含CO_3~（2-）的纳米缺钙羟基磷灰石/聚乳酸复合材料的制备及性能研究
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摘要
骨缺损修复材料一直是生物材料领域的研究热点之一。十多年来,由于组织工程修复材料的诸多优点使得其已逐渐成为骨修复材料发展的方向。组织工程支架材料的发展走过了由单一的生物高分子材料、无机生物陶瓷材料等向复合多孔材料发展的道路。
羟基磷灰石(HA)/有机聚合物复合材料是当前硬组织修复材料研究中的重点之一。HA是构成人骨无机质的主要成分,具有优异的生物相容性和生物活性,能与骨组织形成牢固的键合,一直是近二、三十年骨修复和替代材料研究的热点。但其脆性大,在生理条件下抗疲劳性不强,从而限制了其临床应用。将HA与一些韧性较好、弹性模量与人骨接近的聚合物复合,可以将二者的优良性能充分结合起来,有望得到高强、柔韧、易加工塑形、力学相容性好且具有良好生物相容性和生物活性的新一代骨修复材料。
本文以Ca(NO3)2·4H2O, (NH4)2HPO4和NH4HCO3为原料,采用化学沉淀法辅以微波辐射制备了含碳酸根的纳米缺钙羟基磷灰石(d-CHA),讨论了溶液pH值、微波辐射时间、微波功率等工艺条件对所制得的d-CHA粉体钙磷摩尔比的影响。用XRD、IR、SEM对所制得的粉体进行了分析。研究结果表明:在pH为8～9的范围内,以一个适中的微波功率辐射处理反应溶液1小时,能够在较短时间内合成d-CHA粉体。
本文采用改进的溶液共混-模压成型-沥滤法来制备d-CHA/PLA多孔复合材料,希望得到具有良好生物相容性、力学性能及生物降解性,能符合骨细胞生长需要的组织工程支架材料,通过对d-CHA/PLA用量比及孔隙率等参数的控制,来调节材料的机械性能与生物降解速率。并利用XRD、IR、SEM等现代化分析手段,以及化学物理分析方法,对复合材料的成分、微观结构、孔隙率、吸水率、抗压强度等性能进行了分析和表征。
研究结果表明,采用化学沉淀法辅以微波辐射所制备的d-CHA是制备复合材料的理想原料。在制备d-CHA/PLA多孔复合材料时,当致孔剂含量为60%~70%时,复合材料的孔隙率可达60%~70%,能满足细胞生长的要求。材料的抗压强度可以达到3MPa,符合骨组织工程的要求。实验还发现,当PLA/d-CHA用量比相同时,致孔剂加入量越大,复合材料孔隙率越高,力学强度越低。PLA与d-CHA用量不同对支架材料力学性能有明显的影响,其它条件相同时,d-CHA/PLA用量比为2:8的情况下支架材料具有相对较好的成型性及抗压强度。将上述制得的d-CHA/PLA多孔复合材料,浸泡在模拟体液(SBF)中,置于37℃恒温水浴里,进行体外降解,通过X-射线衍射(XRD)、红外光谱仪(FTIR)及SEM分析,发现有少量的d-CHA转化为类骨磷灰石。由材料的降解试验结果还可以看出,PLA用量越多,或d-CHA用量越少,复合材料的降解速率越快。且降解试验结果显示,d-CHA/PLA比例为2:8的材料降解速率适中,具有较好的生物降解性。
Bone default repairing material is one of the hotspots of Biomaterial research. During the last ten years, Bone tissue engineering had been becoming the developing direction of this field for many of its merits. Biologic matrix has been developed from bio-poly-materials or bioceramics only to bio-composites. Now, the bio-composites have been confirmed to be one of the developing directions of bone tissue engineering matrix materials.
Hydroxyapatite/organic polymer biomedical composite is a hot topic of hard tissue biomaterials research. Hydroxyapatite (HA), the main mineral composition of bone, can form strong bone-bonding with natural bone and has been used extensively for biomedical applications and bone regeneration based on its high biocompatible, bioactive and osteoconductive properties, which has been the research focus of bone repair and substitute materials in resent 20-30 years. However, due to the brittleness, high modulus and fatigue failure in vivo, it is restricted in clinic for un-load bearing bone repair. In order to improve the mechanical property of HA material for hard tissue replacement, study on HA and polymer composite is highlighted. The combination of (HA) bioactivity and (polymer) toughness may result in a new load-bearing bioactive material with good mechanical property, excellent bioactivity and biocompatibility.
In this paper, Ca(NO3)2·4H2O, (NH4)2HPO4 and NH4HCO3 were used as starting materials. Calcium-deficient carbonated HA (d-CHA) nanoparticles were synthesized using a precipitation method assisted with microwave irradiation. The influence of different technical parameters such as pH value of the solution, time and power of microwave irradiation on the Ca/P molar rations of HA powders were discussed. XRD, IR and SEM were used to analyze the HA powders. The results showed that calcium-deficient carbonated HA nanoparticles with high performance could be quickly synthesized by irradiating the reaction solution for 1 h at a moderate microwave power. The pH value of solution ranged from 8～10.
In order to make a kind of bone tissue engineering matrix material with favorable biocompatibility, mechanical properties and biodegradability, a process which consists of a solvent casting stage, a compression molding stage and a leaching stage had been used to fabricate macroporous composites of PLA and d-CHA. The mechanical properties and degradable characteristics of this material could be controlled by adjusting the components ratio and the porosity. The characters of composites, such as composition, microstructure, porosity, water absorption, compressive strength were analyzed with IR, XRD, SEM and some chemistry methods.
The results show that: d-CHA powders synthesized using a precipitation method assisted with microwave irradiation were the best materials to fibracate macroporous composites. The porosity of composites could be different from 60% to 70% when poregen dosage addition was from 60% to 70%, and this porosity was suited cell fostering. The compressive strength of composites was 3MPa, and this compressive strength was suited the demands of bone tissue engineering. When the ratio of PLA and d-CHA was determined, with the increasing of the porogen dosage, the porosity would be increased, and the mechanical properties would be dropped down. Different dosage of PLA andβ-TCP could affect the composites properties. With the same other conditions, d-CHA/PLA=2:8, the composites possessed better advantages for molding and better mechanical properties. The composite samples were immersed in stimulated body fluid(SBF) at 37℃, the samples were characterized by XRD, IR and SEM. The results showed that bone-like apatite was formed on the surface of composites. From the results of degradation experiments, it could be seen that with more PLA given, or amount d-CHA powder reduced, the speed of degrading increased. And the results showed that when d-CHA/PLA was 2:8, the composites possessed mezzo degrading speed and best biodegradability.
羟基磷灰石(HA)/有机聚合物复合材料是当前硬组织修复材料研究中的重点之一。HA是构成人骨无机质的主要成分,具有优异的生物相容性和生物活性,能与骨组织形成牢固的键合,一直是近二、三十年骨修复和替代材料研究的热点。但其脆性大,在生理条件下抗疲劳性不强,从而限制了其临床应用。将HA与一些韧性较好、弹性模量与人骨接近的聚合物复合,可以将二者的优良性能充分结合起来,有望得到高强、柔韧、易加工塑形、力学相容性好且具有良好生物相容性和生物活性的新一代骨修复材料。
本文以Ca(NO3)2·4H2O, (NH4)2HPO4和NH4HCO3为原料,采用化学沉淀法辅以微波辐射制备了含碳酸根的纳米缺钙羟基磷灰石(d-CHA),讨论了溶液pH值、微波辐射时间、微波功率等工艺条件对所制得的d-CHA粉体钙磷摩尔比的影响。用XRD、IR、SEM对所制得的粉体进行了分析。研究结果表明:在pH为8～9的范围内,以一个适中的微波功率辐射处理反应溶液1小时,能够在较短时间内合成d-CHA粉体。
本文采用改进的溶液共混-模压成型-沥滤法来制备d-CHA/PLA多孔复合材料,希望得到具有良好生物相容性、力学性能及生物降解性,能符合骨细胞生长需要的组织工程支架材料,通过对d-CHA/PLA用量比及孔隙率等参数的控制,来调节材料的机械性能与生物降解速率。并利用XRD、IR、SEM等现代化分析手段,以及化学物理分析方法,对复合材料的成分、微观结构、孔隙率、吸水率、抗压强度等性能进行了分析和表征。
研究结果表明,采用化学沉淀法辅以微波辐射所制备的d-CHA是制备复合材料的理想原料。在制备d-CHA/PLA多孔复合材料时,当致孔剂含量为60%~70%时,复合材料的孔隙率可达60%~70%,能满足细胞生长的要求。材料的抗压强度可以达到3MPa,符合骨组织工程的要求。实验还发现,当PLA/d-CHA用量比相同时,致孔剂加入量越大,复合材料孔隙率越高,力学强度越低。PLA与d-CHA用量不同对支架材料力学性能有明显的影响,其它条件相同时,d-CHA/PLA用量比为2:8的情况下支架材料具有相对较好的成型性及抗压强度。将上述制得的d-CHA/PLA多孔复合材料,浸泡在模拟体液(SBF)中,置于37℃恒温水浴里,进行体外降解,通过X-射线衍射(XRD)、红外光谱仪(FTIR)及SEM分析,发现有少量的d-CHA转化为类骨磷灰石。由材料的降解试验结果还可以看出,PLA用量越多,或d-CHA用量越少,复合材料的降解速率越快。且降解试验结果显示,d-CHA/PLA比例为2:8的材料降解速率适中,具有较好的生物降解性。
Bone default repairing material is one of the hotspots of Biomaterial research. During the last ten years, Bone tissue engineering had been becoming the developing direction of this field for many of its merits. Biologic matrix has been developed from bio-poly-materials or bioceramics only to bio-composites. Now, the bio-composites have been confirmed to be one of the developing directions of bone tissue engineering matrix materials.
Hydroxyapatite/organic polymer biomedical composite is a hot topic of hard tissue biomaterials research. Hydroxyapatite (HA), the main mineral composition of bone, can form strong bone-bonding with natural bone and has been used extensively for biomedical applications and bone regeneration based on its high biocompatible, bioactive and osteoconductive properties, which has been the research focus of bone repair and substitute materials in resent 20-30 years. However, due to the brittleness, high modulus and fatigue failure in vivo, it is restricted in clinic for un-load bearing bone repair. In order to improve the mechanical property of HA material for hard tissue replacement, study on HA and polymer composite is highlighted. The combination of (HA) bioactivity and (polymer) toughness may result in a new load-bearing bioactive material with good mechanical property, excellent bioactivity and biocompatibility.
In this paper, Ca(NO3)2·4H2O, (NH4)2HPO4 and NH4HCO3 were used as starting materials. Calcium-deficient carbonated HA (d-CHA) nanoparticles were synthesized using a precipitation method assisted with microwave irradiation. The influence of different technical parameters such as pH value of the solution, time and power of microwave irradiation on the Ca/P molar rations of HA powders were discussed. XRD, IR and SEM were used to analyze the HA powders. The results showed that calcium-deficient carbonated HA nanoparticles with high performance could be quickly synthesized by irradiating the reaction solution for 1 h at a moderate microwave power. The pH value of solution ranged from 8～10.
In order to make a kind of bone tissue engineering matrix material with favorable biocompatibility, mechanical properties and biodegradability, a process which consists of a solvent casting stage, a compression molding stage and a leaching stage had been used to fabricate macroporous composites of PLA and d-CHA. The mechanical properties and degradable characteristics of this material could be controlled by adjusting the components ratio and the porosity. The characters of composites, such as composition, microstructure, porosity, water absorption, compressive strength were analyzed with IR, XRD, SEM and some chemistry methods.
The results show that: d-CHA powders synthesized using a precipitation method assisted with microwave irradiation were the best materials to fibracate macroporous composites. The porosity of composites could be different from 60% to 70% when poregen dosage addition was from 60% to 70%, and this porosity was suited cell fostering. The compressive strength of composites was 3MPa, and this compressive strength was suited the demands of bone tissue engineering. When the ratio of PLA and d-CHA was determined, with the increasing of the porogen dosage, the porosity would be increased, and the mechanical properties would be dropped down. Different dosage of PLA andβ-TCP could affect the composites properties. With the same other conditions, d-CHA/PLA=2:8, the composites possessed better advantages for molding and better mechanical properties. The composite samples were immersed in stimulated body fluid(SBF) at 37℃, the samples were characterized by XRD, IR and SEM. The results showed that bone-like apatite was formed on the surface of composites. From the results of degradation experiments, it could be seen that with more PLA given, or amount d-CHA powder reduced, the speed of degrading increased. And the results showed that when d-CHA/PLA was 2:8, the composites possessed mezzo degrading speed and best biodegradability.
引文
[1]李玉宝.生物医学材料[M].北京:化学工业出版社,2003.
[2]郑学斌,刘宣勇,丁传贤.人体硬组织替代材料的研究进展[J].物理,2003,32(3):159-164.
[3] Tancred DC,Carr AJ,M ccormack BAO.Development of a new synthetic bone graft [J].J Mater Sci:Mater Med,1998 (10):819-823.
[4] T.S.B.Narasaraju,D.E.Phebe.Some physico-chemical aspects of hydroxyapatite [J].Journal of Materials Science,1996,4(17):85-90.
[5]成令忠.组织学与胚胎学[M].北京:人民卫生出版社,1999:40-53.
[6]沈序辉,宋晨路,沈鸽等.有机-羟基磷灰石复合骨替代材料[J].材料科学与工程,1999,17(4):85-90.
[7]材料科学技术百科全书[M],北京:中国大百科全书出版社,1993,927-928.
[8]王慧明,等.四种骨替代材料的人成骨细脆生物相容性研究[J],中国生物医学工程学报, 1996,15(3):239-244.
[9] J.Simeke,R.Sachdeva.Cranial bone apposition and in growth in a porous nickel-titanium implant [J].J.Biomed.Mater.Res.,1995,29:527-533.
[10] Mainil-Varlet.Local infection resistance and mechanical properties of polylactide implants after experimental determination [J].Society for Biomaterials,1998,April,22-26:345.
[11] C.T.Laurencin,et al.Bone resorption mediators elicited by degradation products of orthopedic polymers [J].Society for Biomaterials.1998,April,22-26:309.
[12] Alice Van Siledregt,et al.Hydroxyapatite/polylactide composite for reconstructive surgery [J].1993,10-12.
[13] Antonis G.K.Wetting of Poly (L-lactic acid) and Poly (DL-lactic-co-glycolic acid) foams for Tissue Culture [J].Biomaterials.1994,15(1):55-58.
[14]金丹,裴国献.骨与软骨缺损组织工程学修复研究进展[J].中华骨科杂志,1999,19(7):441-443.
[15] Huipin Yuan,Yubao Li,et al.Tissue response of calcium phosphate cement:a study in dogs [J].Biomaterials,2000,21:219-236.
[16]陈希哲,杨连甲.生物陶瓷与骨组织工程[J],国外医学生物医学工程分册,2000,23(1):6-10.
[17]杨光成,等.自体软骨组织工程的实验研究[J],中华整形外科杂志,2000,16(6):333-335.
[18] Robert Langer.Tissue engineering [J].Science,1993,260:920-926.
[19] Larry L Hench,Julia M Polak,Science,2002,295:1014.
[20]严滢,顾其胜.透明质酸的医学应用研究新进展[J],上海生物医学工程,2001,22(1):40.
[21] Temenoff JS.,Mikos AG.Review Tissue engineering for regeneration of articular cartilage [J].Biomaterials,2000,21:431-440.
[22] Dietmar W H.Scaffolds in tissue engineering bone and cartilage [J].Biomaterials,2000,21:2529-2543.
[23] Itoh S,Shinomiya K,Kawauchi T,The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomaterial and its function as a carrier of rh-BMP-2 [J],Journal of Biomedical Materials Research,2001,54(3):445-453.
[24] Hideki A,Masataka O,Effects of Adriacin-adsorbing HAP-sol on Ca-9 cell Growth [J],Reports of the Institute for Medical and Dental Engineering,1993,(27):39-44.
[25]加纳诚介,山崎淳司,青木秀希等.ハィドロキシァバタィト微结晶体の各种药剂吸着特性おょび徐放性[J],Drug Delivery System,1993,8(6):467-471.
[26]张士成,李世普.磷灰石超微粉对癌细胞作用的初步研究[J],武汉工业大学学报,1996,18(1):5-8.
[27]夏清华,陈道达,闫玉华等.HASM对W-256细胞系DNA含量及细胞周期的影响[J],武汉工业大学学报,1999,1(3):20-21.
[28] Monma H , Kamiya T . Preparation of hydroxyapatite by the hydrolysis of brushite [J].J.Mater.Sci.,1987,(22):4247-4250.
[29] Monma H,Ueno S,Kanazawa T,Properties of hydroxyapatite prepared by the hydrolysis of tricalcioum phosphate [J].J.Chem.Tech.Biotechnol.,1981,31:15-24.
[30]徐光亮,聂轶霞,赖振宇.水热合成羟基磷灰石纳米粉体的研究[J],无机材料学报,2002,17(3):600-604.
[31]童一平,李粉玲,余沐磷.溶胶-凝胶法制备羟基磷灰石工艺条件的探讨[J],中国陶瓷,2002,38(4):16-17.
[32]童一平,余木磷,钟秀兰等.羟基磷灰石合成工艺研究,化学研究与应用,2002,14(1):93-95.
[33] Lim G K,Wang J,et al..Nanosized hydroxyapatite powers from micro emulsions and emulsions stabilized by a biodegradable surfactant [J],Journal Material Chemistry,1999,(9):1635-1639.
[34] E.Mavropoulos,et al..Dissolution of calcium-deficient hydroxyapatite synthesized at different conditions [J].Materials Characterization,2003,(50):203–207.
[35] P.Kasten,et al..Ectopic bone formation associated with mesenchymal stem cells in a resorbable calcium deficient hydroxyapatite carrier [J].Biomaterials,2005,(26):5879-5889.
[36] M.Aizawa,et al..Syntheses of calcium-deficient apatite fibers by a homogeneous precipitation method and their characterizations [J].Journal of the European Ceramic Society,2006,(26):501-507.
[37]张弛,陈峥嵘,林建平,等.聚乳酸涂层的多孔羟基磷灰石负载软骨细胞移植修复兔关节软骨缺损[J].上海医科大学学报.2000,27(2):86-92.
[38]全大萍,卢泽俭,李世普,等.聚DL-丙交酯/羟基磷灰石复合材料(Ⅰ)制备及力学性能[J].中国生物医学工程学报.2001,20(6):485-488.
[39] Cha Y,Pitt CG.The biodegradability of polyester blends [J].Biomaterials.1990,11:108-111.
[40]李玉宝.生物医学材料.北京:化学工业出版社,2003.
[41] Yamasaki H,Saki H.Biomaterials[J],1992,13:308.
[42] Garcia A J,Ducheyne P,et al.J Biomed Mater Res[J],1998,40(1):48-56.
[43] Duan Yourong,Wang Chaoyuan,et al.J Inorganic Mater [J],2002,17(3):552.
[44] He Binglin,Ma Jianbiao.Science Founds of China [J],1996,3:165.
[45] Duan Yourong . The Formation and Characteristic of the Bone-Like Apatite and the Establishment of the Dynamic Model in Vitro in the Ca-P Ceramics [D].Chengdu:Sichuan University,2002.
[46] Constantz BR,Ison IC,Fulmer MT,et al.Skeletal repair by in situ formation of the mineral phase of bone [J].Science,1995,267(24):1796-1799.
[47] M.Jarcho,C.H.Bolen.Hydroxylapatite synthesis and characterization in dense polycrystalline form [J],J Materials Sci.,1976,11:2027-2031.
[48] A.Osaka,Y.Miura,K.Takeuchi,et al.Calcium apatite prepared from calcium hydroxide and orthophosphoric acid [J].J.Mater.Sic:Mater.Med.,1991,2:51.
[49] P.Parhi,A.Romanan,et al.A convenient route for the synthesis of hydroxyapatite through a novel microwave-mediated metathesis reaction [J],Materials Letters 58(2004)3610-3612.
[50]杨正文,蒋引珊,等.微波法快速制备高稳定性纳米羟基磷灰石[J],无机材料学报,2004, 19(4):839-844.
[51] Jingou Ji,et al.Synthesis of HA/β-TCP biphasic bioceramic powders by a modified co-precipitation method [J].Journal of Functional Materials,2003,34(5):597-599.
[52] C.M.Vaz,R.L.Reis,A.M.Cunha.Use of coupling agents to enhance the interfacial interaction in starch-EVOH/hydroxyapatite compsites.Biomaterials.23(2002)629-635.
[53] Huang Zhiliang,Liu Yu,Zhang Yu,et al.FT-IR Investigation on Crystal Chemistry of Various CO32--Substituted Hydroxyapatite Solid Solutions [J].Chinese Journal of Inorganic Chemistry 2002,18(5):469-473.
[54] Laurencin CT,Attawia MA,et a1.Tissue engineered bone regeneration using degradable polymers.The formulation of mineralized matrices [J].Bone,1996(1):93-99.
[55] Ignjatovic N,Savic V,Najman S,et a1.A Study of Hap/PLLA composite as a substitute for bone powder,using FTIR spectroscopy [J].Biomaterials,2001,22:571-575.
[56] Soriano I,Evora C.Formulation of Calcium Phosphates/Poly(d,l-lactide)blends containing gentamicin for bone implantation[J].Journal of Controlled release,2000,68:121-134.
[57] Ishaug-Riley SL,Crane GM,Gurlek A,et al.Ectopicbone formation by marrow stromal osteoblast transplantation using poly (DL-lactic-co-glycolicacid) foam simplanted into the rat mesentery [J].J Biomed Mater Res,1997,36(1):1.
[58] de Brunijn JD,Yuan H,Dekker R,et al.,Bone Engineering,Ed.by J.E.Davies,em squared incorporated,Toronto,Canada,2000,421-431.
[59]段友容,王朝元,陈继镛等.致密磷酸钙陶瓷在动态SBF中类骨磷灰石层形成研究[J].无机材料学报,2002,17(3):552-555.
[60] Dorozhkina E.I.,Dorozhkin S.V.Surface mineralisation of hydroxyapatite in modified simulated body fluid (mSBF) with higher amounts of hydrogencarbonate ions.Colloids and surfaces [J] .Physicochemical and Engineering Aspects,2002,10:41-48.
[2]郑学斌,刘宣勇,丁传贤.人体硬组织替代材料的研究进展[J].物理,2003,32(3):159-164.
[3] Tancred DC,Carr AJ,M ccormack BAO.Development of a new synthetic bone graft [J].J Mater Sci:Mater Med,1998 (10):819-823.
[4] T.S.B.Narasaraju,D.E.Phebe.Some physico-chemical aspects of hydroxyapatite [J].Journal of Materials Science,1996,4(17):85-90.
[5]成令忠.组织学与胚胎学[M].北京:人民卫生出版社,1999:40-53.
[6]沈序辉,宋晨路,沈鸽等.有机-羟基磷灰石复合骨替代材料[J].材料科学与工程,1999,17(4):85-90.
[7]材料科学技术百科全书[M],北京:中国大百科全书出版社,1993,927-928.
[8]王慧明,等.四种骨替代材料的人成骨细脆生物相容性研究[J],中国生物医学工程学报, 1996,15(3):239-244.
[9] J.Simeke,R.Sachdeva.Cranial bone apposition and in growth in a porous nickel-titanium implant [J].J.Biomed.Mater.Res.,1995,29:527-533.
[10] Mainil-Varlet.Local infection resistance and mechanical properties of polylactide implants after experimental determination [J].Society for Biomaterials,1998,April,22-26:345.
[11] C.T.Laurencin,et al.Bone resorption mediators elicited by degradation products of orthopedic polymers [J].Society for Biomaterials.1998,April,22-26:309.
[12] Alice Van Siledregt,et al.Hydroxyapatite/polylactide composite for reconstructive surgery [J].1993,10-12.
[13] Antonis G.K.Wetting of Poly (L-lactic acid) and Poly (DL-lactic-co-glycolic acid) foams for Tissue Culture [J].Biomaterials.1994,15(1):55-58.
[14]金丹,裴国献.骨与软骨缺损组织工程学修复研究进展[J].中华骨科杂志,1999,19(7):441-443.
[15] Huipin Yuan,Yubao Li,et al.Tissue response of calcium phosphate cement:a study in dogs [J].Biomaterials,2000,21:219-236.
[16]陈希哲,杨连甲.生物陶瓷与骨组织工程[J],国外医学生物医学工程分册,2000,23(1):6-10.
[17]杨光成,等.自体软骨组织工程的实验研究[J],中华整形外科杂志,2000,16(6):333-335.
[18] Robert Langer.Tissue engineering [J].Science,1993,260:920-926.
[19] Larry L Hench,Julia M Polak,Science,2002,295:1014.
[20]严滢,顾其胜.透明质酸的医学应用研究新进展[J],上海生物医学工程,2001,22(1):40.
[21] Temenoff JS.,Mikos AG.Review Tissue engineering for regeneration of articular cartilage [J].Biomaterials,2000,21:431-440.
[22] Dietmar W H.Scaffolds in tissue engineering bone and cartilage [J].Biomaterials,2000,21:2529-2543.
[23] Itoh S,Shinomiya K,Kawauchi T,The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomaterial and its function as a carrier of rh-BMP-2 [J],Journal of Biomedical Materials Research,2001,54(3):445-453.
[24] Hideki A,Masataka O,Effects of Adriacin-adsorbing HAP-sol on Ca-9 cell Growth [J],Reports of the Institute for Medical and Dental Engineering,1993,(27):39-44.
[25]加纳诚介,山崎淳司,青木秀希等.ハィドロキシァバタィト微结晶体の各种药剂吸着特性おょび徐放性[J],Drug Delivery System,1993,8(6):467-471.
[26]张士成,李世普.磷灰石超微粉对癌细胞作用的初步研究[J],武汉工业大学学报,1996,18(1):5-8.
[27]夏清华,陈道达,闫玉华等.HASM对W-256细胞系DNA含量及细胞周期的影响[J],武汉工业大学学报,1999,1(3):20-21.
[28] Monma H , Kamiya T . Preparation of hydroxyapatite by the hydrolysis of brushite [J].J.Mater.Sci.,1987,(22):4247-4250.
[29] Monma H,Ueno S,Kanazawa T,Properties of hydroxyapatite prepared by the hydrolysis of tricalcioum phosphate [J].J.Chem.Tech.Biotechnol.,1981,31:15-24.
[30]徐光亮,聂轶霞,赖振宇.水热合成羟基磷灰石纳米粉体的研究[J],无机材料学报,2002,17(3):600-604.
[31]童一平,李粉玲,余沐磷.溶胶-凝胶法制备羟基磷灰石工艺条件的探讨[J],中国陶瓷,2002,38(4):16-17.
[32]童一平,余木磷,钟秀兰等.羟基磷灰石合成工艺研究,化学研究与应用,2002,14(1):93-95.
[33] Lim G K,Wang J,et al..Nanosized hydroxyapatite powers from micro emulsions and emulsions stabilized by a biodegradable surfactant [J],Journal Material Chemistry,1999,(9):1635-1639.
[34] E.Mavropoulos,et al..Dissolution of calcium-deficient hydroxyapatite synthesized at different conditions [J].Materials Characterization,2003,(50):203–207.
[35] P.Kasten,et al..Ectopic bone formation associated with mesenchymal stem cells in a resorbable calcium deficient hydroxyapatite carrier [J].Biomaterials,2005,(26):5879-5889.
[36] M.Aizawa,et al..Syntheses of calcium-deficient apatite fibers by a homogeneous precipitation method and their characterizations [J].Journal of the European Ceramic Society,2006,(26):501-507.
[37]张弛,陈峥嵘,林建平,等.聚乳酸涂层的多孔羟基磷灰石负载软骨细胞移植修复兔关节软骨缺损[J].上海医科大学学报.2000,27(2):86-92.
[38]全大萍,卢泽俭,李世普,等.聚DL-丙交酯/羟基磷灰石复合材料(Ⅰ)制备及力学性能[J].中国生物医学工程学报.2001,20(6):485-488.
[39] Cha Y,Pitt CG.The biodegradability of polyester blends [J].Biomaterials.1990,11:108-111.
[40]李玉宝.生物医学材料.北京:化学工业出版社,2003.
[41] Yamasaki H,Saki H.Biomaterials[J],1992,13:308.
[42] Garcia A J,Ducheyne P,et al.J Biomed Mater Res[J],1998,40(1):48-56.
[43] Duan Yourong,Wang Chaoyuan,et al.J Inorganic Mater [J],2002,17(3):552.
[44] He Binglin,Ma Jianbiao.Science Founds of China [J],1996,3:165.
[45] Duan Yourong . The Formation and Characteristic of the Bone-Like Apatite and the Establishment of the Dynamic Model in Vitro in the Ca-P Ceramics [D].Chengdu:Sichuan University,2002.
[46] Constantz BR,Ison IC,Fulmer MT,et al.Skeletal repair by in situ formation of the mineral phase of bone [J].Science,1995,267(24):1796-1799.
[47] M.Jarcho,C.H.Bolen.Hydroxylapatite synthesis and characterization in dense polycrystalline form [J],J Materials Sci.,1976,11:2027-2031.
[48] A.Osaka,Y.Miura,K.Takeuchi,et al.Calcium apatite prepared from calcium hydroxide and orthophosphoric acid [J].J.Mater.Sic:Mater.Med.,1991,2:51.
[49] P.Parhi,A.Romanan,et al.A convenient route for the synthesis of hydroxyapatite through a novel microwave-mediated metathesis reaction [J],Materials Letters 58(2004)3610-3612.
[50]杨正文,蒋引珊,等.微波法快速制备高稳定性纳米羟基磷灰石[J],无机材料学报,2004, 19(4):839-844.
[51] Jingou Ji,et al.Synthesis of HA/β-TCP biphasic bioceramic powders by a modified co-precipitation method [J].Journal of Functional Materials,2003,34(5):597-599.
[52] C.M.Vaz,R.L.Reis,A.M.Cunha.Use of coupling agents to enhance the interfacial interaction in starch-EVOH/hydroxyapatite compsites.Biomaterials.23(2002)629-635.
[53] Huang Zhiliang,Liu Yu,Zhang Yu,et al.FT-IR Investigation on Crystal Chemistry of Various CO32--Substituted Hydroxyapatite Solid Solutions [J].Chinese Journal of Inorganic Chemistry 2002,18(5):469-473.
[54] Laurencin CT,Attawia MA,et a1.Tissue engineered bone regeneration using degradable polymers.The formulation of mineralized matrices [J].Bone,1996(1):93-99.
[55] Ignjatovic N,Savic V,Najman S,et a1.A Study of Hap/PLLA composite as a substitute for bone powder,using FTIR spectroscopy [J].Biomaterials,2001,22:571-575.
[56] Soriano I,Evora C.Formulation of Calcium Phosphates/Poly(d,l-lactide)blends containing gentamicin for bone implantation[J].Journal of Controlled release,2000,68:121-134.
[57] Ishaug-Riley SL,Crane GM,Gurlek A,et al.Ectopicbone formation by marrow stromal osteoblast transplantation using poly (DL-lactic-co-glycolicacid) foam simplanted into the rat mesentery [J].J Biomed Mater Res,1997,36(1):1.
[58] de Brunijn JD,Yuan H,Dekker R,et al.,Bone Engineering,Ed.by J.E.Davies,em squared incorporated,Toronto,Canada,2000,421-431.
[59]段友容,王朝元,陈继镛等.致密磷酸钙陶瓷在动态SBF中类骨磷灰石层形成研究[J].无机材料学报,2002,17(3):552-555.
[60] Dorozhkina E.I.,Dorozhkin S.V.Surface mineralisation of hydroxyapatite in modified simulated body fluid (mSBF) with higher amounts of hydrogencarbonate ions.Colloids and surfaces [J] .Physicochemical and Engineering Aspects,2002,10:41-48.