二氧化钛纳米管材料成骨及抗菌实验研究
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摘要
人工关节置换术后假体周围感染是人工关节置换术后灾难性的并发症，已经感染的人工关节及生物膜没有特殊有效的治疗方法，因此感染的预防非常重要。钛纳米管材料由于其纳米级的细微结构和规则的空间构造，具有优良的生物相容性同时也是天然的载药系统。因而通过钛合金内置物纳米管表面负载抗菌药物，可成为促进成骨长入，预防假体细菌粘附生长的有效方法，并可为预防治疗假体周围松动感染提供新的思路和选择。
目的：首先通过电化学阳极氧化法制备出二氧化钛纳米管涂层并进行结构表征和电镜观察，控制不同的制备条件下制备不同纳米管孔径的材料并比较其结构特性。然后在钛纳米管材料表面进行骨髓间充质干细胞的培养，观察其粘附，生长和分化的活性，并在不同的纳米结构表面进行比较，探讨纳米管结构对成骨细胞的作用。而后在已制备的钛纳米管材料表面负载庆大霉素，进行载药和释药的研究，分别在体外和体内进行实验观察载药钛纳米管材料对金葡菌的抑菌作用。
方法：
1.在氢氟酸和中性氟化物溶液中分别用电化学阳极氧化法制备钛纳米管材料。应用X射线能谱分析其表面元素，X射线衍射仪分析其晶体结构，电镜下观察和测量其结构特征，测量表面接触角和表面粗糙度。控制不同的电压制备不同纳米孔径的钛纳米管材料。
2.在钛纳米管材料表面培养骨髓间充质干细胞，应用MTT法观察其活性，荧光显微镜及电镜观察其形态，观察其粘附生长和分化情况。并与纯钛表面进行比较。尤其在不同孔径的钛纳米管材料表面进行干细胞的培养，观察其粘附和分化能力，分析其与钛纳米管表面结构的相互关系。
3.应用负压吸附法在钛纳米管材料表面负载庆大霉素，计算其药物负载率。通过高分子聚合物覆盖，观察其对药物释放曲线的影响。在体外实验中，比较载药和未载药的钛纳米管材料表面的金葡菌的粘附生长情况，并同样进行成骨细胞培养观察载药是否会对钛纳米管的促成骨作用产生影响。在体内实验中，通过在小鼠双下肢的对照实验，比较载庆大霉素纳米管材料在体内对金葡菌的抑制作用。
结果：1.应用电化学阳极氧化法制备出钛纳米管材料，其在400°C热处理后主要为锐钛矿型，电镜下观察到其完整的纳米管形成的过程。控制不同的恒定电压可制备出不同孔径（随电压递增）的纳米管材料。
2.钛纳米管材料表面较纯钛对骨髓间充质细胞有显著的促进粘附，生长和分化的作用，不同孔径的钛纳米管材料表面对间充质干细胞的作用有所不同，管径小时促进其粘附和生长，管径大时干细胞形态变长，分化成骨能力增强。
3.钛纳米材料表面可有效负载庆大霉素，其释药曲线存在爆发性释放，在其表面覆盖高分子聚合物可有效延长其释放时间。体外实验证实载药钛纳米管材料可有效抑制金葡菌生长，并同时仍有促成骨作用。体内实验中载药钛纳米管可有效预防小鼠肢体感染。
结论：1.电化学阳极氧化法可简单有效制备钛纳米管材料，并可控制其表面结构参数。
2.钛纳米材料表面与成骨细胞系列有优良的生物相容性，促进材料表面成骨加强内植物骨融合稳定性。
3.钛纳米管材料表面可有效吸附抗菌药物，并具有有效的抗菌能力，对预防治疗假体周围感染具有良好的临床应用前景。
Prosthetic joint infection is the most serious complication after joint prosthesis replacements, causing the failure of the prosthesis or the limb mortality. There is no effective conservative way to eradicate the microorganisms. Then the prevention of the infection is extraordinary important. Owing to the ability to mimic the dimensions of constituent components of natural bone and possibility to serve as nanoreserviors for drug delivery, self-ordered nanotubular titania seems to be a promising coating for joint prosthesis to prevent the prosthetic joint infection and enhance the osseointegration.
Objective:In the first part, the purpose of the study is to fabricate the titania nanotubes using an anodization process, to analyze the surface microtopography and components and to study the correlation between the anodiztion voltage and the pore size of nanotubes. In the second part, the proliferation and differentiation of mesenchymal stem cells(MSCs) was investigated on the surface of titania nanotubes compared with titanium surface. The MSCs behavior in response to the different nanotube sizes also were explored. In the third part, the drug release kinetics from the titanium nanotubes loaded with gentamicin and the effect on Staphylococcus areus adhesion and proliferation were studied. Then the effects of the gentamicin-loaded titania nanotubes on the reduction of infection rates in a rat infection prophylaxis model were also explored.
Materials and methods:
1. TiO2nanotube arrays were fabricated in a two-eclectrochenmical cell using HF aqueous solution and the buffered electrolytes of NH4F and NH4H2PO4respectively at constant voltage. The surface elements composition was analyzed using X-ray electromagnetic pectrum. The crystal structures were analyzed using X-ray diffraction and the surface topography were observed with scanning electron microscope(SEM). We also measure the contact angle and the surface roughness. A series of voltages ranging rfom5V to25V were used to efbricate different diameter nanatubes on theanodized titanium sufraces.
2. Mesenchymal stem cells were isolated rfom C57BL/6mice and seeded onnanotubes ittanium sirfaces of different pore sizes along with titanium surfaces ascontrol group. The interaction of cells with these surfaces was investigated in terms ofthe ability to adhere, proliferate and differentiate on them. The cell viability wasinvestigated using a commercially available MTT assay. The cell morphology wasexamined using a lfuorescence microscope and SEM.
3. The nanotubes were loaded with gentamicin and the loading eiffciency wascalculated. The gentamicin release kinetics were investigated especially after titaniananotube coated with polymers. The effects of nanotube titanium loaded withgentamicin on Staphylococcus areus were investigated and the effects on bone cellstfinctionality were evaluated in vitro. Also the nanotube titanium loaded withgentamicin was inserted into the femora of the rat peirprosthetic infection model. Andthe inhibition of bacterial attachment and proliferation compared with controlnanotube titanium were investigated.
Results:
1. The anatase structure of Ti02nanotube surfaces were fabricated on the bulktitanium using an anodization technique and heattreated at400°C. The developmentrfom the bulk titanium to nanotubes ittanium was observed by SEM.The fabricationstrategies (to change the voltage or else) was able to precisely control the nanotubediameter and length.
2. The nanotubuular titania surfaces provide a efvorable template for the growthand differentiation of MSCs than lfat titanium surfaces. A very dramatic change inMSCs behavior in a relatively narrow range of nanotube dimensions was observed.Small nanotubes promoted adhesion without noticeable differentiation, whereas largernanotubes elicited a stem cell elongation, which dinduced cytoskeletal stress andselective differentiation into osteoblast-like cells.
3. The nanotubes titanium coiid be effectively iflled with the gentamicin and thebirst release in the ifrst6hours could be reduced by the biocompatible polymerscoating. The drug eluting nanotubes signiifcantly reduce bacterial adhesion on thesurfaces in vitro. The titanium nanotubes loaded with getamicin could suppressbacteiral colonization and prevent bioiflm formation in the rat infection model in vivo.
Conclusions:
1. Ti02nanotube arrays could be fabricated by electrochemical anodizationeffectively and economically. The parameters of nanotube structure could be preciselytuned.
2. Titanium nanotubes coiid enhance the osseointegration of the MSCs owing tothe excellent biocompatibility to the natural bone.
3. Titanium nanotubes iflled with antibacterial drugs could inhibit the adhesionand growing of the bacteiral in vitro and in vivo, which indicate a promising future fortherapy and prevention of prosthetic joint infections.
目的：首先通过电化学阳极氧化法制备出二氧化钛纳米管涂层并进行结构表征和电镜观察，控制不同的制备条件下制备不同纳米管孔径的材料并比较其结构特性。然后在钛纳米管材料表面进行骨髓间充质干细胞的培养，观察其粘附，生长和分化的活性，并在不同的纳米结构表面进行比较，探讨纳米管结构对成骨细胞的作用。而后在已制备的钛纳米管材料表面负载庆大霉素，进行载药和释药的研究，分别在体外和体内进行实验观察载药钛纳米管材料对金葡菌的抑菌作用。
方法：
1.在氢氟酸和中性氟化物溶液中分别用电化学阳极氧化法制备钛纳米管材料。应用X射线能谱分析其表面元素，X射线衍射仪分析其晶体结构，电镜下观察和测量其结构特征，测量表面接触角和表面粗糙度。控制不同的电压制备不同纳米孔径的钛纳米管材料。
2.在钛纳米管材料表面培养骨髓间充质干细胞，应用MTT法观察其活性，荧光显微镜及电镜观察其形态，观察其粘附生长和分化情况。并与纯钛表面进行比较。尤其在不同孔径的钛纳米管材料表面进行干细胞的培养，观察其粘附和分化能力，分析其与钛纳米管表面结构的相互关系。
3.应用负压吸附法在钛纳米管材料表面负载庆大霉素，计算其药物负载率。通过高分子聚合物覆盖，观察其对药物释放曲线的影响。在体外实验中，比较载药和未载药的钛纳米管材料表面的金葡菌的粘附生长情况，并同样进行成骨细胞培养观察载药是否会对钛纳米管的促成骨作用产生影响。在体内实验中，通过在小鼠双下肢的对照实验，比较载庆大霉素纳米管材料在体内对金葡菌的抑制作用。
结果：1.应用电化学阳极氧化法制备出钛纳米管材料，其在400°C热处理后主要为锐钛矿型，电镜下观察到其完整的纳米管形成的过程。控制不同的恒定电压可制备出不同孔径（随电压递增）的纳米管材料。
2.钛纳米管材料表面较纯钛对骨髓间充质细胞有显著的促进粘附，生长和分化的作用，不同孔径的钛纳米管材料表面对间充质干细胞的作用有所不同，管径小时促进其粘附和生长，管径大时干细胞形态变长，分化成骨能力增强。
3.钛纳米材料表面可有效负载庆大霉素，其释药曲线存在爆发性释放，在其表面覆盖高分子聚合物可有效延长其释放时间。体外实验证实载药钛纳米管材料可有效抑制金葡菌生长，并同时仍有促成骨作用。体内实验中载药钛纳米管可有效预防小鼠肢体感染。
结论：1.电化学阳极氧化法可简单有效制备钛纳米管材料，并可控制其表面结构参数。
2.钛纳米材料表面与成骨细胞系列有优良的生物相容性，促进材料表面成骨加强内植物骨融合稳定性。
3.钛纳米管材料表面可有效吸附抗菌药物，并具有有效的抗菌能力，对预防治疗假体周围感染具有良好的临床应用前景。
Prosthetic joint infection is the most serious complication after joint prosthesis replacements, causing the failure of the prosthesis or the limb mortality. There is no effective conservative way to eradicate the microorganisms. Then the prevention of the infection is extraordinary important. Owing to the ability to mimic the dimensions of constituent components of natural bone and possibility to serve as nanoreserviors for drug delivery, self-ordered nanotubular titania seems to be a promising coating for joint prosthesis to prevent the prosthetic joint infection and enhance the osseointegration.
Objective:In the first part, the purpose of the study is to fabricate the titania nanotubes using an anodization process, to analyze the surface microtopography and components and to study the correlation between the anodiztion voltage and the pore size of nanotubes. In the second part, the proliferation and differentiation of mesenchymal stem cells(MSCs) was investigated on the surface of titania nanotubes compared with titanium surface. The MSCs behavior in response to the different nanotube sizes also were explored. In the third part, the drug release kinetics from the titanium nanotubes loaded with gentamicin and the effect on Staphylococcus areus adhesion and proliferation were studied. Then the effects of the gentamicin-loaded titania nanotubes on the reduction of infection rates in a rat infection prophylaxis model were also explored.
Materials and methods:
1. TiO2nanotube arrays were fabricated in a two-eclectrochenmical cell using HF aqueous solution and the buffered electrolytes of NH4F and NH4H2PO4respectively at constant voltage. The surface elements composition was analyzed using X-ray electromagnetic pectrum. The crystal structures were analyzed using X-ray diffraction and the surface topography were observed with scanning electron microscope(SEM). We also measure the contact angle and the surface roughness. A series of voltages ranging rfom5V to25V were used to efbricate different diameter nanatubes on theanodized titanium sufraces.
2. Mesenchymal stem cells were isolated rfom C57BL/6mice and seeded onnanotubes ittanium sirfaces of different pore sizes along with titanium surfaces ascontrol group. The interaction of cells with these surfaces was investigated in terms ofthe ability to adhere, proliferate and differentiate on them. The cell viability wasinvestigated using a commercially available MTT assay. The cell morphology wasexamined using a lfuorescence microscope and SEM.
3. The nanotubes were loaded with gentamicin and the loading eiffciency wascalculated. The gentamicin release kinetics were investigated especially after titaniananotube coated with polymers. The effects of nanotube titanium loaded withgentamicin on Staphylococcus areus were investigated and the effects on bone cellstfinctionality were evaluated in vitro. Also the nanotube titanium loaded withgentamicin was inserted into the femora of the rat peirprosthetic infection model. Andthe inhibition of bacterial attachment and proliferation compared with controlnanotube titanium were investigated.
Results:
1. The anatase structure of Ti02nanotube surfaces were fabricated on the bulktitanium using an anodization technique and heattreated at400°C. The developmentrfom the bulk titanium to nanotubes ittanium was observed by SEM.The fabricationstrategies (to change the voltage or else) was able to precisely control the nanotubediameter and length.
2. The nanotubuular titania surfaces provide a efvorable template for the growthand differentiation of MSCs than lfat titanium surfaces. A very dramatic change inMSCs behavior in a relatively narrow range of nanotube dimensions was observed.Small nanotubes promoted adhesion without noticeable differentiation, whereas largernanotubes elicited a stem cell elongation, which dinduced cytoskeletal stress andselective differentiation into osteoblast-like cells.
3. The nanotubes titanium coiid be effectively iflled with the gentamicin and thebirst release in the ifrst6hours could be reduced by the biocompatible polymerscoating. The drug eluting nanotubes signiifcantly reduce bacterial adhesion on thesurfaces in vitro. The titanium nanotubes loaded with getamicin could suppressbacteiral colonization and prevent bioiflm formation in the rat infection model in vivo.
Conclusions:
1. Ti02nanotube arrays could be fabricated by electrochemical anodizationeffectively and economically. The parameters of nanotube structure could be preciselytuned.
2. Titanium nanotubes coiid enhance the osseointegration of the MSCs owing tothe excellent biocompatibility to the natural bone.
3. Titanium nanotubes iflled with antibacterial drugs could inhibit the adhesionand growing of the bacteiral in vitro and in vivo, which indicate a promising future fortherapy and prevention of prosthetic joint infections.
引文
[1]. National Hospital Discharge Survey. Survey results and products.Available atAtlanta: Center for Disease Control and Prevention, ;2009[last access14.09.10].
[2]. UK National Joint Registry. Available at,2009[last access14.09.10]
[3]. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of pri-mary and revision hip and knee arthroplasty in the United States from2005to2030. J Bone Joint Surg Am2007;89(4):780-5.
[4]. Kurtz SM, Ong KL, Lau E, Bozic KJ, Berry D, Parvizi J. Prosthetic joint infection risk after TKA in the Medicare population. Clin Orthop Relat Res2010;468:52-56
[5]Ong KL, Kurtz SM, Lau E, Bozic KJ, Berry DJ, Parvizi J. Prosthetic joint infection risk after total hip arthroplasty in the Medicare population. J Ar-throplasty2009;24:105-109
[6]Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RSJ, Barrack RL. Diagnosis of infected total knee:findings of a multicenter database. Clin Orthop Relat Res2008;466:2628-2633
[7]Volin SJ, Hinrichs SH, Garvin KL. Two-stage re-implantation of total joint infections:a comparison of resistant and non-resistant organisms. Clin Orthop Relat Res2004;427:94-100
[8]Cataldo MA, Petrosillo N, Cipriani M, Cauda R, Tacconelli E. Prosthetic joint infection:recent developments in diagnosis and management. J Infect.2010Dec;61(6):443-8. doi:10.1016/j.jinf.2010.09.033. Epub2010Oct7.
[9]Amann R, Fuchs BM. Single-cell identification in microbial commu-nities by improved fluorescence in situ hybridization techniques. Nat. Rev. Microbiol.2008;6:339-4
[10]Peel TN, Buising KL, Choong PF.Prosthetic joint infection:challenges of diagnosis and treatment. ANZ J Surg.2011Jan;81(1-2):32-9
[11]Gomez E, Cazanave C, Cunningham SA, Greenwood-Quaintance KE, Steckelberg JM, Uhl JR, Hanssen AD, Karau MJ, Schmidt SM, Osmon DR, Berbari EF, Mandrekar J, Patel R. Prosthetic joint infection diagnosis using broad-range PCR of biofilms dislodged from knee and hip arthroplasty surfaces using sonication.J Clin Microbiol.2012Nov;50(11):3501-8.
[12]Matar WY, Jafari SM, Restrepo C, Austin M, Purtill JJ, Parvizi J. Preventing infection in total joint arthroplasty. J Bone Joint Surg Am.2010Dec;92Suppl2:36-46.
[13]Lucke M, Wildemann B, Sadoni S, Surke C, Schiller R, Stemberger A, Raschke M, Haas NP, Schmidmaier G. Systemic versus local application of gentamicin in prophylaxis of implant-related osteomyelitis in a rat model.Bone.2005May;36(5):770-8. Epub2005Mar24.
[14]Stigter M, de Groot K, Layrolle P. Incorporation of tobramycin into biomimetic hydroxyapatite coating on titanium. Bio materials2002;3:4143-53.
[15]Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, Domann E, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless joint prostheses on the reduction of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[16]Lu YP, Li MS, Li ST, Wang ZG, Zhu RF. Plasma-sprayed hydroxyapatite+titania composite bond coat for hydroxyapatite coating on titanium substrate.Biomaterials.2004Aug;25(18):4393-403.
[17]Frutos Cabanillas P, Diez Pena E, Barrales-Rienda JM, Frutos G.Validation and in vitro characterization of antibiotic-loaded bone cement release. Int J Pharm2000;209:15-26.
[18]Price JS, Tencer AF, Arm DM, Bohach GA. Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res1996;30:281-6.
[19]Silverman LD, Lukashova L, Herman OT, Lane JM, Boskey AL Release of gentamicin from a tricalcium phosphate bone implant. J Orthop Res2007;25:23-9.
[20]Hanssen AD, Spangehl MJ. Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements.Clin Orthop Relat Res.2004;427:79-85
[21]Dyce J, Olmstead ML. Removal of infected canine cemented total hip prostheses using a femoral window technique. Vet Surg.2002;31:552-560.
[22]Neut D, van de Belt H, Stokroos I, van Horn JR, van der Mei HC, Busscher HJ. Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery.J Antimicrob Che-mother.2001;47:885-891.
[23]Youngman JR, Ridgway GL, Haddad FS. Antibiotic-loaded cement in revision joint replacement. Hosp Med.2003;64:613-616.
[24]Gosden PE, MacGowan AP, Bannister GC. Importance of air quality and related factors in the prevention of infection in orthopaedic implant surgery. J Hosp Infect.1998;39:173-180.
[25]Hopkins C.C. Recognition of endemic and epidemic prosthetic de-vice infections: the role of surveillance, the hospital infection control practitioner, and the hospital epidemiologist. Infect Dis Clin North Am.1989;3:211-220.
[26]Antoci V Jr, Adams CS, Hickok NJ, Shapiro IM, Parvizi J. Vancomycin bound to Ti rods reduces periprosthetic infection:preliminary study.Clin Orthop Relat Res.2007Aug;461:88-95.
[27]Kim HW, Kim HE, Salih V, Knowles JC. Hydroxyapatite and titania sol-gel composite coatings on titanium for hard tissue implants; mechanical and in vitro biological performance. J Biomed Mater Res B Appl Biomater.2005Jan15；72(1):1-8.
[28]Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC, Kent GM. The effect of porous surface configuration on the tensile strength of fixation of implants by bone ingrowth.Clin Orthop Relat Res.1980Jun;(149):291-8.
[29]Antoci V Jr, King SB, Jose B, Parvizi J, Zeiger AR, Wickstrom E, Freeman TA, Composto RJ, Ducheyne P, Shapiro IM, Hickok NJ, Adams CS. Vancomycin covalently bonded to titanium alloy prevents bacterial colonization.J Orthop Res.2007Jul;25(7):858-66.
[30]Antoci V Jr, Adams CS, Parvizi J, Davidson HM, Composto RJ, Freeman TA, Wickstrom E, Ducheyne P, Jungkind D, Shapiro IM, Hickok NJ. The inhibition of Staphylococcus epidermidis biofilm formation by vancomycin-modified titanium alloy and implications for the treatment of periprosthetic infection. Biomaterials.2008Dec;29(35):4684-90. doi:10.1016/j.biomaterials.2008.08.016. Epub2008Sep23.
[31]Balasundarama G, Webster TJ. A perspective on nanophase materials for orthopedic implant applications[J]. Mater Chem,2006,16:3737-3745
[32]Talmage DW, Talmage RV. Calcium homeostasis:how bone solubility relates to all aspects of bone physio logy. J Musculoskelet Neuronal Interact.2007Apr-Jun;7(2):108-12
[33]de Jonge LT, Leeuwenburgh SC, Wolke JG, Jansen JA. Organic-inorganic surface modifications for titanium implant surfaces.Pharm Res.2008Oct;25(10):2357-69. doi:10.1007/s11095-008-9617-0. Epub2008May29.
[34]Narayanan R, Seshadri SK, Kwon TY, Kim KH. Calcium phosphate-based coatings on titanium and its alloys.J Biomed Mater Res B Appl Biomater.2008Apr;85(1):279-99.
[35]Das K, Bose S, Bandyopadhyay A, Karandikar B, Gibbins BL. Surface coatings for improvement of bone cell materials and antimicrobial activities of Ti implants. J Biomed Mater Res B Appl Biomater.2008Nov;87(2):455-60. doi:10.1002/jbm.b.31125.
[36]Balasundaram G, Yao C, Webster TJ. TiO2nanotubes functionalized with regions of bone morphogenetic protein-2increases osteoblast adhesion[J]. Biomed Mater Res A.2008,84(2):447-453
[37]Edwards N, Mitchel SB,Pratt A. Silver compound antimicrobial composite European Patent Application,1987,251:783
[38]Liall SY,Read DC,Push WJ.Interaction of silver nitrate with readily identifiable groups:relationship to the antibacterial action of silver ions. Let Appl Micrebiol。1997,25:279-283.
[39]. Zhao L, Wang H, Huo K, Cui L, Zhang W, Ni H, Zhang Y, Wu Z, Chu PK. Antibacterial nano-structured titania coating incorporated with silver nanoparticles. Bio materials.2011Aug;32(24):5706-16. doi:10.1016/j.biomaterials.2011.04.040. Epub2011May12.
[40]Yao C, Balasundaram G, Webster T. Use of anodized titanium in drug delivery applications. Mater Res Soc Symp Proc V-01.2007.951E:28-29.
[41]Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA. Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes.Biomaterials.2007Nov;28(32):4880-8. Epub2007Aug13.
[42]. Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, Domann E, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless joint prostheses on the reduction of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[43]. Hersel U, Dahmen C, Kessler H. RGD modified polymers:biomaterials for stimulated cell adhesion and beyond.Biomaterials.2003Nov;24(24):4385-415.
[1] Mor GK，Prakasam HE, Varghese OK, Shankar K，Girmes CA. Vertically orientedTi-Fe-0nanotube array iflms: toward a useful mateiral architecture for solar spectrumwater photoelectrolysis. Nano Lett.2007Aug;7(8):2356-64. Epub2007Jul3.
[2] Mor GK, Varghese OK, Wilke RH, Sharma S，Shankar K, Latempa TJ，Choi KS，Grimes CA. P-type Cu--Ti--0nanotube arrays and their use in self-biasedheterojunction photoelectrochemical diodes ofr hydrogen generation. Nano Lett.2008Jul;8(7):1906-ll. doi:10.1021/nl080572y. Epub2008Jun10.
[3JIIJIMA S.Helical microtubules of graphitic carbon[J].Nature,1991,354:56-58.
[4]K. Varghese, D. Gong, M. Paulose, K. G. Ong，E. G. Die key and C. A. Grimes, Adv.Mater.,2003，15，624-627.
[5]G. K. M or, M. A. Caryalho, O. K. Varghese, M. V. Pishko andC. A. Grimes,J. Mater. Res.,2004,19,628-634.
[6]Varghese OK, Mor GK, Grimes CA, Paulose M, Mukherjee N. A titania nanotube-array room-temperature sensor for selective detection of hydrogen at low concentrations. J Nanosci Nanotechnol.2004Sep;4(7):733-7.
[7]M. Paulose, O. K. Varghese, G. K. Mor, C. A. Grimes andK. G. Ong, Nanotechnology,2006,17,398-402.
[8]Varghese OK, Paulose M, Shankar K, Mor GK, Grimes CA. Water-photolysis properties of micron-length highly-ordered titania nanotube-arrays.J Nanosci Nanotechnol.2005Jul;5(7):1158-65.
[9]G. K. M or, O. K. Varghese, R. H. T. Wilkie, S. Sharma,K. Shankar, T. J. Latempa, K. S. Choi and C. A. Grimes, NanoLett,2008,8,1906-19
[10]Linder L, Carlsson A, Marsal L, Bjursten LM, Bra°nemark PI.Clinical aspects of osseointegration in joint replacement. J Bone Joint Surg [Br]1988;70:550-555
[11]J. H. Jung, H. Kobayashi, K. J. C. van Bommel, S. Shinkai andT. Shimizu, Chem. Mater.,2002,14,1445-1447.
[12]B. B. Lakshmi, P. K. Dorhout and C. R. Martin, Chem. Mater.,1997,9,857-862.
[13]H. Imai, Y. Takei, K. Shimizu, M. M atsuda and H. Hirashima. J. Mater. Chem.,1999,9,2971-2972.
[14]A. Michailowski, D. Aimawlwai, G. S. Cheng and M. Moskovits,Chem. Phys. Lett.,2001,349,1-5.
[15]32S. Kobayashi, N. Hamasaki, M. Suzuki, M. Kimura, H.Shirai and K. Hanabusa, J.Am. Chem. Soc.,2002,124,6550-6551.
[16]Z. R. R. Tian, J. A. Voigt, J. Liu, B. Mckenzie and H. F. Xu, J. Am. Chem. Soc.2003,125,12384-12385.
[17]T. Kasuga, M. Hiramatsu, A. Hoson, T. Sekino and K. Niihara,Langmuir,1998,14,3160-3163.
[18]Webster TJ. Nanophase ceramics as improved bone tissue en-gineering materials. Am Ceram Soc Bull2003;82:1-8.
[19]. Ashley ET, Covington LL, Bishop BG, Breault LG Ailingand failing endosseous dental implants:A literature review.J Contemp Dent Pract2003;4:35-50.
[20]. Buser D, Nydegger T, Oxland T, Cochran DL, Schenk RK,Hirt HP, Snetivy D, Nolte LP. Interface shear strength of tita-niumimplants with a sanblasted and acid-etched surface:A biomechanicalstudy in the maxilla of miniature pigs.J Biomed Mater Res1999;45:75-83.
[21]. Webster TJ. Nanophase ceramics:The future of orthopedic anddental implant material. In:Ying JY, editor. Nanostructur-edmaterials. New York:Academy Press;2001. p125-166.
[22]. Bra°nemark PI, Hansson BO, Adell R, Breine U, Lindstro" mJ,Halle n O, Ohman A. Osseointegrated implants in the treat-ment of the edentulous jaw. Experience from a10-year pe-riod. Scand J Plast Reconstr Surg Suppl1977;16:1-132.
[23]Li P. Biomimetic nano-apatite coating capable of promoting bone ingrowth. J Biomed Mater Res A2003;66:79-85.
[24]Webster TJ, Ejiofor JU. Increased osteoblast adhesion on nanophase metals:Ti, Ti6A14V, and CoCrMo. Biomaterials2004;25:4731-4739.
[25]Popat KC, Leary Swan EE, Mukhatyar V, Chatvanichkul KI,Mor GK, Grimes CA, Desai TA. Influence of nanoporous alu-mina membranes on long-term osteoblast response. Biomate-rials2005;26:4516-4522.
[26]. Sato M, Sambito MA, Aslani A, Kalkhoran NM, SlamovichEB, Webster TJ. Increased osteoblast functions on undopedand yttrium-doped nanocrystalline hydroxyapatite coatings on titanium. Biomaterials2006;27:2358-2369.
[27]. Colon G, Ward BC, Webster TJ. Increased osteoblast anddecreased Staphylococcus epidermidis functions on nanophaseZnO and TiO2. J Biomed Mater Res A2006;78:595-604.
[28]Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA.Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nano-tubes. Biomaterials2007;28:4880-4888.
[29]Popat KC, Eltgroth M, LaTempa TJ, Grimes CA, Desai TA.Titania nanotubes:A novel platform for drug-eluting coatings for medical implants? Small2007;3:1878-1881.
[30]C.M. Lieber, Solid State Commun.1998,107,607.
[31]C. N. R. Rao, A. Mller, A. K. Cheetham, The Chemistry ofNanomaterials: Synthesis, Properties and Applications, Wiley-VCH, Weinheim, Germany,2006.
[32]C. Weisbuch, B. Vinter, Quantum Semiconductor Structures:Fundamentals and Applications, Elsevier, Amsterdam,1991.
[33]Vladkova R.Chlorophyll a self-assembly in polar solvent-water mixtures. Photochem Photobiol.2000Jan;71(1):71-83
[34]J. M. Macak, H. Tsuchiya, A. Ghicov, K. Yasuda, R. Hahn, S.Bauer, P. Schmuki,Curr. Opin. Solid State Mater. Sci.2007,11,3.
[35]I. Paramasivam, H. Jha, P. Schmuki, unpublished results.
[36]S. Bauer, P. Schmuki, J. Park, K. von der Mark, C. von Wil-mowsky, K. A. Schlegel, F. W. Neukam, unpublished results.
[37]Y. Suzuki, S. Yoshikawa, J.Mater. Res.2004,19,982.
[38]Eustis S, el-Sayed MA. Why gold nanoparticles are more precious than pretty gold:noble metal surface plasmon resonance and its enhancement of the radiative and nonradiative properties of nanocrystals of different shapes.Chem Soc Rev.2006Mar;35(3):209-17.Epub2005Dec16.
[39]G. H. Du, Q. Chen, R. C. Che, Z. Y. Yuan, L. M. Peng, Appl.Phys. Lett.2001,79,3702-3704;
[40]M. Adachi, Y. Murata, S. Yoshikawa. Chem. Lett.2000,29,942.
[41]M. Adachi, Y. Murata, I. Okada, S. Yoshikawa, J. Electro-chem. Soc.2003,150, G488.
[42]H. H. Ou, S. L. Lo, Sep. Purif. Technol.2007,58,179.
[43]S. Uchida, R. Chiba, M. Tomiha, N. Masaki, M. Shirai,Electrochemistry2002,70,418.
[44]Zwilling V, Darque-Ceretti E, Boutry-Forveille A, David D, Perrin MY, Aucouturier M. Structure and physicochemistry of anodic oxide films on titanium and TA6V alloy. Surf. Interface Anal (1999),27,629-637
[45]D. Gong, C. A. Grimes, O. K. Varghese, W. Hu, R. S. Singh,Z. Chen and E. C Dickey, J. Mater. Res.,2001,16,3331-3334.
[46]E. Balaur, J. M. Macak, H. Tsuchiya and P. Schmuki, J. Mater.Chem.,2006,15,4488-4891.
[47]K. Shankar, G. K. Mor, A. Fitzgerald and C. A. Grimes, J. Phys.Chem. C,2007,111,21-26
[48]43E. Balaur, J. M. Macak, H. Tsuchiya and P. Schmuki, J. Mater.Chem.,2006,15,4488-4891.
[49]J. M. Macak and P. Schmuki, Electrochim. Acta,2006,52,1258-1264.
[50]V. Zwilling, M. Aucouturier and E. Darque-Ceretti, Electrochim.Acta,1999,45,921-929.
[51]46V. Zwilling, E. Darque-Ceretti, A. Boutry-Forveille, M. Y. Perrinand M. Aucouturier, Surf. Interface Anal.,1999,27,629-637.
[52]S. Yoriya, H. E. Prakasam, O. K. Varghese, K. Shankar,M. Paulose, G. K. Mor, T. J. Latempa and C. A. Grimes,Sens.Lett.,2006,4,334-339.
[53]K. Shankar, G. K. Mor, A. Fitzgerald and C. A. Grimes, J. Phys.Chem. C,2007,111,21-2
[54]58N. K. Allam, K. Shankar and C. A. Grimes, J. Mater. Chem,2008,18,2341-2346.
[55]X. Chen, M. Schriver, T. Suen and S. S. Mao. Thin Solid Films,2007,515,8511-8514.
[56]J. P. Frayret, R. Pointeau and A. Caprani, Electrochim. Acta,1981,26,1783-1788.
[57]Albu SR, Kim D, Schmuki P. Growth of aligned TiO2bamboo-type nanotubes and highly ordered nanolace. Angew. Chem. Int. Ed. Engl.47(10),1916-1919(2008).
[58]Bauer S, Kleber S, Schmuki P. TiO2nanotubes:tailoring the geometry in H3PO4/HF electrolytes. Electrochem. Commun.2006,8(8),1321-1325.
[59]H. Tsuchiya, S. Berger, J. M. Macak, A. Ghicov, P. Schmuki,Electrochem. Commun.2007,9,2397.
[60]S. Berger, H. Tsuchiya, P. Schmuki, Chem. Mater.2008,20,3245.
[61]Parkhutik V P, Shershulsky V I. Phys. D. Appl. Phys.1992,25:1258-1263
[62]Lee W J, Alhoshan M, Smyrl W H.J. Electrochem. Soc.20116,153:499-505
[1]WebsterTJ. Nanophase ceramics as improved bone tissue engineer-ing mateirals.Am Ceram Soc Bull2003;82(6):1—8
[2]HulbertSF, Morirson SJ, Klawitter JJ. Tissue reaction to three ceramics of porousand non-porous structures. J Biomed Mater Res1972;6(5):347—74
[3]BobynJD, Pilliar RM, Cameron HU, Weatherly GC. The optimum pore size forthe ifxation of porous-sirfaced metal implants by the ingrowth of bone. Clin OrthopRelat Res1980(150):263-70.
[4]LeeTM，Wang BC，Yang YC，Chang E, Yang CY. Compairson of plasma-sprayedhydroxyapatite coatings and hydroxyapatite/trical-cium phosphate composite coatings:in vivo study. J Biomed Mater Res2001;55(3):360-7.
[5]PopatKC，Daniels RH, EXibrow RS, Hardev V，Desai TA. Nanostructured surfacesfor bone bio temp lating applications. J Orthop Res2006;24(4):619-27.
[6]Popat KC, Leary Swan EE, Mukhatyar V, Chatvanichkul KI, Mor GK, Girmes CA,et al. Inlfuence of nanoporous alumina membranes on long-term osteoblast response.Bio materials2005；26(22):4516-22.
[7]Swan EE，Popat KC，Desai TA. Peptide-immobilized nanoporous aluminamembranes for enhanced osteoblast adhesion. Biomaterials2005;26(14):1969-76.
[8]Swan EE，Popat KC, Grimes CA，Desai TA. Fabrication and evaluation ofnanoporous alumina membranes for osteoblast culture. J Biomed Mater Res A2005;72(3):288-95.
[9]BauerTW, Taylor SK，Jiang M，Medendorp SV. An indirect compairson ofthird-body wear in retrieved hydroxyapatite-coated, porous, and cemented femoralcomponents. Clin Orthop Relat Res1994(298):11-8.
[10]Bloebaum RD, Beeks D，Dorr LD, Savory CG，DuPont JA, Hofmann AA.Complications with hydroxyapatite particulate separation in total hip arthroplasty.Clin Orthop Relat Res1994(298):19-26.
[11]LinderL, Carlsson A, Marsal L, Bjursten LM, Branemark PL Clinical aspects ofosseointegration in joint replacement. A histological study of titanium implants. JBone Joint Surg Br1988;70:550.
[12]Pilliar RM, Lee LJ, Maniatopoulos C. Observation on the effect of movement onbone ingrowth into porous-sirfaced implants. Clin Orthop Rel Res1986;208:108.
[13]Satomi K, Akagawa Y, Nikai H，Tsiru H. Bone-implant interface structures atfernontapping and tapping insertion of screw-type titanium alloy endosseous implants. JProsthet Dent1988;59:339.
[14]Feng B，Weng J，Yang BC，Qu SX，Zhang XD. Characterization of surface oxideiflms on titanium and adhesion of osteoblast. Bioma-teirals2003;24:4663.
[15]Puleo DA, Holleran LA, Doremus RH, Bizios R. Osteoblast responses toorthopedic implant materials in vitro. J Biomed Mater Res1991;25:711.
[16]Salata O. Applications of nanoparticles in biology and medicine. JNanobio technology2004;2:3.
[17]Satsangi A, Satsangi N，Glover R, Satsangi RK, Ong JL. Osteoblast response tophospholipid modiifed titanium sirface. Biomateirals2003;24:4585
[18]WuC，Ramaswamy Y, Liu X，Wang G，Zreiqat H. Plasma-sprayed CaTiSi05ceramic coating on Ti-6A1-4V with excellent bonding strength, stability and cellularbioactivity. J R Soc Interface2009;6(31):159-68.
[19]Liu X，Morra M，Carpi A, Li B. Bio active calcium silicate ceramics and coatings.Biomed Pharmacother2008;62(8):526—9.
[20]MacakJM，Tsuchiya H，Ghicov A，Yasuda K，Hahn R, Bauer S，Schmuki P.Self-organized electrochemical formation, properties and applications. Ciu*r OpinSolid State Mater Sci2007;11:3-18.
[21]SunH，Wu C，Dai K，Chang J，Tang T. Proliferation and osteoblasticdifferentiation of human bone marrow-derived stromal cells on akermanite-bioactiveceramics. Biomaterials2006;27:5651-5657.
[22]GregoryCA，Gunn WG，Peister A，Prockop DJ. An Alizairn red-based assay ofmineralization by adherent cells in culture: Comparison with cetylpyridinium chlorideextrac-tion. Anal Biochem2004;329:77-84.
[23]Chirstenson EM, Anseth KS，van den Beucken JJ, Chan CK，Ercan B，Jansen JA，Laurencin CT, Li WJ, Mirugan R, Nair LS, Ramakrishna S，Tuan RS, Webster TJ,Mikos AG. Nanobiomaterial applications in orthopedics. J Orthop Res.2007Jan;25(l):ll-22.
[24]McNamara LE, McMurray RJ, Biggs MJ，Kantawong F, Oreffo RO, Dalby MJ.Nanotopographical control of stem cell differentiation.J Tissue Eng.2010Aug18;2010:120623. doi:10.4061/2010/120623.
[25]NakaharaH, Dennis JE, Bruder SP, Haynesworth SE，Lennon DP, Caplan AL Invitro differentiation of bone and hyper-trophic cartilage rfom peirosteal-deirved cells.Exp Cell Res1991;195:492-503.
[26].Service RF. Tissue engineers build new bone. Science2000;289:1498.
[27].Wakitani S，Saito T, Caplan AL Myogenic cells derived rfom rat bone marrowmesenchymal stem cells exposed to5-azacy-tidine. Muscle Nerve1995;18:1417-1426.
[28]Webster TJ，Ejiofor JU. Increased osteoblast adhesion on nanophase metals: Ti,Ti6A14V，and CoCrMo. Biomateirals2004;25(19):4731—9.
[29]Webster TJ, Ergun C，Doremus RH, Siege1RW, Bizios R. Enhanced tfincitons ofosteoblasts on nanophase ceramics. Biomaterials2000;21(17):1803-10.
[30]Dalby MJ，McCloy D，Robertson M，Agheli H，Sutherland D，Afrfossman S，et al.Osteoprogenitor response to semi-ordered and random nanotopographies.Biomaterials2006;27(15):2980-7.
[38] Dalby MJ, McCloy D，Robertson M，Wilkinson CD，Oreffo RO. Osteoprogenitorresponse to deifned topographies with nanoscale depths. Biomateirals2006;27(8):1306-15.
[32] Meng S，Zhang Z, Rouabhia M. Accelerated osteoblast mineralization on aconductive substrate by multiple electrical stimulation. J Bone Miner Metab.2011Sep;29(5):535-44. doi:10.1007/s00774-010-0257-l.Epub2011Feb17.
[33] Forsprecher J，Wang Z, Goldberg HA, Kaartinen MT. Transglutaminase-mediatedoligomerization promotes osteoblast adhesive properties of osteopontin and bonesialoprotein. Cell Adh Migr.2011Jan-Feb;5(l):65-72. doi:10.4161/cam.5.1.13369.Epub2011Jan1.
[34] Park J, Bauer S, Schlegel KA, Neukam FW, von der Mark K, Schmuki P. Ti02nanotube surfaces:15nm—an optimal length scale of surface topography for celladhesion and differentiation. Small.2009Mar;5(6):666-71. doi:10.1002/smll.200801476.
[35] Park J，Bauer S，von der Mark K，Schmuki P. Nanosize and vitality: Ti02nanotube diameter directs cell fate. Nano Lett.2007Jun;7(6):1686-91. Epub2007May16.
[36] Hosseinkhani H，Hosseinkhani M，Tian F, Kobayashi H，Tabata Y. Osteogenicdifferentiation of mesenchymal stem cells in self-assembled peptide-anphiphilenanofibers. Biomaterials.2006Aug;27(22):4079-86. Epub2006Apr5.
[37] Lavenus S，Berreur M，Tirchet V，Pilet P, Louarn G, Layrolle P. Adhesion andosteogenic differentiation of human mesenchymal stem cells on titanium nanopores.Eur Cell Mater.2011Aug26;22:84-96; discussion96.
[38]Yao C, Slamovich EB，Webster TJ. Enhanced osteoblast fiinc-tions on anodizedtitanium with nanotube-like structures. J Biomed Mater Res A2008;85:157-166.
[39] On*AW, Helmke BP, Blackman BR, Schwartz MA. Mechanisms ofmechanotransduction. Dev Cell.2006Jan;10(l):ll-20.
[40] Dalby MJ，Gadegaard N，Tare R，Andar A, Riehle MO, Herzyk P, Wilkinson CD，Oreffo RO. The control of human mesenchymal cell differentiation using nanoscalesymmetry and disorder. Nat Mater.2007Dec;6(12):997-1003. Epub2007Sep23.
[41] Dalby MJ, McCloy D，Robertson M，Agheli H，Sutherland D，Afrfossman S,Oreffo RO. Osteoprogenitor response to semi-ordered and random nanotopographies.Bio materials.2006May;27(l5):2980-7. Epub2006Jan27.
[42] Engler AJ, Sen S，Sweeney HL, Discher DE. Matrix elasticity directs stem celllineage specification. Cell.2006Aug25;126(4):677-89.
[1] Drews J. Drug discovery: a historical perspective. Science.2000Mar17;287(5460):1960-4
[2], Mainardes RM, Silva LP. Drug delivery systems: past, present, and future. Ciu*rDrug Targets.2004Jul;5(5):449-55.
[3], Fahr A，Liu X. Drug delivery strategies for poorly water-soluble drugs. ExpertOpin Drug Deliv.2007Jul;4(4):403-16.
[4], El-Aneed A. An overview of current delivery systems in cancer gene therapy.JControl Release.2004Jan8;94(1):1-14.
[5]Amiji MM. Nanotechnology for targeted drug and gene delivery.Nanome dNanotechnol Biol Med2006;2:299-300
[6] Kayser0，Lemke A，Trejo NH. The impact of nanobiotechnology on thedevelopment of new drug delivery systems. Ciu*r Pharm Bio techno12005;6:3-5
[7]De Villiers MM，Aramwit P, Kwon GS. Eds. Nanotechnology in drug delivery.Spirnger, AAPS Press2009
[8] Van D，McGuire T, Langer R. Small scale systems ofr in vivo drug delivery.NatBiotechnol2003;21:1184-91
[9] Wei C, Wei W, Morris M, Kondo E, Gorbounov M, Tomalia DA. Nanomedicineand drug delivery. Med Clin North Am.2007Sep;91(5):863-70.
[10] Hughes GA. N anostructure-mediated drug delivery. N anome dicine，Nanotechnology, Biology and Medicine2005;1:22-30
[11]Vallet-Regi' M. Balas F. Arcos D Mesoporous Mateirals for Drug DeliveryAngew Chem Int Ed2007;46:7548-58
[12] Wang S. Ordered mesoporous materials for drug delivery. MicroporousMesoporous Mater2009;l17:1-9
[13]Son SJ，Bai X，Nan A, et al. Template synthesis of multifunctional nanotubes forcontrolled release. J Controlled Release2006;114:143-52
[14]Schmid G. Materials in nanoporous alumina. J Mater Chem2002;12:1231-8
[15]Ghicov A，Schmuki P. Self-ordering electrochemistry: a review on growth andtfinctionality of Ti02nanotubes and other self-aligned MOx structures. ChemCommun2009;20:2791-808
[16]Grimes CA. Synthesis and application of highly ordered arrays of Ti02nanotubes.J Mater Chem2007;17:1451-7
[17] Jain AK, Panchagnula R. Skeletal drug delivery systems. Int J Pharm.2000Sep25;206(1-2):1-12.
[18] Drews J.Intent and coincidence in pharmaceutical discovery. The impact ofbiotechnology. Arzneimittelforschung.1995Aug;45(8):934-9
[19] Mainardes RM, Silva LP. Drug delivery systems: past, present, and future. Ciu*rDrug Targets.2004Jul;5(5):449-55.
[20] Buchholz HW, Els on RA, Engelbrecht E, Lodenkamper H，Rottger J，Siegel A.Management of deep infection of total hip replacement J Bone Joint Siu*g Br.1981;63-B(3):342-53.
[21] Soimdrapandian C，Sa B，Datta S. Organic-inorganic composites for bone drugdelivery. AAPS PharmSciTech.2009;10(4):1158-71. doi:10.1208/sl2249-009-9308-0.Epub2009Oct20.
[22] Simchi A，Tamjid E, Pishbin F, Boccaccini AR. Recent progress in inorganic andcomposite coatings with bactericidal capability for orthopaedic applications.Nanomedicine.2011Feb;7(l):22-39. doi:10.1016/j.nano.2010.10.005. Epub2010Nov2.
[23] Lewis G. Alternative acrylic bone cement formulations for cementedarthroplasties: present status, key issues, and future prospects J Biomed Mater Res BAppl Bio mater.2008Feb;84(2):301-19.
[24] Hoppe A，Giildal NS，Boccaccini AR. A review of the biological response toionic dissolution products from bioactive glasses and glass-ceramics. Biomateirals.201lApr;32(l1):2757-74. doi:10.1016/j.biomaterials.2011.01.004. Epub2011Feb2.
[25] Wu C，Chang J，Xiao Y. Mesoporous bioactive glasses as drug delivery andbone tissue regeneration platforms. Therapeutic Delivery2(9),1189-1198(2011).
[26] Arcos D，Vallet-Regi M. Sol-gel silica-based biomateirals and bone tissueregeneration. Acta Bio mater.2010Aug;6(8):2874-88. doi:10.1016/j.actbio.2010.02.012. Epub2010Feb10.
[27] Cerruti M，Sahai N. Silicate biomateirals for orthopedic and dental implants.Rev. Mineral Geochem.2006;64:283-313.
[28]Torrado S，Frutos P, Frutos G. Gentamicin bone cements: characteirsation andrelease (in vitro and in vivo assays). Int. J. Pharm2001;217(1-2):57-69.
[29] Timko BP, Whitehead K，Gao W. Advances in drug delivery. In: AnnualReview of Materials Research, Volume41. Annual reviews, Palo Alto, CA，USA，1-20(2011).
[30] Losic D，Simovic S. Self-ordered nanopore and nanotube platforms for drugdelivery applications. Expert Opin Drug Deliv.2009Dec;6(12):1363-81. doi:10.1517/17425240903300857.
[31]Gristina AG，Oga M，Webb LX, Hobgood CD. Adherent bacterial colonizationinthe pathogenesis of osteomyelitis. Science1985;228:990-3
[32]Nelson CL. The ciurent status of material used for depot delivery of drugs.Clinical Orthopaedics and Related Research2004;427:72-8.
[33]Burny F, Donkerwolcke M，Moulart F, Bourgois R, Puers R, Van SchuylenberghK，et al. Concept, design and fabrication of smart orthopedic implants. MedicalEngineering and Physics2000;22:469-79.
[34] Fairman R, Akerfeldt KS. Peptides as novel smart materials. Ciurent Opinion inStructural Biology2005;15:453-63.
[35]Popat KC，Eltgroth M，La Temp a TJ. Titania nanotubes: A novel platform fordrug-eluting coatings for medical implants. Small2007;3:1878-81
[36] Gulati K，Aw MS，Findlay D，Losic D. Local drug delivery to the bone bydrug-releasing implants: perspectives of nano-engineered titania nanotube arrays.Ther Deliv.2012Jul;3(7):857-73.
[37] Gulati K, Ramakirshnan S，Aw MS, Atkins GJ, Findlay DM, Losic D.Biocompatible polymer coating of titania nanotube arrays for improved drug elutionand osteoblast adhesion. Acta Bio mater.2012Jan;8(1):449-56. doi:10.1016/j.actbio.2011.09.004. Epub2011Sep8.
[38]Martin HJ, Schulz KH，Bumgardner JD，Schneider JA. Enhanced bonding ofchitosan to implant quality titanium via four treatment combinations. Thin Solid Films2008;516(18):6277—86.
[39] Smith LJ，Swaim JS，Yao C，Haberstroh KM，Naiman EA，Webster TJ. Increasedosteoblast cell density on nanostructured PLGA-coated nanostructured titanium fororthopedic applications. Int J Nanomed2007;2(3):493-9.
[40]Ueno H, Yamada H, Tanaka I，Kaba N, Matsuura M, Okimura M. Acceleratingeffects of chitosan for healing at early phase of experimental open wound in dogs.Bio materials1999;20(15):1407-14.
[41] Kinrg S，Devlin H，Fu E, Ho KY, Liang SY, Hsieh YD. The osteoinductive effectof chitosan-collagen composites around piu*e titanium implant surfaces in rats. JPeirodontal Res2011;46(1):126-33.
[42] Webster TJ, Smith TA. Increased osteoblast function on PLGA compositescontaining nanophase titania. J Biomed Mater Res Part A2005;74A(4):677-86
[43]An YH, Freidman RJ. Concise review of mechanisms of bacterial adhesion tobiomaterial surfaces. J Biomed Mater Res1998;43:33848.
[44] Antoci V Jr, Adams CS，Hickok NJ，Shapiro IM，Parvizi J. Vancomycin boiuid toTi rods reduces periprosthetic infection: preliminary study. Clin Orthop Relat Res.2007Aug;461:88-95.
[1]. National Hospital Discharge Survey. Survey results and products.Available at Atlanta: Center forDisease Control and Prevention<, http://www.cdc.gov/nchs/nhdsdt_proucts.hml>;2009[last access14.09.10].
[2]. UK National Joint Registry. Available at,2009[last access14.09.10]
[3]. Kurtz S, Ong K, Lau E, Mow at F, Halpern M. Projections of pri-mary and revision hip and kneearthroplasty in the United States from2005to2030.J Bone Joint Surg Am2007;89(4):780-5.
[4]. Spormann C, AchermannY, Simmen BR, Schwyzer HK, Vogt M, Goldhahn J, Kolling C.Treatment strategies for periprosthetic infections after primary elbow arthroplasty. J Shoulder ElbowSurg.2012Aug;21(8):992-1000. Epub2012Jan4.
[5]. Spangehl MJ, Masri BA, Oconnell JX, Dun-can CP. Prospective analysis of preoperative andintraoperative investigations for the diagnosis of infection at the sites of two hundred. J Bone JointSurg Am.1999May;81(5):672-83
[6]. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med.2004Oct14;351(16):1645-54.
[7]. Hsieh PH, Lee MS, Hsu KY, Chang YH, Shih HN, Ueng SW. Gram-negative prosthetic jointinfections: risk factors and outcome of treatment. Clin Infect Dis2009;49(7):1036-43.
[8]. Maria Adriana Cataldo, Nicola Petrosillo, Michela Cipriani,Roberto Cauda, EvelinaTacconelli.Prostheti c joint infecti on: Recent developments in diagnosis and management. Journalof Infection.2010;61:443-448
[9].24. Salgado CD, Dash S, Cantey JR, Marculescu CE. Higher risk of failure of methicillin-resistantStaphylococcus aureus prosthetic joint infections. Clin Orthop Relat Res2007;461:48-53
[10]. Pechous R, Ledala N, Wilkinson BJ, Jayaswal RK. Regulation of the expression of cell wallstress stimulon member gene msrAl in methicillin-susceptible or-resistant Staphylococcus aureus.Antimicrob Agents Chemother.2004Aug;48(8):3057-63.
[11]. Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections.Infect Dis Clin North Am.2005Dec;19(4):885-914.
[12]. Berbari EF, Marculescu C, Sia I, Lahr BD, Hans sen AD, Steckelberg JM, Gullerud R, OsmonDR.Culture-negative prosthetic joint infection. Clin Infect Dis.2007Nov l;45(9):1113-9. Epub2007Sep26.
[13]. Lauderdale KJ, Malone CL, Boles BR, Morcuende J, Horswill AR. Biofilm dispersal ofcommunity-associated methic illin-res is tant Staphylococcus aureus on orthopedic implant material.JOrthop Res.2010Jan;28(l):55-61.
[14].Mah TF, Pitts B, PellockB, Walker GC, Stewart PS, O'Toole G A A genetic basis forPseudomonas aeruginosa biofilm antibiotic resistance. Nature2003;426:306-10.
[15]. Nuryastuti T, Krom BP, Aman AT, Busscher HJ, van der Mei HC. Ica-expression and gentamicinsusceptibility of Staphylococcus epidermidis biofilm on orthopedic implant biomaterials.J BiomedMater Res A.2011Feb;96(2):365-71.
[16]. Yao Y, Sturdevant DE, Otto M. Genomewide analysis of gene expression in Staphylococcusepidermidis biofilms: insights into the pathophysiology of S. epidermidis biofilms and the role ofphenol-soluble modulins in formation of biofilms. J Infect Dis.2005Jan15;191(2):289-98. Epub2004Dec10.
[17]. Wolz C, Goerke C, Landmann R, Zimmerli W, Fluckiger U. Transcription of clumping factor Ain attached and unattached Staphylococcus aureus in vitro and during device-related infection.InfectImmun.2002Jun;70(6):2758-62.
[18]. Darouiche RO. Device-associated infections: a macroproblem that starts with microadherence.Clin Infect Dis.2001Nov l;33(9):1567-72. Epub2001Sep26.
[19]. Schwank S, Rajacic Z, Zimmerli W&Blaser J. Impact of bacterial biofilm formation on in vitroand in vivo activities of antibiotics. Antimicrobial Agents and Chemotherapy1998;42(4):895-898.
[20]. Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP. The involvementof cell-to-cell signals in the development of a bacterial biofilm. Science.1998Apr10;280(5361):295-8.
[21]. Lee LY, Ong SL, Ng WJ. Biofilm morphology and nitrification activities: recovery of nitrifyingbiofilm particles covered with heterotrophic outgrowth. Bioresour Technol.2004Nov;95(2):209-14.
[22]. Sheldon AT Jr. Antibiotic resistance: a survival strategy. Clin Lab Sci.2005Summer;18(3):170-80.
[23]. Bernthal NM, Stavrakis AI, Billi F, Cho JS, Kremen TJ, Simon SI, Cheung AL, Finerman GA,Lieberman JR, Adams JS, Miller LS. A mouse model of post-arthroplasty Staphylococcus aureus jointinfection to evaluate in vivo the efficacy of antimicrobial implant coatings. PLoS One.2010Sep7;5(9):el2580.
[24] Darouiche RO, Dhir A, Miller AJ, Landon GC, Raad II, Musher DM. Vancomycin penetrationinto biofilm cover-ing infected prostheses and effect on bacteria. J Infect Dis1994;170:720-3.
[25]. Lewis K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc)2005;70:267-74.
[26]. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol2002;292:107-13
[27]. Roberts ME, Stewart PS. Modelling protection from antimicrobial agents in biofilms through theformation of persister cells. Microbiology2005;151:75-80.
[28]. Bays ton R. Biofilms and prosthetic devices. In: Community structure and cooperation inbiofilms (eds. Allison D G, Gilbert P, Lappin-Scott H M, Wilson M). Cambridge university press2000:295-308
[29]. Vaudaux P, Kelley W L, Lew D P. Staphylococcus aureus small colony variants: difficult todiagnose and difficult to treat. Clin Infect Dis2006;43:968-70
[30]. Von Eiff C, Proctor R A, Peters G. Staphylococcus aureus small colony variants: formation andclinical impact. Int J Clin Pract2000;115: S44-9.
[31]. Trampuz A, Piper KE, Jacobson MJ, Hans sen AD, Unni KK, Osmon DR, Mandrekar JN,Cockerill FR, Steckelberg JM, Greenleaf JF, Patel R.Sonication of removed hip and knee prosthesesfor diagnosis of infection. N Engl J Med.2007Aug16;357(7):654-63.
[32].Spanu T, Romano L, D'Inzeo T, Masucci L, Albanese A, Papacci F, Marchese E, Sanguinetti M,Fadda G. Recurrent ventriculoperitoneal shunt infection caused by small-colony variants ofStaphylococcus aureus. Clin Infect Dis2005;41:48-52
[33]. Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C. Interleukin-6, procalcitoninand TNF-alpha: markers of peri-prosthetic infection following total joint replacement. J Bone JointSurg Br.2007Jan;89(1):94-9.
[34]. Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RS, Barrack RL. Diagnosis of infectedtotal knee: findings of amulticenter database.Clin Orthop Relat Res.2008Nov;466(ll):2628-33.Epub2008Sep10.
[35]. Miiller M, Morawietz L, Has art O, Strube P, Perka C, Tohtz S. Diagnosis of periprostheticinfection following total hip arthroplasty—evaluation of the diagnostic values of pre-andintraoperative parameters and the associated strategy to preoperatively select patients with a highprobability of joint infection. J Orthop Surg Res.2008Jul21;3:31.
[36].Frances Borrego A, Martinez FM, Cebrian Parra JL, Graneda DS,Crespo RG, Lopez-Duran SternL. Diagnosis of infection in hip and knee revision surgery: intraoperative frozen section analysis.Int. Orthop.2007;31:33-7
[37]. Sendi P, Frei R, Maurer TB, Trampuz A, Zimmerli W, Graber P. Escherichia coli variants inperiprosthetic joint infection: diagnostic challenges with sessile bacteria and sonication.J ClinMicrobiol.2010May;48(5):1720-5. Epub2010Mar24.
[38] Sorli L, Puig L, Torres-Claramunt R, Gonzalez A, Alier A, Knobel H, Salvado M, Horcajada JP.The relationship between microbiology results in the second of a two-stage exchange procedure usingcement spacers and the outcome after revision total joint replacement for infection: the use ofsonication to aid bacteriological analysis.J Bone Joint Surg Br.2012Feb;94(2):249-53.
[39]. Fihman V, Hannouche D, Bousson V, Bardin T, Liote F, Raskine L, Riahi J, Sanson-Le Pors MJ,Bergot. Improved diagnosis specificity in bone and joint infections using molecular techniques.J Infect.2007Dec;55(6):510-7. Epub2007Oct29.
[40] Amann R, Fuchs BM. Single-cell identification in microbial commu-nities by improvedfluorescence in situ hybridization techniques. Nat.Rev. Microbiol.2008;6:339^
[41] Peel TN, Buising KL, Choong PF.Prosthetic joint infection: challenges of diagnosis and treatment.ANZJ Surg.2011Jan;81(l-2):32-9
[42] Gomez E, Cazanave C, Cunningham SA, Greenwood-Quaintance KE, Steckelberg JM, Uhl JR,Hanssen AD, Karau MJ, Schmidt SM, Osmon DR, Berbari EF, Mandrekar J, Patel R. Prosthetic jointinfection diagnosis using broad-range PCR of biofilms dislodged from knee and hip arthroplastysurfaces using sonic ation.J Clin Microbiol.2012Nov;50(11):3501-8.
[43]. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med.2009Aug20;361(8):787-94.
[44]. Hofmann AA, Goldberg TD, Tanner AM, Cook TM. Ten-year experience using an articulatingantibiotic cement hip spacer for the treatment of chronically infected total hip. J Arthroplasty.2005Oct;20(7):874-9.
[45].Hofmann AA, Goldberg, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplastyusing an articulating spacer:2-to12-year experience. Clin Orthop Relat Res.2005;430(1):125-131
[46] Jackson WO, Schmalzried TP. Limited role of direct exchange arthroplasty in the treatment ofinfected total hip replacements. Clin Orthop Relat Res.2000;(381):101-105.
[47]. Buechel FF. The infected total knee arthroplasty: just when you thought it was over. JArthroplasty.2004;19(4suppl1):51-55.
[48]. Berdal JE, Skramm I, Mowinckel P, Gulbrandsen P, Bj0rnholt JV. Use of rifampicin andciprofloxacin combination therapy after surgical debridement in the treatment of early manifestationprosthetic joint infections. Clin Microbiol Infect.2005Oct;ll(10):843-5.
[49]. Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L,et al. Linezolid in the treatmentof gram-positive prosthetic joint infections. J Antimicrob Chemother2005;55(3):387-90.
[50]. Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L, Pipino F, Cruciani M, BassettiD. Linezolid in the treatment of Gram-positive prosthetic joint infections.J Antimicrob Chemother.2005Mar;55(3):387-90. Epub2005Feb10.
[51]. Nguyen S, Pasquet A, Legout L, Beltrand E, Dubreuil L, Migaud H, Yazdanpanah Y, SennevilleE. Efficacy and tolerance of rifampicin-linezolid compared with rifampicin-cotrimoxazolecombinations in prolonged oral therapy for bone and joint infections. Clin Microbiol Infect.2009Dec;15(12):1163-9. Epub2009May4.
[52].Falagas ME, Giannopoulou KP, Ntziora F, Papagelopoulos PJ.Daptomycin for treatment ofpatients with bone and joint in-fections: a systematic review of the clinical evidence. Int J AntimicrobAgents2007Sep;30(3):202-9.
[53]. Smith K, Perez A, Ramage G, Gemmell CG, Lang S. Comparison of biofilm-associated cellsurvival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to theantibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin. Int J Antimicrob Agents.2009Apr;33(4):374-8. Epub2008Dec19.
[54]. Matar WY, Jafari SM, Restrepo C, Austin M, Purtill J J, Parvizi J. Preventing infection in totaljoint arthroplasty. J Bone Joint Surg Am.2010Dec;92Suppl2:36-46.
[55]. Lucke M, Wildemann B, Sadoni S, Surke C, Schiller R, Stemberger A, Raschke M, Haas NP,Schmidmaier G. Systemic versus local application of gentamicin in prophylaxis of implant-relatedosteomyelitis in a rat model.Bone.2005May;36(5):770-8. Epub2005Mar24.
[56]. Stigter M, de Groot K, Layrolle P. Incorporation of tobramycin into biomimetic hydroxy apatitecoating on titanium. Biomaterials2002;3:4143-53.
[57]. Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, DomannE, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless jointprostheses on the reduciton of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[58] Ere an B, Kummer KM, Tarquinio KM, Webster TJ. Decreased Staphylococcus aureus biofilmgrowth on anodized nanotubular titanium and the effect of electrical stimulation. Acta Biomater.2011Jul;7(7):3003-12.
[59] Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA.B Decreased Staphylococcusepidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nano tubes.Biomaterials.2007Nov;28(32):4880-8. Epub2007Aug13.
[60] Gulati K, Aw MS, Losic D. Drug-eluting Ti wires with titania nanotube arrays for bone fixationand reduced bone infection.Nanoscale Res Lett.2011Oct31;6:571.
[61] Antoc i V Jr, Adams CS, Parvizi J, Davidson HM, Compos to RJ, Freeman TA, Wicks trom E,Ducheyne P, Jungkind D, Shapiro IM, Hickok NJ. The inhibition of Staphylococcus epidermidisbiofilm formation by vancomycin-modified titanium alloy and implications for the treatment ofperiprosthetic infection.Biomaterials.2008Dec;29(35):4684-90.《中华关节外科杂志》2012年12月刊
[2]. UK National Joint Registry. Available at,
[3]. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of pri-mary and revision hip and knee arthroplasty in the United States from2005to2030. J Bone Joint Surg Am2007;89(4):780-5.
[4]. Kurtz SM, Ong KL, Lau E, Bozic KJ, Berry D, Parvizi J. Prosthetic joint infection risk after TKA in the Medicare population. Clin Orthop Relat Res2010;468:52-56
[5]Ong KL, Kurtz SM, Lau E, Bozic KJ, Berry DJ, Parvizi J. Prosthetic joint infection risk after total hip arthroplasty in the Medicare population. J Ar-throplasty2009;24:105-109
[6]Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RSJ, Barrack RL. Diagnosis of infected total knee:findings of a multicenter database. Clin Orthop Relat Res2008;466:2628-2633
[7]Volin SJ, Hinrichs SH, Garvin KL. Two-stage re-implantation of total joint infections:a comparison of resistant and non-resistant organisms. Clin Orthop Relat Res2004;427:94-100
[8]Cataldo MA, Petrosillo N, Cipriani M, Cauda R, Tacconelli E. Prosthetic joint infection:recent developments in diagnosis and management. J Infect.2010Dec;61(6):443-8. doi:10.1016/j.jinf.2010.09.033. Epub2010Oct7.
[9]Amann R, Fuchs BM. Single-cell identification in microbial commu-nities by improved fluorescence in situ hybridization techniques. Nat. Rev. Microbiol.2008;6:339-4
[10]Peel TN, Buising KL, Choong PF.Prosthetic joint infection:challenges of diagnosis and treatment. ANZ J Surg.2011Jan;81(1-2):32-9
[11]Gomez E, Cazanave C, Cunningham SA, Greenwood-Quaintance KE, Steckelberg JM, Uhl JR, Hanssen AD, Karau MJ, Schmidt SM, Osmon DR, Berbari EF, Mandrekar J, Patel R. Prosthetic joint infection diagnosis using broad-range PCR of biofilms dislodged from knee and hip arthroplasty surfaces using sonication.J Clin Microbiol.2012Nov;50(11):3501-8.
[12]Matar WY, Jafari SM, Restrepo C, Austin M, Purtill JJ, Parvizi J. Preventing infection in total joint arthroplasty. J Bone Joint Surg Am.2010Dec;92Suppl2:36-46.
[13]Lucke M, Wildemann B, Sadoni S, Surke C, Schiller R, Stemberger A, Raschke M, Haas NP, Schmidmaier G. Systemic versus local application of gentamicin in prophylaxis of implant-related osteomyelitis in a rat model.Bone.2005May;36(5):770-8. Epub2005Mar24.
[14]Stigter M, de Groot K, Layrolle P. Incorporation of tobramycin into biomimetic hydroxyapatite coating on titanium. Bio materials2002;3:4143-53.
[15]Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, Domann E, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless joint prostheses on the reduction of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[16]Lu YP, Li MS, Li ST, Wang ZG, Zhu RF. Plasma-sprayed hydroxyapatite+titania composite bond coat for hydroxyapatite coating on titanium substrate.Biomaterials.2004Aug;25(18):4393-403.
[17]Frutos Cabanillas P, Diez Pena E, Barrales-Rienda JM, Frutos G.Validation and in vitro characterization of antibiotic-loaded bone cement release. Int J Pharm2000;209:15-26.
[18]Price JS, Tencer AF, Arm DM, Bohach GA. Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res1996;30:281-6.
[19]Silverman LD, Lukashova L, Herman OT, Lane JM, Boskey AL Release of gentamicin from a tricalcium phosphate bone implant. J Orthop Res2007;25:23-9.
[20]Hanssen AD, Spangehl MJ. Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements.Clin Orthop Relat Res.2004;427:79-85
[21]Dyce J, Olmstead ML. Removal of infected canine cemented total hip prostheses using a femoral window technique. Vet Surg.2002;31:552-560.
[22]Neut D, van de Belt H, Stokroos I, van Horn JR, van der Mei HC, Busscher HJ. Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery.J Antimicrob Che-mother.2001;47:885-891.
[23]Youngman JR, Ridgway GL, Haddad FS. Antibiotic-loaded cement in revision joint replacement. Hosp Med.2003;64:613-616.
[24]Gosden PE, MacGowan AP, Bannister GC. Importance of air quality and related factors in the prevention of infection in orthopaedic implant surgery. J Hosp Infect.1998;39:173-180.
[25]Hopkins C.C. Recognition of endemic and epidemic prosthetic de-vice infections: the role of surveillance, the hospital infection control practitioner, and the hospital epidemiologist. Infect Dis Clin North Am.1989;3:211-220.
[26]Antoci V Jr, Adams CS, Hickok NJ, Shapiro IM, Parvizi J. Vancomycin bound to Ti rods reduces periprosthetic infection:preliminary study.Clin Orthop Relat Res.2007Aug;461:88-95.
[27]Kim HW, Kim HE, Salih V, Knowles JC. Hydroxyapatite and titania sol-gel composite coatings on titanium for hard tissue implants; mechanical and in vitro biological performance. J Biomed Mater Res B Appl Biomater.2005Jan15；72(1):1-8.
[28]Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC, Kent GM. The effect of porous surface configuration on the tensile strength of fixation of implants by bone ingrowth.Clin Orthop Relat Res.1980Jun;(149):291-8.
[29]Antoci V Jr, King SB, Jose B, Parvizi J, Zeiger AR, Wickstrom E, Freeman TA, Composto RJ, Ducheyne P, Shapiro IM, Hickok NJ, Adams CS. Vancomycin covalently bonded to titanium alloy prevents bacterial colonization.J Orthop Res.2007Jul;25(7):858-66.
[30]Antoci V Jr, Adams CS, Parvizi J, Davidson HM, Composto RJ, Freeman TA, Wickstrom E, Ducheyne P, Jungkind D, Shapiro IM, Hickok NJ. The inhibition of Staphylococcus epidermidis biofilm formation by vancomycin-modified titanium alloy and implications for the treatment of periprosthetic infection. Biomaterials.2008Dec;29(35):4684-90. doi:10.1016/j.biomaterials.2008.08.016. Epub2008Sep23.
[31]Balasundarama G, Webster TJ. A perspective on nanophase materials for orthopedic implant applications[J]. Mater Chem,2006,16:3737-3745
[32]Talmage DW, Talmage RV. Calcium homeostasis:how bone solubility relates to all aspects of bone physio logy. J Musculoskelet Neuronal Interact.2007Apr-Jun;7(2):108-12
[33]de Jonge LT, Leeuwenburgh SC, Wolke JG, Jansen JA. Organic-inorganic surface modifications for titanium implant surfaces.Pharm Res.2008Oct;25(10):2357-69. doi:10.1007/s11095-008-9617-0. Epub2008May29.
[34]Narayanan R, Seshadri SK, Kwon TY, Kim KH. Calcium phosphate-based coatings on titanium and its alloys.J Biomed Mater Res B Appl Biomater.2008Apr;85(1):279-99.
[35]Das K, Bose S, Bandyopadhyay A, Karandikar B, Gibbins BL. Surface coatings for improvement of bone cell materials and antimicrobial activities of Ti implants. J Biomed Mater Res B Appl Biomater.2008Nov;87(2):455-60. doi:10.1002/jbm.b.31125.
[36]Balasundaram G, Yao C, Webster TJ. TiO2nanotubes functionalized with regions of bone morphogenetic protein-2increases osteoblast adhesion[J]. Biomed Mater Res A.2008,84(2):447-453
[37]Edwards N, Mitchel SB,Pratt A. Silver compound antimicrobial composite European Patent Application,1987,251:783
[38]Liall SY,Read DC,Push WJ.Interaction of silver nitrate with readily identifiable groups:relationship to the antibacterial action of silver ions. Let Appl Micrebiol。1997,25:279-283.
[39]. Zhao L, Wang H, Huo K, Cui L, Zhang W, Ni H, Zhang Y, Wu Z, Chu PK. Antibacterial nano-structured titania coating incorporated with silver nanoparticles. Bio materials.2011Aug;32(24):5706-16. doi:10.1016/j.biomaterials.2011.04.040. Epub2011May12.
[40]Yao C, Balasundaram G, Webster T. Use of anodized titanium in drug delivery applications. Mater Res Soc Symp Proc V-01.2007.951E:28-29.
[41]Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA. Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes.Biomaterials.2007Nov;28(32):4880-8. Epub2007Aug13.
[42]. Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, Domann E, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless joint prostheses on the reduction of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[43]. Hersel U, Dahmen C, Kessler H. RGD modified polymers:biomaterials for stimulated cell adhesion and beyond.Biomaterials.2003Nov;24(24):4385-415.
[1] Mor GK，Prakasam HE, Varghese OK, Shankar K，Girmes CA. Vertically orientedTi-Fe-0nanotube array iflms: toward a useful mateiral architecture for solar spectrumwater photoelectrolysis. Nano Lett.2007Aug;7(8):2356-64. Epub2007Jul3.
[2] Mor GK, Varghese OK, Wilke RH, Sharma S，Shankar K, Latempa TJ，Choi KS，Grimes CA. P-type Cu--Ti--0nanotube arrays and their use in self-biasedheterojunction photoelectrochemical diodes ofr hydrogen generation. Nano Lett.2008Jul;8(7):1906-ll. doi:10.1021/nl080572y. Epub2008Jun10.
[3JIIJIMA S.Helical microtubules of graphitic carbon[J].Nature,1991,354:56-58.
[4]K. Varghese, D. Gong, M. Paulose, K. G. Ong，E. G. Die key and C. A. Grimes, Adv.Mater.,2003，15，624-627.
[5]G. K. M or, M. A. Caryalho, O. K. Varghese, M. V. Pishko andC. A. Grimes,J. Mater. Res.,2004,19,628-634.
[6]Varghese OK, Mor GK, Grimes CA, Paulose M, Mukherjee N. A titania nanotube-array room-temperature sensor for selective detection of hydrogen at low concentrations. J Nanosci Nanotechnol.2004Sep;4(7):733-7.
[7]M. Paulose, O. K. Varghese, G. K. Mor, C. A. Grimes andK. G. Ong, Nanotechnology,2006,17,398-402.
[8]Varghese OK, Paulose M, Shankar K, Mor GK, Grimes CA. Water-photolysis properties of micron-length highly-ordered titania nanotube-arrays.J Nanosci Nanotechnol.2005Jul;5(7):1158-65.
[9]G. K. M or, O. K. Varghese, R. H. T. Wilkie, S. Sharma,K. Shankar, T. J. Latempa, K. S. Choi and C. A. Grimes, NanoLett,2008,8,1906-19
[10]Linder L, Carlsson A, Marsal L, Bjursten LM, Bra°nemark PI.Clinical aspects of osseointegration in joint replacement. J Bone Joint Surg [Br]1988;70:550-555
[11]J. H. Jung, H. Kobayashi, K. J. C. van Bommel, S. Shinkai andT. Shimizu, Chem. Mater.,2002,14,1445-1447.
[12]B. B. Lakshmi, P. K. Dorhout and C. R. Martin, Chem. Mater.,1997,9,857-862.
[13]H. Imai, Y. Takei, K. Shimizu, M. M atsuda and H. Hirashima. J. Mater. Chem.,1999,9,2971-2972.
[14]A. Michailowski, D. Aimawlwai, G. S. Cheng and M. Moskovits,Chem. Phys. Lett.,2001,349,1-5.
[15]32S. Kobayashi, N. Hamasaki, M. Suzuki, M. Kimura, H.Shirai and K. Hanabusa, J.Am. Chem. Soc.,2002,124,6550-6551.
[16]Z. R. R. Tian, J. A. Voigt, J. Liu, B. Mckenzie and H. F. Xu, J. Am. Chem. Soc.2003,125,12384-12385.
[17]T. Kasuga, M. Hiramatsu, A. Hoson, T. Sekino and K. Niihara,Langmuir,1998,14,3160-3163.
[18]Webster TJ. Nanophase ceramics as improved bone tissue en-gineering materials. Am Ceram Soc Bull2003;82:1-8.
[19]. Ashley ET, Covington LL, Bishop BG, Breault LG Ailingand failing endosseous dental implants:A literature review.J Contemp Dent Pract2003;4:35-50.
[20]. Buser D, Nydegger T, Oxland T, Cochran DL, Schenk RK,Hirt HP, Snetivy D, Nolte LP. Interface shear strength of tita-niumimplants with a sanblasted and acid-etched surface:A biomechanicalstudy in the maxilla of miniature pigs.J Biomed Mater Res1999;45:75-83.
[21]. Webster TJ. Nanophase ceramics:The future of orthopedic anddental implant material. In:Ying JY, editor. Nanostructur-edmaterials. New York:Academy Press;2001. p125-166.
[22]. Bra°nemark PI, Hansson BO, Adell R, Breine U, Lindstro" mJ,Halle n O, Ohman A. Osseointegrated implants in the treat-ment of the edentulous jaw. Experience from a10-year pe-riod. Scand J Plast Reconstr Surg Suppl1977;16:1-132.
[23]Li P. Biomimetic nano-apatite coating capable of promoting bone ingrowth. J Biomed Mater Res A2003;66:79-85.
[24]Webster TJ, Ejiofor JU. Increased osteoblast adhesion on nanophase metals:Ti, Ti6A14V, and CoCrMo. Biomaterials2004;25:4731-4739.
[25]Popat KC, Leary Swan EE, Mukhatyar V, Chatvanichkul KI,Mor GK, Grimes CA, Desai TA. Influence of nanoporous alu-mina membranes on long-term osteoblast response. Biomate-rials2005;26:4516-4522.
[26]. Sato M, Sambito MA, Aslani A, Kalkhoran NM, SlamovichEB, Webster TJ. Increased osteoblast functions on undopedand yttrium-doped nanocrystalline hydroxyapatite coatings on titanium. Biomaterials2006;27:2358-2369.
[27]. Colon G, Ward BC, Webster TJ. Increased osteoblast anddecreased Staphylococcus epidermidis functions on nanophaseZnO and TiO2. J Biomed Mater Res A2006;78:595-604.
[28]Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA.Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nano-tubes. Biomaterials2007;28:4880-4888.
[29]Popat KC, Eltgroth M, LaTempa TJ, Grimes CA, Desai TA.Titania nanotubes:A novel platform for drug-eluting coatings for medical implants? Small2007;3:1878-1881.
[30]C.M. Lieber, Solid State Commun.1998,107,607.
[31]C. N. R. Rao, A. Mller, A. K. Cheetham, The Chemistry ofNanomaterials: Synthesis, Properties and Applications, Wiley-VCH, Weinheim, Germany,2006.
[32]C. Weisbuch, B. Vinter, Quantum Semiconductor Structures:Fundamentals and Applications, Elsevier, Amsterdam,1991.
[33]Vladkova R.Chlorophyll a self-assembly in polar solvent-water mixtures. Photochem Photobiol.2000Jan;71(1):71-83
[34]J. M. Macak, H. Tsuchiya, A. Ghicov, K. Yasuda, R. Hahn, S.Bauer, P. Schmuki,Curr. Opin. Solid State Mater. Sci.2007,11,3.
[35]I. Paramasivam, H. Jha, P. Schmuki, unpublished results.
[36]S. Bauer, P. Schmuki, J. Park, K. von der Mark, C. von Wil-mowsky, K. A. Schlegel, F. W. Neukam, unpublished results.
[37]Y. Suzuki, S. Yoshikawa, J.Mater. Res.2004,19,982.
[38]Eustis S, el-Sayed MA. Why gold nanoparticles are more precious than pretty gold:noble metal surface plasmon resonance and its enhancement of the radiative and nonradiative properties of nanocrystals of different shapes.Chem Soc Rev.2006Mar;35(3):209-17.Epub2005Dec16.
[39]G. H. Du, Q. Chen, R. C. Che, Z. Y. Yuan, L. M. Peng, Appl.Phys. Lett.2001,79,3702-3704;
[40]M. Adachi, Y. Murata, S. Yoshikawa. Chem. Lett.2000,29,942.
[41]M. Adachi, Y. Murata, I. Okada, S. Yoshikawa, J. Electro-chem. Soc.2003,150, G488.
[42]H. H. Ou, S. L. Lo, Sep. Purif. Technol.2007,58,179.
[43]S. Uchida, R. Chiba, M. Tomiha, N. Masaki, M. Shirai,Electrochemistry2002,70,418.
[44]Zwilling V, Darque-Ceretti E, Boutry-Forveille A, David D, Perrin MY, Aucouturier M. Structure and physicochemistry of anodic oxide films on titanium and TA6V alloy. Surf. Interface Anal (1999),27,629-637
[45]D. Gong, C. A. Grimes, O. K. Varghese, W. Hu, R. S. Singh,Z. Chen and E. C Dickey, J. Mater. Res.,2001,16,3331-3334.
[46]E. Balaur, J. M. Macak, H. Tsuchiya and P. Schmuki, J. Mater.Chem.,2006,15,4488-4891.
[47]K. Shankar, G. K. Mor, A. Fitzgerald and C. A. Grimes, J. Phys.Chem. C,2007,111,21-26
[48]43E. Balaur, J. M. Macak, H. Tsuchiya and P. Schmuki, J. Mater.Chem.,2006,15,4488-4891.
[49]J. M. Macak and P. Schmuki, Electrochim. Acta,2006,52,1258-1264.
[50]V. Zwilling, M. Aucouturier and E. Darque-Ceretti, Electrochim.Acta,1999,45,921-929.
[51]46V. Zwilling, E. Darque-Ceretti, A. Boutry-Forveille, M. Y. Perrinand M. Aucouturier, Surf. Interface Anal.,1999,27,629-637.
[52]S. Yoriya, H. E. Prakasam, O. K. Varghese, K. Shankar,M. Paulose, G. K. Mor, T. J. Latempa and C. A. Grimes,Sens.Lett.,2006,4,334-339.
[53]K. Shankar, G. K. Mor, A. Fitzgerald and C. A. Grimes, J. Phys.Chem. C,2007,111,21-2
[54]58N. K. Allam, K. Shankar and C. A. Grimes, J. Mater. Chem,2008,18,2341-2346.
[55]X. Chen, M. Schriver, T. Suen and S. S. Mao. Thin Solid Films,2007,515,8511-8514.
[56]J. P. Frayret, R. Pointeau and A. Caprani, Electrochim. Acta,1981,26,1783-1788.
[57]Albu SR, Kim D, Schmuki P. Growth of aligned TiO2bamboo-type nanotubes and highly ordered nanolace. Angew. Chem. Int. Ed. Engl.47(10),1916-1919(2008).
[58]Bauer S, Kleber S, Schmuki P. TiO2nanotubes:tailoring the geometry in H3PO4/HF electrolytes. Electrochem. Commun.2006,8(8),1321-1325.
[59]H. Tsuchiya, S. Berger, J. M. Macak, A. Ghicov, P. Schmuki,Electrochem. Commun.2007,9,2397.
[60]S. Berger, H. Tsuchiya, P. Schmuki, Chem. Mater.2008,20,3245.
[61]Parkhutik V P, Shershulsky V I. Phys. D. Appl. Phys.1992,25:1258-1263
[62]Lee W J, Alhoshan M, Smyrl W H.J. Electrochem. Soc.20116,153:499-505
[1]WebsterTJ. Nanophase ceramics as improved bone tissue engineer-ing mateirals.Am Ceram Soc Bull2003;82(6):1—8
[2]HulbertSF, Morirson SJ, Klawitter JJ. Tissue reaction to three ceramics of porousand non-porous structures. J Biomed Mater Res1972;6(5):347—74
[3]BobynJD, Pilliar RM, Cameron HU, Weatherly GC. The optimum pore size forthe ifxation of porous-sirfaced metal implants by the ingrowth of bone. Clin OrthopRelat Res1980(150):263-70.
[4]LeeTM，Wang BC，Yang YC，Chang E, Yang CY. Compairson of plasma-sprayedhydroxyapatite coatings and hydroxyapatite/trical-cium phosphate composite coatings:in vivo study. J Biomed Mater Res2001;55(3):360-7.
[5]PopatKC，Daniels RH, EXibrow RS, Hardev V，Desai TA. Nanostructured surfacesfor bone bio temp lating applications. J Orthop Res2006;24(4):619-27.
[6]Popat KC, Leary Swan EE, Mukhatyar V, Chatvanichkul KI, Mor GK, Girmes CA,et al. Inlfuence of nanoporous alumina membranes on long-term osteoblast response.Bio materials2005；26(22):4516-22.
[7]Swan EE，Popat KC，Desai TA. Peptide-immobilized nanoporous aluminamembranes for enhanced osteoblast adhesion. Biomaterials2005;26(14):1969-76.
[8]Swan EE，Popat KC, Grimes CA，Desai TA. Fabrication and evaluation ofnanoporous alumina membranes for osteoblast culture. J Biomed Mater Res A2005;72(3):288-95.
[9]BauerTW, Taylor SK，Jiang M，Medendorp SV. An indirect compairson ofthird-body wear in retrieved hydroxyapatite-coated, porous, and cemented femoralcomponents. Clin Orthop Relat Res1994(298):11-8.
[10]Bloebaum RD, Beeks D，Dorr LD, Savory CG，DuPont JA, Hofmann AA.Complications with hydroxyapatite particulate separation in total hip arthroplasty.Clin Orthop Relat Res1994(298):19-26.
[11]LinderL, Carlsson A, Marsal L, Bjursten LM, Branemark PL Clinical aspects ofosseointegration in joint replacement. A histological study of titanium implants. JBone Joint Surg Br1988;70:550.
[12]Pilliar RM, Lee LJ, Maniatopoulos C. Observation on the effect of movement onbone ingrowth into porous-sirfaced implants. Clin Orthop Rel Res1986;208:108.
[13]Satomi K, Akagawa Y, Nikai H，Tsiru H. Bone-implant interface structures atfernontapping and tapping insertion of screw-type titanium alloy endosseous implants. JProsthet Dent1988;59:339.
[14]Feng B，Weng J，Yang BC，Qu SX，Zhang XD. Characterization of surface oxideiflms on titanium and adhesion of osteoblast. Bioma-teirals2003;24:4663.
[15]Puleo DA, Holleran LA, Doremus RH, Bizios R. Osteoblast responses toorthopedic implant materials in vitro. J Biomed Mater Res1991;25:711.
[16]Salata O. Applications of nanoparticles in biology and medicine. JNanobio technology2004;2:3.
[17]Satsangi A, Satsangi N，Glover R, Satsangi RK, Ong JL. Osteoblast response tophospholipid modiifed titanium sirface. Biomateirals2003;24:4585
[18]WuC，Ramaswamy Y, Liu X，Wang G，Zreiqat H. Plasma-sprayed CaTiSi05ceramic coating on Ti-6A1-4V with excellent bonding strength, stability and cellularbioactivity. J R Soc Interface2009;6(31):159-68.
[19]Liu X，Morra M，Carpi A, Li B. Bio active calcium silicate ceramics and coatings.Biomed Pharmacother2008;62(8):526—9.
[20]MacakJM，Tsuchiya H，Ghicov A，Yasuda K，Hahn R, Bauer S，Schmuki P.Self-organized electrochemical formation, properties and applications. Ciu*r OpinSolid State Mater Sci2007;11:3-18.
[21]SunH，Wu C，Dai K，Chang J，Tang T. Proliferation and osteoblasticdifferentiation of human bone marrow-derived stromal cells on akermanite-bioactiveceramics. Biomaterials2006;27:5651-5657.
[22]GregoryCA，Gunn WG，Peister A，Prockop DJ. An Alizairn red-based assay ofmineralization by adherent cells in culture: Comparison with cetylpyridinium chlorideextrac-tion. Anal Biochem2004;329:77-84.
[23]Chirstenson EM, Anseth KS，van den Beucken JJ, Chan CK，Ercan B，Jansen JA，Laurencin CT, Li WJ, Mirugan R, Nair LS, Ramakrishna S，Tuan RS, Webster TJ,Mikos AG. Nanobiomaterial applications in orthopedics. J Orthop Res.2007Jan;25(l):ll-22.
[24]McNamara LE, McMurray RJ, Biggs MJ，Kantawong F, Oreffo RO, Dalby MJ.Nanotopographical control of stem cell differentiation.J Tissue Eng.2010Aug18;2010:120623. doi:10.4061/2010/120623.
[25]NakaharaH, Dennis JE, Bruder SP, Haynesworth SE，Lennon DP, Caplan AL Invitro differentiation of bone and hyper-trophic cartilage rfom peirosteal-deirved cells.Exp Cell Res1991;195:492-503.
[26].Service RF. Tissue engineers build new bone. Science2000;289:1498.
[27].Wakitani S，Saito T, Caplan AL Myogenic cells derived rfom rat bone marrowmesenchymal stem cells exposed to5-azacy-tidine. Muscle Nerve1995;18:1417-1426.
[28]Webster TJ，Ejiofor JU. Increased osteoblast adhesion on nanophase metals: Ti,Ti6A14V，and CoCrMo. Biomateirals2004;25(19):4731—9.
[29]Webster TJ, Ergun C，Doremus RH, Siege1RW, Bizios R. Enhanced tfincitons ofosteoblasts on nanophase ceramics. Biomaterials2000;21(17):1803-10.
[30]Dalby MJ，McCloy D，Robertson M，Agheli H，Sutherland D，Afrfossman S，et al.Osteoprogenitor response to semi-ordered and random nanotopographies.Biomaterials2006;27(15):2980-7.
[38] Dalby MJ, McCloy D，Robertson M，Wilkinson CD，Oreffo RO. Osteoprogenitorresponse to deifned topographies with nanoscale depths. Biomateirals2006;27(8):1306-15.
[32] Meng S，Zhang Z, Rouabhia M. Accelerated osteoblast mineralization on aconductive substrate by multiple electrical stimulation. J Bone Miner Metab.2011Sep;29(5):535-44. doi:10.1007/s00774-010-0257-l.Epub2011Feb17.
[33] Forsprecher J，Wang Z, Goldberg HA, Kaartinen MT. Transglutaminase-mediatedoligomerization promotes osteoblast adhesive properties of osteopontin and bonesialoprotein. Cell Adh Migr.2011Jan-Feb;5(l):65-72. doi:10.4161/cam.5.1.13369.Epub2011Jan1.
[34] Park J, Bauer S, Schlegel KA, Neukam FW, von der Mark K, Schmuki P. Ti02nanotube surfaces:15nm—an optimal length scale of surface topography for celladhesion and differentiation. Small.2009Mar;5(6):666-71. doi:10.1002/smll.200801476.
[35] Park J，Bauer S，von der Mark K，Schmuki P. Nanosize and vitality: Ti02nanotube diameter directs cell fate. Nano Lett.2007Jun;7(6):1686-91. Epub2007May16.
[36] Hosseinkhani H，Hosseinkhani M，Tian F, Kobayashi H，Tabata Y. Osteogenicdifferentiation of mesenchymal stem cells in self-assembled peptide-anphiphilenanofibers. Biomaterials.2006Aug;27(22):4079-86. Epub2006Apr5.
[37] Lavenus S，Berreur M，Tirchet V，Pilet P, Louarn G, Layrolle P. Adhesion andosteogenic differentiation of human mesenchymal stem cells on titanium nanopores.Eur Cell Mater.2011Aug26;22:84-96; discussion96.
[38]Yao C, Slamovich EB，Webster TJ. Enhanced osteoblast fiinc-tions on anodizedtitanium with nanotube-like structures. J Biomed Mater Res A2008;85:157-166.
[39] On*AW, Helmke BP, Blackman BR, Schwartz MA. Mechanisms ofmechanotransduction. Dev Cell.2006Jan;10(l):ll-20.
[40] Dalby MJ，Gadegaard N，Tare R，Andar A, Riehle MO, Herzyk P, Wilkinson CD，Oreffo RO. The control of human mesenchymal cell differentiation using nanoscalesymmetry and disorder. Nat Mater.2007Dec;6(12):997-1003. Epub2007Sep23.
[41] Dalby MJ, McCloy D，Robertson M，Agheli H，Sutherland D，Afrfossman S,Oreffo RO. Osteoprogenitor response to semi-ordered and random nanotopographies.Bio materials.2006May;27(l5):2980-7. Epub2006Jan27.
[42] Engler AJ, Sen S，Sweeney HL, Discher DE. Matrix elasticity directs stem celllineage specification. Cell.2006Aug25;126(4):677-89.
[1] Drews J. Drug discovery: a historical perspective. Science.2000Mar17;287(5460):1960-4
[2], Mainardes RM, Silva LP. Drug delivery systems: past, present, and future. Ciu*rDrug Targets.2004Jul;5(5):449-55.
[3], Fahr A，Liu X. Drug delivery strategies for poorly water-soluble drugs. ExpertOpin Drug Deliv.2007Jul;4(4):403-16.
[4], El-Aneed A. An overview of current delivery systems in cancer gene therapy.JControl Release.2004Jan8;94(1):1-14.
[5]Amiji MM. Nanotechnology for targeted drug and gene delivery.Nanome dNanotechnol Biol Med2006;2:299-300
[6] Kayser0，Lemke A，Trejo NH. The impact of nanobiotechnology on thedevelopment of new drug delivery systems. Ciu*r Pharm Bio techno12005;6:3-5
[7]De Villiers MM，Aramwit P, Kwon GS. Eds. Nanotechnology in drug delivery.Spirnger, AAPS Press2009
[8] Van D，McGuire T, Langer R. Small scale systems ofr in vivo drug delivery.NatBiotechnol2003;21:1184-91
[9] Wei C, Wei W, Morris M, Kondo E, Gorbounov M, Tomalia DA. Nanomedicineand drug delivery. Med Clin North Am.2007Sep;91(5):863-70.
[10] Hughes GA. N anostructure-mediated drug delivery. N anome dicine，Nanotechnology, Biology and Medicine2005;1:22-30
[11]Vallet-Regi' M. Balas F. Arcos D Mesoporous Mateirals for Drug DeliveryAngew Chem Int Ed2007;46:7548-58
[12] Wang S. Ordered mesoporous materials for drug delivery. MicroporousMesoporous Mater2009;l17:1-9
[13]Son SJ，Bai X，Nan A, et al. Template synthesis of multifunctional nanotubes forcontrolled release. J Controlled Release2006;114:143-52
[14]Schmid G. Materials in nanoporous alumina. J Mater Chem2002;12:1231-8
[15]Ghicov A，Schmuki P. Self-ordering electrochemistry: a review on growth andtfinctionality of Ti02nanotubes and other self-aligned MOx structures. ChemCommun2009;20:2791-808
[16]Grimes CA. Synthesis and application of highly ordered arrays of Ti02nanotubes.J Mater Chem2007;17:1451-7
[17] Jain AK, Panchagnula R. Skeletal drug delivery systems. Int J Pharm.2000Sep25;206(1-2):1-12.
[18] Drews J.Intent and coincidence in pharmaceutical discovery. The impact ofbiotechnology. Arzneimittelforschung.1995Aug;45(8):934-9
[19] Mainardes RM, Silva LP. Drug delivery systems: past, present, and future. Ciu*rDrug Targets.2004Jul;5(5):449-55.
[20] Buchholz HW, Els on RA, Engelbrecht E, Lodenkamper H，Rottger J，Siegel A.Management of deep infection of total hip replacement J Bone Joint Siu*g Br.1981;63-B(3):342-53.
[21] Soimdrapandian C，Sa B，Datta S. Organic-inorganic composites for bone drugdelivery. AAPS PharmSciTech.2009;10(4):1158-71. doi:10.1208/sl2249-009-9308-0.Epub2009Oct20.
[22] Simchi A，Tamjid E, Pishbin F, Boccaccini AR. Recent progress in inorganic andcomposite coatings with bactericidal capability for orthopaedic applications.Nanomedicine.2011Feb;7(l):22-39. doi:10.1016/j.nano.2010.10.005. Epub2010Nov2.
[23] Lewis G. Alternative acrylic bone cement formulations for cementedarthroplasties: present status, key issues, and future prospects J Biomed Mater Res BAppl Bio mater.2008Feb;84(2):301-19.
[24] Hoppe A，Giildal NS，Boccaccini AR. A review of the biological response toionic dissolution products from bioactive glasses and glass-ceramics. Biomateirals.201lApr;32(l1):2757-74. doi:10.1016/j.biomaterials.2011.01.004. Epub2011Feb2.
[25] Wu C，Chang J，Xiao Y. Mesoporous bioactive glasses as drug delivery andbone tissue regeneration platforms. Therapeutic Delivery2(9),1189-1198(2011).
[26] Arcos D，Vallet-Regi M. Sol-gel silica-based biomateirals and bone tissueregeneration. Acta Bio mater.2010Aug;6(8):2874-88. doi:10.1016/j.actbio.2010.02.012. Epub2010Feb10.
[27] Cerruti M，Sahai N. Silicate biomateirals for orthopedic and dental implants.Rev. Mineral Geochem.2006;64:283-313.
[28]Torrado S，Frutos P, Frutos G. Gentamicin bone cements: characteirsation andrelease (in vitro and in vivo assays). Int. J. Pharm2001;217(1-2):57-69.
[29] Timko BP, Whitehead K，Gao W. Advances in drug delivery. In: AnnualReview of Materials Research, Volume41. Annual reviews, Palo Alto, CA，USA，1-20(2011).
[30] Losic D，Simovic S. Self-ordered nanopore and nanotube platforms for drugdelivery applications. Expert Opin Drug Deliv.2009Dec;6(12):1363-81. doi:10.1517/17425240903300857.
[31]Gristina AG，Oga M，Webb LX, Hobgood CD. Adherent bacterial colonizationinthe pathogenesis of osteomyelitis. Science1985;228:990-3
[32]Nelson CL. The ciurent status of material used for depot delivery of drugs.Clinical Orthopaedics and Related Research2004;427:72-8.
[33]Burny F, Donkerwolcke M，Moulart F, Bourgois R, Puers R, Van SchuylenberghK，et al. Concept, design and fabrication of smart orthopedic implants. MedicalEngineering and Physics2000;22:469-79.
[34] Fairman R, Akerfeldt KS. Peptides as novel smart materials. Ciurent Opinion inStructural Biology2005;15:453-63.
[35]Popat KC，Eltgroth M，La Temp a TJ. Titania nanotubes: A novel platform fordrug-eluting coatings for medical implants. Small2007;3:1878-81
[36] Gulati K，Aw MS，Findlay D，Losic D. Local drug delivery to the bone bydrug-releasing implants: perspectives of nano-engineered titania nanotube arrays.Ther Deliv.2012Jul;3(7):857-73.
[37] Gulati K, Ramakirshnan S，Aw MS, Atkins GJ, Findlay DM, Losic D.Biocompatible polymer coating of titania nanotube arrays for improved drug elutionand osteoblast adhesion. Acta Bio mater.2012Jan;8(1):449-56. doi:10.1016/j.actbio.2011.09.004. Epub2011Sep8.
[38]Martin HJ, Schulz KH，Bumgardner JD，Schneider JA. Enhanced bonding ofchitosan to implant quality titanium via four treatment combinations. Thin Solid Films2008;516(18):6277—86.
[39] Smith LJ，Swaim JS，Yao C，Haberstroh KM，Naiman EA，Webster TJ. Increasedosteoblast cell density on nanostructured PLGA-coated nanostructured titanium fororthopedic applications. Int J Nanomed2007;2(3):493-9.
[40]Ueno H, Yamada H, Tanaka I，Kaba N, Matsuura M, Okimura M. Acceleratingeffects of chitosan for healing at early phase of experimental open wound in dogs.Bio materials1999;20(15):1407-14.
[41] Kinrg S，Devlin H，Fu E, Ho KY, Liang SY, Hsieh YD. The osteoinductive effectof chitosan-collagen composites around piu*e titanium implant surfaces in rats. JPeirodontal Res2011;46(1):126-33.
[42] Webster TJ, Smith TA. Increased osteoblast function on PLGA compositescontaining nanophase titania. J Biomed Mater Res Part A2005;74A(4):677-86
[43]An YH, Freidman RJ. Concise review of mechanisms of bacterial adhesion tobiomaterial surfaces. J Biomed Mater Res1998;43:33848.
[44] Antoci V Jr, Adams CS，Hickok NJ，Shapiro IM，Parvizi J. Vancomycin boiuid toTi rods reduces periprosthetic infection: preliminary study. Clin Orthop Relat Res.2007Aug;461:88-95.
[1]. National Hospital Discharge Survey. Survey results and products.Available at Atlanta: Center forDisease Control and Prevention<, http://www.cdc.gov/nchs/nhdsdt_proucts.hml>;2009[last access14.09.10].
[2]. UK National Joint Registry. Available at,
[3]. Kurtz S, Ong K, Lau E, Mow at F, Halpern M. Projections of pri-mary and revision hip and kneearthroplasty in the United States from2005to2030.J Bone Joint Surg Am2007;89(4):780-5.
[4]. Spormann C, AchermannY, Simmen BR, Schwyzer HK, Vogt M, Goldhahn J, Kolling C.Treatment strategies for periprosthetic infections after primary elbow arthroplasty. J Shoulder ElbowSurg.2012Aug;21(8):992-1000. Epub2012Jan4.
[5]. Spangehl MJ, Masri BA, Oconnell JX, Dun-can CP. Prospective analysis of preoperative andintraoperative investigations for the diagnosis of infection at the sites of two hundred. J Bone JointSurg Am.1999May;81(5):672-83
[6]. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med.2004Oct14;351(16):1645-54.
[7]. Hsieh PH, Lee MS, Hsu KY, Chang YH, Shih HN, Ueng SW. Gram-negative prosthetic jointinfections: risk factors and outcome of treatment. Clin Infect Dis2009;49(7):1036-43.
[8]. Maria Adriana Cataldo, Nicola Petrosillo, Michela Cipriani,Roberto Cauda, EvelinaTacconelli.Prostheti c joint infecti on: Recent developments in diagnosis and management. Journalof Infection.2010;61:443-448
[9].24. Salgado CD, Dash S, Cantey JR, Marculescu CE. Higher risk of failure of methicillin-resistantStaphylococcus aureus prosthetic joint infections. Clin Orthop Relat Res2007;461:48-53
[10]. Pechous R, Ledala N, Wilkinson BJ, Jayaswal RK. Regulation of the expression of cell wallstress stimulon member gene msrAl in methicillin-susceptible or-resistant Staphylococcus aureus.Antimicrob Agents Chemother.2004Aug;48(8):3057-63.
[11]. Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections.Infect Dis Clin North Am.2005Dec;19(4):885-914.
[12]. Berbari EF, Marculescu C, Sia I, Lahr BD, Hans sen AD, Steckelberg JM, Gullerud R, OsmonDR.Culture-negative prosthetic joint infection. Clin Infect Dis.2007Nov l;45(9):1113-9. Epub2007Sep26.
[13]. Lauderdale KJ, Malone CL, Boles BR, Morcuende J, Horswill AR. Biofilm dispersal ofcommunity-associated methic illin-res is tant Staphylococcus aureus on orthopedic implant material.JOrthop Res.2010Jan;28(l):55-61.
[14].Mah TF, Pitts B, PellockB, Walker GC, Stewart PS, O'Toole G A A genetic basis forPseudomonas aeruginosa biofilm antibiotic resistance. Nature2003;426:306-10.
[15]. Nuryastuti T, Krom BP, Aman AT, Busscher HJ, van der Mei HC. Ica-expression and gentamicinsusceptibility of Staphylococcus epidermidis biofilm on orthopedic implant biomaterials.J BiomedMater Res A.2011Feb;96(2):365-71.
[16]. Yao Y, Sturdevant DE, Otto M. Genomewide analysis of gene expression in Staphylococcusepidermidis biofilms: insights into the pathophysiology of S. epidermidis biofilms and the role ofphenol-soluble modulins in formation of biofilms. J Infect Dis.2005Jan15;191(2):289-98. Epub2004Dec10.
[17]. Wolz C, Goerke C, Landmann R, Zimmerli W, Fluckiger U. Transcription of clumping factor Ain attached and unattached Staphylococcus aureus in vitro and during device-related infection.InfectImmun.2002Jun;70(6):2758-62.
[18]. Darouiche RO. Device-associated infections: a macroproblem that starts with microadherence.Clin Infect Dis.2001Nov l;33(9):1567-72. Epub2001Sep26.
[19]. Schwank S, Rajacic Z, Zimmerli W&Blaser J. Impact of bacterial biofilm formation on in vitroand in vivo activities of antibiotics. Antimicrobial Agents and Chemotherapy1998;42(4):895-898.
[20]. Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP. The involvementof cell-to-cell signals in the development of a bacterial biofilm. Science.1998Apr10;280(5361):295-8.
[21]. Lee LY, Ong SL, Ng WJ. Biofilm morphology and nitrification activities: recovery of nitrifyingbiofilm particles covered with heterotrophic outgrowth. Bioresour Technol.2004Nov;95(2):209-14.
[22]. Sheldon AT Jr. Antibiotic resistance: a survival strategy. Clin Lab Sci.2005Summer;18(3):170-80.
[23]. Bernthal NM, Stavrakis AI, Billi F, Cho JS, Kremen TJ, Simon SI, Cheung AL, Finerman GA,Lieberman JR, Adams JS, Miller LS. A mouse model of post-arthroplasty Staphylococcus aureus jointinfection to evaluate in vivo the efficacy of antimicrobial implant coatings. PLoS One.2010Sep7;5(9):el2580.
[24] Darouiche RO, Dhir A, Miller AJ, Landon GC, Raad II, Musher DM. Vancomycin penetrationinto biofilm cover-ing infected prostheses and effect on bacteria. J Infect Dis1994;170:720-3.
[25]. Lewis K. Persister cells and the riddle of biofilm survival. Biochemistry (Mosc)2005;70:267-74.
[26]. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol2002;292:107-13
[27]. Roberts ME, Stewart PS. Modelling protection from antimicrobial agents in biofilms through theformation of persister cells. Microbiology2005;151:75-80.
[28]. Bays ton R. Biofilms and prosthetic devices. In: Community structure and cooperation inbiofilms (eds. Allison D G, Gilbert P, Lappin-Scott H M, Wilson M). Cambridge university press2000:295-308
[29]. Vaudaux P, Kelley W L, Lew D P. Staphylococcus aureus small colony variants: difficult todiagnose and difficult to treat. Clin Infect Dis2006;43:968-70
[30]. Von Eiff C, Proctor R A, Peters G. Staphylococcus aureus small colony variants: formation andclinical impact. Int J Clin Pract2000;115: S44-9.
[31]. Trampuz A, Piper KE, Jacobson MJ, Hans sen AD, Unni KK, Osmon DR, Mandrekar JN,Cockerill FR, Steckelberg JM, Greenleaf JF, Patel R.Sonication of removed hip and knee prosthesesfor diagnosis of infection. N Engl J Med.2007Aug16;357(7):654-63.
[32].Spanu T, Romano L, D'Inzeo T, Masucci L, Albanese A, Papacci F, Marchese E, Sanguinetti M,Fadda G. Recurrent ventriculoperitoneal shunt infection caused by small-colony variants ofStaphylococcus aureus. Clin Infect Dis2005;41:48-52
[33]. Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C. Interleukin-6, procalcitoninand TNF-alpha: markers of peri-prosthetic infection following total joint replacement. J Bone JointSurg Br.2007Jan;89(1):94-9.
[34]. Parvizi J, Ghanem E, Sharkey P, Aggarwal A, Burnett RS, Barrack RL. Diagnosis of infectedtotal knee: findings of amulticenter database.Clin Orthop Relat Res.2008Nov;466(ll):2628-33.Epub2008Sep10.
[35]. Miiller M, Morawietz L, Has art O, Strube P, Perka C, Tohtz S. Diagnosis of periprostheticinfection following total hip arthroplasty—evaluation of the diagnostic values of pre-andintraoperative parameters and the associated strategy to preoperatively select patients with a highprobability of joint infection. J Orthop Surg Res.2008Jul21;3:31.
[36].Frances Borrego A, Martinez FM, Cebrian Parra JL, Graneda DS,Crespo RG, Lopez-Duran SternL. Diagnosis of infection in hip and knee revision surgery: intraoperative frozen section analysis.Int. Orthop.2007;31:33-7
[37]. Sendi P, Frei R, Maurer TB, Trampuz A, Zimmerli W, Graber P. Escherichia coli variants inperiprosthetic joint infection: diagnostic challenges with sessile bacteria and sonication.J ClinMicrobiol.2010May;48(5):1720-5. Epub2010Mar24.
[38] Sorli L, Puig L, Torres-Claramunt R, Gonzalez A, Alier A, Knobel H, Salvado M, Horcajada JP.The relationship between microbiology results in the second of a two-stage exchange procedure usingcement spacers and the outcome after revision total joint replacement for infection: the use ofsonication to aid bacteriological analysis.J Bone Joint Surg Br.2012Feb;94(2):249-53.
[39]. Fihman V, Hannouche D, Bousson V, Bardin T, Liote F, Raskine L, Riahi J, Sanson-Le Pors MJ,Bergot. Improved diagnosis specificity in bone and joint infections using molecular techniques.J Infect.2007Dec;55(6):510-7. Epub2007Oct29.
[40] Amann R, Fuchs BM. Single-cell identification in microbial commu-nities by improvedfluorescence in situ hybridization techniques. Nat.Rev. Microbiol.2008;6:339^
[41] Peel TN, Buising KL, Choong PF.Prosthetic joint infection: challenges of diagnosis and treatment.ANZJ Surg.2011Jan;81(l-2):32-9
[42] Gomez E, Cazanave C, Cunningham SA, Greenwood-Quaintance KE, Steckelberg JM, Uhl JR,Hanssen AD, Karau MJ, Schmidt SM, Osmon DR, Berbari EF, Mandrekar J, Patel R. Prosthetic jointinfection diagnosis using broad-range PCR of biofilms dislodged from knee and hip arthroplastysurfaces using sonic ation.J Clin Microbiol.2012Nov;50(11):3501-8.
[43]. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med.2009Aug20;361(8):787-94.
[44]. Hofmann AA, Goldberg TD, Tanner AM, Cook TM. Ten-year experience using an articulatingantibiotic cement hip spacer for the treatment of chronically infected total hip. J Arthroplasty.2005Oct;20(7):874-9.
[45].Hofmann AA, Goldberg, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplastyusing an articulating spacer:2-to12-year experience. Clin Orthop Relat Res.2005;430(1):125-131
[46] Jackson WO, Schmalzried TP. Limited role of direct exchange arthroplasty in the treatment ofinfected total hip replacements. Clin Orthop Relat Res.2000;(381):101-105.
[47]. Buechel FF. The infected total knee arthroplasty: just when you thought it was over. JArthroplasty.2004;19(4suppl1):51-55.
[48]. Berdal JE, Skramm I, Mowinckel P, Gulbrandsen P, Bj0rnholt JV. Use of rifampicin andciprofloxacin combination therapy after surgical debridement in the treatment of early manifestationprosthetic joint infections. Clin Microbiol Infect.2005Oct;ll(10):843-5.
[49]. Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L,et al. Linezolid in the treatmentof gram-positive prosthetic joint infections. J Antimicrob Chemother2005;55(3):387-90.
[50]. Bassetti M, Vitale F, Melica G, Righi E, Di Biagio A, Molfetta L, Pipino F, Cruciani M, BassettiD. Linezolid in the treatment of Gram-positive prosthetic joint infections.J Antimicrob Chemother.2005Mar;55(3):387-90. Epub2005Feb10.
[51]. Nguyen S, Pasquet A, Legout L, Beltrand E, Dubreuil L, Migaud H, Yazdanpanah Y, SennevilleE. Efficacy and tolerance of rifampicin-linezolid compared with rifampicin-cotrimoxazolecombinations in prolonged oral therapy for bone and joint infections. Clin Microbiol Infect.2009Dec;15(12):1163-9. Epub2009May4.
[52].Falagas ME, Giannopoulou KP, Ntziora F, Papagelopoulos PJ.Daptomycin for treatment ofpatients with bone and joint in-fections: a systematic review of the clinical evidence. Int J AntimicrobAgents2007Sep;30(3):202-9.
[53]. Smith K, Perez A, Ramage G, Gemmell CG, Lang S. Comparison of biofilm-associated cellsurvival following in vitro exposure of meticillin-resistant Staphylococcus aureus biofilms to theantibiotics clindamycin, daptomycin, linezolid, tigecycline and vancomycin. Int J Antimicrob Agents.2009Apr;33(4):374-8. Epub2008Dec19.
[54]. Matar WY, Jafari SM, Restrepo C, Austin M, Purtill J J, Parvizi J. Preventing infection in totaljoint arthroplasty. J Bone Joint Surg Am.2010Dec;92Suppl2:36-46.
[55]. Lucke M, Wildemann B, Sadoni S, Surke C, Schiller R, Stemberger A, Raschke M, Haas NP,Schmidmaier G. Systemic versus local application of gentamicin in prophylaxis of implant-relatedosteomyelitis in a rat model.Bone.2005May;36(5):770-8. Epub2005Mar24.
[56]. Stigter M, de Groot K, Layrolle P. Incorporation of tobramycin into biomimetic hydroxy apatitecoating on titanium. Biomaterials2002;3:4143-53.
[57]. Alt V, Bitschnau A, Osterling J, Sewing A, Meyer C, Kraus R, Meissner SA, Wenisch S, DomannE, Schnettler R. The effects of combined gentamicin-hydroxyapatite coating for cementless jointprostheses on the reduciton of infection rates in a rabbit infection prophylaxis model. Biomaterials.2006Sep;27(26):4627-34. Epub2006May19.
[58] Ere an B, Kummer KM, Tarquinio KM, Webster TJ. Decreased Staphylococcus aureus biofilmgrowth on anodized nanotubular titanium and the effect of electrical stimulation. Acta Biomater.2011Jul;7(7):3003-12.
[59] Popat KC, Eltgroth M, Latempa TJ, Grimes CA, Desai TA.B Decreased Staphylococcusepidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nano tubes.Biomaterials.2007Nov;28(32):4880-8. Epub2007Aug13.
[60] Gulati K, Aw MS, Losic D. Drug-eluting Ti wires with titania nanotube arrays for bone fixationand reduced bone infection.Nanoscale Res Lett.2011Oct31;6:571.
[61] Antoc i V Jr, Adams CS, Parvizi J, Davidson HM, Compos to RJ, Freeman TA, Wicks trom E,Ducheyne P, Jungkind D, Shapiro IM, Hickok NJ. The inhibition of Staphylococcus epidermidisbiofilm formation by vancomycin-modified titanium alloy and implications for the treatment ofperiprosthetic infection.Biomaterials.2008Dec;29(35):4684-90.《中华关节外科杂志》2012年12月刊
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