Hilibrand, A.; Albert, T.J.; Wetzel, T.; McCulloch, J.A. A pilot study evaluating the safety and efficacy of OP-1 Putty (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis for degenerative spondylolisthesis. Spine,  2004, 29(17), 1885-1892.
[http://dx.doi.org/10.1097/01.brs.0000137062.79201.98] [PMID: 15534410] 
[97] 
Vaccaro, A.R.; Patel, T.; Fischgrund, J.; Anderson, D.G.; Truumees, E.; Herkowitz, H.; Phillips, F.; Hilibrand, A.; Albert, T.J. A 2-year follow-up pilot study evaluating the safety and efficacy of op-1 putty (rhbmp-7) as an adjunct to iliac crest autograft in posterolateral lumbar fusions. Eur. Spine J.,  2005, 14(7), 623-629.
[http://dx.doi.org/10.1007/s00586-004-0845-7] [PMID: 15672240] 
[98] 
Vaccaro, A.R.; Whang, P.G.; Patel, T.; Phillips, F.M.; Anderson, D.G.; Albert, T.J.; Hilibrand, A.S.; Brower, R.S.; Kurd, M.F.; Appannagari, A.; Patel, M.; Fischgrund, J.S. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J.,  2008, 8(3), 457-465.
[http://dx.doi.org/10.1016/j.spinee.2007.03.012] [PMID: 17588821] 
[99] 
El Bialy, I.; Jiskoot, W.; Reza Nejadnik, M. Formulation, delivery and stability of bone morphogenetic proteins for effective bone regeneration. Pharm. Res.,  2017, 34(6), 1152-1170.
[http://dx.doi.org/10.1007/s11095-017-2147-x] [PMID: 28342056] 
[100] 
Kofron, M.D.; Laurencin, C.T. Bone tissue engineering by gene delivery. Adv. Drug Deliv. Rev.,  2006, 58(4), 555-576.
[http://dx.doi.org/10.1016/j.addr.2006.03.008] [PMID: 16790291] 
[101] 
Lü, K.; Zeng, D.; Zhang, Y.; Xia, L.; Xu, L.; Kaplan, D.L.; Jiang, X.; Zhang, F. BMP-2 gene modified canine bMSCs promote ectopic bone formation mediated by a nonviral PEI derivative. Ann. Biomed. Eng.,  2011, 39(6), 1829-1839.
[http://dx.doi.org/10.1007/s10439-011-0276-7] [PMID: 21347550] 
[102] 
Wegman, F.; Geuze, R.E.; van der Helm, Y.J.; Cumhur Öner, F.; Dhert, W.J.A.; Alblas, J. Gene delivery of bone morphogenetic protein-2 plasmid DNA promotes bone formation in a large animal model. J. Tissue Eng. Regen. Med.,  2014, 8(10), 763-770.
[http://dx.doi.org/10.1002/term.1571] [PMID: 22888035] 
[103] 
Balmayor, E.R.; van Griensven, M. Gene therapy for bone engineering. Front. Bioeng. Biotechnol.,  2015, 3, 9.
[http://dx.doi.org/10.3389/fbioe.2015.00009] [PMID: 25699253] 
[104] 
Li, J.; Lin, J.; Yu, W.; Song, X.; Hu, Q.; Xu, J.H.; Wang, H.; Mehl, C. BMP-2 plasmid DNA-loaded chitosan films - A new strategy for bone engineering. J. Craniomaxillofac. Surg.,  2017, 45(12), 2084-2091.
[http://dx.doi.org/10.1016/j.jcms.2017.10.005] [PMID: 29126771] 
[105] 
Reddi, A.H. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat. Biotechnol.,  1998, 16(3), 247-252.
[http://dx.doi.org/10.1038/nbt0398-247] [PMID: 9528003] 
[106] 
Granjeiro, J.M.; Oliveira, R.C.; Bustos-Valenzuela, J.C.; Sogayar, M.C.; Taga, R. Bone morphogenetic proteins: from structure to clinical use. Braz. J. Med. Biol. Res.,  2005, 38(10), 1463-1473.
[http://dx.doi.org/10.1590/S0100-879X2005001000003] [PMID: 16172739] 
[107] 
Kaneko, H.; Arakawa, T.; Mano, H.; Kaneda, T.; Ogasawara, A.; Nakagawa, M.; Toyama, Y.; Yabe, Y.; Kumegawa, M.; Hakeda, Y. Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone,  2000, 27(4), 479-486.
[http://dx.doi.org/10.1016/S8756-3282(00)00358-6] [PMID: 11033442] 
[108] 
Langenfeld, E.M.; Kong, Y.; Langenfeld, J. Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene,  2006, 25(5), 685-692.
[http://dx.doi.org/10.1038/sj.onc.1209110] [PMID: 16247476] 
[109] 
Garrison, K.R.; Donell, S.; Ryder, J.; Shemilt, I.; Mugford, M.; Harvey, I.; Song, F. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.  Health Technol. Assess,  2007, 11(30), 1-150. iii-iv.
[http://dx.doi.org/10.3310/hta11300] [PMID: 17669279] 
[110] 
Toth, J.M.; Boden, S.D.; Burkus, J.K.; Badura, J.M.; Peckham, S.M.; McKay, W.F. Short-term osteoclastic activity induced by locally high concentrations of recombinant human bone morphogenetic protein-2 in a cancellous bone environment. Spine,  2009, 34(6), 539-550.
[http://dx.doi.org/10.1097/BRS.0b013e3181952695] [PMID: 19240666] 
[111] 
Carragee, E.J.; Hurwitz, E.L.; Weiner, B.K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J.,  2011, 11(6), 471-491.
[http://dx.doi.org/10.1016/j.spinee.2011.04.023] [PMID: 21729796] 
[112] 
Woo, E.J. Adverse events after recombinant human BMP2 in nonspinal orthopaedic procedures. Clin. Orthop. Relat. Res.,  2013, 471(5), 1707-1711.
[http://dx.doi.org/10.1007/s11999-012-2684-x] [PMID: 23132207] 
[113] 
Chan, D.S.; Garland, J.; Infante, A.; Sanders, R.W.; Sagi, H.C. Wound complications associated with bone morphogenetic protein-2 in orthopaedic trauma surgery. J. Orthop. Trauma,  2014, 28(10), 599-604.
[http://dx.doi.org/10.1097/BOT.0000000000000117] [PMID: 24682163] 
[114] 
Yamamoto, M.; Takahashi, Y.; Tabata, Y. Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng.,  2006, 12(5), 1305-1311.
[http://dx.doi.org/10.1089/ten.2006.12.1305] [PMID: 16771643] 
[115] 
Wang, J.; Guo, J.; Liu, J.; Wei, L.; Wu, G. BMP-functionalised coatings to promote osteogenesis for orthopaedic implants. Int. J. Mol. Sci.,  2014, 15(6), 10150-10168.
[http://dx.doi.org/10.3390/ijms150610150] [PMID: 24914764] 
[116] 
Lee, E.J.; Kim, H.E. Accelerated bony defect healing by chitosan/silica hybrid membrane with localized bone morphogenetic protein-2 delivery. Mater. Sci. Eng. C,  2016, 59, 339-345.
[http://dx.doi.org/10.1016/j.msec.2015.10.001] [PMID: 26652382] 
[117] 
Agrawal, V.; Sinha, M. A review on carrier systems for bone morphogenetic protein-2. J. Biomed. Mater. Res. B Appl. Biomater.,  2017, 105(4), 904-925.
[http://dx.doi.org/10.1002/jbm.b.33599] [PMID: 26728994] 
[118] 
Maisani, M.; Sindhu, K.R.; Fenelon, M.; Siadous, R.; Rey, S.; Mantovani, D.; Chassande, O. Prolonged delivery of BMP-2 by a non-polymer hydrogel for bone defect regeneration. Drug Deliv. Transl. Res.,  2018, 8(1), 178-190.
[http://dx.doi.org/10.1007/s13346-017-0451-y] [PMID: 29192408] 
[119] 
Lee, J.K.; Choi, D.S.; Jang, I.; Choi, W.Y. Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with recombinant human bone morphogenetic protein-2: a pilot in vivo study. Int. J. Nanomedicine,  2015, 10, 1145-1154.
[PMID: 25709438] 
[120] 
Lai, M.; Cai, K.; Zhao, L.; Chen, X.; Hou, Y.; Yang, Z. Surface functionalization of TiO2 nanotubes with bone morphogenetic protein 2 and its synergistic effect on the differentiation of mesenchymal stem cells. Biomacromolecules,  2011, 12(4), 1097-1105.
[http://dx.doi.org/10.1021/bm1014365] [PMID: 21381690] 
[121] 
Ma, Y.; Zhang, Z.; Liu, Y.; Li, H.; Wang, N.; Liu, W.; Li, W.; Jin, L.; Wang, J.; Chen, S. Nanotubes functionalized with BMP2 knuckle peptide improve the osseointegration of titanium implants in Rabbits. J. Biomed. Nanotechnol.,  2015, 11(2), 236-244.
[http://dx.doi.org/10.1166/jbn.2015.2006] [PMID: 26349299] 
[122] 
Jia, Z.; Xiu, P.; Li, M.; Xu, X.; Shi, Y.; Cheng, Y.; Wei, S.; Zheng, Y.; Xi, T.; Cai, H.; Liu, Z. Bioinspired anchoring AgNPs onto micro-nanoporous TiO2 orthopedic coatings: Trap-killing of bacteria, surface-regulated osteoblast functions and host responses. Biomaterials,  2016, 75, 203-222.
[http://dx.doi.org/10.1016/j.biomaterials.2015.10.035] [PMID: 26513414] 
[123] 
Cheng, L.; Sun, X.; Zhao, X.; Wang, L.; Yu, J.; Pan, G.; Li, B.; Yang, H.; Zhang, Y.; Cui, W. Surface biofunctional drug-loaded electrospun fibrous scaffolds for comprehensive repairing hypertrophic scars. Biomaterials,  2016, 83, 169-181.
[http://dx.doi.org/10.1016/j.biomaterials.2016.01.002] [PMID: 26774564] 
[124] 
Ku, S.H.; Park, C.B. Human endothelial cell growth on mussel-inspired nanofiber scaffold for vascular tissue engineering. Biomaterials,  2010, 31(36), 9431-9437.
[http://dx.doi.org/10.1016/j.biomaterials.2010.08.071] [PMID: 20880578] 
[125] 
Yang, K.; Lee, J.S.; Kim, J.; Lee, Y.B.; Shin, H.; Um, S.H.; Kim, J.B.; Park, K.I.; Lee, H.; Cho, S.W. Polydopamine-mediated surface modification of scaffold materials for human neural stem cell engineering. Biomaterials,  2012, 33(29), 6952-6964.
[http://dx.doi.org/10.1016/j.biomaterials.2012.06.067] [PMID: 22809643] 
[126] 
Kao, C.T.; Lin, C.C.; Chen, Y.W.; Yeh, C.H.; Fang, H.Y.; Shie, M.Y. Poly(dopamine) coating of 3D printed poly(lactic acid) scaffolds for bone tissue engineering. Mater. Sci. Eng. C,  2015, 56, 165-173.
[http://dx.doi.org/10.1016/j.msec.2015.06.028] [PMID: 26249577] 
[127] 
Saito, A.; Suzuki, Y.; Ogata, S-i.; Ohtsuki, C.; Tanihara, M. Activation of osteo-progenitor cells by a novel synthetic peptide derived from the bone morphogenetic protein-2 knuckle epitope. Biochim. Biophys. Acta,  2003, 1651(1-2), 60-67.
[http://dx.doi.org/10.1016/S1570-9639(03)00235-8] [PMID: 14499589] 
[128] 
Balasundaram, G.; Yao, C.; Webster, T.J. TiO2 nanotubes functionalized with regions of bone morphogenetic protein-2 increases osteoblast adhesion. J. Biomed. Mater. Res. A,  2008, 84(2), 447-453.
[http://dx.doi.org/10.1002/jbm.a.31388] [PMID: 17618492] 
[129] 
Hu, Y.; Cai, K.; Luo, Z.; Xu, D.; Xie, D.; Huang, Y.; Yang, W.; Liu, P. TiO2 nanotubes as drug nanoreservoirs for the regulation of mobility and differentiation of mesenchymal stem cells. Acta Biomater.,  2012, 8(1), 439-448.
[http://dx.doi.org/10.1016/j.actbio.2011.10.021] [PMID: 22040682] 
[130] 
Zhang, X.; Yu, Q.; Wang, Y.A.; Zhao, J. Dose reduction of bone morphogenetic protein-2 for bone regeneration using a delivery system based on lyophilization with trehalose. Int. J. Nanomedicine,  2018, 13, 403-414.
[http://dx.doi.org/10.2147/IJN.S150875] [PMID: 29391797] 
[131] 
Jansen, J.A.; Vehof, J.W.M.; Ruhé, P.Q.; Kroeze-Deutman, H.; Kuboki, Y.; Takita, H.; Hedberg, E.L.; Mikos, A.G. Growth factor-loaded scaffolds for bone engineering. J.
Control. Release,  2005, 101(1-3 SPEC. ISS), 127-136.
[http://dx.doi.org/10.1016/j.jconrel.2004.07.005] 
[132] 
Zhang, Y.; Li, M.; Gao, L.; Duan, K.; Wang, J.; Weng, J.; Feng, B. Effect of dexamethasone, β-glycerophosphate, OGP and BMP2 in TiO2 nanotubes on differentiation of MSCs. Mater. Technol.,  2016, 31(10), 603-612.
[http://dx.doi.org/10.1080/10667857.2016.1152655] 
[133] 
Zhang, X.; Zhang, Z.; Shen, G.; Zhao, J. Enhanced osteogenic activity and anti-inflammatory properties of Lenti-BMP-2-loaded TiO2 nanotube layers fabricated by lyophilization following trehalose addition. Int. J. Nanomedicine,  2016, 11, 429-439.
[PMID: 26869786] 
[134] 
Sugiyama, O.; An, D.S.; Kung, S.P.K.; Feeley, B.T.; Gamradt, S.; Liu, N.Q.; Chen, I.S.Y.; Lieberman, J.R. Lentivirus-mediated gene transfer induces long-term transgene expression of BMP-2 in vitro and new bone formation in vivo. Mol. Ther.,  2005, 11(3), 390-398.
[http://dx.doi.org/10.1016/j.ymthe.2004.10.019] [PMID: 15727935] 
[135] 
Policastro, G.M.; Becker, M.L. Osteogenic growth peptide and its use as a bio-conjugate in regenerative medicine applications. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol.,  2016, 8(3), 449-464.
[http://dx.doi.org/10.1002/wnan.1376] [PMID: 26391307] 
[136] 
Pigossi, S.C.; Medeiros, M.C.; Saska, S.; Cirelli, J.A.; Scarel-Caminaga, R.M. Role of osteogenic growth peptide (OGP) and OGP(10-14) in bone regeneration: A review. Int. J. Mol. Sci.,  2016, 17(11), 1885.
[http://dx.doi.org/10.3390/ijms17111885] [PMID: 27879684] 
[137] 
Bab, I.; Gazit, D.; Muhlrad, A.; Shteyer, A. Regenerating bone marrow produces a potent growth-promoting activity to osteogenic cells. Endocrinology,  1988, 123(1), 345-352.
[http://dx.doi.org/10.1210/endo-123-1-345] [PMID: 3164264] 
[138] 
Greenberg, Z.; Chorev, M.; Muhlrad, A.; Shteyer, A.; Namdar-Attar, M.; Casap, N.; Tartakovsky, A.; Vidson, M.; Bab, I. Structural and functional characterization of osteogenic growth peptide from human serum: identity with rat and mouse homologs. J. Clin. Endocrinol. Metab.,  1995, 80(8), 2330-2335.
[PMID: 7629225] 
[139] 
Chen, Z.X.; Chang, M.; Peng, Y.L.; Zhao, L.; Zhan, Y.R.; Wang, L.J.; Wang, R. Osteogenic growth peptide C-terminal pentapeptide [OGP(10-14)] acts on rat bone marrow mesenchymal stem cells to promote differentiation to osteoblasts and to inhibit differentiation to adipocytes. Regul. Pept.,  2007, 142(1-2), 16-23.
[http://dx.doi.org/10.1016/j.regpep.2007.01.003] [PMID: 17331598] 
[140] 
Zhu, H.B.; Guo, D.Z.; Yang, S.J.; Zhang, Y.H.; Wang, H.; Guo, H.T.; Zhang, Y.; Cheng, D.C. Osteogenic actions of the osteogenic growth peptide on bovine marrow mesenchymal stromal cells in culture. Vet. Med. (Praha),  2008, 53(9), 501-509.
[http://dx.doi.org/10.17221/1981-VETMED] 
[141] 
Brager, M.A.; Patterson, M.J.; Connolly, J.F.; Nevo, Z. Osteogenic growth peptide normally stimulated by blood loss and marrow ablation has local and systemic effects on fracture healing in rats. J. Orthop. Res.,  2000, 18(1), 133-139.
[http://dx.doi.org/10.1002/jor.1100180119] [PMID: 10716289] 
[142] 
Gabet, Y.; Müller, R.; Regev, E.; Sela, J.; Shteyer, A.; Salisbury, K.; Chorev, M.; Bab, I. Osteogenic growth peptide modulates fracture callus structural and mechanical properties. Bone,  2004, 35(1), 65-73.
[http://dx.doi.org/10.1016/j.bone.2004.03.025] [PMID: 15207742] 
[143] 
Sun, Y.Q.; Ashhurst, D.E. Osteogenic growth peptide enhances the rate of fracture healing in rabbits. Cell Biol. Int.,  1998, 22(4), 313-319.
[http://dx.doi.org/10.1006/cbir.1998.0253] [PMID: 10101048] 
[144] 
Chen, Y.C.; Bab, I.; Mansur, N.; Muhlrad, A.; Shteyer, A.; Namdar-Attar, M.; Gavish, H.; Vidson, M.; Chorev, M. Structure-bioactivity of C-terminal pentapeptide of osteogenic growth peptide.[OGP(10-14)]. J. Pept. Res.,  2000, 56(3), 147-156.
[http://dx.doi.org/10.1034/j.1399-3011.2000.00763.x] [PMID: 11007271] 
[145] 
Gazit, D.; Shteyer, A.; Bab, I. Further characterization of osteogenic-cell growth promoting activity derived from healing bone marrow. Connect. Tissue Res.,  1989, 23(2-3), 153-161.
[http://dx.doi.org/10.3109/03008208909002415] [PMID: 2630168] 
[146] 
Gavish, H.; Bab, I.; Tartakovsky, A.; Chorev, M.; Mansur, N.; Greenberg, Z.; Namdar-Attar, M.; Muhlrad, A. Human alpha 2-macroglobulin is an osteogenic growth peptide-binding protein. Biochemistry,  1997, 36(48), 14883-14888.
[http://dx.doi.org/10.1021/bi971670t] [PMID: 9398211] 
[147] 
Gabarin, N.; Gavish, H.; Muhlrad, A.; Chen, Y.C.; Namdar-Attar, M.; Nissenson, R.A.; Chorev, M.; Bab, I. Mitogenic G(i) protein-MAP kinase signaling cascade in MC3T3-E1 osteogenic cells: activation by C-terminal pentapeptide of osteogenic growth peptide [OGP(10-14)] and attenuation of activation by cAMP. J. Cell. Biochem.,  2001, 81(4), 594-603.
[http://dx.doi.org/10.1002/jcb.1083] [PMID: 11329614] 
[148] 
Chen, Y.C.; Muhlrad, A.; Shteyer, A.; Vidson, M.; Bab, I.; Chorev, M. Bioactive pseudopeptidic analogues and cyclostereoisomers of osteogenic growth peptide C-terminal pentapeptide, OGP(10-14). J. Med. Chem.,  2002, 45(8), 1624-1632.
[http://dx.doi.org/10.1021/jm010479l] [PMID: 11931616] 
[149] 
Yamazaki, T.; Ro, S.; Goodman, M.; Chung, N.N.; Schiller, P.W. A topochemical approach to explain morphiceptin bioactivity. J. Med. Chem.,  1993, 36(6), 708-719.
[http://dx.doi.org/10.1021/jm00058a007] [PMID: 8384662] 
[150] 
Miguel, S.M.; Namdar-Attar, M.; Noh, T.; Frenkel, B.; Bab, I. ERK1/2-activated de novo Mapkapk2 synthesis is essential for osteogenic growth peptide mitogenic signaling in osteoblastic cells. J. Biol. Chem.,  2005, 280(45), 37495-37502.
[http://dx.doi.org/10.1074/jbc.M503861200] [PMID: 16150701] 
[151] 
Hill, C.S.; Wynne, J.; Treisman, R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell,  1995, 81(7), 1159-1170.
[http://dx.doi.org/10.1016/S0092-8674(05)80020-0] [PMID: 7600583] 
[152] 
Strzelecka-Kiliszek, A.; Mebarek, S.; Roszkowska, M.; Buchet, R.; Magne, D.; Pikula, S. Functions of Rho family of small GTPases and Rho-associated coiled-coil kinases in bone cells during differentiation and mineralization. Biochim. Biophys. Acta, Gen. Subj.,  2017, 1861(5 Pt A), 1009-1023.
[http://dx.doi.org/10.1016/j.bbagen.2017.02.005] [PMID: 28188861] 
[153] 
McBeath, R.; Pirone, D.M.; Nelson, C.M.; Bhadriraju, K.; Chen, C.S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell,  2004, 6(4), 483-495.
[http://dx.doi.org/10.1016/S1534-5807(04)00075-9] [PMID: 15068789] 
[154] 
Chen, Z.; Wang, X.; Shao, Y.; Shi, D.; Chen, T.; Cui, D.; Jiang, X. Synthetic osteogenic growth peptide promotes differentiation of human bone marrow mesenchymal stem cells to osteoblasts via RhoA/ROCK pathway. Mol. Cell. Biochem.,  2011, 358(1-2), 221-227.
[http://dx.doi.org/10.1007/s11010-011-0938-7] [PMID: 21739156] 
[155] 
Taylor, B.C.; Schreiner, P.J.; Zmuda, J.M.; Li, J.; Moffett, S.P.; Beck, T.J.; Cummings, S.R.; Lee, J.M.; Walker, K.; Ensrud, K.E. SOF Research Group. Association of endothelial nitric oxide synthase genotypes with bone mineral density, bone loss, hip structure, and risk of fracture in older women: the SOF study. Bone,  2006, 39(1), 174-180.
[http://dx.doi.org/10.1016/j.bone.2005.12.080] [PMID: 16503213] 
[156] 
Lai, M.; Jin, Z.; Su, Z. Surface modification of TiO2 nanotubes with osteogenic growth peptide to enhance osteoblast differentiation. Mater. Sci. Eng. C,  2017, 73, 490-497.
[http://dx.doi.org/10.1016/j.msec.2016.12.083] [PMID: 28183637] 
[157] 
Fioravanti, C.; Frustaci, I.; Armellin, E.; Condò, R.; Arcuri, C.; Cerroni, L. Autologous blood preparations rich in platelets, fibrin and growth factors. Oral Implantol. (Rome),  2016, 8(4), 96-113.
[PMID: 28042422] 
[158] 
Wang, J.S.; Aspenberg, P. Basic fibroblast growth factor enhances bone-graft incorporation: dose and time dependence in rats. J. Orthop. Res.,  1996, 14(2), 316-323.
[http://dx.doi.org/10.1002/jor.1100140222] [PMID: 8648512] 
[159] 
Goodman, S.B.; Song, Y.; Yoo, J.Y.; Fox, N.; Trindade, M.C.D.; Kajiyama, G.; Ma, T.; Regula, D.; Brown, J.; Smith, R.L. Local infusion of FGF-2 enhances bone ingrowth in rabbit chambers in the presence of polyethylene particles. J. Biomed. Mater. Res. A,  2003, 65(4), 454-461.
[http://dx.doi.org/10.1002/jbm.a.3000] [PMID: 12761835] 
[160] 
Valo, H.; Peltonen, L.; Vehviläinen, S.; Karjalainen, M.; Kostiainen, R.; Laaksonen, T.; Hirvonen, J. Electrospray encapsulation of hydrophilic and hydrophobic drugs in poly(L-lactic acid) nanoparticles. Small,  2009, 5(15), 1791-1798.
[http://dx.doi.org/10.1002/smll.200801907] [PMID: 19360725] 
[161] 
Delgado, J.J.; Sánchez, E.; Baro, M.; Reyes, R.; Évora, C.; Delgado, A. A platelet derived growth factor delivery system for bone regeneration. J. Mater. Sci. Mater. Med.,  2012, 23(8), 1903-1912.
[http://dx.doi.org/10.1007/s10856-012-4661-z] [PMID: 22576317] 
[162] 
Park, J.; Bauer, S.; Pittrof, A.; Killian, M.S.; Schmuki, P.; von der Mark, K. Synergistic control of mesenchymal stem cell differentiation by nanoscale surface geometry and immobilized growth factors on TiO2 nanotubes. Small,  2012, 8(1), 98-107.
[http://dx.doi.org/10.1002/smll.201100790] [PMID: 22095845] 
[163] 
Bauer, S.; Park, J.; Pittrof, A.; Song, Y-Y.; von der Mark, K.; Schmuki, P. Covalent functionalization of TiO2 nanotube arrays with EGF and BMP-2 for modified behavior towards mesenchymal stem cells. Integr. Biol.,  2011, 3(9), 927-936.
[http://dx.doi.org/10.1039/c0ib00155d] [PMID: 21829821] 
[164] 
Park, J.M.; Koak, J.Y.; Jang, J.H.; Han, C.H.; Kim, S.K.; Heo, S.J. Osseointegration of anodized titanium implants coated with fibroblast growth factor-fibronectin (FGF-FN) fusion protein. Int. J. Oral Maxillofac. Implants,  2006, 21(6), 859-866.
[PMID: 17190295] 
[165] 
Shim, I.K.; Chung, H.J.; Jung, M.R.; Nam, S.Y.; Lee, S.Y.; Lee, H.; Heo, S.J.; Lee, S.J. Biofunctional porous anodized titanium implants for enhanced bone regeneration. J. Biomed. Mater. Res. A,  2014, 102(10), 3639-3648.
[http://dx.doi.org/10.1002/jbm.a.35026] [PMID: 24265190] 
[166] 
Zhang, W.; Jin, Y.; Qian, S.; Li, J.; Chang, Q.; Ye, D.; Pan, H.; Zhang, M.; Cao, H.; Liu, X.; Jiang, X. Vacuum extraction enhances rhPDGF-BB immobilization on nanotubes to improve implant osseointegration in ovariectomized rats. Nanomedicine (Lond.),  2014, 10(8), 1809-1818.
[http://dx.doi.org/10.1016/j.nano.2014.07.002] [PMID: 25042134] 
[167] 
Hollinger, J.O.; Onikepe, A.O.; MacKrell, J.; Einhorn, T.; Bradica, G.; Lynch, S.; Hart, C.E. Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet-derived growth factor-BB and an injectable beta-tricalcium phosphate/collagen matrix. J. Orthop. Res.,  2008, 26(1), 83-90.
[http://dx.doi.org/10.1002/jor.20453] [PMID: 17676626] 
[168] 
Zhang, Y.; Cheng, N.; Miron, R.; Shi, B.; Cheng, X. Delivery of PDGF-B and BMP-7 by mesoporous bioglass/silk fibrin scaffolds for the repair of osteoporotic defects. Biomaterials,  2012, 33(28), 6698-6708.
[http://dx.doi.org/10.1016/j.biomaterials.2012.06.021] [PMID: 22763224] 
[169] 
Alam, S.; Ueki, K.; Nakagawa, K.; Marukawa, K.; Hashiba, Y.; Yamamoto, E.; Sakulsak, N.; Iseki, S. Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.,  2009, 107(1), 22-29.
[http://dx.doi.org/10.1016/j.tripleo.2008.06.025] [PMID: 18755616] 
[170] 
Anbinder, A.L.; Junqueira, J.C.; Mancini, M.N.; Balducci, I.; Rocha, R.F.; Carvalho, Y.R. Influence of simvastatin on bone regeneration of tibial defects and blood cholesterol level in rats. Braz. Dent. J.,  2006, 17(4), 267-273.
[http://dx.doi.org/10.1590/S0103-64402006000400001] [PMID: 17262137] 
[171] 
Takeno, A.; Kanazawa, I.; Tanaka, K.; Notsu, M.; Yokomoto-Umakoshi, M.; Sugimoto, T. Simvastatin rescues homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by decreasing the expressions of NADPH oxidase 1 and 2. Endocr. J.,  2016, 63(4), 389-395.
[http://dx.doi.org/10.1507/endocrj.EJ15-0480] [PMID: 26842590] 
[172] 
Liao, J.K.; Laufs, U. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol.,  2005, 45(8), 89-118.
[http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095748] [PMID: 15822172] 
[173] 
Garrett, I.R.; Mundy, G.R. The role of statins as potential targets for bone formation. Arthritis Res.,  2002, 4(4), 237-240.
[http://dx.doi.org/10.1186/ar413] [PMID: 12106493] 
[174] 
Mundy, G.; Garrett, R.; Harris, S.; Chan, J.; Chen, D.; Rossini, G.; Boyce, B.; Zhao, M.; Gutierrez, G.; Melton, L.J.; Harris, S.E.; Chen, D.; Harris, S.E.; Ghosh-Choudhury, N.; Rossouw, J.E.; Lewis, B.; Rifkind, B.M.; Law, M.R.; Wald, N.J.; Thompson, S.G.; Rao, S.; Gowen, M.; Mundy, G.R.; Traianedes, K.; Dallas, M.R.; Garrett, I.R.; Mundy, G.R.; Bonewald, L.F.; Boyce, B.F.; Aufdemorte, T.B.; Garrett, I.R.; Yates, A.J.P.; Mundy, G.R.; Sabatini, M.; Boyce, B.; Aufdemorte, T.; Bonewald, L.; Mundy, G.R.; Yates, A.J.P.; Marcelli, C.; Yates, A.J.P.; Mundy, G.R.; Jilka, R.L.; Luckman, S.P.; Rogers, M.J.; Fisher, J.E.; Rogers, M.J.; Cuevas, P. Stimulation of bone formation in vitro and in rodents by statins. Science,  1999, 286(5446), 1946-1949.
[http://dx.doi.org/10.1126/science.286.5446.1946] [PMID: 10583956] 
[175] 
Apostu, D.; Lucaciu, O.; Lucaciu, G.D.O.; Crisan, B.; Crisan, L.; Baciut, M.; Onisor, F.; Baciut, G.; Câmpian, R.S.; Bran, S. Systemic drugs that influence titanium implant osseointegration. Drug Metab. Rev.,  2017, 49(1), 92-104.
[http://dx.doi.org/10.1080/03602532.2016.1277737] [PMID: 28030966] 
[176] 
Fu, J-H.; Bashutski, J.D.; Al-Hezaimi, K.; Wang, H-L. Statins, glucocorticoids, and nonsteroidal anti-inflammatory drugs: their influence on implant healing. Implant Dent.,  2012, 21(5), 362-367.
[http://dx.doi.org/10.1097/ID.0b013e3182611ff6] [PMID: 22968569] 
[177] 
Horiuchi, N.; Maeda, T. Statins and bone metabolism. Oral Dis.,  2006, 12(2), 85-101.
[http://dx.doi.org/10.1111/j.1601-0825.2005.01172.x] [PMID: 16476028] 
[178] 
Oryan, A.; Kamali, A.; Moshiri, A. Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions. J. Control. Release,  2015, 215, 12-24.
[http://dx.doi.org/10.1016/j.jconrel.2015.07.022] [PMID: 26226345] 
[179] 
Sugiyama, M.; Kodama, T.; Konishi, K.; Abe, K.; Asami, S.; Oikawa, S. Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem. Biophys. Res. Commun.,  2000, 271(3), 688-692.
[http://dx.doi.org/10.1006/bbrc.2000.2697] [PMID: 10814523] 
[180] 
Hughes, A.; Rogers, M.J.; Idris, A.I.; Crockett, J.C. A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo. Calcif. Tissue Int.,  2007, 81(5), 403-413.
[http://dx.doi.org/10.1007/s00223-007-9078-1] [PMID: 17982704] 
[181] 
Chen, P.Y.; Sun, J.S.; Tsuang, Y.H.; Chen, M.H.; Weng, P.W.; Lin, F.H. Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway. Nutr. Res.,  2010, 30(3), 191-199.
[http://dx.doi.org/10.1016/j.nutres.2010.03.004] [PMID: 20417880] 
[182] 
Ishihara, T.; Miyazaki, M.; Notani, N.; Kanezaki, S.; Kawano, M.; Tsumura, H. Locally applied simvastatin promotes bone formation in a rat model of spinal fusion. J. Orthop. Res.,  2017, 35(9), 1942-1948.
[http://dx.doi.org/10.1002/jor.23479] [PMID: 27862237] 
[183] 
Kaji, H.; Naito, J.; Inoue, Y.; Sowa, H.; Sugimoto, T.; Chihara, K. Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor-β-Smad3 pathway. Horm. Metab. Res.,  2008, 40(11), 746-751.
[http://dx.doi.org/10.1055/s-0028-1082051] [PMID: 18622892] 
[184] 
Moshiri, A.; Sharifi, A.M.; Oryan, A. Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations. Clin. Exp. Pharmacol. Physiol.,  2016, 43(7), 659-684.
[http://dx.doi.org/10.1111/1440-1681.12577] [PMID: 27061579] 
[185] 
Sowa, H.; Kaji, H.; Yamaguchi, T.; Sugimoto, T.; Chihara, K. Smad3 promotes alkaline phosphatase activity and mineralization of osteoblastic MC3T3-E1 cells. J. Bone Miner. Res.,  2002, 17(7), 1190-1199.
[http://dx.doi.org/10.1359/jbmr.2002.17.7.1190] [PMID: 12096832] 
[186] 
Borton, A.J.; Frederick, J.P.; Datto, M.B.; Wang, X-F.; Weinstein, R.S. The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis. J. Bone Miner. Res.,  2001, 16(10), 1754-1764.
[http://dx.doi.org/10.1359/jbmr.2001.16.10.1754] [PMID: 11585338] 
[187] 
Pahan, K. Lipid-lowering drugs. Cell. Mol. Life Sci.,  2006, 63(10), 1165-1178.
[http://dx.doi.org/10.1007/s00018-005-5406-7] [PMID: 16568248] 
[188] 
Edwards, C.J.; Spector, T.D. Statins as modulators of bone formation. Arthritis Res.,  2002, 4(3), 151-153.
[http://dx.doi.org/10.1186/ar399] [PMID: 12010563] 
[189] 
Ohnaka, K.; Shimoda, S.; Nawata, H.; Shimokawa, H.; Kaibuchi, K.; Iwamoto, Y.; Takayanagi, R. Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem. Biophys. Res. Commun.,  2001, 287(2), 337-342.
[http://dx.doi.org/10.1006/bbrc.2001.5597] [PMID: 11554731] 
[190] 
Sawada, N.; Liao, J.K. Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis. Antioxid. Redox Signal.,  2014, 20(8), 1251-1267.
[http://dx.doi.org/10.1089/ars.2013.5524] [PMID: 23919640] 
[191] 
Tai, I.C.; Wang, Y.H.; Chen, C.H.; Chuang, S.C.; Chang, J.K.; Ho, M.L. Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation. Int. J. Nanomedicine,  2015, 10, 5881-5894.
[PMID: 26451103] 
[192] 
Hwang, R.; Lee, E.J.; Kim, M.H.; Li, S-Z.; Jin, Y-J.; Rhee, Y.; Kim, Y.M.; Lim, S-K. Calcyclin, a Ca2+ ion-binding protein, contributes to the anabolic effects of simvastatin on bone. J. Biol. Chem.,  2004, 279(20), 21239-21247.
[http://dx.doi.org/10.1074/jbc.M312771200] [PMID: 14973129] 
[193] 
Fang, W.; Zhao, S.; He, F.; Liu, L.; Yang, G. Influence of simvastatin-loaded implants on osseointegration in an ovariectomized animal model. BioMed Res. Int.,  2015, 2015831504
[http://dx.doi.org/10.1155/2015/831504] [PMID: 25893198] 
[194] 
Yang, F.; Zhao, S.F.; Zhang, F.; He, F.M.; Yang, G.L. Simvastatin-loaded porous implant surfaces stimulate preosteoblasts differentiation: an in vitro study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.,  2011, 111(5), 551-556.
[http://dx.doi.org/10.1016/j.tripleo.2010.06.018] [PMID: 20952225] 
[195] 
Ahn, K.S.; Sethi, G.; Chaturvedi, M.M.; Aggarwal, B.B. Simvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand through modulation of NF-kappaB pathway. Int. J. Cancer,  2008, 123(8), 1733-1740.
[http://dx.doi.org/10.1002/ijc.23745] [PMID: 18688862] 
[196] 
Esposito, K.; Capuano, A.; Sportiello, L.; Giustina, A.; Giugliano, D. Should we abandon statins in the prevention of bone fractures? Endocrine,  2013, 44(2), 326-333.
[http://dx.doi.org/10.1007/s12020-013-9924-z] [PMID: 23526261] 
[197] 
Yamashita, M.; Otsuka, F.; Mukai, T.; Yamanaka, R.; Otani, H.; Matsumoto, Y.; Nakamura, E.; Takano, M.; Sada, K.E.; Makino, H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul. Pept.,  2010, 162(1-3), 99-108.
[http://dx.doi.org/10.1016/j.regpep.2010.03.003] [PMID: 20346376] 
[198] 
Issa, J.P.M.; Ingraci de Lucia, C.; Dos Santos Kotake, B.G.; Gonçalves Gonzaga, M.; Tocchini de Figueiredo, F.A.; Mizusaki Iyomasa, D.; Macedo, A.P.; Ervolino, E. The effect of simvastatin treatment on bone repair of femoral fracture in animal model. Growth Factors,  2015, 33(2), 139-148.
[http://dx.doi.org/10.3109/08977194.2015.1011270] [PMID: 25798995] 
[199] 
Terukina, T.; Saito, H.; Tomita, Y.; Hattori, Y.; Otsuka, M. Development and effect of a sustainable and controllable simvastatin-releasing device based on PLGA microspheres/carbonate apatite cement composite: In vitro evaluation for use as a drug delivery system from bone-like biomaterial. J. Drug Deliv. Sci. Technol.,  2017, 37, 74-80.
[http://dx.doi.org/10.1016/j.jddst.2016.10.007] 
[200] 
Kureishi, Y.; Luo, Z.; Shiojima, I.; Bialik, A.; Fulton, D.; Lefer, D.J.; Sessa, W.C.; Walsh, K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat. Med.,  2000, 6(9), 1004-1010.
[http://dx.doi.org/10.1038/79510] [PMID: 10973320] 
[201] 
Du, G.; Song, Y.; Zhang, T.; Ma, L.; Bian, N.; Chen, X.; Feng, J.; Chang, Q.; Li, Z. Simvastatin attenuates TNFαinduced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int. J. Mol. Med.,  2014, 34(1), 177-182.
[http://dx.doi.org/10.3892/ijmm.2014.1740] [PMID: 24718722] 
[202] 
Yueyi, C.; Xiaoguang, H.; Jingying, W.; Quansheng, S.; Jie, T.; Xin, F.; Yingsheng, X.; Chunli, S. Calvarial defect healing by recruitment of autogenous osteogenic stem cells using locally applied simvastatin. Biomaterials,  2013, 34(37), 9373-9380.
[http://dx.doi.org/10.1016/j.biomaterials.2013.08.060] [PMID: 24016857] 
[203] 
Kheirallah, M.; Almeshaly, H. Simvastatin, dosage and delivery system for supporting bone regeneration, an update review. J. Oral Maxillofac. Surg. Med. Pathol.,  2016, 28(3), 205-209.
[http://dx.doi.org/10.1016/j.ajoms.2015.10.005] 
[204] 
Lai, M.; Jin, Z.; Yang, X.; Wang, H.; Xu, K. The controlled release of simvastatin from TiO2 nanotubes to promote osteoblast differentiation and inhibit osteoclast resorption. Appl. Surf. Sci.,  2017, 396, 1741-1751.
[http://dx.doi.org/10.1016/j.apsusc.2016.11.228] 
[205] 
Thylin, M.R.; McConnell, J.C.; Schmid, M.J.; Reckling, R.R.; Ojha, J.; Bhattacharyya, I.; Marx, D.B.; Reinhardt, R.A. Effects of simvastatin gels on murine calvarial bone. J. Periodontol.,  2002, 73(10), 1141-1148.
[http://dx.doi.org/10.1902/jop.2002.73.10.1141] [PMID: 12416771] 
[206] 
Stein, D.; Lee, Y.; Schmid, M.J.; Killpack, B.; Genrich, M.A.; Narayana, N.; Marx, D.B.; Cullen, D.M.; Reinhardt, R.A. Local simvastatin effects on mandibular bone growth and inflammation. J. Periodontol.,  2005, 76(11), 1861-1870.
[http://dx.doi.org/10.1902/jop.2005.76.11.1861] [PMID: 16274305] 
[207] 
Kim, Y.C.; Song, S.B.; Lee, M.H.; Kang, K.I.; Lee, H.; Paik, S.G.; Kim, K.E.; Kim, Y.S. Simvastatin induces caspase-independent apoptosis in LPS-activated RAW264.7 macrophage cells. Biochem. Biophys. Res. Commun.,  2006, 339(3), 1007-1014.
[http://dx.doi.org/10.1016/j.bbrc.2005.11.099] [PMID: 16325779] 
[208] 
Kim, Y.C.; Song, S.B.; Lee, S.K.; Park, S.M.; Kim, Y.S. The nuclear orphan receptor NR4A1 is involved in the apoptotic pathway induced by LPS and Simvastatin in RAW 264.7 macrophages. Immune Netw.,  2014, 14(2), 116-122.
[http://dx.doi.org/10.4110/in.2014.14.2.116] [PMID: 24851101] 
[209] 
Stojadinovic, O.; Lebrun, E.; Pastar, I.; Kirsner, R.; Davis, S.C.; Tomic-Canic, M. Statins as potential therapeutic agents for healing disorders. Expert. Rev. Dermatol.,  2010, 5(6), 689-698.
[http://dx.doi.org/10.1586/edm.10.60] 
[210] 
Elavarasu, S.; Suthanthiran, T.K.; Naveen, D. Statins: A new era in local drug delivery. J. Pharm. Bioallied Sci.,  2012, 4(Suppl. 2), S248-S251.
[http://dx.doi.org/10.4103/0975-7406.100225] [PMID: 23066263] 
[211] 
Lazzerini, P.E.; Lorenzini, S.; Selvi, E.; Capecchi, P.L.; Chindamo, D.; Bisogno, S.; Ghittoni, R.; Natale, M.R.; Caporali, F.; Giuntini, S.; Marcolongo, R.; Galeazzi, M.; Laghi-Pasini, F. Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1β-stimulated synoviocytes from rheumatoid arthritis patients. Clin. Exp. Rheumatol.,  2007, 25(5), 696-700.
[PMID: 18078616] 
[212] 
Ayukawa, Y.; Okamura, A.; Koyano, K. Simvastatin promotes osteogenesis around titanium implants. Clin. Oral Implants Res.,  2004, 15(3), 346-350.
[http://dx.doi.org/10.1046/j.1600-0501.2003.01015.x] [PMID: 15142098] 
[213] 
Ayukawa, Y.; Ogino, Y.; Moriyama, Y.; Atsuta, I.; Jinno, Y.; Kihara, M.; Tsukiyama, Y.; Koyano, K. Simvastatin enhances bone formation around titanium implants in rat tibiae. J. Oral Rehabil.,  2010, 37(2), 123-130.
[http://dx.doi.org/10.1111/j.1365-2842.2009.02011.x] [PMID: 19889034] 
[214] 
Ayukawa, Y.; Yasukawa, E.; Moriyama, Y.; Ogino, Y.; Wada, H.; Atsuta, I.; Koyano, K. Local application of statin promotes bone repair through the suppression of osteoclasts and the enhancement of osteoblasts at bone-healing sites in rats. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.,  2009, 107(3), 336-342.
[http://dx.doi.org/10.1016/j.tripleo.2008.07.013] [PMID: 18801677] 
[215] 
Wong, R.W.K.; Rabie, A.B.M. Early healing pattern of statin-induced osteogenesis. Br. J. Oral Maxillofac. Surg.,  2005, 43(1), 46-50.
[http://dx.doi.org/10.1016/j.bjoms.2004.08.014] [PMID: 15620774] 
[216] 
Yan, Q.; Xiao, L.Q.; Tan, L.; Sun, W.; Wu, T.; Chen, L.W.; Mei, Y.; Shi, B. Controlled release of simvastatin-loaded thermo-sensitive PLGA-PEG-PLGA hydrogel for bone tissue regeneration: in vitro and in vivo characteristics. J. Biomed. Mater. Res. A,  2015, 103(11), 3580-3589.
[http://dx.doi.org/10.1002/jbm.a.35499] [PMID: 25969423] 
[217] 
Zhang, J.; Wang, H.; Shi, J.; Wang, Y.; Lai, K.; Yang, X.; Chen, X.; Yang, G. Combination of simvastatin, calcium silicate/gypsum, and gelatin and bone regeneration in rabbit calvarial defects. Sci. Rep.,  2016, 6(158), 23422.
[http://dx.doi.org/10.1038/srep23422] [PMID: 26996657] 
[218] 
Moriyama, Y.; Ayukawa, Y.; Ogino, Y.; Atsuta, I.; Todo, M.; Takao, Y.; Koyano, K. Local application of fluvastatin improves peri-implant bone quantity and mechanical properties: a rodent study. Acta Biomater.,  2010, 6(4), 1610-1618.
[http://dx.doi.org/10.1016/j.actbio.2009.10.045] [PMID: 19887121] 
[219] 
Gutierrez, G.E.; Lalka, D.; Garrett, I.R.; Rossini, G.; Mundy, G.R. Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos. Int.,  2006, 17(7), 1033-1042.
[http://dx.doi.org/10.1007/s00198-006-0079-0] [PMID: 16758140] 
[220] 
Meier, C.R.; Schlienger, R.G.; Kraenzlin, M.E.; Schlegel, B.; Jick, H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA,  2000, 283(24), 3205-3210.
[http://dx.doi.org/10.1001/jama.283.24.3205] [PMID: 10866867] 
[221] 
Wang, Z.; Li, Y.; Zhou, F.; Piao, Z.; Hao, J. Effects of statins on bone mineral density and fracture risk: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore),  2016, 95(22)e3042
[http://dx.doi.org/10.1097/MD.0000000000003042] [PMID: 27258488] 
[222] 
An, T.; Hao, J.; Sun, S.; Li, R.; Yang, M.; Cheng, G.; Zou, M. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos. Int.,  2017, 28(1), 47-57.
[http://dx.doi.org/10.1007/s00198-016-3844-8] [PMID: 27888285] 
[223] 
Pauly, S.; Luttosch, F.; Morawski, M.; Haas, N.P.; Schmidmaier, G.; Wildemann, B. Simvastatin locally applied from a biodegradable coating of osteosynthetic implants improves fracture healing comparable to BMP-2 application. Bone,  2009, 45(3), 505-511.
[http://dx.doi.org/10.1016/j.bone.2009.05.010] [PMID: 19464400] 
[224] 
Tai, I.C.; Fu, Y-C.; Wang, C-K.; Chang, J-K.; Ho, M-L. Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair. Int. J. Nanomedicine,  2013, 8, 3895-3904.
[PMID: 24143094] 
[225] 
Hamelin, B.A.; Turgeon, J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci.,  1998, 19(1), 26-37.
[http://dx.doi.org/10.1016/S0165-6147(97)01147-4] [PMID: 9509899] 
[226] 
Guyton, J.R. Benefit versus risk in statin treatment. Am. J. Cardiol.,  2006, 97(8A), 95C-97C.
[http://dx.doi.org/10.1016/j.amjcard.2005.12.016] [PMID: 16581337] 
[227] 
Chauhan, A.S.; Maria, A.; Managutti, A. Efficacy of simvastatin in bone regeneration after surgical removal of mandibular third molars: A clinical pilot study. J. Maxillofac. Oral Surg.,  2015, 14(3), 578-585.
[http://dx.doi.org/10.1007/s12663-014-0697-6] [PMID: 26225047] 
[228] 
Encarnação, I.C.; Xavier, C.C.F.; Bobinski, F.; dos Santos, A.R.S.; Corrêa, M.; de Freitas, S.F.T.; Aragonez, A.; Goldfeder, E.M.; Cordeiro, M.M.R. Analysis of bone repair and inflammatory process caused by simvastatin combined with PLGA+HA+βTCP scaffold. Implant Dent.,  2016, 25(1), 140-148.
[http://dx.doi.org/10.1097/ID.0000000000000359] [PMID: 26606285] 
[229] 
Gentile, P.; Nandagiri, V.K.; Daly, J.; Chiono, V.; Mattu, C.; Tonda-Turo, C.; Ciardelli, G.; Ramtoola, Z. Localised controlled release of simvastatin from porous chitosan-gelatin scaffolds engrafted with simvastatin loaded PLGA-microparticles for bone tissue engineering application. Mater. Sci. Eng. C,  2016, 59, 249-257.
[http://dx.doi.org/10.1016/j.msec.2015.10.014] [PMID: 26652371] 
[230] 
Liu, X.; Li, X.; Li, S.; Zhou, X.; Li, S.; Wang, Q.; Dai, J.; Lai, R.; Xie, L.; Zhong, M.; Zhang, Y.; Zhou, L. An in vitro study of a titanium surface modified by simvastatin-loaded titania nanotubes-micelles. J. Biomed. Nanotechnol.,  2014, 10(2), 194-204.
[http://dx.doi.org/10.1166/jbn.2014.1810] [PMID: 24738328] 
[231] 
Liu, X.; Zhang, Y.; Li, S.; Wang, Y.; Sun, T.; Li, Z.; Cai, L.; Wang, X.; Zhou, L.; Lai, R. Study of a new bone-targeting titanium implant-bone interface. Int. J. Nanomedicine,  2016, 11(11), 6307-6324.
[http://dx.doi.org/10.2147/IJN.S119520] [PMID: 27932879] 
[232] 
Woo, J-T.; Yonezawa, T.; Nagai, K. Phytochemicals that stimulate osteoblastic differentiation and bone formation. J. Oral Biosci.,  2010, 52(1), 15-21.
[http://dx.doi.org/10.1016/S1349-0079(10)80003-9] 
[233] 
Hardcastle, A.C.; Aucott, L.; Reid, D.M.; Macdonald, H.M. Associations between dietary flavonoid intakes and bone health in a Scottish population. J. Bone Miner. Res.,  2011, 26(5), 941-947.
[http://dx.doi.org/10.1002/jbmr.285] [PMID: 21541996] 
[234] 
Preethi Soundarya, S.; Sanjay, V.; Haritha Menon, A.; Dhivya, S.; Selvamurugan, N. Effects of flavonoids incorporated biological macromolecules based scaffolds in bone tissue engineering. Int. J. Biol. Macromol.,  2018, 110, 74-87.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.09.014] [PMID: 28893682] 
[235] 
Cui, L.; Liu, X.; Tian, Y.; Xie, C.; Li, Q.; Cui, H.; Sun, C. Flavonoids, flavonoid subclasses, and esophageal cancer risk: A meta-analysis of epidemiologic studies. Nutrients,  2016, 8(6), 350.
[http://dx.doi.org/10.3390/nu8060350] [PMID: 27338463] 
[236] 
Cao, J.; Lu, Q.; Liu, N.; Zhang, Y.X.; Wang, J.; Zhang, M.; Wang, H.B.; Sun, W.C. Sciadopitysin suppresses RANKL-mediated osteoclastogenesis and prevents bone loss in LPS-treated mice. Int. Immunopharmacol.,  2017, 49, 109-117.
[http://dx.doi.org/10.1016/j.intimp.2017.05.029] [PMID: 28575726] 
[237] 
Srivastava, S.; Bankar, R.; Roy, P. Assessment of the role of flavonoids for inducing osteoblast differentiation in isolated mouse bone marrow derived mesenchymal stem cells. Phytomedicine,  2013, 20(8-9), 683-690.
[http://dx.doi.org/10.1016/j.phymed.2013.03.001] [PMID: 23570998] 
[238] 
Lee, C.H.; Huang, Y.L.; Liao, J.F.; Chiou, W.F. Ugonin K promotes osteoblastic differentiation and mineralization by activation of p38 MAPK- and ERK-mediated expression of Runx2 and osterix. Eur. J. Pharmacol.,  2011, 668(3), 383-389.
[http://dx.doi.org/10.1016/j.ejphar.2011.06.059] [PMID: 21806985] 
[239] 
Zhang, J.F.; Li, G.; Chan, C.Y.; Meng, C.L.; Lin, M.C.; Chen, Y.C.; He, M.L.; Leung, P.C.; Kung, H.F. Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/beta-catenin signaling pathway. Mol. Cell. Endocrinol.,  2010, 314(1), 70-74.
[http://dx.doi.org/10.1016/j.mce.2009.08.012] [PMID: 19703516] 
[240] 
Song, L.; Zhao, J.; Zhang, X.; Li, H.; Zhou, Y. Icariin induces osteoblast proliferation, differentiation and mineralization through estrogen receptor-mediated ERK and JNK signal activation. Eur. J. Pharmacol.,  2013, 714(1-3), 15-22.
[http://dx.doi.org/10.1016/j.ejphar.2013.05.039] [PMID: 23764463] 
[241] 
Huang, S.; Zhang, C-P.; Wang, K.; Li, G.Q.; Hu, F-L. Recent advances in the chemical composition of propolis. Molecules,  2014, 19(12), 19610-19632.
[http://dx.doi.org/10.3390/molecules191219610] [PMID: 25432012] 
[242] 
Somsanith, N.; Kim, Y.K.; Jang, Y.S.; Lee, Y.H.; Yi, H.K.; Jang, J.H.; Kim, K.A.; Bae, T.S.; Lee, M.H. Enhancing of osseointegration with propolis-loaded TiO2 nanotubes in rat mandible for dental implants. Materials (Basel),  2018, 11(1), 61.
[http://dx.doi.org/10.3390/ma11010061] [PMID: 29301269] 
[243] 
Huang, J-M.; Bao, Y.; Xiang, W.; Jing, X-Z.; Guo, J-C.; Yao, X-D.; Wang, R.; Guo, F-J. Icariin regulates the bidirectional differentiation of bone marrow mesenchymal stem cells through canonical Wnt signaling pathway. Evid. Based Complement. Alternat. Med.,  2017, 20178085325
[http://dx.doi.org/10.1155/2017/8085325] [PMID: 29445413] 
[244] 
Wu, Y.; Xia, L.; Zhou, Y.; Xu, Y.; Jiang, X. Icariin induces osteogenic differentiation of bone mesenchymal stem cells in a MAPK-dependent manner. Cell Prolif.,  2015, 48(3), 375-384.
[http://dx.doi.org/10.1111/cpr.12185] [PMID: 25867119] 
[245] 
Huang, J.; Yuan, L.; Wang, X.; Zhang, T.L.; Wang, K. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro. Life Sci.,  2007, 81(10), 832-840.
[http://dx.doi.org/10.1016/j.lfs.2007.07.015] [PMID: 17764702] 
[246] 
Cao, H.; Ke, Y.; Zhang, Y.; Zhang, C.J.; Qian, W.; Zhang, G.L. Icariin stimulates MC3T3-E1 cell proliferation and differentiation through up-regulation of bone morphogenetic protein-2. Int. J. Mol. Med.,  2012, 29(3), 435-439.
[PMID: 22109711] 
[247] 
Chung, B.H.; Kim, J.D.; Kim, C.K.; Kim, J.H.; Won, M.H.; Lee, H.S.; Dong, M.S.; Ha, K.S.; Kwon, Y.G.; Kim, Y.M. Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells. Biochem. Biophys. Res. Commun.,  2008, 376(2), 404-408.
[http://dx.doi.org/10.1016/j.bbrc.2008.09.001] [PMID: 18789310] 
[248] 
Zhang, Y.; Chen, L.; Liu, C.; Feng, X.; Wei, L.; Shao, L. Self-assembly chitosan/gelatin composite coating on icariin-modified TiO2nanotubes for the regulation of osteoblast bioactivity. Mater. Des.,  2016, 92, 471-479.
[http://dx.doi.org/10.1016/j.matdes.2015.12.023] 
[249] 
Zhang, Y.; Liu, C.; Chen, L.; Chen, A.; Feng, X.; Shao, L. Icariin-loaded TiO2 nanotubes for regulation of the bioactivity of bone marrow cells. J. Nanomater.,  2018, 20181810846
[http://dx.doi.org/10.1155/2018/1810846] 
[250] 
Dai, Y.; Liu, H.R.; Xia, L.L.; Zhou, Z. Preparation and characterization of icariin/PHBV drug delivery coatings on anodic oxidized titanium. Trans. Nonferrous Met. Soc. China,  2011, 21(11), 2448-2453.
[http://dx.doi.org/10.1016/S1003-6326(11)61035-2] 
[251] 
Yamaguchi, M. Role of nutritional zinc in the prevention of osteoporosis. Mol. Cell. Biochem.,  2010, 338(1-2), 241-254.
[http://dx.doi.org/10.1007/s11010-009-0358-0] [PMID: 20035439] 
[252] 
Coleman, J.E. Structure and mechanism of alkaline phosphatase. Annu. Rev. Biophys. Biomol. Struct.,  1992, 21, 441-483.
[http://dx.doi.org/10.1146/annurev.bb.21.060192.002301] [PMID: 1525473] 
[253] 
Beyersmann, D.; Haase, H. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals,  2001, 14(3-4), 331-341.
[http://dx.doi.org/10.1023/A:1012905406548] [PMID: 11831463] 
[254] 
Hirano, T.; Murakami, M.; Fukada, T.; Nishida, K.; Yamasaki, S.; Suzuki, T. Roles of zinc and zinc signaling in immunity: zinc as an intracellular signaling molecule. Adv. Immunol.,  2008, 97, 149-176.
[http://dx.doi.org/10.1016/S0065-2776(08)00003-5] [PMID: 18501770] 
[255] 
Qiao, Y.; Zhang, W.; Tian, P.; Meng, F.; Zhu, H.; Jiang, X.; Liu, X.; Chu, P.K. Stimulation of bone growth following zinc incorporation into biomaterials. Biomaterials,  2014, 35(25), 6882-6897.
[http://dx.doi.org/10.1016/j.biomaterials.2014.04.101] [PMID: 24862443] 
[256] 
Yusa, K.; Yamamoto, O.; Takano, H.; Fukuda, M.; Iino, M. Zinc-modified titanium surface enhances osteoblast differentiation of dental pulp stem cells in vitro. Sci. Rep.,  2016, 6, 29462.
[http://dx.doi.org/10.1038/srep29462] [PMID: 27387130] 
[257] 
Ikeuchi, M.; Ito, A.; Dohi, Y.; Ohgushi, H.; Shimaoka, H.; Yonemasu, K.; Tateishi, T. Osteogenic differentiation of cultured rat and human bone marrow cells on the surface of zinc-releasing calcium phosphate ceramics. J. Biomed. Mater. Res. A,  2003, 67(4), 1115-1122.
[http://dx.doi.org/10.1002/jbm.a.10041] [PMID: 14624496] 
[258] 
Wang, T.; Zhang, J.C.; Chen, Y.; Xiao, P.G.; Yang, M.S. Effect of zinc ion on the osteogenic and adipogenic differentiation of mouse primary bone marrow stromal cells and the adipocytic trans-differentiation of mouse primary osteoblasts. J. Trace Elem. Med. Biol.,  2007, 21(2), 84-91.
[http://dx.doi.org/10.1016/j.jtemb.2007.01.002] [PMID: 17499147] 
[259] 
Seo, H.J.; Cho, Y.E.; Kim, T.; Shin, H.I.; Kwun, I.S. Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells. Nutr. Res. Pract.,  2010, 4(5), 356-361.
[http://dx.doi.org/10.4162/nrp.2010.4.5.356] [PMID: 21103080] 
[260] 
Huo, K.; Zhang, X.; Wang, H.; Zhao, L.; Liu, X.; Chu, P.K. Osteogenic activity and antibacterial effects on titanium surfaces modified with Zn-incorporated nanotube arrays. Biomaterials,  2013, 34(13), 3467-3478.
[http://dx.doi.org/10.1016/j.biomaterials.2013.01.071] [PMID: 23439134] 
[261] 
Raghupathi, K.R.; Koodali, R.T.; Manna, A.C. Size-dependent bacterial growth inhibition and mechanism of antibacterial activity of zinc oxide nanoparticles. Langmuir,  2011, 27(7), 4020-4028.
[http://dx.doi.org/10.1021/la104825u] [PMID: 21401066] 
[262] 
Stankic, S.; Suman, S.; Haque, F.; Vidic, J. Pure and multi metal oxide nanoparticles: synthesis, antibacterial and cytotoxic properties. J. Nanobiotechnology,  2016, 14(1), 73.
[http://dx.doi.org/10.1186/s12951-016-0225-6] [PMID: 27776555] 
[263] 
Kumar, R.; Umar, A.; Kumar, G.; Nalwa, H.S. Antimicrobial properties of ZnO nanomaterials: A review. Ceram. Int.,  2017, 43(5), 3940-3961.
[http://dx.doi.org/10.1016/j.ceramint.2016.12.062] 
[264] 
Pelgrift, R.Y.; Friedman, A.J. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv. Drug Deliv. Rev.,  2013, 65(13-14), 1803-1815.
[http://dx.doi.org/10.1016/j.addr.2013.07.011] [PMID: 23892192] 
[265] 
Patrinoiu, G.; Calderón-Moreno, J.M.; Chifiriuc, C.M.; Saviuc, C.; Birjega, R.; Carp, O. Tunable ZnO spheres with high anti-biofilm and antibacterial activity via a simple green hydrothermal route. J. Colloid Interface Sci.,  2016, 462, 64-74.
[http://dx.doi.org/10.1016/j.jcis.2015.09.059] [PMID: 26433479] 
[266] 
Jones, N.; Ray, B.; Ranjit, K.T.; Manna, A.C. Antibacterial activity of ZnO nanoparticle suspensions on a broad spectrum of microorganisms. FEMS Microbiol. Lett.,  2008, 279(1), 71-76.
[http://dx.doi.org/10.1111/j.1574-6968.2007.01012.x] [PMID: 18081843] 
[267] 
Aydin Sevinç, B.; Hanley, L. Antibacterial activity of dental composites containing zinc oxide nanoparticles. J. Biomed. Mater. Res. B Appl. Biomater.,  2010, 94(1), 22-31.
[http://dx.doi.org/10.1002/jbm.b.31620] [PMID: 20225252] 
[268] 
Song, W.; Zhang, J.; Guo, J.; Zhang, J.; Ding, F.; Li, L.; Sun, Z. Role of the dissolved zinc ion and reactive oxygen species in cytotoxicity of ZnO nanoparticles. Toxicol. Lett.,  2010, 199(3), 389-397.
[http://dx.doi.org/10.1016/j.toxlet.2010.10.003] [PMID: 20934491] 
[269] 
Premanathan, M.; Karthikeyan, K.; Jeyasubramanian, K.; Manivannan, G. Selective toxicity of ZnO nanoparticles toward Gram-positive bacteria and cancer cells by apoptosis through lipid peroxidation. Nanomedicine (Lond.),  2011, 7(2), 184-192.
[http://dx.doi.org/10.1016/j.nano.2010.10.001] [PMID: 21034861] 
[270] 
Applerot, G.; Lellouche, J.; Perkas, N.; Nitzan, Y.; Gedanken, A.; Banin, E. ZnO nanoparticle-coated surfaces inhibit bacterial biofilm formation and increase antibiotic susceptibility. RSC Advances,  2012, 2(6), 2314-2321.
[http://dx.doi.org/10.1039/c2ra00602b] 
[271] 
Abdulkareem, E.H.; Memarzadeh, K.; Allaker, R.P.; Huang, J.; Pratten, J.; Spratt, D. Anti-biofilm activity of zinc oxide and hydroxyapatite nanoparticles as dental implant coating materials. J. Dent.,  2015, 43(12), 1462-1469.
[http://dx.doi.org/10.1016/j.jdent.2015.10.010] [PMID: 26497232] 
[272] 
Liu, W.; Su, P.; Chen, S.; Wang, N.; Ma, Y.; Liu, Y.; Wang, J.; Zhang, Z.; Li, H.; Webster, T.J. Synthesis of TiO2 nanotubes with ZnO nanoparticles to achieve antibacterial properties and stem cell compatibility. Nanoscale,  2014, 6(15), 9050-9062.
[http://dx.doi.org/10.1039/C4NR01531B] [PMID: 24971593] 
[273] 
Liu, W.; Su, P.; Gonzales, A., III; Chen, S.; Wang, N.; Wang, J.; Li, H.; Zhang, Z.; Webster, T.J. Optimizing stem cell functions and antibacterial properties of TiO2 nanotubes incorporated with ZnO nanoparticles: experiments and modeling. Int. J. Nanomedicine,  2015, 10, 1997-2019.
[http://dx.doi.org/10.2147/IJN.S74418] [PMID: 25792833] 
[274] 
Elizabeth, E.; Baranwal, G.; Krishnan, A.G.; Menon, D.; Nair, M. ZnO nanoparticle incorporated nanostructured metallic titanium for increased mesenchymal stem cell response and antibacterial activity. Nanotechnology,  2014, 25(11)115101
[http://dx.doi.org/10.1088/0957-4484/25/11/115101] [PMID: 24561517] 
[275] 
Li, Y.; Xiong, W.; Zhang, C.; Gao, B.; Guan, H.; Cheng, H.; Fu, J.; Li, F. Enhanced osseointegration and antibacterial action of zinc-loaded titania-nanotube-coated titanium substrates: in vitro and in vivo studies. J. Biomed. Mater. Res. A,  2014, 102(11), 3939-3950.
[http://dx.doi.org/10.1002/jbm.a.35060] [PMID: 24339384] 
[276] 
Bonnelye, E.; Chabadel, A.; Saltel, F.; Jurdic, P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone,  2008, 42(1), 129-138.
[http://dx.doi.org/10.1016/j.bone.2007.08.043] [PMID: 17945546] 
[277] 
Marie, P.J. Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. Curr. Opin. Rheumatol.,  2006, 18(Suppl. 1), S11-S15.
[http://dx.doi.org/10.1097/01.bor.0000229522.89546.7b] [PMID: 16735840] 
[278] 
Yang, F.; Yang, D.; Tu, J.; Zheng, Q.; Cai, L.; Wang, L. Strontium enhances osteogenic differentiation of mesenchymal stem cells and in vivo bone formation by activating Wnt/catenin signaling. Stem Cells,  2011, 29(6), 981-991.
[http://dx.doi.org/10.1002/stem.646] [PMID: 21563277] 
[279] 
Peng, S.; Liu, X.S.; Huang, S.; Li, Z.; Pan, H.; Zhen, W.; Luk, K.D.; Guo, X.E.; Lu, W.W. The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin. Bone,  2011, 49(6), 1290-1298.
[http://dx.doi.org/10.1016/j.bone.2011.08.031] [PMID: 21925296] 
[280] 
Trouvin, A.P.; Goëb, V. Receptor activator of nuclear factor-κB ligand and osteoprotegerin: maintaining the balance to prevent bone loss. Clin. Interv. Aging,  2010, 5, 345-354.
[PMID: 21228900] 
[281] 
Fromigué, O.; Haÿ, E.; Barbara, A.; Marie, P.J. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J. Biol. Chem.,  2010, 285(33), 25251-25258.
[http://dx.doi.org/10.1074/jbc.M110.110502] [PMID: 20554534] 
[282] 
Caverzasio, J. Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone,  2008, 42(6), 1131-1136.
[http://dx.doi.org/10.1016/j.bone.2008.02.010] [PMID: 18378206] 
[283] 
Fromigué, O.; Haÿ, E.; Barbara, A.; Petrel, C.; Traiffort, E.; Ruat, M.; Marie, P.J. Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. J. Cell. Mol. Med.,  2009, 13(8B), 2189-2199.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00673.x] [PMID: 20141614] 
[284] 
Lv, H.; Huang, X.; Jin, S.; Guo, R.; Wu, W. [Strontium ranelate promotes osteogenic differentiation of rat bone mesenchymal stem cells through bone morphogenetic protein-2/Smad signaling pathway]. Nan Fang Yi Ke Da Xue Xue Bao,  2013, 33(3), 376-381.
[PMID: 23529235] 
[285] 
Peng, S.; Zhou, G.; Luk, K.D.; Cheung, K.M.; Li, Z.; Lam, W.M.; Zhou, Z.; Lu, W.W. Strontium promotes osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway. Cell. Physiol. Biochem.,  2009, 23(1-3), 165-174.
[http://dx.doi.org/10.1159/000204105] [PMID: 19255511] 
[286] 
Hu, J-F.; Liao, J-Q.; Zhang, W-J.; Xu, L.; Zhi, X-M.; Lin, K.; Wu, W. Strontium ranelate promotes osteogenic differentiation of rat bone mesenchymal stem cells through Hedgehog/Gli1 signaling pathway. Chin. J. Pathophysiology,  2015, 31(2), 234-238.
[http://dx.doi.org/10.3969/j.issn.1000-4718.2015.02.008] 
[287] 
Meunier, P.J.; Roux, C.; Seeman, E.; Ortolani, S.; Badurski, J.E.; Spector, T.D.; Cannata, J.; Balogh, A.; Lemmel, E.M.; Pors-Nielsen, S.; Rizzoli, R.; Genant, H.K.; Reginster, J.Y. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J. Med.,  2004, 350(5), 459-468.
[http://dx.doi.org/10.1056/NEJMoa022436] [PMID: 14749454] 
[288] 
Reginster, J.Y.; Seeman, E.; De Vernejoul, M.C.; Adami, S.; Compston, J.; Phenekos, C.; Devogelaer, J.P.; Curiel, M.D.; Sawicki, A.; Goemaere, S.; Sorensen, O.H.; Felsenberg, D.; Meunier, P.J. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J. Clin. Endocrinol. Metab.,  2005, 90(5), 2816-2822.
[http://dx.doi.org/10.1210/jc.2004-1774] [PMID: 15728210] 
[289] 
Audran, M.; Jakob, F.J.; Palacios, S.; Brandi, M.L.; Bröll, H.; Hamdy, N.A.; McCloskey, E.V. A large prospective European cohort study of patients treated with strontium ranelate and followed up over 3 years. Rheumatol. Int.,  2013, 33(9), 2231-2239.
[http://dx.doi.org/10.1007/s00296-012-2594-y] [PMID: 23455629] 
[290] 
Lee, C.H.; Kim, Y.J.; Jang, J.H.; Park, J.W. Modulating macrophage polarization with divalent cations in nanostructured titanium implant surfaces. Nanotechnology,  2016, 27(8)085101
[http://dx.doi.org/10.1088/0957-4484/27/8/085101] [PMID: 26807875] 
[291] 
Yuan, X.; Cao, H.; Wang, J.; Tang, K.; Li, B.; Zhao, Y.; Cheng, M.; Qin, H.; Liu, X.; Zhang, X. Immunomodulatory effects of calcium and strontium co-doped titanium oxides on osteogenesis. Front. Immunol.,  2017, 8, 1196.
[http://dx.doi.org/10.3389/fimmu.2017.01196] [PMID: 29033930] 
[292] 
Xin, Y.; Jiang, J.; Huo, K.; Hu, T.; Chu, P.K.; Bioactive, P. Bioactive SrTiO(3) nanotube arrays: strontium delivery platform on Ti-based osteoporotic bone implants. ACS Nano,  2009, 3(10), 3228-3234.
[http://dx.doi.org/10.1021/nn9007675] [PMID: 19736918] 
[293] 
Zhao, L.; Wang, H.; Huo, K.; Zhang, X.; Wang, W.; Zhang, Y.; Wu, Z.; Chu, P.K. The osteogenic activity of strontium loaded titania nanotube arrays on titanium substrates. Biomaterials,  2013, 34(1), 19-29.
[http://dx.doi.org/10.1016/j.biomaterials.2012.09.041] [PMID: 23046755] 
[294] 
Dang, Y.; Zhang, L.; Song, W.; Chang, B.; Han, T.; Zhang, Y.; Zhao, L. In vivo osseointegration of Ti implants with a strontium-containing nanotubular coating. Int. J. Nanomedicine,  2016, 11, 1003-1011.
[PMID: 27042055] 
[295] 
Mi, B.; Xiong, W.; Xu, N.; Guan, H.; Fang, Z.; Liao, H.; Zhang, Y.; Gao, B.; Xiao, X.; Fu, J.; Li, F. Strontium-loaded titania nanotube arrays repress osteoclast differentiation through multiple signalling pathways: In vitro and in vivo studies. Sci. Rep.,  2017, 7(1), 2328.
[http://dx.doi.org/10.1038/s41598-017-02491-9] [PMID: 28539667] 
[296] 
Carlisle, E.M. Silicon in: Trace elements in human and animal nutrition, 5th ed; Mertz, W., Ed.; Academic Press: San Diego, USA, 1986, pp. 373-390.
[http://dx.doi.org/10.1016/B978-0-08-092469-4.50011-X] 
[297] 
Carlisle, E.M. Silicon: a possible factor in bone calcification. Science,  1970, 167(3916), 279-280.
[http://dx.doi.org/10.1126/science.167.3916.279] [PMID: 5410261] 
[298] 
Han, P.; Wu, C.; Xiao, Y. The effect of silicate ions on proliferation, osteogenic differentiation and cell signalling pathways (WNT and SHH) of bone marrow stromal cells. Biomater. Sci.,  2013, 1(4), 379-392.
[http://dx.doi.org/10.1039/C2BM00108J] 
[299] 
Mladenović, Ž.; Johansson, A.; Willman, B.; Shahabi, K.; Björn, E.; Ransjö, M. Soluble silica inhibits osteoclast formation and bone resorption in vitro. Acta Biomater.,  2014, 10(1), 406-418.
[http://dx.doi.org/10.1016/j.actbio.2013.08.039] [PMID: 24016843] 
[300] 
Dashnyam, K.; El-Fiqi, A.; Buitrago, J.O.; Perez, R.A.; Knowles, J.C.; Kim, H.W. A mini review focused on the proangiogenic role of silicate ions released from silicon-containing biomaterials. J. Tissue Eng.,  2017, 82041731417707339
[http://dx.doi.org/10.1177/2041731417707339] [PMID: 28560015] 
[301] 
Li, H.; Chang, J. Stimulation of proangiogenesis by calcium silicate bioactive ceramic. Acta Biomater.,  2013, 9(2), 5379-5389.
[http://dx.doi.org/10.1016/j.actbio.2012.10.019] [PMID: 23088882] 
[302] 
Li, H.; Chang, J. Bioactive silicate materials stimulate angiogenesis in fibroblast and endothelial cell co-culture system through paracrine effect. Acta Biomater.,  2013, 9(6), 6981-6991.
[http://dx.doi.org/10.1016/j.actbio.2013.02.014] [PMID: 23416471] 
[303] 
Li, H.; Xue, K.; Kong, N.; Liu, K.; Chang, J. Silicate bioceramics enhanced vascularization and osteogenesis through stimulating interactions between endothelia cells and bone marrow stromal cells. Biomaterials,  2014, 35(12), 3803-3818.
[http://dx.doi.org/10.1016/j.biomaterials.2014.01.039] [PMID: 24486216] 
[304] 
Dashnyam, K.; Jin, G.Z.; Kim, J.H.; Perez, R.; Jang, J.H.; Kim, H.W. Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF. Biomaterials,  2017, 116, 145-157.
[http://dx.doi.org/10.1016/j.biomaterials.2016.11.053] [PMID: 27918936] 
[305] 
Zhao, X.; Wang, T.; Qian, S.; Liu, X.; Sun, J.; Li, B. Silicon-doped titanium dioxide nanotubes promoted bone formation on titanium implants. Int. J. Mol. Sci.,  2016, 17(3), 292.
[http://dx.doi.org/10.3390/ijms17030292] [PMID: 26927080] 
[306] 
Bai, L.; Wu, R.; Wang, Y.; Wang, X.; Zhang, X.; Huang, X.; Qin, L.; Hang, R.; Zhao, L.; Tang, B. Osteogenic and angiogenic activities of silicon-incorporated TiO2 nanotube arrays. J. Mater. Chem. B Mater. Biol. Med.,  2016, 4(33), 5548-5559.
[http://dx.doi.org/10.1039/C6TB01109H] 
[307] 
Habibovic, P.; Barralet, J.E. Bioinorganics and biomaterials: bone repair. Acta Biomater.,  2011, 7(8), 3013-3026.
[http://dx.doi.org/10.1016/j.actbio.2011.03.027] [PMID: 21453799] 
[308] 
D’Andrea, L.D.; Romanelli, A.; Di Stasi, R.; Pedone, C. Bioinorganic aspects of angiogenesis. Dalton Trans.,  2010, 39(33), 7625-7636.
[http://dx.doi.org/10.1039/c002439b] [PMID: 20535417] 
[309] 
Sen, C.K.; Khanna, S.; Venojarvi, M.; Trikha, P.; Ellison, E.C.; Hunt, T.K.; Roy, S. Copper-induced vascular endothelial growth factor expression and wound healing. Am. J. Physiol. Heart Circ. Physiol.,  2002, 282(5), H1821-H1827.
[http://dx.doi.org/10.1152/ajpheart.01015.2001] [PMID: 11959648] 
[310] 
Li, Q.F.; Ding, X.Q.; Kang, Y.J. Copper promotion of angiogenesis in isolated rat aortic ring: role of vascular endothelial growth factor. J. Nutr. Biochem.,  2014, 25(1), 44-49.
[http://dx.doi.org/10.1016/j.jnutbio.2013.08.013] [PMID: 24314864] 
[311] 
Engleka, K.A.; Maciag, T. Inactivation of human fibroblast growth factor-1 (FGF-1) activity by interaction with copper ions involves FGF-1 dimer formation induced by copper-catalyzed oxidation. J. Biol. Chem.,  1992, 267(16), 11307-11315.
[PMID: 1375939] 
[312] 
Soncin, F.; Guitton, J.D.; Cartwright, T.; Badet, J. Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells. Biochem. Biophys. Res. Commun.,  1997, 236(3), 604-610.
[http://dx.doi.org/10.1006/bbrc.1997.7018] [PMID: 9245697] 
[313] 
Feng, W.; Ye, F.; Xue, W.; Zhou, Z.; Kang, Y.J. Copper regulation of hypoxia-inducible factor-1 activity. Mol. Pharmacol.,  2009, 75(1), 174-182.
[http://dx.doi.org/10.1124/mol.108.051516] [PMID: 18842833] 
[314] 
Gérard, C.; Bordeleau, L.J.; Barralet, J.; Doillon, C.J. The stimulation of angiogenesis and collagen deposition by copper. Biomaterials,  2010, 31(5), 824-831.
[http://dx.doi.org/10.1016/j.biomaterials.2009.10.009] [PMID: 19854506] 
[315] 
Kalaivani, S.; Singh, R.K.; Ganesan, V.; Kannan, S. Effect of copper (Cu2+) inclusion on the bioactivity and antibacterial behavior of calcium silicate coatings on titanium metal. J. Mater. Chem. B Mater. Biol. Med.,  2014, 2(7), 846-858.
[http://dx.doi.org/10.1039/C3TB21522A] 
[316] 
Liu, J.; Li, F.; Liu, C.; Wang, H.; Ren, B.; Yang, K.; Zhang, E. Effect of Cu content on the antibacterial activity of titanium-copper sintered alloys. Mater. Sci. Eng. C,  2014, 35, 392-400.
[http://dx.doi.org/10.1016/j.msec.2013.11.028] [PMID: 24411393] 
[317] 
Yu, L.; Jin, G.; Ouyang, L.; Wang, D.; Qiao, Y.; Liu, X. Antibacterial activity, osteogenic and angiogenic behaviors of copper-bearing titanium synthesized by PIII&D. J. Mater. Chem. B Mater. Biol. Med.,  2016, 4(7), 1296-1309.
[http://dx.doi.org/10.1039/C5TB02300A] 
[318] 
Luo, J.; Hein, C.; Mücklich, F.; Solioz, M. Killing of bacteria by copper, cadmium, and silver surfaces reveals relevant physicochemical parameters. Biointerphases,  2017, 12(2)020301
[http://dx.doi.org/10.1116/1.4980127] [PMID: 28407716] 
[319] 
Espírito Santo, C.; Lam, E.W.; Elowsky, C.G.; Quaranta, D.; Domaille, D.W.; Chang, C.J.; Grass, G. Bacterial killing by dry metallic copper surfaces. Appl. Environ. Microbiol.,  2011, 77(3), 794-802.
[http://dx.doi.org/10.1128/AEM.01599-10] [PMID: 21148701] 
[320] 
Santo, C.E.; Quaranta, D.; Grass, G. Antimicrobial metallic copper surfaces kill Staphylococcus haemolyticus via membrane damage. MicrobiologyOpen,  2012, 1(1), 46-52.
[http://dx.doi.org/10.1002/mbo3.2] [PMID: 22950011] 
[321] 
Warnes, S.L.; Caves, V.; Keevil, C.W. Mechanism of copper surface toxicity in Escherichia coli O157:H7 and Salmonella involves immediate membrane depolarization followed by slower rate of DNA destruction which differs from that observed for Gram-positive bacteria. Environ. Microbiol.,  2012, 14(7), 1730-1743.
[http://dx.doi.org/10.1111/j.1462-2920.2011.02677.x] [PMID: 22176893] 
[322] 
Warnes, S.L.; Keevil, C.W. Mechanism of copper surface toxicity in vancomycin-resistant enterococci following wet or dry surface contact. Appl. Environ. Microbiol.,  2011, 77(17), 6049-6059.
[http://dx.doi.org/10.1128/AEM.00597-11] [PMID: 21742916] 
[323] 
Warnes, S.L.; Green, S.M.; Michels, H.T.; Keevil, C.W. Biocidal efficacy of copper alloys against pathogenic enterococci involves degradation of genomic and plasmid DNAs. Appl. Environ. Microbiol.,  2010, 76(16), 5390-5401.
[http://dx.doi.org/10.1128/AEM.03050-09] [PMID: 20581191] 
[324] 
Zhang, W.; Chu, P.K. Enhancement of antibacterial properties and biocompatibility of polyethylene by silver and copper plasma immersion ion implantation. Surf. Coat. Tech.,  2008, 203(5), 909-912.
[http://dx.doi.org/10.1016/j.surfcoat.2008.08.023] 
[325] 
Wu, C.; Zhou, Y.; Xu, M.; Han, P.; Chen, L.; Chang, J.; Xiao, Y. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials,  2013, 34(2), 422-433.
[http://dx.doi.org/10.1016/j.biomaterials.2012.09.066] [PMID: 23083929] 
[326] 
Shi, M.; Chen, Z.; Farnaghi, S.; Friis, T.; Mao, X.; Xiao, Y.; Wu, C. Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis. Acta Biomater.,  2016, 30, 334-344.
[http://dx.doi.org/10.1016/j.actbio.2015.11.033] [PMID: 26596565] 
[327] 
Burghardt, I.; Lüthen, F.; Prinz, C.; Kreikemeyer, B.; Zietz, C.; Neumann, H.G.; Rychly, J. A dual function of copper in designing regenerative implants. Biomaterials,  2015, 44, 36-44.
[http://dx.doi.org/10.1016/j.biomaterials.2014.12.022] [PMID: 25617124] 
[328] 
Ren, L.; Wong, H.M.; Yan, C.H.; Yeung, K.W.; Yang, K. Osteogenic ability of Cu-bearing stainless steel. J. Biomed. Mater. Res. B Appl. Biomater.,  2015, 103(7), 1433-1444.
[http://dx.doi.org/10.1002/jbm.b.33318] [PMID: 25418073] 
[329] 
Prinz, C.; Elhensheri, M.; Rychly, J.; Neumann, H.G. Antimicrobial and bone-forming activity of a copper coated implant in a rabbit model. J. Biomater. Appl.,  2017, 32(2), 139-149.
[http://dx.doi.org/10.1177/0885328217713356] [PMID: 28599578] 
[330] 
Wang, X.; Qiao, J.; Yuan, F.; Hang, R.; Huang, X.; Tang, B. In situ growth of self-organized Cu-containing nano-tubes and nano-pores on Ti90-xCu10Alx (x=0, 45) alloys by one-pot anodization and evaluation of their antimicrobial activity and cytotoxicity. Surf. Coat. Tech.,  2014, 240, 167-178.
[http://dx.doi.org/10.1016/j.surfcoat.2013.12.036] 
[331] 
Hang, R.; Gao, A.; Huang, X.; Wang, X.; Zhang, X.; Qin, L.; Tang, B. Antibacterial activity and cytocompatibility of Cu-Ti-O nanotubes. J. Biomed. Mater. Res. A,  2014, 102(6), 1850-1858.
[http://dx.doi.org/10.1002/jbm.a.34847] [PMID: 23907848] 
[332] 
Zong, M.; Bai, L.; Liu, Y.; Wang, X.; Zhang, X.; Huang, X.; Hang, R.; Tang, B. Antibacterial ability and angiogenic activity of Cu-Ti-O nanotube arrays. Mater. Sci. Eng. C,  2017, 71, 93-99.
[http://dx.doi.org/10.1016/j.msec.2016.09.077] [PMID: 27987791] 
[333] 
Rai, M.K.; Deshmukh, S.D.; Ingle, A.P.; Gade, A.K. Silver nanoparticles: the powerful nanoweapon against multidrug-resistant bacteria. J. Appl. Microbiol.,  2012, 112(5), 841-852.
[http://dx.doi.org/10.1111/j.1365-2672.2012.05253.x] [PMID: 22324439] 
[334] 
Franci, G.; Falanga, A.; Galdiero, S.; Palomba, L.; Rai, M.; Morelli, G.; Galdiero, M. Silver nanoparticles as potential antibacterial agents. Molecules,  2015, 20(5), 8856-8874.
[http://dx.doi.org/10.3390/molecules20058856] [PMID: 25993417] 
[335] 
Silver, S. Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. FEMS Microbiol. Rev.,  2003, 27(2-3), 341-353.
[http://dx.doi.org/10.1016/S0168-6445(03)00047-0] [PMID: 12829274] 
[336] 
Albers, C.E.; Hofstetter, W.; Siebenrock, K.A.; Landmann, R.; Klenke, F.M. In vitro cytotoxicity of silver nanoparticles on osteoblasts and osteoclasts at antibacterial concentrations. Nanotoxicology,  2013, 7(1), 30-36.
[http://dx.doi.org/10.3109/17435390.2011.626538] [PMID: 22013878] 
[337] 
Pauksch, L.; Hartmann, S.; Rohnke, M.; Szalay, G.; Alt, V.; Schnettler, R.; Lips, K.S. Biocompatibility of silver nanoparticles and silver ions in primary human mesenchymal stem cells and osteoblasts. Acta Biomater.,  2014, 10(1), 439-449.
[http://dx.doi.org/10.1016/j.actbio.2013.09.037] [PMID: 24095782] 
[338] 
Kalishwaralal, K. BarathManiKanth, S.; Pandian, S.R.; Deepak, V.; Gurunathan, S. Silver nanoparticles impede the biofilm formation by Pseudomonas aeruginosa and Staphylococcus epidermidis. Colloids Surf. B Biointerfaces,  2010, 79(2), 340-344.
[http://dx.doi.org/10.1016/j.colsurfb.2010.04.014] [PMID: 20493674] 
[339] 
Mohanty, S.; Mishra, S.; Jena, P.; Jacob, B.; Sarkar, B.; Sonawane, A. An investigation on the antibacterial, cytotoxic, and antibiofilm efficacy of starch-stabilized silver nanoparticles. Nanomedicine (Lond.),  2012, 8(6), 916-924.
[http://dx.doi.org/10.1016/j.nano.2011.11.007] [PMID: 22115597] 
[340] 
Liu, X.; He, W.; Fang, Z.; Kienzle, A.; Feng, Q. Influence of silver nanoparticles on osteogenic differentiation of human mesenchymal stem cells. J. Biomed. Nanotechnol.,  2014, 10(7), 1277-1285.
[http://dx.doi.org/10.1166/jbn.2014.1824] [PMID: 24804548] 
[341] 
Sengstock, C.; Diendorf, J.; Epple, M.; Schildhauer, T.A.; Köller, M. Effect of silver nanoparticles on human mesenchymal stem cell differentiation. Beilstein J. Nanotechnol.,  2014, 5, 2058-2069.
[http://dx.doi.org/10.3762/bjnano.5.214] [PMID: 25551033] 
[342] 
Zhang, R.; Lee, P.; Lui, V.C.; Chen, Y.; Liu, X.; Lok, C.N.; To, M.; Yeung, K.W.; Wong, K.K. Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model. Nanomedicine (Lond.),  2015, 11(8), 1949-1959.
[http://dx.doi.org/10.1016/j.nano.2015.07.016] [PMID: 26282383] 
[343] 
Mahmood, M.; Li, Z.; Casciano, D.; Khodakovskaya, M.V.; Chen, T.; Karmakar, A.; Dervishi, E.; Xu, Y.; Mustafa, T.; Watanabe, F.; Fejleh, A.; Whitlow, M.; Al-Adami, M.; Ghosh, A.; Biris, A.S. Nanostructural materials increase mineralization in bone cells and affect gene expression through miRNA regulation. J. Cell. Mol. Med.,  2011, 15(11), 2297-2306.
[http://dx.doi.org/10.1111/j.1582-4934.2010.01234.x] [PMID: 21143388] 
[344] 
Park, M.V.; Neigh, A.M.; Vermeulen, J.P.; de la Fonteyne, L.J.; Verharen, H.W.; Briedé, J.J.; van Loveren, H.; de Jong, W.H. The effect of particle size on the cytotoxicity, inflammation, developmental toxicity and genotoxicity of silver nanoparticles. Biomaterials,  2011, 32(36), 9810-9817.
[http://dx.doi.org/10.1016/j.biomaterials.2011.08.085] [PMID: 21944826] 
[345] 
Locht, L.J.; Smidt, K.; Rungby, J.; Stoltenberg, M.; Larsen, A. Uptake of silver from metallic silver surfaces induces cell death and a pro-inflammatory response in cultured J774 macrophages. Histol. Histopathol.,  2011, 26(6), 689-697.
[PMID: 21472684] 
[346] 
Hussain, S.M.; Hess, K.L.; Gearhart, J.M.; Geiss, K.T.; Schlager, J.J. In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol. In Vitro,  2005, 19(7), 975-983.
[http://dx.doi.org/10.1016/j.tiv.2005.06.034] [PMID: 16125895] 
[347] 
De Jong, W.H.; Van Der Ven, L.T.; Sleijffers, A.; Park, M.V.; Jansen, E.H.; Van Loveren, H.; Vandebriel, R.J. Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats. Biomaterials,  2013, 34(33), 8333-8343.
[http://dx.doi.org/10.1016/j.biomaterials.2013.06.048] [PMID: 23886731] 
[348] 
Li, H.; Cui, Q.; Feng, B.; Wang, J.; Lu, X.; Weng, J. Antibacterial activity of TiO2 nanotubes: Influence of crystal phase, morphology and Ag deposition. Appl. Surf. Sci.,  2013, 284, 179-183.
[http://dx.doi.org/10.1016/j.apsusc.2013.07.076] 
[349] 
Das, K.; Bose, S.; Bandyopadhyay, A.; Karandikar, B.; Gibbins, B.L. Surface coatings for improvement of bone cell materials and antimicrobial activities of Ti implants. J. Biomed. Mater. Res. B Appl. Biomater.,  2008, 87(2), 455-460.
[http://dx.doi.org/10.1002/jbm.b.31125] [PMID: 18481793] 
[350] 
Zhao, L.; Wang, H.; Huo, K.; Cui, L.; Zhang, W.; Ni, H.; Zhang, Y.; Wu, Z.; Chu, P.K. Antibacterial nano-structured titania coating incorporated with silver nanoparticles. Biomaterials,  2011, 32(24), 5706-5716.
[http://dx.doi.org/10.1016/j.biomaterials.2011.04.040] [PMID: 21565401] 
[351] 
Gao, A.; Hang, R.; Huang, X.; Zhao, L.; Zhang, X.; Wang, L.; Tang, B.; Ma, S.; Chu, P.K. The effects of titania nanotubes with embedded silver oxide nanoparticles on bacteria and osteoblasts. Biomaterials,  2014, 35(13), 4223-4235.
[http://dx.doi.org/10.1016/j.biomaterials.2014.01.058] [PMID: 24529392] 
[352] 
Piszczek, P.; Lewandowska, Ż.; Radtke, A.; Jędrzejewski, T.; Kozak, W.; Sadowska, B.; Szubka, M.; Talik, E.; Fiori, F. Biocompatibility of titania nanotube coatings enriched with silver nanograins by chemical vapor deposition. Nanomaterials (Basel),  2017, 7(9), 274.
[http://dx.doi.org/10.3390/nano7090274] [PMID: 28914821] 
[353] 
Roguska, A.; Belcarz, A.; Piersiak, T.; Pisarek, M.; Ginalska, G.; Lewandowska, M. Evaluation of the antibacterial activity of Ag-loaded TiO2 nanotubes. Eur. J. Inorg. Chem.,  2012, 2012(32), 5199-5206.
[http://dx.doi.org/10.1002/ejic.201200508] 
[354] 
Mei, S.; Wang, H.; Wang, W.; Tong, L.; Pan, H.; Ruan, C.; Ma, Q.; Liu, M.; Yang, H.; Zhang, L.; Cheng, Y.; Zhang, Y.; Zhao, L.; Chu, P.K. Antibacterial effects and biocompatibility of titanium surfaces with graded silver incorporation in titania nanotubes. Biomaterials,  2014, 35(14), 4255-4265.
[http://dx.doi.org/10.1016/j.biomaterials.2014.02.005] [PMID: 24565524] 
[355] 
Zhang, Y.; Dong, C.; Yang, S.; Chiu, T.W.; Wu, J.; Xiao, K.; Huang, Y.; Li, X. Enhanced silver loaded antibacterial titanium implant coating with novel hierarchical effect. J. Biomater. Appl.,  2018, 32(9), 1289-1299.
[http://dx.doi.org/10.1177/0885328218755538] [PMID: 29417864] 
[356] 
Huang, Y.; Shen, X.; Qiao, H.; Yang, H.; Zhang, X.; Liu, Y.; Yang, H. Biofunctional Sr- and Si-loaded titania nanotube coating of Ti surfaces by anodization-hydrothermal process. Int. J. Nanomedicine,  2018, 13, 633-640.
[http://dx.doi.org/10.2147/IJN.S147969] [PMID: 29440890] 
[357] 
Alves, S.A.; Ribeiro, A.R.; Gemini-Piperni, S.; Silva, R.C.; Saraiva, A.M.; Leite, P.E.; Perez, G.; Oliveira, S.M.; Araujo, J.R.; Archanjo, B.S.; Rodrigues, M.E.; Henriques, M.; Celis, J.P.; Shokuhfar, T.; Borojevic, R.; Granjeiro, J.M.; Rocha, L.A. TiO2 nanotubes enriched with calcium, phosphorous and zinc: promising bio-selective functional surfaces for osseointegrated titanium implants. RSC Advances,  2017, 7(78), 49720-49738.
[http://dx.doi.org/10.1039/C7RA08263K] 
[358] 
Roguska, A.; Pisarek, M.; Andrzejczuk, M.; Lewandowska, M. Synthesis and characterization of ZnO and Ag nanoparticle-loaded TiO2 nanotube composite layers intended for antibacterial coatings. Thin Solid Films,  2014, 553, 173-178.
[http://dx.doi.org/10.1016/j.tsf.2013.11.057] 
[359] 
Roguska, A.; Belcarz, A.; Pisarek, M.; Ginalska, G.; Lewandowska, M. TiO2 nanotube composite layers as delivery system for ZnO and Ag nanoparticles - an unexpected overdose effect decreasing their antibacterial efficacy. Mater. Sci. Eng. C,  2015, 51, 158-166.
[http://dx.doi.org/10.1016/j.msec.2015.02.046] [PMID: 25842121] 
[360] 
Cheng, H.; Xiong, W.; Fang, Z.; Guan, H.; Wu, W.; Li, Y.; Zhang, Y.; Alvarez, M.M.; Gao, B.; Huo, K.; Xu, J.; Xu, N.; Zhang, C.; Fu, J.; Khademhosseini, A.; Li, F. Strontium (Sr) and silver (Ag) loaded nanotubular structures with combined osteoinductive and antimicrobial activities. Acta Biomater.,  2016, 31, 388-400.
[http://dx.doi.org/10.1016/j.actbio.2015.11.046] [PMID: 26612413] 
[361] 
Chen, Y.; Gao, A.; Bai, L.; Wang, Y.; Wang, X.; Zhang, X.; Huang, X.; Hang, R.; Tang, B.; Chu, P.K. Antibacterial, osteogenic, and angiogenic activities of SrTiO3 nanotubes embedded with Ag2O nanoparticles. Mater. Sci. Eng. C,  2017, 75, 1049-1058.
[http://dx.doi.org/10.1016/j.msec.2017.03.014] [PMID: 28415389] 
[362] 
Huang, Y.; Zhang, X.; Zhang, H.; Qiao, H.; Zhang, X.; Jia, T.; Han, S.; Gao, Y.; Xiao, H.; Yang, H. Fabrication of silver- and strontium-doped hydroxyapatite/TiO2 nanotube bilayer coatings for enhancing bactericidal effect and osteoinductivity. Ceram. Int.,  2017, 43(1, Part B), 992-1007.
[http://dx.doi.org/10.1016/j.ceramint.2016.10.031] 
[363] 
Losic, D.; Simovic, S. Self-ordered nanopore and nanotube platforms for drug delivery applications. Expert Opin. Drug Deliv.,  2009, 6(12), 1363-1381.
[http://dx.doi.org/10.1517/17425240903300857] [PMID: 19860534] 
[364] 
Losic, D.; Aw, M.S.; Santos, A.; Gulati, K.; Bariana, M. Titania nanotube arrays for local drug delivery: recent advances and perspectives. Expert Opin. Drug Deliv.,  2015, 12(1), 103-127.
[http://dx.doi.org/10.1517/17425247.2014.945418] [PMID: 25376706] 
[365] 
Kohanski, M.A.; Dwyer, D.J.; Collins, J.J. How antibiotics kill bacteria: from targets to networks. Nat. Rev. Microbiol.,  2010, 8(6), 423-435.
[http://dx.doi.org/10.1038/nrmicro2333] [PMID: 20440275] 
[366] 
Gulati, K.; Aw, M.S.; Losic, D. Drug-eluting Ti wires with titania nanotube arrays for bone fixation and reduced bone infection. Nanoscale Res. Lett.,  2011, 6(1), 571-571.
[http://dx.doi.org/10.1186/1556-276X-6-571] [PMID: 22039969] 
[367] 
Çalışkan, N.; Bayram, C.; Erdal, E.; Karahaliloğlu, Z.; Denkbaş, E.B. Titania nanotubes with adjustable dimensions for drug reservoir sites and enhanced cell adhesion. Mater. Sci. Eng. C,  2014, 35, 100-105.
[http://dx.doi.org/10.1016/j.msec.2013.10.033] [PMID: 24411357] 
[368] 
Lin, W.T.; Tan, H.L.; Duan, Z.L.; Yue, B.; Ma, R.; He, G.; Tang, T.T. Inhibited bacterial biofilm formation and improved osteogenic activity on gentamicin-loaded titania nanotubes with various diameters. Int. J. Nanomedicine,  2014, 9, 1215-1230.
[PMID: 24634583] 
[369] 
Yang, Y.; Ao, H.Y.; Yang, S.B.; Wang, Y.G.; Lin, W.T.; Yu, Z.F.; Tang, T.T. In vivo evaluation of the anti-infection potential of gentamicin-loaded nanotubes on titania implants. Int. J. Nanomedicine,  2016, 11, 2223-2234.
[PMID: 27274245] 
[370] 
Cioffi, G.A.; Terezhalmy, G.T.; Taybos, G.M. Total joint replacement: a consideration for antimicrobial prophylaxis. Oral Surg. Oral Med. Oral Pathol.,  1988, 66(1), 124-129.
[http://dx.doi.org/10.1016/0030-4220(88)90079-5] [PMID: 2970053] 
[371] 
Liu, D.; He, C.; Liu, Z.; Xu, W. Gentamicin coating of nanotubular anodized titanium implant reduces implant-related osteomyelitis and enhances bone biocompatibility in rabbits. Int. J. Nanomedicine,  2017, 12(12), 5461-5471.
[http://dx.doi.org/10.2147/IJN.S137137] [PMID: 28814863] 
[372] 
Yao, C.; Webster, T.J. Prolonged antibiotic delivery from anodized nanotubular titanium using a co-precipitation drug loading method. J. Biomed. Mater. Res. B Appl. Biomater.,  2009, 91(2), 587-595.
[http://dx.doi.org/10.1002/jbm.b.31433] [PMID: 19582847] 
[373] 
Feng, W.; Geng, Z.; Li, Z.; Cui, Z.; Zhu, S.; Liang, Y.; Liu, Y.; Wang, R.; Yang, X. Controlled release behaviour and antibacterial effects of antibiotic-loaded titania nanotubes. Mater. Sci. Eng. C,  2016, 62, 105-112.
[http://dx.doi.org/10.1016/j.msec.2016.01.046] [PMID: 26952403] 
[374] 
Kumeria, T.; Mon, H.; Aw, M.S.; Gulati, K.; Santos, A.; Griesser, H.J.; Losic, D. Advanced biopolymer-coated drug-releasing titania nanotubes (TNTs) implants with simultaneously enhanced osteoblast adhesion and antibacterial properties. Colloids Surf. B Biointerfaces,  2015, 130, 255-263.
[http://dx.doi.org/10.1016/j.colsurfb.2015.04.021] [PMID: 25944564] 
[375] 
Kang, H.K.; Park, Y. Glycopeptide antibiotics: Structure and mechanisms of action. J. Bacteriol. Virol.,  2015, 45(2), 67-78.
[http://dx.doi.org/10.4167/jbv.2015.45.2.67] 
[376] 
Hatzenbuehler, J.; Pulling, T.J. Diagnosis and management of osteomyelitis. Am. Fam. Physician,  2011, 84(9), 1027-1033.
[PMID: 22046943] 
[377] 
Hidayat, L.K.; Hsu, D.I.; Quist, R.; Shriner, K.A.; Wong-Beringer, A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch. Intern. Med.,  2006, 166(19), 2138-2144.
[http://dx.doi.org/10.1001/archinte.166.19.2138] [PMID: 17060545] 
[378] 
Citron, D.M.; Tyrrell, K.L.; Goldstein, E.J.C. Comparative in vitro activities of dalbavancin and seven comparator agents against 41 Staphylococcus species cultured from osteomyelitis infections and 18 VISA and hVISA strains. Diagn. Microbiol. Infect. Dis.,  2014, 79(4), 438-440.
[http://dx.doi.org/10.1016/j.diagmicrobio.2014.05.014] [PMID: 24972854] 
[379] 
Arciola, C.R.; Campoccia, D.; Gamberini, S.; Donati, M.E.; Pirini, V.; Visai, L.; Speziale, P.; Montanaro, L. Antibiotic resistance in exopolysaccharide-forming Staphylococcus epidermidis clinical isolates from orthopaedic implant infections. Biomaterials,  2005, 26(33), 6530-6535.
[http://dx.doi.org/10.1016/j.biomaterials.2005.04.031] [PMID: 15949842] 
[380] 
Rathbone, C.R.; Cross, J.D.; Brown, K.V.; Murray, C.K.; Wenke, J.C. Effect of various concentrations of antibiotics on osteogenic cell viability and activity. J. Orthop. Res.,  2011, 29(7), 1070-1074.
[http://dx.doi.org/10.1002/jor.21343] [PMID: 21567453] 
[381] 
Zhang, H.; Sun, Y.; Tian, A.; Xue, X.X.; Wang, L.; Alquhali, A.; Bai, X. Improved antibacterial activity and biocompatibility on vancomycin-loaded TiO2 nanotubes: in vivo and in vitro studies. Int. J. Nanomedicine,  2013, 8, 4379-4389.
[http://dx.doi.org/10.2147/IJN.S53221] [PMID: 24403827] 
[382] 
Ionita, D.; Bajenaru-Georgescu, D.; Totea, G.; Mazare, A.; Schmuki, P.; Demetrescu, I. Activity of vancomycin release from bioinspired coatings of hydroxyapatite or TiO2 nanotubes. Int. J. Pharm.,  2017, 517(1-2), 296-302.
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.062] [PMID: 27913240] 
[383] 
Abo El-Sooud, K.; Al-Tarazi, Y.H.; Al-Bataineh, M.M. Comparative pharmacokinetics and bioavailability of amoxycillin in chickens after intravenous, intramuscular and oral administrations. Vet. Res. Commun.,  2004, 28(7), 599-607.
[http://dx.doi.org/10.1023/B:VERC.0000042869.44153.b9] [PMID: 15563107] 
[384] 
Gordon, C.; Regamey, C.; Kirby, W.M.M. Comparative clinical pharmacology of amoxicillin and ampicillin administered orally. Antimicrob. Agents Chemother.,  1972, 1(6), 504-507.
[http://dx.doi.org/10.1128/AAC.1.6.504] [PMID: 4680813] 
[385] 
Brogden, R.N.; Heel, R.C.; Speight, T.M.; Avery, G.S. Amoxycillin injectable: a review of its antibacterial spectrum, pharmacokinetics and therapeutic use. Drugs,  1979, 18(3), 169-184.
[http://dx.doi.org/10.2165/00003495-197918030-00001] [PMID: 387371] 
[386] 
Bush, K. β-lactam antibiotics: Penicillin, and other β-lactam
antibiot-ics In: Antibiotic and Chemotherapy: Anti-infective
Agents and Their Use in Therapy,; 8th ed.; Finch R.G.,
G.D., Norrby S.R., Whitley R.J., Ed.; Churchill Livingstone:
Edinburgh, UK, 2003; pp. 224-278.
[387] 
Amin, A.S.; El-Ansary, A.L.; Issa, Y.M. Colorimetric determination of amoxycillin in pure form and in pharmaceutical preparations. Talanta,  1994, 41(5), 691-694.
[http://dx.doi.org/10.1016/0039-9140(94)80050-2] [PMID: 18965984] 
[388] 
Nagaralli, B.S.; Seetharamappa, J.; Melwanki, M.B. Sensitive spectrophotometric methods for the determination of amoxycillin, ciprofloxacin and piroxicam in pure and pharmaceutical formulations. J. Pharm. Biomed. Anal.,  2002, 29(5), 859-864.
[http://dx.doi.org/10.1016/S0731-7085(02)00210-8] [PMID: 12093519] 
[389] 
Kaur, S.P.; Rao, R.; Nanda, S. Amoxicillin: A broad spectrum antibiotic. J. Pharm. Pharm. Sci.,  2011, 3(3), 30-37.
[390] 
Andrade, N.K.d.; Ramacciato, J.C.; Carvalho, P.S.P.d.; Groppo, F.C.; Motta, R.H.L. Evaluation of two amoxicillin protocols for antibiotic prophylaxis in implant placement surgeries. Rev. Gaucha Odontol.,  2017, 65(3), 249-253.
[http://dx.doi.org/10.1590/1981-863720170002000103371] 
[391] 
Lee, J.H.; Moon, S.K.; Kim, K.M.; Kim, K.N. Modification of TiO(2) nanotube surfaces by electro-spray deposition of amoxicillin combined with PLGA for bactericidal effects at surgical implantation sites. Acta Odontol. Scand.,  2013, 71(1), 168-174.
[http://dx.doi.org/10.3109/00016357.2011.654256] [PMID: 22299831] 
[392] 
Maryam, L.; Khan, A.U. A Mechanism of synergistic effect of streptomycin and cefotaxime on CTX-M-15 type β-lactamase producing strain of E. cloacae: A first report. Front. Microbiol.,  2016, 7, 2007.
[http://dx.doi.org/10.3389/fmicb.2016.02007] [PMID: 28018328] 
[393] 
Yocum, R.R.; Rasmussen, J.R.; Strominger, J.L. The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase. J. Biol. Chem.,  1980, 255(9), 3977-3986.
[PMID: 7372662] 
[394] 
Spratt, B.G. The mechanism of action of penicillin. Sci. Prog.,  1978, 65(257), 101-128.
[PMID: 343249] 
[395] 
Sharma, D.; Cukras, A.R.; Rogers, E.J.; Southworth, D.R.; Green, R. Mutational analysis of S12 protein and implications for the accuracy of decoding by the ribosome. J. Mol. Biol.,  2007, 374(4), 1065-1076.
[http://dx.doi.org/10.1016/j.jmb.2007.10.003] [PMID: 17967466] 
[396] 
Yao, C.; Webster, T.J. Nano-surface modification on titanium implants for drug delivery. Proc. MRS,  2008, 1054, 140-145.
[397] 
Eaninwene, G.I.I.; Yao, C.; Webster, T.J. Enhanced osteoblast adhesion to drug-coated anodized nanotubular titanium surfaces. Int. J. Nanomedicine,  2008, 3(2), 257-264.
[PMID: 18686785] 
[398] 
Bahar, A.A.; Ren, D. Antimicrobial peptides. Pharmaceuticals (Basel),  2013, 6(12), 1543-1575.
[http://dx.doi.org/10.3390/ph6121543] [PMID: 24287494] 
[399] 
Wang, G. Human antimicrobial peptides and proteins. Pharmaceuticals (Basel),  2014, 7(5), 545-594.
[http://dx.doi.org/10.3390/ph7050545] [PMID: 24828484] 
[400] 
Hancock, R.E.W.; Diamond, G. The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol.,  2000, 8(9), 402-410.
[http://dx.doi.org/10.1016/S0966-842X(00)01823-0] [PMID: 10989307] 
[401] 
Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature,  2002, 415(6870), 389-395.
[http://dx.doi.org/10.1038/415389a] [PMID: 11807545] 
[402] 
Diamond, G.; Beckloff, N.; Weinberg, A.; Kisich, K.O. The roles of antimicrobial peptides in innate host defense. Curr. Pharm. Des.,  2009, 15(21), 2377-2392.
[http://dx.doi.org/10.2174/138161209788682325] [PMID: 19601838] 
[403] 
Hancock, R.E.W.; Sahl, H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol.,  2006, 24(12), 1551-1557.
[http://dx.doi.org/10.1038/nbt1267] [PMID: 17160061] 
[404] 
Pasupuleti, M.; Schmidtchen, A.; Malmsten, M. Antimicrobial peptides: key components of the innate immune system. Crit. Rev. Biotechnol.,  2012, 32(2), 143-171.
[http://dx.doi.org/10.3109/07388551.2011.594423] [PMID: 22074402] 
[405] 
Scott, M.G.; Rosenberger, C.M.; Gold, M.R.; Finlay, B.B.; Hancock, R.E.W. An alpha-helical cationic antimicrobial peptide selectively modulates macrophage responses to lipopolysaccharide and directly alters macrophage gene expression. J. Immunol.,  2000, 165(6), 3358-3365.
[http://dx.doi.org/10.4049/jimmunol.165.6.3358] [PMID: 10975854] 
[406] 
Hancock, R.E.W.; Scott, M.G. The role of antimicrobial peptides in animal defenses. Proc. Natl. Acad. Sci. USA,  2000, 97(16), 8856-8861.
[http://dx.doi.org/10.1073/pnas.97.16.8856] [PMID: 10922046] 
[407] 
Nakatsuji, T.; Gallo, R.L. Antimicrobial peptides: old molecules with new ideas. J. Invest. Dermatol.,  2012, 132(3 Pt 2), 887-895.
[http://dx.doi.org/10.1038/jid.2011.387] [PMID: 22158560] 
[408] 
Salvado, M.D.; Di Gennaro, A.; Lindbom, L.; Agerberth, B.; Haeggström, J.Z. Cathelicidin LL-37 induces angiogenesis via PGE2-EP3 signaling in endothelial cells, in vivo inhibition by aspirin. Arterioscler. Thromb. Vasc. Biol.,  2013, 33(8), 1965-1972.
[http://dx.doi.org/10.1161/ATVBAHA.113.301851] [PMID: 23766266] 
[409] 
Kittaka, M.; Shiba, H.; Kajiya, M.; Fujita, T.; Iwata, T.; Rathvisal, K.; Ouhara, K.; Takeda, K.; Fujita, T.; Komatsuzawa, H.; Kurihara, H. The antimicrobial peptide LL37 promotes bone regeneration in a rat calvarial bone defect. Peptides,  2013, 46, 136-142.
[http://dx.doi.org/10.1016/j.peptides.2013.06.001] [PMID: 23770151] 
[410] 
Zhang, Z.; Shively, J.E. Acceleration of bone repair in NOD/SCID mice by human monoosteophils, novel LL-37-activated monocytes. PLoS One,  2013, 8(7)e67649
[http://dx.doi.org/10.1371/journal.pone.0067649] [PMID: 23844045] 
[411] 
Ma, M.; Kazemzadeh-Narbat, M.; Hui, Y.; Lu, S.; Ding, C.; Chen, D.D.Y.; Hancock, R.E.W.; Wang, R. Local delivery of antimicrobial peptides using self-organized TiO2 nanotube arrays for peri-implant infections. J. Biomed. Mater. Res. A,  2012, 100(2), 278-285.
[http://dx.doi.org/10.1002/jbm.a.33251] [PMID: 22045618] 
[412] 
Kazemzadeh-Narbat, M.; Lai, B.F.L.; Ding, C.; Kizhakkedathu, J.N.; Hancock, R.E.W.; Wang, R. Multilayered coating on titanium for controlled release of antimicrobial peptides for the prevention of implant-associated infections. Biomaterials,  2013, 34(24), 5969-5977.
[http://dx.doi.org/10.1016/j.biomaterials.2013.04.036] [PMID: 23680363] 
Rights & Permissions Print Cite
Article Metrics
33
3
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666190726123229	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

基于Titania纳米管和活性剂的药物输送系统，用于增强骨植入物的骨整合

摘要

当代药物化学

基于Titania纳米管和活性剂的药物输送系统，用于增强骨植入物的骨整合

摘要 Play Pause

Related Journals

Related Books

Related Articles

摘要
