自固化磷酸钙微球的制备及其结构与性能的表征
|
摘要
口腔科和整形外科对磷酸钙微球填充修复材料有着迫切的需要,而在临床应用中,磷酸钙微球需要具有良好的生物相容性、生物活性、抗崩解性、可降解、易于操作和方便载入药物等功能性成分。磷酸钙微球的制备工艺有两种:一种是在微球成球后经过烧结处理,另一种是用高分子粘结剂粘结成球,不经烧结处理。这两种方法制备的微球不能同时保证良好的可降解吸收性和抗崩解性,也无法同步载药而导致载药量小、包封率低的问题。
针对上述问题,本研究以磷酸钙骨水泥为原料,采用反相乳液法制备了一种新型的自固化磷酸钙微球,微球的粒径范围为100~1000μm,中位径在388~605μm之间,内部有43.4%~66.7%的凝胶孔和微孔。通过正交试验探讨了各种因素对微球粒径的影响,研究表明,随着随着液固比或油液相体积比的增大,微球粒径减小;随着明胶含量的提高,微球粒径增大;随着搅拌速度的提高,微球粒径先减小后增大。获得了稳定制备微球的优化工艺参数为:搅拌速度为200 r/min,明胶浓度为8% (w/v),油水相比例为5∶1,液固比为2.0 mL/g。实验结果表明,所制备微球的自然堆积安息角为28.4~33.0°,说明微球流动性好。设计圆筒状模具表征了微球填充体的抗压性能,结果表明微球有良好的韧性,不易破碎,有利于临床操作。经过充分水化后,微球的抗压性能显著提高。体外抗崩解实验表明,微球在模拟生理条件下微球在模拟生理条件下12小时内不发生崩解,具有良好的抗崩解性。MTT法细胞毒性试验表明,微球有良好的细胞相容性。在微球制备过程中同步复合广谱抗生素药物:硫酸庆大霉素,并进行药物释放试验,研究结果表明,自固化磷酸钙微球的释放呈现明显的三段式释放:第一阶段(前3小时内)出现一定程度的GS快速突释;第二阶段(第3小时到第48小时内),GS的溶出速度较快,是一个减速释放阶段;第三阶段(从第3天到第6天),药物缓慢匀速释放,是一个恒速释放阶段。第6天之后,基本上不再有药物溶出,说明药物释放时间大约为6天。CPC微球的释放动力学特性符合化学控制扩散模型,具有一定的药物缓释效果。所制备的自固化磷酸钙微球有望用作牙槽骨缺损填充修复材料及牙槽嵴增高材料、增宽用材料等;还可用作为药物载体材料。
另外,通过液滴冷凝法制备了大粒径的自固化磷酸钙微球,微球的粒径在2~3 mm范围内,表面平整,粒径分布较窄,实验结果表明,当液固比为2.0 mL/g时微球呈椭球状,当液固比为3.0 mL/g时微球呈良好的球形,此方法制备的自固化磷酸钙微球的水化结晶不够完全,力学强度较低。通过挤出滚圆法制备了粒径均一的自固化磷酸钙球粒,可根据网板大小选择粒径在0.5~2 mm之间的微球,微球成球的液固比在0.3~0.6 mL/g之间,研究表明,挤出滚圆法制备的球粒粒径均一,强度较高且制备效率高。
Apatite microspheres are in great needs in periodontal surgery and orthopedic surgery. As for clinical use, such microspheres should be good at biocompatibility, bioactivity, biodegradation, anti-disintegration, easy to be operated and be convenient for the incorporation of drugs or other functional components. Generally, there are two ways to fabricate the apatite microspheres, the one is sintering the as-prepared microspheres to form a ceramic apatite microspheres, and the other one is directly using binders of adhesives to form the microspheres. However, microspheres prepared through these two ways don’t perform well in degradation and anti-disintegration at the same time, and drugs cannot be incorporated simultaneously during the preparatioin, which will result in a low drug loading and encapsulation efficiency.
In this study, novel self-setting calcium phosphate microspheres were prepared by the employment of a reversed emulsion method, to solve the above problems. The diameter of the microspheres distributed from 100μm to 1000μm with a median diameter between 388-605μm, with a porosity between 43.4%-66.7%. An orthogonal test indicated that the microspheres’s diameter decreased with the increase of the liquid to powder ratio or the oil to water ratio, increased with the gelatin concentration, and increased first and then decreased with the increase of agitating speed. The processing parameters for preparation of the microspheres were optimized to be: an agitating speed of 200 r/min, a gelatin concentration of 8% (w/v), an oil to water ratio of 5:1, and a liquid to powder ratio of 2.0 mL/g. The angle of repose of the microspheres was measured to be 28.4°-31.6°, indicating good flowability. Microspheres with rough surface were figured out by an etching method. The compressive test showed that the microspheres were non-brittle, which is in favor of clinical applications. The compressive performance of the microspheres was significantly improved after full hydration at 37℃and 97% humidity. Anti-disintegration test revealed the microspheres was endurable in simulated physiological conditions and MTT test indicated the microspheres were biocompatible. Gentamicin was incorporated into the microspheres simultaneously during the granulation process, and related drug releasing experiment was carried out, which exhibited drug release form the microspheres demonstrate a typical three-phase release profiles: the drug release profiles exhibited a burst release at the first 3 hours, a deceleration release in the followed 1 and a half days, and a nearly a constant velocity in the third to six days, as a result, the CPC microspheres can be used as slow releaseing drug carrier, and it was a potential candidate for bone defect filling and repair at non-load-bearing sites.
Self-setting calcium phosphate microspheres with bigger granule sizes were produced through a droplet-freezing process. The diameter of the microspheres distributed from 2-3 mm, with an even suface. The microspheres with a ellipsoidal shape when the liquid to powder ratio was 2.0 mL/g, while with a spherical shape when the ratio was 3.0 mL/g. Self-setting calcium phosphate microspheres with narrow granule sizes distribution were produced through a extrusion- spheronization process, and the liquid to powder ratio was 0.3-0.6 mL/g, the microspheres had better compressive strength.
针对上述问题,本研究以磷酸钙骨水泥为原料,采用反相乳液法制备了一种新型的自固化磷酸钙微球,微球的粒径范围为100~1000μm,中位径在388~605μm之间,内部有43.4%~66.7%的凝胶孔和微孔。通过正交试验探讨了各种因素对微球粒径的影响,研究表明,随着随着液固比或油液相体积比的增大,微球粒径减小;随着明胶含量的提高,微球粒径增大;随着搅拌速度的提高,微球粒径先减小后增大。获得了稳定制备微球的优化工艺参数为:搅拌速度为200 r/min,明胶浓度为8% (w/v),油水相比例为5∶1,液固比为2.0 mL/g。实验结果表明,所制备微球的自然堆积安息角为28.4~33.0°,说明微球流动性好。设计圆筒状模具表征了微球填充体的抗压性能,结果表明微球有良好的韧性,不易破碎,有利于临床操作。经过充分水化后,微球的抗压性能显著提高。体外抗崩解实验表明,微球在模拟生理条件下微球在模拟生理条件下12小时内不发生崩解,具有良好的抗崩解性。MTT法细胞毒性试验表明,微球有良好的细胞相容性。在微球制备过程中同步复合广谱抗生素药物:硫酸庆大霉素,并进行药物释放试验,研究结果表明,自固化磷酸钙微球的释放呈现明显的三段式释放:第一阶段(前3小时内)出现一定程度的GS快速突释;第二阶段(第3小时到第48小时内),GS的溶出速度较快,是一个减速释放阶段;第三阶段(从第3天到第6天),药物缓慢匀速释放,是一个恒速释放阶段。第6天之后,基本上不再有药物溶出,说明药物释放时间大约为6天。CPC微球的释放动力学特性符合化学控制扩散模型,具有一定的药物缓释效果。所制备的自固化磷酸钙微球有望用作牙槽骨缺损填充修复材料及牙槽嵴增高材料、增宽用材料等;还可用作为药物载体材料。
另外,通过液滴冷凝法制备了大粒径的自固化磷酸钙微球,微球的粒径在2~3 mm范围内,表面平整,粒径分布较窄,实验结果表明,当液固比为2.0 mL/g时微球呈椭球状,当液固比为3.0 mL/g时微球呈良好的球形,此方法制备的自固化磷酸钙微球的水化结晶不够完全,力学强度较低。通过挤出滚圆法制备了粒径均一的自固化磷酸钙球粒,可根据网板大小选择粒径在0.5~2 mm之间的微球,微球成球的液固比在0.3~0.6 mL/g之间,研究表明,挤出滚圆法制备的球粒粒径均一,强度较高且制备效率高。
Apatite microspheres are in great needs in periodontal surgery and orthopedic surgery. As for clinical use, such microspheres should be good at biocompatibility, bioactivity, biodegradation, anti-disintegration, easy to be operated and be convenient for the incorporation of drugs or other functional components. Generally, there are two ways to fabricate the apatite microspheres, the one is sintering the as-prepared microspheres to form a ceramic apatite microspheres, and the other one is directly using binders of adhesives to form the microspheres. However, microspheres prepared through these two ways don’t perform well in degradation and anti-disintegration at the same time, and drugs cannot be incorporated simultaneously during the preparatioin, which will result in a low drug loading and encapsulation efficiency.
In this study, novel self-setting calcium phosphate microspheres were prepared by the employment of a reversed emulsion method, to solve the above problems. The diameter of the microspheres distributed from 100μm to 1000μm with a median diameter between 388-605μm, with a porosity between 43.4%-66.7%. An orthogonal test indicated that the microspheres’s diameter decreased with the increase of the liquid to powder ratio or the oil to water ratio, increased with the gelatin concentration, and increased first and then decreased with the increase of agitating speed. The processing parameters for preparation of the microspheres were optimized to be: an agitating speed of 200 r/min, a gelatin concentration of 8% (w/v), an oil to water ratio of 5:1, and a liquid to powder ratio of 2.0 mL/g. The angle of repose of the microspheres was measured to be 28.4°-31.6°, indicating good flowability. Microspheres with rough surface were figured out by an etching method. The compressive test showed that the microspheres were non-brittle, which is in favor of clinical applications. The compressive performance of the microspheres was significantly improved after full hydration at 37℃and 97% humidity. Anti-disintegration test revealed the microspheres was endurable in simulated physiological conditions and MTT test indicated the microspheres were biocompatible. Gentamicin was incorporated into the microspheres simultaneously during the granulation process, and related drug releasing experiment was carried out, which exhibited drug release form the microspheres demonstrate a typical three-phase release profiles: the drug release profiles exhibited a burst release at the first 3 hours, a deceleration release in the followed 1 and a half days, and a nearly a constant velocity in the third to six days, as a result, the CPC microspheres can be used as slow releaseing drug carrier, and it was a potential candidate for bone defect filling and repair at non-load-bearing sites.
Self-setting calcium phosphate microspheres with bigger granule sizes were produced through a droplet-freezing process. The diameter of the microspheres distributed from 2-3 mm, with an even suface. The microspheres with a ellipsoidal shape when the liquid to powder ratio was 2.0 mL/g, while with a spherical shape when the ratio was 3.0 mL/g. Self-setting calcium phosphate microspheres with narrow granule sizes distribution were produced through a extrusion- spheronization process, and the liquid to powder ratio was 0.3-0.6 mL/g, the microspheres had better compressive strength.
引文
[1]陆裕朴,胥少汀,葛宝丰.实用骨科学[M].北京,人民军医出版社, 1991: 63-72.
[2]孙磊.同种异体骨移植生物学,中国矫形外科杂志[J]. 1996, 3 (1): 56-58.
[3] Dodd C A F, Fergusson C M, Freedman L, et al. Allograft versus autograft bone in scoliosis surgery [J]. J Bone Joint Surg Br, 1998, 70: 431-434.
[4] Damien C J, Parsons J R. Bone graft and bone graft substitutes: a review of current technology and applications [J]. J Appl Biomater, 1991, 2: 187-208.
[5]衷鸿宾.生物降解吸收型钙磷陶瓷材料[J].中国矫形外科杂志, 1996, 3 (3): 220-222.
[6] Misiek D J, Kent J N, Carr R F. Soft tissue responses to hydroxylapatite particles of different shapes [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42(150).
[7] Frame J W, Brady C L. Augmentation of an atrophic edentulous mandible by interpositional grafting with hydroxylapatite [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (2): 89-92.
[8] Anon. Hydroxylapatite, beta tricalcium phosphate, and autogenous and allogeneic bone for filling periodontal defects, alveolar ridge augmentation, and pulp capping. Council on Dental Materials, Instruments, and Equipment Council on Dental Research Council on Dental Therapeutics. Journal of the American Dental Association, 1984, 108 (5) 822-827.
[9]郑昌琼,冉均国.新型无机材料[M],科学出版社, 2003: 591-592.
[10] Liu CS, Shao H, Chen F, et al. Effects of the granularity of raw materials on the hydration and hardening process of calcium phosphate cement [J]. Biomaterials, 2003, 24(23): 4103-4113.
[11] Liu C S, Shen W. Effect of crystal seeding on the hydration of calcium phosphate cement [J]. Journal of Materials Science: Materials in Medicine, 1997, 8 (12): 803-807.
[12] Yang Q Z, Troczynski T, Liu DM. Influence of apatite seeds on the synthesis of calcium phosphate cement [J]. Biomaterials, 2002, 23(13): 2751-2760.
[13] Barralet J E, Gaunt T, Wright A J, et al. Effect of porosity reduction by compaction on compressive strength and microstructure of calcium phosphate cement [J]. Journal of Biomedical Materials Research, 2002, 63(1): 1-9.
[14] Takagi S, Chow L C, Hirayama S, et al. Properties of elastomeric calcium phosphate cement - chitosan composites [J]. Dent Mater, 2003, 19 (8): 797-804
[15] Wang X, Ma J, Wang Y, et al. Stuctural characterization of phosphorylated chitosan and their applications as effective additives of calcium phosphate cements [J]. Biomaterials 2001, 22 (16): 2247-2255.
[16] Dos Santos L A, Carrodeguas R G, Boschi A O, et al. Fiber-enriched double-setting calcium phosphate bone cement [J]. J Biomed Mater Res,2003,65A: 244-250.
[17] Takahashi K, Fujishiro Y, Yin S, et al, Preparation and compressive strength ofα-tricalcium phosphate based cement dispersed with ceramic particles. Ceramics International, 2004, 30(9): 199-203
[18] Xu H H K, Quinn J B. Whisker-reinforced bioactive composites containing calcium phosphate cement fillers:Effects of filler ratio and surface treatments on mechanicalproperties [J]. Journal of Biomedical Materials Research, 2001,57(2): 165-174.
[19] Guo D, Xu K, Zhao X, etal. Development of a strontium containing hydroxyapatite bone cement [J]. Biomaterials, 2005, 26 (19): 4073-4083.
[20] Sugawara A, Nishiyama M, Kusama R, et al. Histopathological reactions of calcium phosphate cement [J]. Dent Mater J, 1992, 11: 11-16.
[21] Sugawara A, Kusama A, Nishimura S, et al. Histopathological reactions to calcium phosphate cement for bone filling [J]. Dent Mater J, 1993, 12: 691-698.
[22] Chow L C. Development of self-setting calcium phosphate cements [J]. J Ceram Soc Jpn, 1991, 99 (1): 954-963.
[23] Chow L C, Takagi S, Ishikawa K. Hydroxyapatite and related materials [M]. Boca Raton: CRC Press, 1994, 127-137.
[24]沈卫,刘昌胜,顾燕芳.磷酸钙骨水泥的水化反应、凝结时间及抗压强度[J],硅酸盐学报, 1998, 26(2): 129-13.
[25] Barners H A, Hutton J F, Walters K. An introduction to Rheology, Elsevier, USA, 1989.
[26]杨娟娟,叶建东.原料粒度对磷酸钙骨水泥的流变性和可注射性能的影响[J].硅酸盐通报. 2008, 27(2): 207-212.
[27] Liu C S, Shao H F, Chen F Y, et al. Rheological properties of concentrated aqueous injectable calcium phosphate cement slurry [J], Biomaterials, 2006, 7 (29): 5003-50 13.
[28]金晶,刘昌胜.添加剂对磷酸钙骨水泥流变性能的影响[J],华东理工大学学报, 2005, 31(1), 88-91
[29]金晶,盖蔚,刘昌胜.添加剂对磷酸钙骨水泥流变性能的影响[J],华东理工大学学报, 2005, 31(1): 83-87
[30] Ishikawa K, Miyamoto Y, Takechi M, et al. Non-decay type fast-setting calcium phosphate cement: hydroxyapatite putty containing an increased amount of sodium alginate [J]. Journal of Biomedical Material Research, 1997, 36 (3): 393-399
[31] Cherng A, Takagi S, Chow L C, Effects of hydroxypropyl methylcellulose and other gelling agents on the handling properties of calcium phosphate cement [J], Journal of Biomedical Materials Research, 1997, 35(3): 273-277
[32] Takechi M, Miyamoto Y, Ishikawa K, et al. Non-decay type fasting-setting calcium phosphate cement using chitosan [J]. Journal of Material Science: Materials in Medicine, 1996, 7 (6): 317-322
[33] Chen L, Xiang H, Li X L, et al. Improvement of anti-washout performance of calcium phosphate cement using modified starch [J]. Key Engineering Materials, 2007, 1628-1631.
[34]李旭,杨德安,蔡仲雨等,黄原胶对磷酸钙骨水泥性能的影响[J].稀有金属材料工程,2005,34 (1),1124-1126.
[35] Ooms E M, Wolke J G, Jansen J A. Trabecular bone response to injectable calcium phosphate (Ca-P) cement [J]. Journal of Biomedical Material Research, 2002, 61 (1): 9-18.
[36] Frankenburg E P, Goldstein S A, Bauer T W, et a1. Biomechanical and histological evaluation of a calcium phosphate cement [J]. Journal of Bone and Joint Surgery (American volume), 1998, 80 (8): 1112-1124.
[37] Gross UM, Muller-Mai CM, Voigt C. The interface of calcium phosphate and glass-ceramic in bone, a structural analysis [J]. Biomaterials, 1990, 11: 83-85.
[38] Frankenburg EP, Goldstein SA, Bauer TW, et a1. Biomechanical and histological evaluation of a calcium phosphate cement [J]. J Bone Jt Surg Am, 1998, 8O (8): 1112-1124.
[39] Apelt D, Theiss F, E1 Warrak AO, et a1. In vivo behavior of three different injectable hydraulic calcium phosphate cements [J]. Biomaterials, 2004, 25 (78): 1439-145.
[40] Bohner M, Theiss F, Apelt D, et a1. Compositional changes of a dicalcium phosphate dihydrate cement after implantation in sheep [J].Biomaterials,2003,24(20):3463-347.
[41] Rousseau SJ, Bohner M, Frei C. Long-term aging of brushite cements in physiological conditions: an in vitro study [c]. GRIBOI: Shangai, March 14-17, 2002
[42]罗方聪,叶建东.层状结构磷酸钙骨水泥组织工程支架材料的制备与表征[J].硅酸盐通报, 2009, 28 (1), 27-30.
[43] Xiaopeng Qi, Jiandong Ye, Yingjun Wang. Improved injectability and in vitro degradation of a calcium phosphate cement containing poly(lactide-co-glycolide) microspheres [J]. Acta Biomaterialia 2008: 1837-1845.
[44] Maria-Pau Ginebra, Tania Traykova, Josep A. Calcium Phosphate cements: Competitive drug carriers for the musealnskeletal system. Elsevier Bin, 2006, 27: 2 171-2 217.
[45] Bohner M, Lemaitre J, VanLanduyt P, et a1. Gentamicin-loaded hydraulic calcium phosphate bone cement as antibiotic delivery system. J Pbarm Sci, 1997, 6 (5): 565-572.
[46] Bohner M, Lemaitre J, Merckle H P, et a1. Control of aentam-icin release from a calcium phosphate admixed poly (acrylic acid). J Pharm Sci, 2000, 89 (10): 1262-1270
[47] Kamerer DB, Hirsch BE, Snyderman CH, et a1. Hydoxyapatite cement: a new method for achieving watertight closure in transtemporal surgery. Am J Otol, 1994, 15: 47-49.
[48] Verheggen R. Merten HA. Correction of skull defects using hydoxyapatite cement (HAC)-evidence derived from animal experiments and clinical experience. Acta Neurochir (Wien), 2001, 143: 919-926.
[49] Horstmann WG, Verheyen CC. Leemans R. An injectable calcium phosphate cement as a bone-graft substitute in the treatment of displaced lateral tibial plateau fractures. Injury, 2003, 34: 141-144.
[50]苗军,王继芳,郝利波,等.磷酸钙骨水泥复合去甲万古霉素后理化性质改变及药物释放规律的研究.中华创伤骨科杂志, 2004, 6: 648-656.
[51] Tabara Y, Ishii Y. Apatite cement containing cis-diamminediehlorop1afinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation. J Orthop Sci, 2001, 6: 556-565.
[52] Aoki S, Takase Y, Ishikawa T. Evaluation of lining materials and a new concept for lining: alpha-TCP cement or visible light curing calcium hydroxide composition incomposite resin restoration. Bull Tokyo Dent Coil, 1991, 32: 171-181.
[53] Chau J Y, Hutter J W, Mork T O, et a1. An in vitro study of furcation perforation repair using calcium phosphate cement. J Endod, 1997, 23: 588-592.
[54]傅宪辉,沈志刚.微球制备的研究概况及发展[J].力学与实践,2005,27(3):7-13.
[55] Palmieri G F, Bonacucina G, Di Martino, et al. Spray-drying as a method for microparticulate controlled release systems preparation: Advantages and limits. I. Water-soluble drugs[J]. Drug Dev Ind Pharm, 2001, 27(3): 195-204.
[56] Carrasguillo K G, Stanley AM, Aponte-Carro J C, et al. Non- aqueous encapsulation of excipient stabilized spray-freeze dried BSA into poly( lactide-co-glycol-ide) microspheres results in release of native protein[J]. J Controlled Release, 2001, 3: 199-208.
[57]潘家祯,孙晓明,朱大滨,等.挤出滚圆法制备药用微丸I.设备的工作原理及特点[J].中国医药工业杂志, 1998, 29(8): 378-380.
[58]张瑞十,潘家祯,王力文.螺旋挤出—滚圆法制备2mm精细氧化铝小球成球机理的探讨[J].中国陶瓷, 2008, 44(7): 43-46.
[59] Zhang J, Coombs N, Kumacheva E. A new approach to hybrid polymer-metal and polymer-semiconductor particles[J]. Adv Mater, 2002, 14: 1856.
[60] Zhang J, Coombs N, Kumacheva E J. A new approach to hybrid nanocomposite materials with periodic st ructures[J]. Am Chem Soc, 2002, 124: 14512.
[61] Lin Y, Zhang J, Sargent E H. Photonic pseudo-gap-based modification of photoluminescence from CdS nanocrystal satellites around polymer microspheres in a photonic crystal[J]. Appl Phys Lett, 2002, 81: 3134.
[62] Shisho H, Kawahashi N. Titanium compounds as coatings on polystyrene latices and as hollow spheres [J]. Colloid Polym Sci, 2000, 278: 270.
[63] Wang P H, Pan C Y. Polymer metal composite microspheres: Preparation and characterization of poly ( St-co-N)Ni microspheres[J] . Eur Polym J, 2000, 36: 2297.
[64] Caruso F, Caruso R A, Mhwald HCaruso F, Caruso R A, Mêhwald H. Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating[J]. Science, 1998, 282: 1111.
[65] Cheung Herman S. In Vitro Cartilage formation on porous hydroxyapatite ceramic granules [J]. In vitro cellular and developmental biology, 1985, 21 (6): 353-357.
[66] Ono K, Yamamuro T, Nakamura T, et al. Quantitative study on osteoconduction ofapatite-wollastonite containing glass ceramic granules, hydroxyapatite granules and alumina granules [J]. Biomaterials, 1990, 11 (4): 265-271.
[67] Gatti A M,Zaffe D and Poli G P, Biomaterials, 1990, 11: 513
[68] Sautier J M, Nefussi J R, Boulekbache H and Forest N. In Vitro Cell. Dev. B 1990, 26: 1079
[69] Keiko Yamamura, Hisashi Iwata and Toshihisa Yotsuyanag. Synthesis of antibiotic-loaded hydroxyapatite beads and in vitro drug release testing [J]. Journal of Biomedical Materials Research, 1992, 26 (8): 1053-1064.
[70] Hiroshi Yamasaki, Hidetaka Sakai. Osteogenic response to porous hydroxyapatite ceramics under the skin of dogs [J]. Biomaterials, 1992, 13 (5): 308-312.
[71] Byrd H S, Hobar P C, Shewmake K.Augmentation of the craniofaciaI skeleton with porous hydroxyapatite granules [J]. Raat Reconstr Surg, 1993, 91 (1): 15-22.
[72] Wiese K G and Merten H A, Int J Oral Maxillofac Surg, 1993, 22: 306
[73] Lindholm T C, Gao T J and Lindholm T S, Int J Oral Maxillofac Surg 1994, 23: 306
[74] M. Fabbri, G.C. Celotti, A. Ravaglioli. Granulates based on calcium phosphate with controlled morphology and porosity for medical applications: physico-chemical parameters and production technique [J]. Biomaterials, 1994, 15 (6): 474-477.
[75] E. A. Holtgrave, K. Donath. Response of odontoblast-like cells to hydroxyapatite ceramic granules [J]. Biomaterials, 1995, 16 (2): 155-159
[76] E T Baran, K Tuzlakoglu, A J Salgado, et al. Multichannel mould processing of 3D structures from microporous coralline hydroxyapatite granules and chitosan support materials for guided tissue regeneration/engineering [J]. Journal of Materials Science: Materials in Medicine, 2004, 15 (2): 161-165.
[77] P Luo and T G Nieh. Preparing hydroxyapatite powders with controlled morphology [J]. Biomaterials, 1996, 17 (6): 1959-1964.
[78] Norio Kawai, Shigeo Niwa, Motoki Sato, et al. Bone formation by cells from femurs cultured among three-dimensionally arranged hydroxyapatite granules [J]. Journal of Biomedical Materials Research, 1997, 37 (1): 1-8.
[79] Dean-Mo Liu. Fabrication and characterization of porous hydroxyapatite granules [J]. Biomaterials, 1996, 17 (20): 1955-1957.
[80] Vladimir S. Komleva, Serguei M, et al. A method to fabricate porous spherical hydroxyapatite granules intended for time-controlled drug release. Biomaterials, 23 (2002) 3449-3454.
[81] Rodríguez-Lorenzo L M, Vallet-RegíM F and Ferreira J M. Fabrication of poroushydroxyapatite bodies by a new direct consolidation method: starch consolidation [J]. Journal of Biomedical Materials Research , 2002, 60 (2): 232-240.
[82] Zhang J P, Wang Q, Wang A Q. In situ generation of sodium alginate/hydroxyapatite nanocomposite beads as drug controlled release matrices [J]. Acta Biomaterialia, 2010, 6 (2): 445-454.
[83] Tas A C,Preparation of porous apatite granules from calcium phosphate cement [J]. J Mater Sci, 2008, 19: 2231-2239
[84] Faure A, York P and Rowe R C, Process control and scale-up of pharmaceutical wet granulation processes: a review, European Journal of Pharmaceutics and Biopharmaceutics 52 (2001), 269–277.
[85] Vervaet C, Remon J P, Continuous granulation in the pharmaceutical industry [J]. Chem. Eng. Sci., 2005, 60: 3949-3957.
[86] Zaffe D. Some considerations on biomaterials and bone [J]. Micron, 2005, 36 (7-8): 583-592.
[87] Horch H H, Sader R, Pautke C. et al. Synthetic,pure-phase beta-tricalcium phosphate ceramic granules (Cerasorb) for bone regeneration in the reconstructive surgery of the jaws.Int J Oral Maxillofac Surg. 2006, 35(8): 708-713.
[88] Jung R E, Haemmerle C H F, Kokovic E and Weber E, Int. J. Oral Maxillofac. Implants. 22 (2007) 258.
[89] Misiek D J, Kent J N, Carr R F. Soft tissue responses to hydroxylapatite particles of different shapes [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (3), 150-160.
[90] Bodde E W H, Cammaert C T R, Wolke, J G C, et al.. Investigation as to the osteoinductivity of macroporous calcium phosphate cement in goats [J]. Journal of Biomedical Materials Research: Part B, 2007, 83B (1): 161-168.
[91] Ducheyne P, Hench L L, Kagan A, et al. Effect of hydroxyapatite impregnation on skeletal bonding of porous coated implants. [J]. Journal of Biomedical Materials Research, 1980, 14 (3): 225-237.
[92] Frame J W, Brady C L. Augmentation of an atrophic edentulous mandible by interpositional grafting with hydroxylapatite [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (2): 89-92.
[93] Anon. Hydroxylapatite, beta tricalcium phosphate, and autogenous and allogeneic bone for filling periodontal defects, alveolar ridge augmentation, and pulp capping. Council on Dental Materials, Instruments, and Equipment Council on DentalResearch Council on Dental Therapeutics. Journal of the American Dental Association, 1984, 108 (5) 822-827.
[94] Bohner M, Gbureck U, Barralet J E. Technological issues for the development of more efficient calcium phosphate bone cements: a critical assessment [J]. Biomaterials, 2005, 26 (33): 6423-6429.
[95] Xu H H K, Takagi S, Quinn J B, et al. Fast-setting calcium phosphate scaffolds with tailored macropore formation rates for bone regeneration [J]. Journal of Biomedical Material and Research: Part A, 2004, 68A (4): 725-734.
[96] Burguera E F, Xu H H K, Takagi S, et al. High early strength calcium phosphate bone cement: Effects of dicalcium phosphate dihydrate and absorbable fibers [J]. Journal of Biomedical Material and Research: Part A, 2005, 75A (4): 966-975.
[97] Chen A Z, Li Y, Chau F T, et al. Application of organic nonsolvent in the process of solution-enhanced dispersion by supercritical CO2 to prepare puerarin fine particles [J]. Journal of Supercritical Fluids, 2009, 49 (3): 394-402.
[98]陆扬,明胶微球的研究进展[J].明胶科学与技术, 2006, 26(2): 59-61.
[99] Chen L, Xiang H, Li X L, et al. Improvement of anti-washout performance of calcium phosphate cement using modified starch [J]. Key Engineering Materials, 2007, 336-338: 1628-1631.
[100]张淑霞王忆娟黄沙等表面形貌各异的明胶微球制备及其对细胞增殖的影响[J].高分子化学和化学工业,2009,1: 42-46.
[101] Hae-Won Kim, Jonathan C Knowles, Hyoun-Ee Kim, et al。Hydroxyapatite and gelatin composite foams processed via novel freeze-drying and crosslinking for use as temporary hard tissue scaffolds [J]. Journal of Biomedical Material and Research, Part A, 2005, 72A (2): 136-145.
[102]唐世华,曾锡瑞,郑忠.明胶的酶降解反应动力学研究:影响明胶酶降解反应的因素[J].明胶科学与技术, 1994, 14 (4): 199-203.
[103]陈洪叶,赵文丽,李国栋.用单管落球法探讨蓖麻油粘度随温度的变化[J].大学物理实验, 2007, 20 (1): 47-50.
[104]刘耀,刘松青.挤出-滚圆法制备微丸的研究进展[J].中国药学杂志, 2008, 43 (6): 401-405.
[105] Li Q B, You J, Yang L, et a1. Preparation of gegen qinlian pellets by extrusion-spheronization method [J]. Chin Tradit Herbal Drugs, 2005, 36 (10): 1473-1476.
[106] Harrison P J, Newton J M, Rower R C. Flow defects in wet powder mass extrusion [J]. J Pharm Pharmacol, 1985, 37 (2): 81-83.
[107] Maunowski H J, Smith W E. Effects of spheronization process variables on selected tablet properties [J]. J PharmSci, 1974, 63: 285-288.
[108] Baert L, Remon J P. Eibers J A C, et al. Comparison between a gravity feed extruder and a twin scro extruder [J]. Int J Pharm, 1993, 99: 7-12.
[109]孙文晓,张海港,韦卓等.骨修复材料的研究应用现状与展望[J].生物骨科材料与临床研究, 2009, 6 (3): 34-50.
[110] Jain S K, Awasthi A M, Jain N K, et al. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization [J]. Journal of Controlled release, 2005, 107 (2): 300-309.
[111] Wang X P, Chen L, Xiang H, et al. Influence of anti-washout agents on the rheological properties and injectability of a calcium phosphate cement [J]. Journal of Biomedical Material and Research, 2006, 81B (2): 410-418.
[112]蔡舒,姚康德,李鸿祥.羟基磷灰石合成及高温稳定性的研究[J].无机材料学报, 2003, 18 (4): 807-812.
[113] Wang X P, Ye J D, Wang Y J. Hydration mechanism of a novel PCCP plus DCPA cement system [J]. Journal of Materials Science-Materials in Medicine, 2008, 19 (2): 813-816.
[114] Ambard A J, Mueninghoff L. Calcium phosphate cement: review of machanical and biological properties [J]. Journal of Prosthodontics, 2006, 15 (5): 321-328.
[115] Telli C, Serper, A, Dogan, A L, et al. Evaluation of the cytotoxicity of calcium phosphate root canal sealers by MTT assay [J]. Journal of Endodontics, 1999, 25 (12): 811-813.
[116]温世锋,刘清华,郭奇峰等.新型磷酸钙骨水泥与骨髓间充质干细胞的共培养研究[J].临床医学工程, 2009, 16 (11): 1-4.
[117] Maria-Pau Ginebra, Tania Traykova and Josep A Planell. Calcium phosphate cements: Competitive drug carriers for the musculoskeletal system? [J]. Biomaterials 27 (2006) 2171-2177.
[118]郜成莹,叶建东.添加剂和载药方法对庆大霉素/磷酸钙骨水泥载药体系性能及药物体外释放的影响硅酸盐通报,2008,27(2):225-229.
[119] Mathiowitz E, editor. Encyclopaedia of controlled drug delivery. New York: Wiley; 1999.
[120] Ye J D, Wang X P, Wang Y J. Rheological properties of an injectable calcium phosphate bone cement and their relationship with the phase evolution [J]. Key Engineering Materials, 2007, 336-338: 1658-1661.
[121] Lee W K, Park J Y, Yang E H, et a1. J. Control Release, 2002, 84(3): 115-123.
[122]中国药典[M].化学工业出版社, 2000年版二部附录ⅣA第866页.
[2]孙磊.同种异体骨移植生物学,中国矫形外科杂志[J]. 1996, 3 (1): 56-58.
[3] Dodd C A F, Fergusson C M, Freedman L, et al. Allograft versus autograft bone in scoliosis surgery [J]. J Bone Joint Surg Br, 1998, 70: 431-434.
[4] Damien C J, Parsons J R. Bone graft and bone graft substitutes: a review of current technology and applications [J]. J Appl Biomater, 1991, 2: 187-208.
[5]衷鸿宾.生物降解吸收型钙磷陶瓷材料[J].中国矫形外科杂志, 1996, 3 (3): 220-222.
[6] Misiek D J, Kent J N, Carr R F. Soft tissue responses to hydroxylapatite particles of different shapes [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42(150).
[7] Frame J W, Brady C L. Augmentation of an atrophic edentulous mandible by interpositional grafting with hydroxylapatite [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (2): 89-92.
[8] Anon. Hydroxylapatite, beta tricalcium phosphate, and autogenous and allogeneic bone for filling periodontal defects, alveolar ridge augmentation, and pulp capping. Council on Dental Materials, Instruments, and Equipment Council on Dental Research Council on Dental Therapeutics. Journal of the American Dental Association, 1984, 108 (5) 822-827.
[9]郑昌琼,冉均国.新型无机材料[M],科学出版社, 2003: 591-592.
[10] Liu CS, Shao H, Chen F, et al. Effects of the granularity of raw materials on the hydration and hardening process of calcium phosphate cement [J]. Biomaterials, 2003, 24(23): 4103-4113.
[11] Liu C S, Shen W. Effect of crystal seeding on the hydration of calcium phosphate cement [J]. Journal of Materials Science: Materials in Medicine, 1997, 8 (12): 803-807.
[12] Yang Q Z, Troczynski T, Liu DM. Influence of apatite seeds on the synthesis of calcium phosphate cement [J]. Biomaterials, 2002, 23(13): 2751-2760.
[13] Barralet J E, Gaunt T, Wright A J, et al. Effect of porosity reduction by compaction on compressive strength and microstructure of calcium phosphate cement [J]. Journal of Biomedical Materials Research, 2002, 63(1): 1-9.
[14] Takagi S, Chow L C, Hirayama S, et al. Properties of elastomeric calcium phosphate cement - chitosan composites [J]. Dent Mater, 2003, 19 (8): 797-804
[15] Wang X, Ma J, Wang Y, et al. Stuctural characterization of phosphorylated chitosan and their applications as effective additives of calcium phosphate cements [J]. Biomaterials 2001, 22 (16): 2247-2255.
[16] Dos Santos L A, Carrodeguas R G, Boschi A O, et al. Fiber-enriched double-setting calcium phosphate bone cement [J]. J Biomed Mater Res,2003,65A: 244-250.
[17] Takahashi K, Fujishiro Y, Yin S, et al, Preparation and compressive strength ofα-tricalcium phosphate based cement dispersed with ceramic particles. Ceramics International, 2004, 30(9): 199-203
[18] Xu H H K, Quinn J B. Whisker-reinforced bioactive composites containing calcium phosphate cement fillers:Effects of filler ratio and surface treatments on mechanicalproperties [J]. Journal of Biomedical Materials Research, 2001,57(2): 165-174.
[19] Guo D, Xu K, Zhao X, etal. Development of a strontium containing hydroxyapatite bone cement [J]. Biomaterials, 2005, 26 (19): 4073-4083.
[20] Sugawara A, Nishiyama M, Kusama R, et al. Histopathological reactions of calcium phosphate cement [J]. Dent Mater J, 1992, 11: 11-16.
[21] Sugawara A, Kusama A, Nishimura S, et al. Histopathological reactions to calcium phosphate cement for bone filling [J]. Dent Mater J, 1993, 12: 691-698.
[22] Chow L C. Development of self-setting calcium phosphate cements [J]. J Ceram Soc Jpn, 1991, 99 (1): 954-963.
[23] Chow L C, Takagi S, Ishikawa K. Hydroxyapatite and related materials [M]. Boca Raton: CRC Press, 1994, 127-137.
[24]沈卫,刘昌胜,顾燕芳.磷酸钙骨水泥的水化反应、凝结时间及抗压强度[J],硅酸盐学报, 1998, 26(2): 129-13.
[25] Barners H A, Hutton J F, Walters K. An introduction to Rheology, Elsevier, USA, 1989.
[26]杨娟娟,叶建东.原料粒度对磷酸钙骨水泥的流变性和可注射性能的影响[J].硅酸盐通报. 2008, 27(2): 207-212.
[27] Liu C S, Shao H F, Chen F Y, et al. Rheological properties of concentrated aqueous injectable calcium phosphate cement slurry [J], Biomaterials, 2006, 7 (29): 5003-50 13.
[28]金晶,刘昌胜.添加剂对磷酸钙骨水泥流变性能的影响[J],华东理工大学学报, 2005, 31(1), 88-91
[29]金晶,盖蔚,刘昌胜.添加剂对磷酸钙骨水泥流变性能的影响[J],华东理工大学学报, 2005, 31(1): 83-87
[30] Ishikawa K, Miyamoto Y, Takechi M, et al. Non-decay type fast-setting calcium phosphate cement: hydroxyapatite putty containing an increased amount of sodium alginate [J]. Journal of Biomedical Material Research, 1997, 36 (3): 393-399
[31] Cherng A, Takagi S, Chow L C, Effects of hydroxypropyl methylcellulose and other gelling agents on the handling properties of calcium phosphate cement [J], Journal of Biomedical Materials Research, 1997, 35(3): 273-277
[32] Takechi M, Miyamoto Y, Ishikawa K, et al. Non-decay type fasting-setting calcium phosphate cement using chitosan [J]. Journal of Material Science: Materials in Medicine, 1996, 7 (6): 317-322
[33] Chen L, Xiang H, Li X L, et al. Improvement of anti-washout performance of calcium phosphate cement using modified starch [J]. Key Engineering Materials, 2007, 1628-1631.
[34]李旭,杨德安,蔡仲雨等,黄原胶对磷酸钙骨水泥性能的影响[J].稀有金属材料工程,2005,34 (1),1124-1126.
[35] Ooms E M, Wolke J G, Jansen J A. Trabecular bone response to injectable calcium phosphate (Ca-P) cement [J]. Journal of Biomedical Material Research, 2002, 61 (1): 9-18.
[36] Frankenburg E P, Goldstein S A, Bauer T W, et a1. Biomechanical and histological evaluation of a calcium phosphate cement [J]. Journal of Bone and Joint Surgery (American volume), 1998, 80 (8): 1112-1124.
[37] Gross UM, Muller-Mai CM, Voigt C. The interface of calcium phosphate and glass-ceramic in bone, a structural analysis [J]. Biomaterials, 1990, 11: 83-85.
[38] Frankenburg EP, Goldstein SA, Bauer TW, et a1. Biomechanical and histological evaluation of a calcium phosphate cement [J]. J Bone Jt Surg Am, 1998, 8O (8): 1112-1124.
[39] Apelt D, Theiss F, E1 Warrak AO, et a1. In vivo behavior of three different injectable hydraulic calcium phosphate cements [J]. Biomaterials, 2004, 25 (78): 1439-145.
[40] Bohner M, Theiss F, Apelt D, et a1. Compositional changes of a dicalcium phosphate dihydrate cement after implantation in sheep [J].Biomaterials,2003,24(20):3463-347.
[41] Rousseau SJ, Bohner M, Frei C. Long-term aging of brushite cements in physiological conditions: an in vitro study [c]. GRIBOI: Shangai, March 14-17, 2002
[42]罗方聪,叶建东.层状结构磷酸钙骨水泥组织工程支架材料的制备与表征[J].硅酸盐通报, 2009, 28 (1), 27-30.
[43] Xiaopeng Qi, Jiandong Ye, Yingjun Wang. Improved injectability and in vitro degradation of a calcium phosphate cement containing poly(lactide-co-glycolide) microspheres [J]. Acta Biomaterialia 2008: 1837-1845.
[44] Maria-Pau Ginebra, Tania Traykova, Josep A. Calcium Phosphate cements: Competitive drug carriers for the musealnskeletal system. Elsevier Bin, 2006, 27: 2 171-2 217.
[45] Bohner M, Lemaitre J, VanLanduyt P, et a1. Gentamicin-loaded hydraulic calcium phosphate bone cement as antibiotic delivery system. J Pbarm Sci, 1997, 6 (5): 565-572.
[46] Bohner M, Lemaitre J, Merckle H P, et a1. Control of aentam-icin release from a calcium phosphate admixed poly (acrylic acid). J Pharm Sci, 2000, 89 (10): 1262-1270
[47] Kamerer DB, Hirsch BE, Snyderman CH, et a1. Hydoxyapatite cement: a new method for achieving watertight closure in transtemporal surgery. Am J Otol, 1994, 15: 47-49.
[48] Verheggen R. Merten HA. Correction of skull defects using hydoxyapatite cement (HAC)-evidence derived from animal experiments and clinical experience. Acta Neurochir (Wien), 2001, 143: 919-926.
[49] Horstmann WG, Verheyen CC. Leemans R. An injectable calcium phosphate cement as a bone-graft substitute in the treatment of displaced lateral tibial plateau fractures. Injury, 2003, 34: 141-144.
[50]苗军,王继芳,郝利波,等.磷酸钙骨水泥复合去甲万古霉素后理化性质改变及药物释放规律的研究.中华创伤骨科杂志, 2004, 6: 648-656.
[51] Tabara Y, Ishii Y. Apatite cement containing cis-diamminediehlorop1afinum implanted in rabbit femur for sustained release of the anticancer drug and bone formation. J Orthop Sci, 2001, 6: 556-565.
[52] Aoki S, Takase Y, Ishikawa T. Evaluation of lining materials and a new concept for lining: alpha-TCP cement or visible light curing calcium hydroxide composition incomposite resin restoration. Bull Tokyo Dent Coil, 1991, 32: 171-181.
[53] Chau J Y, Hutter J W, Mork T O, et a1. An in vitro study of furcation perforation repair using calcium phosphate cement. J Endod, 1997, 23: 588-592.
[54]傅宪辉,沈志刚.微球制备的研究概况及发展[J].力学与实践,2005,27(3):7-13.
[55] Palmieri G F, Bonacucina G, Di Martino, et al. Spray-drying as a method for microparticulate controlled release systems preparation: Advantages and limits. I. Water-soluble drugs[J]. Drug Dev Ind Pharm, 2001, 27(3): 195-204.
[56] Carrasguillo K G, Stanley AM, Aponte-Carro J C, et al. Non- aqueous encapsulation of excipient stabilized spray-freeze dried BSA into poly( lactide-co-glycol-ide) microspheres results in release of native protein[J]. J Controlled Release, 2001, 3: 199-208.
[57]潘家祯,孙晓明,朱大滨,等.挤出滚圆法制备药用微丸I.设备的工作原理及特点[J].中国医药工业杂志, 1998, 29(8): 378-380.
[58]张瑞十,潘家祯,王力文.螺旋挤出—滚圆法制备2mm精细氧化铝小球成球机理的探讨[J].中国陶瓷, 2008, 44(7): 43-46.
[59] Zhang J, Coombs N, Kumacheva E. A new approach to hybrid polymer-metal and polymer-semiconductor particles[J]. Adv Mater, 2002, 14: 1856.
[60] Zhang J, Coombs N, Kumacheva E J. A new approach to hybrid nanocomposite materials with periodic st ructures[J]. Am Chem Soc, 2002, 124: 14512.
[61] Lin Y, Zhang J, Sargent E H. Photonic pseudo-gap-based modification of photoluminescence from CdS nanocrystal satellites around polymer microspheres in a photonic crystal[J]. Appl Phys Lett, 2002, 81: 3134.
[62] Shisho H, Kawahashi N. Titanium compounds as coatings on polystyrene latices and as hollow spheres [J]. Colloid Polym Sci, 2000, 278: 270.
[63] Wang P H, Pan C Y. Polymer metal composite microspheres: Preparation and characterization of poly ( St-co-N)Ni microspheres[J] . Eur Polym J, 2000, 36: 2297.
[64] Caruso F, Caruso R A, Mhwald HCaruso F, Caruso R A, Mêhwald H. Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating[J]. Science, 1998, 282: 1111.
[65] Cheung Herman S. In Vitro Cartilage formation on porous hydroxyapatite ceramic granules [J]. In vitro cellular and developmental biology, 1985, 21 (6): 353-357.
[66] Ono K, Yamamuro T, Nakamura T, et al. Quantitative study on osteoconduction ofapatite-wollastonite containing glass ceramic granules, hydroxyapatite granules and alumina granules [J]. Biomaterials, 1990, 11 (4): 265-271.
[67] Gatti A M,Zaffe D and Poli G P, Biomaterials, 1990, 11: 513
[68] Sautier J M, Nefussi J R, Boulekbache H and Forest N. In Vitro Cell. Dev. B 1990, 26: 1079
[69] Keiko Yamamura, Hisashi Iwata and Toshihisa Yotsuyanag. Synthesis of antibiotic-loaded hydroxyapatite beads and in vitro drug release testing [J]. Journal of Biomedical Materials Research, 1992, 26 (8): 1053-1064.
[70] Hiroshi Yamasaki, Hidetaka Sakai. Osteogenic response to porous hydroxyapatite ceramics under the skin of dogs [J]. Biomaterials, 1992, 13 (5): 308-312.
[71] Byrd H S, Hobar P C, Shewmake K.Augmentation of the craniofaciaI skeleton with porous hydroxyapatite granules [J]. Raat Reconstr Surg, 1993, 91 (1): 15-22.
[72] Wiese K G and Merten H A, Int J Oral Maxillofac Surg, 1993, 22: 306
[73] Lindholm T C, Gao T J and Lindholm T S, Int J Oral Maxillofac Surg 1994, 23: 306
[74] M. Fabbri, G.C. Celotti, A. Ravaglioli. Granulates based on calcium phosphate with controlled morphology and porosity for medical applications: physico-chemical parameters and production technique [J]. Biomaterials, 1994, 15 (6): 474-477.
[75] E. A. Holtgrave, K. Donath. Response of odontoblast-like cells to hydroxyapatite ceramic granules [J]. Biomaterials, 1995, 16 (2): 155-159
[76] E T Baran, K Tuzlakoglu, A J Salgado, et al. Multichannel mould processing of 3D structures from microporous coralline hydroxyapatite granules and chitosan support materials for guided tissue regeneration/engineering [J]. Journal of Materials Science: Materials in Medicine, 2004, 15 (2): 161-165.
[77] P Luo and T G Nieh. Preparing hydroxyapatite powders with controlled morphology [J]. Biomaterials, 1996, 17 (6): 1959-1964.
[78] Norio Kawai, Shigeo Niwa, Motoki Sato, et al. Bone formation by cells from femurs cultured among three-dimensionally arranged hydroxyapatite granules [J]. Journal of Biomedical Materials Research, 1997, 37 (1): 1-8.
[79] Dean-Mo Liu. Fabrication and characterization of porous hydroxyapatite granules [J]. Biomaterials, 1996, 17 (20): 1955-1957.
[80] Vladimir S. Komleva, Serguei M, et al. A method to fabricate porous spherical hydroxyapatite granules intended for time-controlled drug release. Biomaterials, 23 (2002) 3449-3454.
[81] Rodríguez-Lorenzo L M, Vallet-RegíM F and Ferreira J M. Fabrication of poroushydroxyapatite bodies by a new direct consolidation method: starch consolidation [J]. Journal of Biomedical Materials Research , 2002, 60 (2): 232-240.
[82] Zhang J P, Wang Q, Wang A Q. In situ generation of sodium alginate/hydroxyapatite nanocomposite beads as drug controlled release matrices [J]. Acta Biomaterialia, 2010, 6 (2): 445-454.
[83] Tas A C,Preparation of porous apatite granules from calcium phosphate cement [J]. J Mater Sci, 2008, 19: 2231-2239
[84] Faure A, York P and Rowe R C, Process control and scale-up of pharmaceutical wet granulation processes: a review, European Journal of Pharmaceutics and Biopharmaceutics 52 (2001), 269–277.
[85] Vervaet C, Remon J P, Continuous granulation in the pharmaceutical industry [J]. Chem. Eng. Sci., 2005, 60: 3949-3957.
[86] Zaffe D. Some considerations on biomaterials and bone [J]. Micron, 2005, 36 (7-8): 583-592.
[87] Horch H H, Sader R, Pautke C. et al. Synthetic,pure-phase beta-tricalcium phosphate ceramic granules (Cerasorb) for bone regeneration in the reconstructive surgery of the jaws.Int J Oral Maxillofac Surg. 2006, 35(8): 708-713.
[88] Jung R E, Haemmerle C H F, Kokovic E and Weber E, Int. J. Oral Maxillofac. Implants. 22 (2007) 258.
[89] Misiek D J, Kent J N, Carr R F. Soft tissue responses to hydroxylapatite particles of different shapes [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (3), 150-160.
[90] Bodde E W H, Cammaert C T R, Wolke, J G C, et al.. Investigation as to the osteoinductivity of macroporous calcium phosphate cement in goats [J]. Journal of Biomedical Materials Research: Part B, 2007, 83B (1): 161-168.
[91] Ducheyne P, Hench L L, Kagan A, et al. Effect of hydroxyapatite impregnation on skeletal bonding of porous coated implants. [J]. Journal of Biomedical Materials Research, 1980, 14 (3): 225-237.
[92] Frame J W, Brady C L. Augmentation of an atrophic edentulous mandible by interpositional grafting with hydroxylapatite [J]. Journal of Oral and Maxillofacial Surgery, 1984, 42 (2): 89-92.
[93] Anon. Hydroxylapatite, beta tricalcium phosphate, and autogenous and allogeneic bone for filling periodontal defects, alveolar ridge augmentation, and pulp capping. Council on Dental Materials, Instruments, and Equipment Council on DentalResearch Council on Dental Therapeutics. Journal of the American Dental Association, 1984, 108 (5) 822-827.
[94] Bohner M, Gbureck U, Barralet J E. Technological issues for the development of more efficient calcium phosphate bone cements: a critical assessment [J]. Biomaterials, 2005, 26 (33): 6423-6429.
[95] Xu H H K, Takagi S, Quinn J B, et al. Fast-setting calcium phosphate scaffolds with tailored macropore formation rates for bone regeneration [J]. Journal of Biomedical Material and Research: Part A, 2004, 68A (4): 725-734.
[96] Burguera E F, Xu H H K, Takagi S, et al. High early strength calcium phosphate bone cement: Effects of dicalcium phosphate dihydrate and absorbable fibers [J]. Journal of Biomedical Material and Research: Part A, 2005, 75A (4): 966-975.
[97] Chen A Z, Li Y, Chau F T, et al. Application of organic nonsolvent in the process of solution-enhanced dispersion by supercritical CO2 to prepare puerarin fine particles [J]. Journal of Supercritical Fluids, 2009, 49 (3): 394-402.
[98]陆扬,明胶微球的研究进展[J].明胶科学与技术, 2006, 26(2): 59-61.
[99] Chen L, Xiang H, Li X L, et al. Improvement of anti-washout performance of calcium phosphate cement using modified starch [J]. Key Engineering Materials, 2007, 336-338: 1628-1631.
[100]张淑霞王忆娟黄沙等表面形貌各异的明胶微球制备及其对细胞增殖的影响[J].高分子化学和化学工业,2009,1: 42-46.
[101] Hae-Won Kim, Jonathan C Knowles, Hyoun-Ee Kim, et al。Hydroxyapatite and gelatin composite foams processed via novel freeze-drying and crosslinking for use as temporary hard tissue scaffolds [J]. Journal of Biomedical Material and Research, Part A, 2005, 72A (2): 136-145.
[102]唐世华,曾锡瑞,郑忠.明胶的酶降解反应动力学研究:影响明胶酶降解反应的因素[J].明胶科学与技术, 1994, 14 (4): 199-203.
[103]陈洪叶,赵文丽,李国栋.用单管落球法探讨蓖麻油粘度随温度的变化[J].大学物理实验, 2007, 20 (1): 47-50.
[104]刘耀,刘松青.挤出-滚圆法制备微丸的研究进展[J].中国药学杂志, 2008, 43 (6): 401-405.
[105] Li Q B, You J, Yang L, et a1. Preparation of gegen qinlian pellets by extrusion-spheronization method [J]. Chin Tradit Herbal Drugs, 2005, 36 (10): 1473-1476.
[106] Harrison P J, Newton J M, Rower R C. Flow defects in wet powder mass extrusion [J]. J Pharm Pharmacol, 1985, 37 (2): 81-83.
[107] Maunowski H J, Smith W E. Effects of spheronization process variables on selected tablet properties [J]. J PharmSci, 1974, 63: 285-288.
[108] Baert L, Remon J P. Eibers J A C, et al. Comparison between a gravity feed extruder and a twin scro extruder [J]. Int J Pharm, 1993, 99: 7-12.
[109]孙文晓,张海港,韦卓等.骨修复材料的研究应用现状与展望[J].生物骨科材料与临床研究, 2009, 6 (3): 34-50.
[110] Jain S K, Awasthi A M, Jain N K, et al. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: Preparation and in vitro characterization [J]. Journal of Controlled release, 2005, 107 (2): 300-309.
[111] Wang X P, Chen L, Xiang H, et al. Influence of anti-washout agents on the rheological properties and injectability of a calcium phosphate cement [J]. Journal of Biomedical Material and Research, 2006, 81B (2): 410-418.
[112]蔡舒,姚康德,李鸿祥.羟基磷灰石合成及高温稳定性的研究[J].无机材料学报, 2003, 18 (4): 807-812.
[113] Wang X P, Ye J D, Wang Y J. Hydration mechanism of a novel PCCP plus DCPA cement system [J]. Journal of Materials Science-Materials in Medicine, 2008, 19 (2): 813-816.
[114] Ambard A J, Mueninghoff L. Calcium phosphate cement: review of machanical and biological properties [J]. Journal of Prosthodontics, 2006, 15 (5): 321-328.
[115] Telli C, Serper, A, Dogan, A L, et al. Evaluation of the cytotoxicity of calcium phosphate root canal sealers by MTT assay [J]. Journal of Endodontics, 1999, 25 (12): 811-813.
[116]温世锋,刘清华,郭奇峰等.新型磷酸钙骨水泥与骨髓间充质干细胞的共培养研究[J].临床医学工程, 2009, 16 (11): 1-4.
[117] Maria-Pau Ginebra, Tania Traykova and Josep A Planell. Calcium phosphate cements: Competitive drug carriers for the musculoskeletal system? [J]. Biomaterials 27 (2006) 2171-2177.
[118]郜成莹,叶建东.添加剂和载药方法对庆大霉素/磷酸钙骨水泥载药体系性能及药物体外释放的影响硅酸盐通报,2008,27(2):225-229.
[119] Mathiowitz E, editor. Encyclopaedia of controlled drug delivery. New York: Wiley; 1999.
[120] Ye J D, Wang X P, Wang Y J. Rheological properties of an injectable calcium phosphate bone cement and their relationship with the phase evolution [J]. Key Engineering Materials, 2007, 336-338: 1658-1661.
[121] Lee W K, Park J Y, Yang E H, et a1. J. Control Release, 2002, 84(3): 115-123.
[122]中国药典[M].化学工业出版社, 2000年版二部附录ⅣA第866页.