羟基磷灰石类陶瓷在骨组织工程中的研究与更广泛应用
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摘要
背景:羟基磷灰石类陶瓷与正常人体骨组织中的结构和化学成分十分相近,具有良好的骨诱导骨传导活性及生物相容性,成为骨组织工程中支架的良好材料之一。目的:总结羟基磷灰石类陶瓷材料制备方式、特性及作为骨组织代替物的作用机制和临床应用新进展。方法:以"bioceramics,hydroxylapatite,calcium phosphate,tricalcium phosphate,bone tissue engineering"为检索词,应用计算机检索PubMed数据库2015至2017年发表的相关文献。结果与结论:羟基磷灰石属于六方晶系,是构成天然骨组织中无机成分的主要组成部分,其中呈六方排列的Ca~(2+)、PO_4~(3-)、OH~-易于被许多阳离子和阴离子取代基替换,从而改变羟基磷灰石的机械强度、溶解速率、生物相容性等一些列理化及生物活性。制备羟基磷灰石陶瓷材料的方法分为湿法和干法两大类,根据实际需要与不同方法的优缺点往往是多种制备方法相结合。羟基磷灰石类陶瓷具备的孔隙结构有利于营养物质和骨生长必要成分的输送,以及细胞代谢废物的排除,并且微小孔隙会引起各种内源性骨生长因子在内孔表面的高度吸附和积累,刺激间充质干细胞分化进入成骨细胞,进一步促进发挥骨诱导活性。近年来虽然生物陶瓷材料在临床上作为植入物涂层、缓释药物的载体、骨移植物代替材料等被应用,但在临床方面广泛运用还面临着许多问题与挑战。
BACKGROUND: Hydroxyapatite ceramics have very similar structure and chemical composition to the normal human bone tissue, and also have good osteoinductive activity, osteoconductive activity and biocompatibility, which have become one of the appropriate scaffold materials for bone tissue engineering. OBJECTIVE: To summarize the preparation methods and structural characteristics of hydroxyapatite ceramics as well as their mechanisms of action and clinical applications as bone substitutes. METHODS: A computer-based search of Pub Med database was performed for relevant articles published from 2015 to 2017 using the keywords of "bioceramics, hydroxylapatite, calcium phosphate, tricalcium phosphate, bone tissue engineering". RESULTS AND CONCLUSION: Hydroxyapatite belongs to the hexagonal system and it is the main component of inorganic components that make up natural bone tissues. Among them, Ca~(2+), PO_4~(3-) and OH~- presenting with hexagonal arrangement are easy to be replaced by a variety of cations and anions. Consequently, hydroxyapatites show some changes in mechanical strength, dissolution rate, and biocompatibility. The preparation of hydroxyapatite ceramic materials is divided into wet and dry methods. Based on actual needs, various preparation methods with different advantages and disadvantages are usually combined. In addition, the pore structure of hydroxyapatite ceramics is conducive to the transport of essential components of nutrients and bone growth as well as the elimination of cellular metabolic waste. These tiny pores can cause a high degree of adsorption and accumulation of various endogenous bone growth factors on the inner pore surface, to stimulate the osteogenic differentiation of mesenchymal stem cells and further promote the osteoinductive activity. Although bioceramic materials have been clinically used as coatings for implants, carriers for sustained release drugs, and bone graft substitute materials in recent year, there are still many problems and challenges in the widespread application of bioceramics.
BACKGROUND: Hydroxyapatite ceramics have very similar structure and chemical composition to the normal human bone tissue, and also have good osteoinductive activity, osteoconductive activity and biocompatibility, which have become one of the appropriate scaffold materials for bone tissue engineering. OBJECTIVE: To summarize the preparation methods and structural characteristics of hydroxyapatite ceramics as well as their mechanisms of action and clinical applications as bone substitutes. METHODS: A computer-based search of Pub Med database was performed for relevant articles published from 2015 to 2017 using the keywords of "bioceramics, hydroxylapatite, calcium phosphate, tricalcium phosphate, bone tissue engineering". RESULTS AND CONCLUSION: Hydroxyapatite belongs to the hexagonal system and it is the main component of inorganic components that make up natural bone tissues. Among them, Ca~(2+), PO_4~(3-) and OH~- presenting with hexagonal arrangement are easy to be replaced by a variety of cations and anions. Consequently, hydroxyapatites show some changes in mechanical strength, dissolution rate, and biocompatibility. The preparation of hydroxyapatite ceramic materials is divided into wet and dry methods. Based on actual needs, various preparation methods with different advantages and disadvantages are usually combined. In addition, the pore structure of hydroxyapatite ceramics is conducive to the transport of essential components of nutrients and bone growth as well as the elimination of cellular metabolic waste. These tiny pores can cause a high degree of adsorption and accumulation of various endogenous bone growth factors on the inner pore surface, to stimulate the osteogenic differentiation of mesenchymal stem cells and further promote the osteoinductive activity. Although bioceramic materials have been clinically used as coatings for implants, carriers for sustained release drugs, and bone graft substitute materials in recent year, there are still many problems and challenges in the widespread application of bioceramics.
引文
[1]Capanema NSV,Mansur AAP,Carvalho SM,et al.Niobium-Doped Hydroxyapatite Bioceramics:Synthesis,Characterization and In Vitro Cytocompatibility.Materials(Basel).2015;8(7):4191-4209.
[2]Tamaddon M,Samizadeh S,Wang L,et al.Intrinsic Osteoinductivity of Porous Titanium Scaffold for Bone Tissue Engineering.Int J Biomater.2017.2017:5093063.
[3]Fuh LJ,Huang YJ,Chen WC,et al.Preparation of micro-porous bioceramic containing silicon-substituted hydroxyapatite and beta-tricalcium phosphate.Mater Sci Eng C Mater Biol Appl.2017;75:798-806.
[4]Vollmer NL,Spear JR,Ayers RA.Antimicrobial activity and biologic potential of silver-substituted calcium phosphate constructs produced with self-propagating high-temperature synthesis.J Mater Sci Mater Med.2016;27(6):104.
[5]Gomes S,Kaur A,Grenèche JM,et al.Atomic scale modeling of iron-doped biphasic calcium phosphate bioceramics.Acta Biomater.2017;50:78-88.
[6]Blum C,Brückner T,Ewald A,et al.Mg:Ca ratio as regulating factor for osteoclastic in vitro resorption of struvite biocements.Mater Sci Eng C Mater Biol Appl.2017;73:111-119.
[7]Ke D,Dernell W,Bandyopadhyay A,et al.Doped tricalcium phosphate scaffolds by thermal decomposition of naphthalene:Mechanical properties and in vivo osteogenesis in a rabbit femur model.J Biomed Mater Res B Appl Biomater.2015;103(8):1549-1559.
[8]Schumacher TC,Treccani L,Rezwan K.Effect of silica on porosity,strength,and toughness of pressureless sintered calcium phosphate–zirconia bioceramics.Biomed Mater.2015;10(4):045020.
[9]Denry I,Kuhn LT.Design and characterization of calcium phosphate ceramic scaffolds for bone tissue engineering.Dent Mater.2016;32(1):43-53.
[10]Mbarki M,Sharrock P,Fiallo M,et al.Hydroxyapatite bioceramic with large porosity.Mater Sci Eng C Mater Biol Appl.2017;76:985-990.
[11]Yatongchai C,Placek LM,Curran DJ,et al.Investigating the addition of Si O2–CaO–ZnO–Na2O–Ti O2 bioactive glass to hydroxyapatite:Characterization,mechanical properties and bioactivity.J Biomater Appl.2015;30(5):495-511.
[12]Lindner M,Bergmann C,Telle R,et al.Calcium phosphate scaffolds mimicking the gradient architecture of native long bones.J Biomed Mater Res A.2014;102(10):3677-3684.
[13]Philippart A,Boccaccini AR,Fleck C,et al.Toughening and functionalization of bioactive ceramic and glass bone scaffolds by biopolymer coatings and infiltration:a review of the last 5 years.Expert Rev Med Devices.2015;12(1):93-111.
[14]Duan S,Feng P,Gao C,et al.Microstructure Evolution and Mechanical Properties Improvement in Liquid-Phase-Sintered Hydroxyapatite by Laser Sintering.Materials(Basel).2015;8(3):1162-1175.
[15]Yao MZ,Huang-Fu MY,Liu HN,et al.Fabrication and characterization of drug-loaded nano-hydroxyapatite/polyamide 66 scaffolds modified with carbon nanotubes and silk fibroin.Int J Nanomedicine.2016;11:6181-6194.
[16]Kunert-Keil C,Scholz F,Gedrange T,et al.Comparative study of biphasic calcium phosphate with beta-tricalcium phosphate in rat cranial defects--A molecular-biological and histological study.Ann Anat.2015;199:79-84.
[17]Xie L,Yu H,Deng Y,et al.Preparation,characterization and in vitro dissolution behavior of porous biphasic alpha/beta-tricalcium phosphate bioceramics.Mater Sci Eng C Mater Biol Appl.2016;59:1007-1015.
[18]de Wild M,Amacher F,Bradbury CR,et al.Investigation of structural resorption behavior of biphasic bioceramics with help of gravimetry,muC T,SEM,and XRD.J Biomed Mater Res B Appl Biomater.2016;104(3):546-553.
[19]Lu J,Descamps M,Dejou J,et al.The biodegradation mechanism of calcium phosphate biomaterials in bone.J Biomed Mater Res.2002;63(4):408-412.
[20]Roldán JC,Klünter T,Schulz P,et al.Bone Morphogenetic Protein-7Enhances Degradation of Osteoinductive Bioceramic Implants in an Ectopic Model.Plast Reconstr Surg Glob Open.2017;5(6):e1375.
[21]Bouler JM,Pilet P,Gauthier O,et al.Biphasic calcium phosphate ceramics for bone reconstruction:A review of biological response.Acta Biomater.2017;53:1-12.
[22]Ghosh R,Sarkar R.Synthesis and characterization of sintered beta-tricalcium phosphate:A comparative study on the effect of preparation route.Mater Sci Eng C Mater Biol Appl.2016;67:345-352.
[23]Wang J,Chen Y,Zhu X,et al.Effect of phase composition on protein adsorption and osteoinduction of porous calcium phosphate ceramics in mice.J Biomed Mater Res A.2014;102(12):4234-4243.
[24]Despang F,Bernhardt A,Lode A,et al.Synthesis and physicochemical,in vitro and in vivo evaluation of an anisotropic,nanocrystalline hydroxyapatite bisque scaffold with parallel-aligned pores mimicking the microstructure of cortical bone.J Tissue Eng Regen Med.2015;9(12):E152-166.
[25]Feng P,Deng Y,Duan S,et al.Liquid phase sintered ceramic bone scaffolds by combined laser and furnace.Int J Mol Sci.2014;15(8):14574-14590.
[26]Civinini R,Capone A,Carulli C,et al.The kinetics of remodeling of a calcium sulfate/calcium phosphate bioceramic.J Mater Sci Mater Med.2017;28(9):137.
[27]Rabadan-Ros R,VelásquezP A,Meseguer-Olmo L,et al.Morphological and Structural Study of a Novel Porous Nurse's A Ceramic with Osteoconductive Properties for Tissue Engineering.Materials(Basel).2016;9(6).pii:E474.doi:10.3390/ma9060474.
[28]Sun H,Yang HL.Calcium phosphate scaffolds combined with bone morphogenetic proteins or mesenchymal stem cells in bone tissue engineering.Chin Med J(Engl).2015;128(8):1121-1127.
[29]MatéSánchez de Val JE,Calvo-Guirado JL,Gómez-Moreno G,et al.Influence of hydroxyapatite granule size,porosity,and crystallinity on tissue reaction in vivo.Part A:synthesis,characterization of the materials,and SEM analysis.Clin Oral Implants Res.2016;27(11):1331-1338.
[30]Ros-Tárraga P,Mazón P,Rodríguez MA,et al.Novel Resorbable and Osteoconductive Calcium Silicophosphate Scaffold Induced Bone Formation.Materials(Basel).2016;9(9).pii:E785.doi:10.3390/ma9090785.
[31]Maji K,Dasgupta S,Kundu B,et al.Development of gelatin-chitosanhydroxyapatite based bioactive bone scaffold with controlled pore size and mechanical strength.J Biomater Sci Polym Ed.2015;26(16):1190-1209.
[32]Rustom LE,Boudou T,Lou S,et al.Micropore-induced capillarity enhances bone distribution in vivo in biphasic calcium phosphate scaffolds.Acta Biomater.2016;44:144-154.
[33]Bianchi M,Urquia Edreira ER,Wolke JG,et al.Substrate geometry directs the in vitro mineralization of calcium phosphate ceramics.Acta Biomater.2014;10(2):661-669.
[34]Lobo SE,Glickman R,da Silva WN,et al.Response of stem cells from different origins to biphasic calcium phosphate bioceramics.Cell Tissue Res.2015;361(2):477-495.
[35]Yu X,Tang X1,Gohil SV,et al.Biomaterials for Bone Regenerative Engineering.Adv Healthc Mater.2015;4(9):1268-1285.
[36]Roohani-Esfahani SI,No YJ,Lu Z,et al.A bioceramic with enhanced osteogenic properties to regulate the function of osteoblastic and osteocalastic cells for bone tissue regeneration.Biomed Mater.2016;11(3):035018.
[37]He F,Zhang J,Yang F,et al.In vitro degradation and cell response of calcium carbonate composite ceramic in comparison with other synthetic bone substitute materials.Mater Sci Eng C Mater Biol Appl.2015;50:257-265.
[38]Cushnie EK,Ulery BD,Nelson SJ,et al.Simple Signaling Molecules for Inductive Bone Regenerative Engineering.PLo S One.2014;9(7):e101627.
[39]Harada N,Watanabe Y,Sato K,et al.Bone regeneration in a massive rat femur defect through endochondral ossification achieved with chondrogenically differentiated MSCs in a degradable scaffold.Biomaterials.2014;35(27):7800-7810.
[40]Huang X,Bai S,Lu Q,et al.Osteoinductive-nanoscaled silk/HA composite scaffolds for bone tissue engineering application.J Biomed Mater Res B Appl Biomater.2015;103(7):1402-1414.
[41]Tian J,Qi W,Zhang Y,et al.Bioaggregate Inhibits Osteoclast Differentiation,Fusion,and Bone Resorption In Vitro.J Endod.2015;41(9):1500-1506.
[42]Tae Young A,Kang JH,Kang DJ,et al.Interaction of stem cells with nano hydroxyapatite-fucoidan bionanocomposites for bone tissue regeneration.Int J Biol Macromol.2016;93(Pt B):1488-1491.
[43]Arcos D,Vallet-RegíM.Bioceramics for drug delivery.Acta Materialia.2013;61(3):890-911.
[44]Parent M,Baradari H,Champion E,et al.Design of calcium phosphate ceramics for drug delivery applications in bone diseases:A review of the parameters affecting the loading and release of the therapeutic substance.J Control Release.2017;252:1-17.
[45]Zhu M,Li K,Zhu Y,et al.3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy.Acta Biomater.2015;16:145-55.
[46]Feng DS,Shi J,Wang XJ,et al.Hollow hybrid hydroxyapatite microparticles with sustained and p H-responsive drug delivery properties.RSC Adv.2013;3(47):24975.
[47]Guimond-Lischer S,Ren Q,Braissant O,et al.Vacuum plasma sprayed coatings using ionic silver doped hydroxyapatite powder to prevent bacterial infection of bone implants.Biointerphases.2016;11(2):011012.
[48]Brooks BD,Sinclair KD,Davidoff SN,et al.Molded polymer-coated composite bone void filler improves tobramycin controlled release kinetics.J Biomed Mater Res B Appl Biomater.2014;102(5):1074-1083.
[49]Zheng X,Shi Y,Chen Y,et al.Novel impurity-free hexagonal hydroxyapatite nanotubes for local delivery of antibiotics in orthopedic surgery:in vitro release validation.Int J Clin Exp Med.2015;8(2):2628-2634.
[50]Chia HN,Wu BM.Recent advances in 3D printing of biomaterials.J Biol Eng.2015;9:4.
[2]Tamaddon M,Samizadeh S,Wang L,et al.Intrinsic Osteoinductivity of Porous Titanium Scaffold for Bone Tissue Engineering.Int J Biomater.2017.2017:5093063.
[3]Fuh LJ,Huang YJ,Chen WC,et al.Preparation of micro-porous bioceramic containing silicon-substituted hydroxyapatite and beta-tricalcium phosphate.Mater Sci Eng C Mater Biol Appl.2017;75:798-806.
[4]Vollmer NL,Spear JR,Ayers RA.Antimicrobial activity and biologic potential of silver-substituted calcium phosphate constructs produced with self-propagating high-temperature synthesis.J Mater Sci Mater Med.2016;27(6):104.
[5]Gomes S,Kaur A,Grenèche JM,et al.Atomic scale modeling of iron-doped biphasic calcium phosphate bioceramics.Acta Biomater.2017;50:78-88.
[6]Blum C,Brückner T,Ewald A,et al.Mg:Ca ratio as regulating factor for osteoclastic in vitro resorption of struvite biocements.Mater Sci Eng C Mater Biol Appl.2017;73:111-119.
[7]Ke D,Dernell W,Bandyopadhyay A,et al.Doped tricalcium phosphate scaffolds by thermal decomposition of naphthalene:Mechanical properties and in vivo osteogenesis in a rabbit femur model.J Biomed Mater Res B Appl Biomater.2015;103(8):1549-1559.
[8]Schumacher TC,Treccani L,Rezwan K.Effect of silica on porosity,strength,and toughness of pressureless sintered calcium phosphate–zirconia bioceramics.Biomed Mater.2015;10(4):045020.
[9]Denry I,Kuhn LT.Design and characterization of calcium phosphate ceramic scaffolds for bone tissue engineering.Dent Mater.2016;32(1):43-53.
[10]Mbarki M,Sharrock P,Fiallo M,et al.Hydroxyapatite bioceramic with large porosity.Mater Sci Eng C Mater Biol Appl.2017;76:985-990.
[11]Yatongchai C,Placek LM,Curran DJ,et al.Investigating the addition of Si O2–CaO–ZnO–Na2O–Ti O2 bioactive glass to hydroxyapatite:Characterization,mechanical properties and bioactivity.J Biomater Appl.2015;30(5):495-511.
[12]Lindner M,Bergmann C,Telle R,et al.Calcium phosphate scaffolds mimicking the gradient architecture of native long bones.J Biomed Mater Res A.2014;102(10):3677-3684.
[13]Philippart A,Boccaccini AR,Fleck C,et al.Toughening and functionalization of bioactive ceramic and glass bone scaffolds by biopolymer coatings and infiltration:a review of the last 5 years.Expert Rev Med Devices.2015;12(1):93-111.
[14]Duan S,Feng P,Gao C,et al.Microstructure Evolution and Mechanical Properties Improvement in Liquid-Phase-Sintered Hydroxyapatite by Laser Sintering.Materials(Basel).2015;8(3):1162-1175.
[15]Yao MZ,Huang-Fu MY,Liu HN,et al.Fabrication and characterization of drug-loaded nano-hydroxyapatite/polyamide 66 scaffolds modified with carbon nanotubes and silk fibroin.Int J Nanomedicine.2016;11:6181-6194.
[16]Kunert-Keil C,Scholz F,Gedrange T,et al.Comparative study of biphasic calcium phosphate with beta-tricalcium phosphate in rat cranial defects--A molecular-biological and histological study.Ann Anat.2015;199:79-84.
[17]Xie L,Yu H,Deng Y,et al.Preparation,characterization and in vitro dissolution behavior of porous biphasic alpha/beta-tricalcium phosphate bioceramics.Mater Sci Eng C Mater Biol Appl.2016;59:1007-1015.
[18]de Wild M,Amacher F,Bradbury CR,et al.Investigation of structural resorption behavior of biphasic bioceramics with help of gravimetry,muC T,SEM,and XRD.J Biomed Mater Res B Appl Biomater.2016;104(3):546-553.
[19]Lu J,Descamps M,Dejou J,et al.The biodegradation mechanism of calcium phosphate biomaterials in bone.J Biomed Mater Res.2002;63(4):408-412.
[20]Roldán JC,Klünter T,Schulz P,et al.Bone Morphogenetic Protein-7Enhances Degradation of Osteoinductive Bioceramic Implants in an Ectopic Model.Plast Reconstr Surg Glob Open.2017;5(6):e1375.
[21]Bouler JM,Pilet P,Gauthier O,et al.Biphasic calcium phosphate ceramics for bone reconstruction:A review of biological response.Acta Biomater.2017;53:1-12.
[22]Ghosh R,Sarkar R.Synthesis and characterization of sintered beta-tricalcium phosphate:A comparative study on the effect of preparation route.Mater Sci Eng C Mater Biol Appl.2016;67:345-352.
[23]Wang J,Chen Y,Zhu X,et al.Effect of phase composition on protein adsorption and osteoinduction of porous calcium phosphate ceramics in mice.J Biomed Mater Res A.2014;102(12):4234-4243.
[24]Despang F,Bernhardt A,Lode A,et al.Synthesis and physicochemical,in vitro and in vivo evaluation of an anisotropic,nanocrystalline hydroxyapatite bisque scaffold with parallel-aligned pores mimicking the microstructure of cortical bone.J Tissue Eng Regen Med.2015;9(12):E152-166.
[25]Feng P,Deng Y,Duan S,et al.Liquid phase sintered ceramic bone scaffolds by combined laser and furnace.Int J Mol Sci.2014;15(8):14574-14590.
[26]Civinini R,Capone A,Carulli C,et al.The kinetics of remodeling of a calcium sulfate/calcium phosphate bioceramic.J Mater Sci Mater Med.2017;28(9):137.
[27]Rabadan-Ros R,VelásquezP A,Meseguer-Olmo L,et al.Morphological and Structural Study of a Novel Porous Nurse's A Ceramic with Osteoconductive Properties for Tissue Engineering.Materials(Basel).2016;9(6).pii:E474.doi:10.3390/ma9060474.
[28]Sun H,Yang HL.Calcium phosphate scaffolds combined with bone morphogenetic proteins or mesenchymal stem cells in bone tissue engineering.Chin Med J(Engl).2015;128(8):1121-1127.
[29]MatéSánchez de Val JE,Calvo-Guirado JL,Gómez-Moreno G,et al.Influence of hydroxyapatite granule size,porosity,and crystallinity on tissue reaction in vivo.Part A:synthesis,characterization of the materials,and SEM analysis.Clin Oral Implants Res.2016;27(11):1331-1338.
[30]Ros-Tárraga P,Mazón P,Rodríguez MA,et al.Novel Resorbable and Osteoconductive Calcium Silicophosphate Scaffold Induced Bone Formation.Materials(Basel).2016;9(9).pii:E785.doi:10.3390/ma9090785.
[31]Maji K,Dasgupta S,Kundu B,et al.Development of gelatin-chitosanhydroxyapatite based bioactive bone scaffold with controlled pore size and mechanical strength.J Biomater Sci Polym Ed.2015;26(16):1190-1209.
[32]Rustom LE,Boudou T,Lou S,et al.Micropore-induced capillarity enhances bone distribution in vivo in biphasic calcium phosphate scaffolds.Acta Biomater.2016;44:144-154.
[33]Bianchi M,Urquia Edreira ER,Wolke JG,et al.Substrate geometry directs the in vitro mineralization of calcium phosphate ceramics.Acta Biomater.2014;10(2):661-669.
[34]Lobo SE,Glickman R,da Silva WN,et al.Response of stem cells from different origins to biphasic calcium phosphate bioceramics.Cell Tissue Res.2015;361(2):477-495.
[35]Yu X,Tang X1,Gohil SV,et al.Biomaterials for Bone Regenerative Engineering.Adv Healthc Mater.2015;4(9):1268-1285.
[36]Roohani-Esfahani SI,No YJ,Lu Z,et al.A bioceramic with enhanced osteogenic properties to regulate the function of osteoblastic and osteocalastic cells for bone tissue regeneration.Biomed Mater.2016;11(3):035018.
[37]He F,Zhang J,Yang F,et al.In vitro degradation and cell response of calcium carbonate composite ceramic in comparison with other synthetic bone substitute materials.Mater Sci Eng C Mater Biol Appl.2015;50:257-265.
[38]Cushnie EK,Ulery BD,Nelson SJ,et al.Simple Signaling Molecules for Inductive Bone Regenerative Engineering.PLo S One.2014;9(7):e101627.
[39]Harada N,Watanabe Y,Sato K,et al.Bone regeneration in a massive rat femur defect through endochondral ossification achieved with chondrogenically differentiated MSCs in a degradable scaffold.Biomaterials.2014;35(27):7800-7810.
[40]Huang X,Bai S,Lu Q,et al.Osteoinductive-nanoscaled silk/HA composite scaffolds for bone tissue engineering application.J Biomed Mater Res B Appl Biomater.2015;103(7):1402-1414.
[41]Tian J,Qi W,Zhang Y,et al.Bioaggregate Inhibits Osteoclast Differentiation,Fusion,and Bone Resorption In Vitro.J Endod.2015;41(9):1500-1506.
[42]Tae Young A,Kang JH,Kang DJ,et al.Interaction of stem cells with nano hydroxyapatite-fucoidan bionanocomposites for bone tissue regeneration.Int J Biol Macromol.2016;93(Pt B):1488-1491.
[43]Arcos D,Vallet-RegíM.Bioceramics for drug delivery.Acta Materialia.2013;61(3):890-911.
[44]Parent M,Baradari H,Champion E,et al.Design of calcium phosphate ceramics for drug delivery applications in bone diseases:A review of the parameters affecting the loading and release of the therapeutic substance.J Control Release.2017;252:1-17.
[45]Zhu M,Li K,Zhu Y,et al.3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy.Acta Biomater.2015;16:145-55.
[46]Feng DS,Shi J,Wang XJ,et al.Hollow hybrid hydroxyapatite microparticles with sustained and p H-responsive drug delivery properties.RSC Adv.2013;3(47):24975.
[47]Guimond-Lischer S,Ren Q,Braissant O,et al.Vacuum plasma sprayed coatings using ionic silver doped hydroxyapatite powder to prevent bacterial infection of bone implants.Biointerphases.2016;11(2):011012.
[48]Brooks BD,Sinclair KD,Davidoff SN,et al.Molded polymer-coated composite bone void filler improves tobramycin controlled release kinetics.J Biomed Mater Res B Appl Biomater.2014;102(5):1074-1083.
[49]Zheng X,Shi Y,Chen Y,et al.Novel impurity-free hexagonal hydroxyapatite nanotubes for local delivery of antibiotics in orthopedic surgery:in vitro release validation.Int J Clin Exp Med.2015;8(2):2628-2634.
[50]Chia HN,Wu BM.Recent advances in 3D printing of biomaterials.J Biol Eng.2015;9:4.