复合氰基丙烯酸酯-BMP生物胶预防大鼠牙槽嵴萎缩的实验研究
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摘要
目的：
以骨形态发生蛋白为主药,用α-氰基丙烯酸正丁酯、壳聚糖等为载体,制备成温敏性复合生物胶,植入大鼠即刻拔除下颌切牙的拔牙窝内,观察该胶体对创口的止血、消炎及预防大鼠牙槽嵴萎缩的效果及影响。
方法：
1、以骨形态发生蛋白-2(BMP-2)为主要成分,使用α-氰基丙烯酸正丁酯和水溶性的壳聚糖为载体,p-甘油磷酸钠为辅料,通过药剂学技术制备具有一定止血、抗炎、温敏性及促进新骨生长的复合丙烯酸酯-骨形态发生蛋白生物胶,并使用同样方法制备单纯壳聚糖温敏性胶体用来做对照研究。检测该复合生物胶的生物相容性。
2、选用Wistar大鼠54只,随机分为3组：实验组：植入复合氰基丙烯酸-骨形态发生蛋白生物胶；对照组：植入单纯壳聚糖温敏性胶体；空白对照组：不植入任何材料。
3、动物模型的建立,大鼠下颌切牙拔牙术前12天起,齐牙龈夹断下切牙(3次,3日／次),按常规拔牙方法,完整拔除下颌切牙,以制备拔牙后牙槽嵴萎缩动物模型备用。
4、在拔除大鼠下颌切牙后,在实验组动物模型牙槽窝内即刻植入复合氰基丙烯酸酯-骨形态发生蛋白生物胶,而在对照组动物模型牙槽窝内植入单纯壳聚糖温敏性胶体,空白对照组则不植入任何材料。3组动物常规饲养,在植入后3、6、9周处死,分离切取下颌骨进行研究。
5、对分离后的大鼠下颌骨标本给予高频钼靶扫描仪获得图像信息,所得图像使用Image Pro-Plu6.0软件处理图像,并测得到剩余牙槽嵴相对高度和剩余牙槽嵴相对光密度值,所得数据使用统计学ANVOA分析,研究预防牙槽嵴萎缩的效果。常规病理切片观察牙槽窝内植入材料的生物相容性、降解情况和诱导成骨效果。
结果：
1、制备的复合氰基丙烯酸酯-骨形态发生蛋白生物胶中rhBMP-2含量为100μg/L,半流动性。具有温敏性,在37℃水浴时长约1min可凝固,呈胶冻状。
2、在3、6、9周处死时,实验组的剩余牙槽嵴相对高度和光密度值均明显高于对照组和空白对照组,差异有统计学意义(p<0.05)。
3、常规病理切片显示：实验组牙槽窝新生骨小梁多于对照组和空白对照组,且植入复合生物胶吸收速率与形成骨基本相同；空白对照组炎症反应明显,且成骨不明显。
结论：
1、利用骨形态发生蛋白、α-氰基丙烯酸正丁酯、壳聚糖及甘油磷酸钠等制备为复合氰基丙烯酸酯-骨形态发生蛋白生物胶。胶体稳定性佳,具有一定的温敏性。
2、该复合生物胶在牙拔除术后,止血、粘结固定及预防剩余牙槽嵴的萎缩具有明显的效果,该复合生物胶可以成为预防牙槽嵴萎缩的材料之一,临床应用前景广阔。
Object:
1. Using the bone morphogenetic protein-2, cyanoacrylate and chitosan and others to made the compound biological glue. To study the physical, chemical and biological properties of this compound.
2. To evaluate the effectiveness and feasibility of implantation of the compound bone morphogenetic protein with P-cyanoacrylate and chitosan to preventive absorption of residual alveolar ridge of rat lower incisor alveolar fossa.
Methods:
1. Bone morphogenetic protein (BMP), cyanoacrylate and soluble chitosan were be used to make the compound cyanoacrylate-chitosan-BMP. To use the cyanoacrylate, chitosan and glycerophosphate make the chitosan temperature sensitive biological glue.
2.54wistar rats were divided randomly and equally into three groups: experimental group (compound cyanoacrylate-chitosan-BMP group), control group (chitosan composite group) and blank control group.
3. Animal models, use the needle holder to clamp off the lower incisors (3times,1times/3days) before extraction. After three times, extract the incisors.
4. Compound cyanoacrylate-chitosan-BMP was implanted into rats'alveolar fossa of the experimental group, the chitosan temperature sensitive biological glue was implanted into alveolar fossa of the control group, and alveolar fossa of the blank control group was implanted nothing. Animals were sacrificed after3,6,9weeks, and separated and removed all rats'mandible of every group.
5. To use the mammography scanner take the X-ray film of rats'mandible, to use the software of Image-Pro Plus6.0measured and analysis the X-ray film. Routine histological observation:The joint specimens were exposed; fixed by neutral formalin, colored by HE staining, wrapped and cut into slices by4μm, study and observed them under a microscope.
Results:
1. Compound cyanoacrylate-chitosan-BMP is one kind of glue, which is temperature-sensitive, semi-solid, illiquid, and elastic. There was100μg rhBMP-2in one liter.
2. The relative length values of residual alveolar ridge and optical density test in experimental group was all greater than those of other groups at3,6,9weeks after operation. There was significant difference between experimental and control groups (p<0.05).
3. Optical microscopy showed that new bone formation rate and quality in the experimental group was better than those in the control group and blank control group at3,6,9weeks after implantation.
Conclusion:
Compound cyanoacrylate-chitosan-BMP has good biocompatibility, safe, stability and ability of osteoinduction. It can be used to prevent the absorption of residual alveolar ridge and have more clinical predications.
以骨形态发生蛋白为主药,用α-氰基丙烯酸正丁酯、壳聚糖等为载体,制备成温敏性复合生物胶,植入大鼠即刻拔除下颌切牙的拔牙窝内,观察该胶体对创口的止血、消炎及预防大鼠牙槽嵴萎缩的效果及影响。
方法：
1、以骨形态发生蛋白-2(BMP-2)为主要成分,使用α-氰基丙烯酸正丁酯和水溶性的壳聚糖为载体,p-甘油磷酸钠为辅料,通过药剂学技术制备具有一定止血、抗炎、温敏性及促进新骨生长的复合丙烯酸酯-骨形态发生蛋白生物胶,并使用同样方法制备单纯壳聚糖温敏性胶体用来做对照研究。检测该复合生物胶的生物相容性。
2、选用Wistar大鼠54只,随机分为3组：实验组：植入复合氰基丙烯酸-骨形态发生蛋白生物胶；对照组：植入单纯壳聚糖温敏性胶体；空白对照组：不植入任何材料。
3、动物模型的建立,大鼠下颌切牙拔牙术前12天起,齐牙龈夹断下切牙(3次,3日／次),按常规拔牙方法,完整拔除下颌切牙,以制备拔牙后牙槽嵴萎缩动物模型备用。
4、在拔除大鼠下颌切牙后,在实验组动物模型牙槽窝内即刻植入复合氰基丙烯酸酯-骨形态发生蛋白生物胶,而在对照组动物模型牙槽窝内植入单纯壳聚糖温敏性胶体,空白对照组则不植入任何材料。3组动物常规饲养,在植入后3、6、9周处死,分离切取下颌骨进行研究。
5、对分离后的大鼠下颌骨标本给予高频钼靶扫描仪获得图像信息,所得图像使用Image Pro-Plu6.0软件处理图像,并测得到剩余牙槽嵴相对高度和剩余牙槽嵴相对光密度值,所得数据使用统计学ANVOA分析,研究预防牙槽嵴萎缩的效果。常规病理切片观察牙槽窝内植入材料的生物相容性、降解情况和诱导成骨效果。
结果：
1、制备的复合氰基丙烯酸酯-骨形态发生蛋白生物胶中rhBMP-2含量为100μg/L,半流动性。具有温敏性,在37℃水浴时长约1min可凝固,呈胶冻状。
2、在3、6、9周处死时,实验组的剩余牙槽嵴相对高度和光密度值均明显高于对照组和空白对照组,差异有统计学意义(p<0.05)。
3、常规病理切片显示：实验组牙槽窝新生骨小梁多于对照组和空白对照组,且植入复合生物胶吸收速率与形成骨基本相同；空白对照组炎症反应明显,且成骨不明显。
结论：
1、利用骨形态发生蛋白、α-氰基丙烯酸正丁酯、壳聚糖及甘油磷酸钠等制备为复合氰基丙烯酸酯-骨形态发生蛋白生物胶。胶体稳定性佳,具有一定的温敏性。
2、该复合生物胶在牙拔除术后,止血、粘结固定及预防剩余牙槽嵴的萎缩具有明显的效果,该复合生物胶可以成为预防牙槽嵴萎缩的材料之一,临床应用前景广阔。
Object:
1. Using the bone morphogenetic protein-2, cyanoacrylate and chitosan and others to made the compound biological glue. To study the physical, chemical and biological properties of this compound.
2. To evaluate the effectiveness and feasibility of implantation of the compound bone morphogenetic protein with P-cyanoacrylate and chitosan to preventive absorption of residual alveolar ridge of rat lower incisor alveolar fossa.
Methods:
1. Bone morphogenetic protein (BMP), cyanoacrylate and soluble chitosan were be used to make the compound cyanoacrylate-chitosan-BMP. To use the cyanoacrylate, chitosan and glycerophosphate make the chitosan temperature sensitive biological glue.
2.54wistar rats were divided randomly and equally into three groups: experimental group (compound cyanoacrylate-chitosan-BMP group), control group (chitosan composite group) and blank control group.
3. Animal models, use the needle holder to clamp off the lower incisors (3times,1times/3days) before extraction. After three times, extract the incisors.
4. Compound cyanoacrylate-chitosan-BMP was implanted into rats'alveolar fossa of the experimental group, the chitosan temperature sensitive biological glue was implanted into alveolar fossa of the control group, and alveolar fossa of the blank control group was implanted nothing. Animals were sacrificed after3,6,9weeks, and separated and removed all rats'mandible of every group.
5. To use the mammography scanner take the X-ray film of rats'mandible, to use the software of Image-Pro Plus6.0measured and analysis the X-ray film. Routine histological observation:The joint specimens were exposed; fixed by neutral formalin, colored by HE staining, wrapped and cut into slices by4μm, study and observed them under a microscope.
Results:
1. Compound cyanoacrylate-chitosan-BMP is one kind of glue, which is temperature-sensitive, semi-solid, illiquid, and elastic. There was100μg rhBMP-2in one liter.
2. The relative length values of residual alveolar ridge and optical density test in experimental group was all greater than those of other groups at3,6,9weeks after operation. There was significant difference between experimental and control groups (p<0.05).
3. Optical microscopy showed that new bone formation rate and quality in the experimental group was better than those in the control group and blank control group at3,6,9weeks after implantation.
Conclusion:
Compound cyanoacrylate-chitosan-BMP has good biocompatibility, safe, stability and ability of osteoinduction. It can be used to prevent the absorption of residual alveolar ridge and have more clinical predications.
引文
[1]邱蔚六.口腔颌面外科学[M].北京：人民卫生出版社,2008.
[2]Waite P D, Sastravaha P, Lemons J E. Biologic mechanical advantages of 3 different cranial bone grafting techniques for implant reconstruction of the atrophic maxilla [J]. Journal of oral and maxillofacial surgery,2005,63(1):63-67.
[3]Lekovic V, Camargo P M, Klokkevold P R, et al. Preservation of alveolar bone in extraction sockets using bioabsorbable membranes [J]. Journal of periodontology,1998,69(9):1044-1049.
[4]Cardaropoli D, Cardaropoli G. Preservation of the postextraction alveolar ridge:A clinical and histologic study [J]. The International journal of periodontics & restorative dentistry,2008, 28(5):469.
[5]周婷,陆守昌.重度牙槽嵴萎缩牙槽骨重建的研究进展[J].中华老年口腔医学杂志,2008,6(03)：187-189.
[6]王海云,钟梅,赖仁发.防治牙槽嵴萎缩的研究进展[J].中国口腔种植学杂志,2006,11(001)：44-47.
[7]何建明,徐青.牙槽骨骨量不足的前牙种植[J].中国口腔种植学杂志,2000,5(003)：130-131.
[8]杨东伟,陆晓丽,袁峰,等.新型人工骨植入牙槽窝预防牙槽嵴萎缩的实验研究[J].广东牙病防治,2003,11(001)：8-10.
[9]吴哲,孙宏晨,刘树泰,等.聚乳酸-羟基乙酸-辛伐他汀对拔牙术后剩余牙槽嵴吸收影响的实验研究[J].中华口腔医学杂志,2006,41(12)：
[10]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review [J]. Cellular Signalling,2011,23(4):609-620.
[11]Bais M, Wigner N, Young M, et al. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells [J]. Bone,2009,45(2):254-266.
[12]Reddi A. BMPs:from bone morphogenetic proteins to body morphogenetic proteins [J]. Cytokine & growth factor reviews,2005,16(3):249.
[13]Ijiri S, Nakamura T, Fujisawa Y, et al. Ectopic bone induction in porous apatite-wollastonite-containing glass ceramic combined with bone morphogenetic protein [J]. Journal of biomedical materials research,1997,35(4):421-432.
[14]Jones A A, Buser D, Schenk R, et al. The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model [J]. Journal of periodontology,2006,77(7): 1184-1193.
[15]Raida M, Clement J H, Leek R D, et al. Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis [J]. Journal of cancer research and clinical oncology,2005, 131(11):741-750.
[16]Csiszar A, Smith K E, Koller A, et al. Regulation of bone morphogenetic protein-2 expression in endothelial cells [J]. Circulation,2005,111(18):2364-2372.
[17]Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfal [J]. Endocrine reviews,2000,21(4):393-411.
[18]Yu Y Y, Lieu S, Lu C, et al. Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair [J]. Bone,2010.47(1):65-73.
[19]Wang E A. Rosen V, Cordes P, et al. Purification and characterization of other distinct bone-inducing factors [J]. Proceedings of the National Academy of Sciences,1988,85(24): 9484-9488.
[20]Shea C M, Edgar C M, Einhorn T A, et al. BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis [J]. Journal of cellular biochemistry,2003, 90(6):1112-1127.
[21]Yoshida K, Bessho K, Fujimura K, et al. Osteoinduction capability of recombinant human bone morphogenetic protein-2 in intramuscular and subcutaneous sites:an experimental study [J]. Journal of Cranio-Maxillofacial Surgery,1998,26(2):112-115.
[22]Fromigue O, Marie P, Lomri A. Bone morphogenetic protein-2 and transforming growth factor-β2 interact to modulate human bone marrow stromal cell proliferation and differentiation [J]. Journal of cellular biochemistry,1998,68(4):411-426.
[23]Henkin J. Evaluation of a New Carrier System for rhBMP-2:A Non-Human Primate Mandibular Resection Study [J]. Journal of oral and maxillofacial surgery,2010,68(9):e32-e33.
[24]Shen H, Hu X, Yang F, et al. An injectable scaffold:rhBMP-2-loaded poly (lactide-co-glycolide)/hydroxyapatite composite microspheres [J]. Acta biomaterialia,2010,6(2): 455-465.
[25]孙明林.胡蕴玉.骨形态发生蛋白载体材料的研究和应用现状[J].国外医学：生物医学工程分册,2001,24(003)：128-133.
[26]Kao D, Kubota A, Nevins M, et al. The negative effect of combining rhBMP-2 and Bio-Oss on bone formation for maxillary sinus augmentation [J]. The International journal of periodontics & restorative dentistry,2012,32(1):61.
[27]Seeherman H J, Li X J, Bouxsein M L, et al. rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model [J]. The Journal of Bone & Joint Surgery,2010,92(2):411-426.
[28]Owens K, Glassman S D, Howard J M, et al. Perioperative complications with rhBMP-2 in transforaminal lumbar interbody fusion [J]. European Spine Journal,2011,20(4):612-617.
[29]Lecanda F, Avioli L, Cheng S. Regulation of bone matrix protein expression and induction of diferentiation of human osteoblasts and human bone marrow stromal cells by bone morphgenetic protein-2 [J]. Cell Biochem,1997,67(3):386-396.
[30]Morrison N. Cyanoacrylate glue for saphenous ablation [J]. Veins and Lymphatics,2012,1(1): 1.
[31]Soehendra N, Grimm H, Nam V C, et al. N-butyl-2-cyanoacrylate:a supplement to endoscopic sclerotherapy [J]. Endoscopy,2008,19(06):221-224.
[32]熊林,王建营,延玺,等.丙烯酸酯胶粘剂研究进展[J].中国胶粘剂,2002,11(3)：47-52.
[33]王艳红.α-氰基丙烯酸辛酯医用胶的改性和生物学评价[D]；天津医科大学,2009.
[34]田霞,卢永顺.特种胶粘剂-α-氰基丙烯酸酯系医用胶[J].化工新型材料,2007,S1(3)110-113.
[35]Toriumi D M, O'grady K, Desai D, et al. Use of octyl-2-cyanoacrylate for skin closure in facial plastic surgery [J]. Plastic and reconstructive surgery.1998,102(6):2209-2219.
[36]Shen Y-M, Sun W-B, Chen J, et al. NBCA medical adhesive (n-butyl-2-cyanoacrylate) versus suture for patch fixation in Lichtenstein inguinal herniorrhaphy:A randomized controlled trial [J]. Surgery,2012,151(4):550-555.
[37]陈子达,李玲,邹翰.医用胶粘剂的研究进展[J].化学与粘合,2001,1(5)21-22.
[38]王艳红,顾汉卿.医用粘合剂的发展及临床应用进展[J][J].透析与人工器官,2008,19(3)：23-32.
[39]Woodward S C, Herrmann J B, Cameron J L, et al. Histotoxicity of cyanoacrylate tissue adhesive in the rat [J]. Annals of Surgery,1965,162(1):113.
[40]孙健,谢富强,李平,等复方骨形成蛋白生物复合物预防剩余牙槽嵴吸收实验[J].实用口腔医学杂志,2008,24(006)：801-805.
[41]朱志宏,马承宣,许瑞江.α-氰基丙烯酸正丁酯充填骨缺损腔的特点[J].中国临床康复,2006,10(29)：72-74.
[42]卢凤琦,庄昭霞,曹晶,等.可降解性壳聚糖复合膜的研制与生物学评价[J].生物医学工程学杂志,2003,20(2)：277-280.
[43]郝彤,刘暾,吕双红,等.采用温敏性壳聚糖水凝胶体外构建组织工程化软骨的实验研究[J].解放军医学杂志,2007,32(5)：500-502.
[44]黄洪超,胡永成,刘凤松,等.骨形态发生蛋白载体的研究与应用[J].中国组织工程研究与临床康复,2007,11(014)：2748-2751.
[45]Chenite A, Chaput C, Wang D, et al. Novel injectable neutral solutions of chitosan form biodegradable gels in situ [J]. Biomaterials,2000,21(21):2155-2161.
[46]Kawakami T, Kawai T, Takei N, et al. Evaluation of heterotopic bone formation induced by squalane and bone morphogenetic protein composite [J]. Clinical orthopaedics and related research,1997,337(37)261-266.
[47]杨英军,谢富强,杨晓昀,等.应用水溶性壳聚糖为主要载体的重组人骨形态发生蛋白2缓释系统：降解缓释和成骨作用评价[J].中国组织工程研究与临床康复,2007,11(035)：6929-6933.
[48]Madihally S V, Matthew H W. Porous chitosan scaffolds for tissue engineering [J]. Biomaterials,1999,20(12):1133-1142.
[49]Ravi Kumar M N. A review of chitin and chitosan applications [J]. Reactive and functional polymers,2000,46(1):1-27.
[50]Park D J, Choi B H, Zhu S J, et al. Injectable bone using chitosan-alginate gel/mesenchymal stem cells/BMP-2 composites [J]. Journal of Cranio-Maxillofacial Surgery,2005,33(1):50-54.
[51]Jeong B, Choi Y, Bae Y, et al. New biodegradable polymers for injectable drug delivery systems [J]. Journal of Controlled Release,1999,62(1):109-114.
[52]Chenite A, Buschmann M, Wang D, et al. Rheological characterisation of thermogelling chitosan/glycerol-phosphate solutions [J]. Carbohydrate polymers,2001,46(1):39-47.
[53]Illum L, Farraj N F, Davis S S. Chitosan as a novel nasal delivery system for peptide drugs [J]. Pharmaceutical research,1994,11(8):1186-1189.
[54]刘阳,朱立新,杨宏,等.可注射性纳米羟基磷灰石／壳聚糖复合骨髓间充质干细胞促进骨缺损的修复[J].中国组织工程研究与临床康复,2010,14(034)：6278-6282.
[55]吴哲,孙宏晨,车彦海,等.大鼠下颌切牙拔出后剩余牙槽嵴吸收模型的建立[J].实用口腔医学杂志,2007，23(001)：36-39.
[56]王元占.常用实验动物的麻醉[J].中国比较医学杂志,2004,14(4)：245-247.
[57]张凤仙.水合氯醛溶液的配制及使用注意事项[J].海峡药学,2002,14(3)：10-11.
[58]Devlin H, Sloan P. Early bone healing events in the human extraction socket [J]. International journal of oral and maxillofacial surgery,2002,31(6):641-645.
[59]Hwang S-J, Jung J-G, Jung J-U, et al. Vertical alveolar bone distraction at molar region using lag screw principle [J]. Journal of oral and maxillofacial surgery,2004,62(7):787-794.
[60]Rachmiel A, Srouji S, Peled M. Alveolar ridge augmentation by distraction osteogenesis [J]. International journal of oral and maxillofacial surgery,2001,30(6):510.
[61]Schropp L, Wenzel A, Kostopoulos L, et al. Bone healing and soft tissue contour changes following single-tooth extraction:a clinical and radiographic 12-month prospective study [J]. International Journal of Periodontics and Restorative Dentistry,2003,23(4):313-324.
[62]高宁,李宁毅,贾暮云,等rhBMP-2与聚乳酸复合体植入犬拔牙创对牙槽骨再生的影响[J].齐鲁医学杂志,2004,19(6)：481-483.
[63]Block M S, Almerico B, Crawford C, et al. Bone response to functioning implants in dog mandibular alveolar ridges augmented with distraction osteogenesis [J]. The International journal of oral & maxillofacial implants,1998,13(3):342.
[64]金黎明,刘万顺,韩宝芹,等.骨缺损治疗方法的研究现状[J].中国临床康复,2006,10(001)：144-146.
[65]Hile L, Linklater D. Use of 2-octyl cyanoacrylate for the repair of a fractured molar tooth [J]. Annals of emergency medicine,2006,47(5):424-426.
[66]Jensen O T, Cockrell R, Kuhike L, et al. Anterior maxillary alveolar distraction osteogenesis: a prospective 5-year clinical study [J]. The International journal of oral & maxillofacial implants, 2002,17(1):52.
[67]余占海,刘武,岑远坤.种植体固定的三明治法增高牙槽嵴的实验研究[J].口腔颌面修复学杂志,2003,4(2)：8]-83.
[68]陈军,韩加祥,连文海.拔牙创内植羟基磷灰石对牙槽嵴保持作用的研究[J].中华口腔医学杂志,1999,34(2)：125-125.
[69]Sigurdsson T, Fu E, Tatakis D, et al. Bone morphogenetic protein-2 for peri-implant bone regeneration and osseointegration [J]. Clinical Oral Implants Research,1997,8(5):367-374.
[70]Chiapasco M, Consolo U, Bianchi A, et al. Alveolar distraction osteogenesis for the correction of vertically deficient edentulous ridges:a multicenter prospective study on humans [J]. The Journal of Prosthetic Dentistry,2004,92(6):587.
[71]Nishimura I, Damiani P, Atwood D. Resorption of residual ridges (RRR) in rats [J]. Journal of Dental Research,1987,66(12):1753-1757.
[72]Elsubeihi E S, Heersche J N M. Quantitative assessment of post-extraction healing and alveolar ridge remodelling of the mandible in female rats [J]. Archives of Oral Biology,2004, 49(5):401-412.
[73]Sigurdsson T J, Fu E, Tatakis D N, et al. Bone morphogenetic protein-2 for peri-implant bone regeneration and osseointegration [J]. Clinical Oral Implants Research,1997,8(5):367-374.
[74]黄元瑾rhBMP-2及不同载体在种植体周围骨缺损修复中的应用研究[D]；南方医科大学，2010.
[75]金琼.胶原-羟磷灰石复合膜引导骨组织再生的动物实验研究[J].华西口腔医学杂志,2011,29(1)：21-26.
[76]Manjubala I, Scheler S, Bossert J, et al. Mineralisation of chitosan scaffolds with nano-apatite formation by double diffusion technique [J]. Acta biomaterialia,2006,2(1):75-84.
[77]Wang A, Ao Q, Cao W, et al. Porous chitosan tubular scaffolds with knitted outer wall and controllable inner structure for nerve tissue engineering [J]. Journal of Biomedical Materials Research Part A,2006,79(1):36-46.
[78]Kim S, Tsao H, Kang Y, et al. In vitro evaluation of an injectable chitosan gel for sustained local delivery of BMP-2 for osteoblastic differentiation [J]. Journal of Biomedical Materials Research Part B:Applied Biomaterials,2011,
[79]黄鑫,孟国林,刘建,等.rh-BMP-2壳聚糖微球的制备及体外检测[J].中国矫形外科杂志,2009,17(15)：1172-1174.
[80]吴道澄,万明习.注射用人骨形成蛋白纳米微粒的制备与性质[J].应用化学,2002,19(007)：613-616.
[81]谢富强,孙健,杨英军,等.复方骨形成蛋白生物膜植入牙槽窝的实验研究[J].口腔颌面外科杂志,2009,19(1)：18-22.
[1]Urist M R, Nilsson O, Rasmussen J, et al. Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs [J]. Clinical orthopaedics and related research,1987,214(295-296).
[2]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review [J]. Cellular Signalling,2011,23(4):609-620.
[3]Rosen V. BMP2 signaling in bone development and repair [J]. Cytokine & growth factor reviews,2009,20(5):475-480.
[4]Seeherman H, Wozney J, Li R. Bone morphogenetic protein delivery systems [J]. Spine,2002, 27(16S):S16-S23.
[5]Hogan B L M. Bone morphogenetic proteins in development [J]. Current opinion in genetics & development,1996,6(4):432-438.
[6]Cook S D, Dalton J E, Tan E H, et al. In vivo evaluation of recombinant human osteogenic protein (rhOP-1) implants as a bone graft substitute for spinal fusions [J]. Spine,1994,19(15): 1655.
[7]Kawai T, Mieki A, Ohno Y, et al. Osteoinductive activity of composites of bone morphogenetic protein and pure titanium [J]. Clinical orthopaedics and related research,1993, 290(296.
[8]Kherani N, Shmayda W. Gas handling systems using titanium-sponge and uranium bulk getters [J]. Fusion Technol;(United States),1985,8(CONF-850405-):
[9]Aoki H. Science and medical applications of hydroxyapatite [M]. Ishiyaku Euroamerica, 1991.
[10]Swetha M, Sahithi K, Moorthi A, et al. Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering [J]. International journal of biological macromolecules, 2010,47(1):1-4.
[11]Bhumiratana S, Grayson W L, Castaneda A, et al. Nucleation and growth of mineralized bone matrix on silk-hydroxyapatite composite scaffolds [J]. Biomaterials,2011,32(11):2812-2820.
[12]Magin M N, Delling G. Improved lumbar vertebral interbody fusion using rhOP-1:a comparison of autogenous bone graft, bovine hydroxylapatite (Bio-Oss), and BMP-7 (rhOP-1) in sheep [J]. Spine,2001,26(5):469-478.
[13]Liang G Yang Y, Oh S, et al. Ectopic osteoinduction and early degradation of recombinant human bone morphogenetic protein-2-loaded porous< i>β-tricalcium phosphate in mice [J]. Biomaterials,2005,26(20):4265-4271.
[14]Motskin M, Wright D, Muller K, et al. Hydroxyapatite nano and microparticles:correlation of particle properties with cytotoxicity and biostability [J]. Biomaterials,2009,30(19):3307-3317.
[15]Kamegai A, Shimamura N, Naitou K, et al. Bone formation under the influence of bone morphogenetic protein/self-setting apatite cement composite as a delivery system [J]. Bio-medical materials and engineering.1994,4(4):291-307.
[16]Bais M. Wigner N, Young M, et al. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells [J]. Bone,2009,45(2):254-266.
[17]Arosarena O A, Collins W L. Bone regeneration in the rat mandible with bone morphogenetic protein-2:a comparison of two carriers [J]. Otolaryngology-Head and Neck Surgery,2005,132(4): 592-597.
[18]Jones A A, Buser D, Schenk R, et al. The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model [J]. Journal of periodontology,2006,77(7): 1184-1193.
[19]Akamaru-T, Suh D, Boden S D, et al. Simple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion [J]. Spine,2003,28(5):429.
[20]Murakami N, Saito N, Horiuchi H, et al. Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer [J]. Journal of biomedical materials research,2002,62(2): 169-174.
[21]Seeherman H J, Bouxsein M, Kim H, et al. Recombinant human bone morphogenetic protein-2 delivered in an injectable calcium phosphate paste accelerates osteotomy-site healing in a nonhuman primate model [J]. The Journal of Bone and Joint Surgery (American),2004,86(9): 1961-1972.
[22]刘通方,刘建,孟国林,等注射型磷酸钙骨水泥／纤维蛋白胶作为BMP注射性载体的可行性研究[J].第四军医大学学报,2006,27(14)：1296-1299.
[23]李亚非,胡蕴玉.四种可溶性载体对骨形态发生蛋白在小鼠体内诱导成骨活性的影响[J].中华骨科杂志,1997,17(2)：117-119.
[24]Erbe E M, Clineff T D, Bagga C S, et al. Bone restorative carrier mediums [M]. Google Patents.2009.
[25]王玮,尹庆水,张余.重组人骨形态发生蛋白2壳聚糖纳米微球的制备及体外细胞毒性[J].中国组织工程研究与临床康复,2011,15(25)：46114614.
[26]Park J, Ries J, Gelse K, et al. Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer:a comparison of adenoviral vectors and liposomes [J]. Gene therapy,2003, 10(13):1089-1098.
[2]Waite P D, Sastravaha P, Lemons J E. Biologic mechanical advantages of 3 different cranial bone grafting techniques for implant reconstruction of the atrophic maxilla [J]. Journal of oral and maxillofacial surgery,2005,63(1):63-67.
[3]Lekovic V, Camargo P M, Klokkevold P R, et al. Preservation of alveolar bone in extraction sockets using bioabsorbable membranes [J]. Journal of periodontology,1998,69(9):1044-1049.
[4]Cardaropoli D, Cardaropoli G. Preservation of the postextraction alveolar ridge:A clinical and histologic study [J]. The International journal of periodontics & restorative dentistry,2008, 28(5):469.
[5]周婷,陆守昌.重度牙槽嵴萎缩牙槽骨重建的研究进展[J].中华老年口腔医学杂志,2008,6(03)：187-189.
[6]王海云,钟梅,赖仁发.防治牙槽嵴萎缩的研究进展[J].中国口腔种植学杂志,2006,11(001)：44-47.
[7]何建明,徐青.牙槽骨骨量不足的前牙种植[J].中国口腔种植学杂志,2000,5(003)：130-131.
[8]杨东伟,陆晓丽,袁峰,等.新型人工骨植入牙槽窝预防牙槽嵴萎缩的实验研究[J].广东牙病防治,2003,11(001)：8-10.
[9]吴哲,孙宏晨,刘树泰,等.聚乳酸-羟基乙酸-辛伐他汀对拔牙术后剩余牙槽嵴吸收影响的实验研究[J].中华口腔医学杂志,2006,41(12)：
[10]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review [J]. Cellular Signalling,2011,23(4):609-620.
[11]Bais M, Wigner N, Young M, et al. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells [J]. Bone,2009,45(2):254-266.
[12]Reddi A. BMPs:from bone morphogenetic proteins to body morphogenetic proteins [J]. Cytokine & growth factor reviews,2005,16(3):249.
[13]Ijiri S, Nakamura T, Fujisawa Y, et al. Ectopic bone induction in porous apatite-wollastonite-containing glass ceramic combined with bone morphogenetic protein [J]. Journal of biomedical materials research,1997,35(4):421-432.
[14]Jones A A, Buser D, Schenk R, et al. The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model [J]. Journal of periodontology,2006,77(7): 1184-1193.
[15]Raida M, Clement J H, Leek R D, et al. Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis [J]. Journal of cancer research and clinical oncology,2005, 131(11):741-750.
[16]Csiszar A, Smith K E, Koller A, et al. Regulation of bone morphogenetic protein-2 expression in endothelial cells [J]. Circulation,2005,111(18):2364-2372.
[17]Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfal [J]. Endocrine reviews,2000,21(4):393-411.
[18]Yu Y Y, Lieu S, Lu C, et al. Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair [J]. Bone,2010.47(1):65-73.
[19]Wang E A. Rosen V, Cordes P, et al. Purification and characterization of other distinct bone-inducing factors [J]. Proceedings of the National Academy of Sciences,1988,85(24): 9484-9488.
[20]Shea C M, Edgar C M, Einhorn T A, et al. BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis [J]. Journal of cellular biochemistry,2003, 90(6):1112-1127.
[21]Yoshida K, Bessho K, Fujimura K, et al. Osteoinduction capability of recombinant human bone morphogenetic protein-2 in intramuscular and subcutaneous sites:an experimental study [J]. Journal of Cranio-Maxillofacial Surgery,1998,26(2):112-115.
[22]Fromigue O, Marie P, Lomri A. Bone morphogenetic protein-2 and transforming growth factor-β2 interact to modulate human bone marrow stromal cell proliferation and differentiation [J]. Journal of cellular biochemistry,1998,68(4):411-426.
[23]Henkin J. Evaluation of a New Carrier System for rhBMP-2:A Non-Human Primate Mandibular Resection Study [J]. Journal of oral and maxillofacial surgery,2010,68(9):e32-e33.
[24]Shen H, Hu X, Yang F, et al. An injectable scaffold:rhBMP-2-loaded poly (lactide-co-glycolide)/hydroxyapatite composite microspheres [J]. Acta biomaterialia,2010,6(2): 455-465.
[25]孙明林.胡蕴玉.骨形态发生蛋白载体材料的研究和应用现状[J].国外医学：生物医学工程分册,2001,24(003)：128-133.
[26]Kao D, Kubota A, Nevins M, et al. The negative effect of combining rhBMP-2 and Bio-Oss on bone formation for maxillary sinus augmentation [J]. The International journal of periodontics & restorative dentistry,2012,32(1):61.
[27]Seeherman H J, Li X J, Bouxsein M L, et al. rhBMP-2 induces transient bone resorption followed by bone formation in a nonhuman primate core-defect model [J]. The Journal of Bone & Joint Surgery,2010,92(2):411-426.
[28]Owens K, Glassman S D, Howard J M, et al. Perioperative complications with rhBMP-2 in transforaminal lumbar interbody fusion [J]. European Spine Journal,2011,20(4):612-617.
[29]Lecanda F, Avioli L, Cheng S. Regulation of bone matrix protein expression and induction of diferentiation of human osteoblasts and human bone marrow stromal cells by bone morphgenetic protein-2 [J]. Cell Biochem,1997,67(3):386-396.
[30]Morrison N. Cyanoacrylate glue for saphenous ablation [J]. Veins and Lymphatics,2012,1(1): 1.
[31]Soehendra N, Grimm H, Nam V C, et al. N-butyl-2-cyanoacrylate:a supplement to endoscopic sclerotherapy [J]. Endoscopy,2008,19(06):221-224.
[32]熊林,王建营,延玺,等.丙烯酸酯胶粘剂研究进展[J].中国胶粘剂,2002,11(3)：47-52.
[33]王艳红.α-氰基丙烯酸辛酯医用胶的改性和生物学评价[D]；天津医科大学,2009.
[34]田霞,卢永顺.特种胶粘剂-α-氰基丙烯酸酯系医用胶[J].化工新型材料,2007,S1(3)110-113.
[35]Toriumi D M, O'grady K, Desai D, et al. Use of octyl-2-cyanoacrylate for skin closure in facial plastic surgery [J]. Plastic and reconstructive surgery.1998,102(6):2209-2219.
[36]Shen Y-M, Sun W-B, Chen J, et al. NBCA medical adhesive (n-butyl-2-cyanoacrylate) versus suture for patch fixation in Lichtenstein inguinal herniorrhaphy:A randomized controlled trial [J]. Surgery,2012,151(4):550-555.
[37]陈子达,李玲,邹翰.医用胶粘剂的研究进展[J].化学与粘合,2001,1(5)21-22.
[38]王艳红,顾汉卿.医用粘合剂的发展及临床应用进展[J][J].透析与人工器官,2008,19(3)：23-32.
[39]Woodward S C, Herrmann J B, Cameron J L, et al. Histotoxicity of cyanoacrylate tissue adhesive in the rat [J]. Annals of Surgery,1965,162(1):113.
[40]孙健,谢富强,李平,等复方骨形成蛋白生物复合物预防剩余牙槽嵴吸收实验[J].实用口腔医学杂志,2008,24(006)：801-805.
[41]朱志宏,马承宣,许瑞江.α-氰基丙烯酸正丁酯充填骨缺损腔的特点[J].中国临床康复,2006,10(29)：72-74.
[42]卢凤琦,庄昭霞,曹晶,等.可降解性壳聚糖复合膜的研制与生物学评价[J].生物医学工程学杂志,2003,20(2)：277-280.
[43]郝彤,刘暾,吕双红,等.采用温敏性壳聚糖水凝胶体外构建组织工程化软骨的实验研究[J].解放军医学杂志,2007,32(5)：500-502.
[44]黄洪超,胡永成,刘凤松,等.骨形态发生蛋白载体的研究与应用[J].中国组织工程研究与临床康复,2007,11(014)：2748-2751.
[45]Chenite A, Chaput C, Wang D, et al. Novel injectable neutral solutions of chitosan form biodegradable gels in situ [J]. Biomaterials,2000,21(21):2155-2161.
[46]Kawakami T, Kawai T, Takei N, et al. Evaluation of heterotopic bone formation induced by squalane and bone morphogenetic protein composite [J]. Clinical orthopaedics and related research,1997,337(37)261-266.
[47]杨英军,谢富强,杨晓昀,等.应用水溶性壳聚糖为主要载体的重组人骨形态发生蛋白2缓释系统：降解缓释和成骨作用评价[J].中国组织工程研究与临床康复,2007,11(035)：6929-6933.
[48]Madihally S V, Matthew H W. Porous chitosan scaffolds for tissue engineering [J]. Biomaterials,1999,20(12):1133-1142.
[49]Ravi Kumar M N. A review of chitin and chitosan applications [J]. Reactive and functional polymers,2000,46(1):1-27.
[50]Park D J, Choi B H, Zhu S J, et al. Injectable bone using chitosan-alginate gel/mesenchymal stem cells/BMP-2 composites [J]. Journal of Cranio-Maxillofacial Surgery,2005,33(1):50-54.
[51]Jeong B, Choi Y, Bae Y, et al. New biodegradable polymers for injectable drug delivery systems [J]. Journal of Controlled Release,1999,62(1):109-114.
[52]Chenite A, Buschmann M, Wang D, et al. Rheological characterisation of thermogelling chitosan/glycerol-phosphate solutions [J]. Carbohydrate polymers,2001,46(1):39-47.
[53]Illum L, Farraj N F, Davis S S. Chitosan as a novel nasal delivery system for peptide drugs [J]. Pharmaceutical research,1994,11(8):1186-1189.
[54]刘阳,朱立新,杨宏,等.可注射性纳米羟基磷灰石／壳聚糖复合骨髓间充质干细胞促进骨缺损的修复[J].中国组织工程研究与临床康复,2010,14(034)：6278-6282.
[55]吴哲,孙宏晨,车彦海,等.大鼠下颌切牙拔出后剩余牙槽嵴吸收模型的建立[J].实用口腔医学杂志,2007，23(001)：36-39.
[56]王元占.常用实验动物的麻醉[J].中国比较医学杂志,2004,14(4)：245-247.
[57]张凤仙.水合氯醛溶液的配制及使用注意事项[J].海峡药学,2002,14(3)：10-11.
[58]Devlin H, Sloan P. Early bone healing events in the human extraction socket [J]. International journal of oral and maxillofacial surgery,2002,31(6):641-645.
[59]Hwang S-J, Jung J-G, Jung J-U, et al. Vertical alveolar bone distraction at molar region using lag screw principle [J]. Journal of oral and maxillofacial surgery,2004,62(7):787-794.
[60]Rachmiel A, Srouji S, Peled M. Alveolar ridge augmentation by distraction osteogenesis [J]. International journal of oral and maxillofacial surgery,2001,30(6):510.
[61]Schropp L, Wenzel A, Kostopoulos L, et al. Bone healing and soft tissue contour changes following single-tooth extraction:a clinical and radiographic 12-month prospective study [J]. International Journal of Periodontics and Restorative Dentistry,2003,23(4):313-324.
[62]高宁,李宁毅,贾暮云,等rhBMP-2与聚乳酸复合体植入犬拔牙创对牙槽骨再生的影响[J].齐鲁医学杂志,2004,19(6)：481-483.
[63]Block M S, Almerico B, Crawford C, et al. Bone response to functioning implants in dog mandibular alveolar ridges augmented with distraction osteogenesis [J]. The International journal of oral & maxillofacial implants,1998,13(3):342.
[64]金黎明,刘万顺,韩宝芹,等.骨缺损治疗方法的研究现状[J].中国临床康复,2006,10(001)：144-146.
[65]Hile L, Linklater D. Use of 2-octyl cyanoacrylate for the repair of a fractured molar tooth [J]. Annals of emergency medicine,2006,47(5):424-426.
[66]Jensen O T, Cockrell R, Kuhike L, et al. Anterior maxillary alveolar distraction osteogenesis: a prospective 5-year clinical study [J]. The International journal of oral & maxillofacial implants, 2002,17(1):52.
[67]余占海,刘武,岑远坤.种植体固定的三明治法增高牙槽嵴的实验研究[J].口腔颌面修复学杂志,2003,4(2)：8]-83.
[68]陈军,韩加祥,连文海.拔牙创内植羟基磷灰石对牙槽嵴保持作用的研究[J].中华口腔医学杂志,1999,34(2)：125-125.
[69]Sigurdsson T, Fu E, Tatakis D, et al. Bone morphogenetic protein-2 for peri-implant bone regeneration and osseointegration [J]. Clinical Oral Implants Research,1997,8(5):367-374.
[70]Chiapasco M, Consolo U, Bianchi A, et al. Alveolar distraction osteogenesis for the correction of vertically deficient edentulous ridges:a multicenter prospective study on humans [J]. The Journal of Prosthetic Dentistry,2004,92(6):587.
[71]Nishimura I, Damiani P, Atwood D. Resorption of residual ridges (RRR) in rats [J]. Journal of Dental Research,1987,66(12):1753-1757.
[72]Elsubeihi E S, Heersche J N M. Quantitative assessment of post-extraction healing and alveolar ridge remodelling of the mandible in female rats [J]. Archives of Oral Biology,2004, 49(5):401-412.
[73]Sigurdsson T J, Fu E, Tatakis D N, et al. Bone morphogenetic protein-2 for peri-implant bone regeneration and osseointegration [J]. Clinical Oral Implants Research,1997,8(5):367-374.
[74]黄元瑾rhBMP-2及不同载体在种植体周围骨缺损修复中的应用研究[D]；南方医科大学，2010.
[75]金琼.胶原-羟磷灰石复合膜引导骨组织再生的动物实验研究[J].华西口腔医学杂志,2011,29(1)：21-26.
[76]Manjubala I, Scheler S, Bossert J, et al. Mineralisation of chitosan scaffolds with nano-apatite formation by double diffusion technique [J]. Acta biomaterialia,2006,2(1):75-84.
[77]Wang A, Ao Q, Cao W, et al. Porous chitosan tubular scaffolds with knitted outer wall and controllable inner structure for nerve tissue engineering [J]. Journal of Biomedical Materials Research Part A,2006,79(1):36-46.
[78]Kim S, Tsao H, Kang Y, et al. In vitro evaluation of an injectable chitosan gel for sustained local delivery of BMP-2 for osteoblastic differentiation [J]. Journal of Biomedical Materials Research Part B:Applied Biomaterials,2011,
[79]黄鑫,孟国林,刘建,等.rh-BMP-2壳聚糖微球的制备及体外检测[J].中国矫形外科杂志,2009,17(15)：1172-1174.
[80]吴道澄,万明习.注射用人骨形成蛋白纳米微粒的制备与性质[J].应用化学,2002,19(007)：613-616.
[81]谢富强,孙健,杨英军,等.复方骨形成蛋白生物膜植入牙槽窝的实验研究[J].口腔颌面外科杂志,2009,19(1)：18-22.
[1]Urist M R, Nilsson O, Rasmussen J, et al. Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs [J]. Clinical orthopaedics and related research,1987,214(295-296).
[2]Bragdon B, Moseychuk O, Saldanha S, et al. Bone morphogenetic proteins:a critical review [J]. Cellular Signalling,2011,23(4):609-620.
[3]Rosen V. BMP2 signaling in bone development and repair [J]. Cytokine & growth factor reviews,2009,20(5):475-480.
[4]Seeherman H, Wozney J, Li R. Bone morphogenetic protein delivery systems [J]. Spine,2002, 27(16S):S16-S23.
[5]Hogan B L M. Bone morphogenetic proteins in development [J]. Current opinion in genetics & development,1996,6(4):432-438.
[6]Cook S D, Dalton J E, Tan E H, et al. In vivo evaluation of recombinant human osteogenic protein (rhOP-1) implants as a bone graft substitute for spinal fusions [J]. Spine,1994,19(15): 1655.
[7]Kawai T, Mieki A, Ohno Y, et al. Osteoinductive activity of composites of bone morphogenetic protein and pure titanium [J]. Clinical orthopaedics and related research,1993, 290(296.
[8]Kherani N, Shmayda W. Gas handling systems using titanium-sponge and uranium bulk getters [J]. Fusion Technol;(United States),1985,8(CONF-850405-):
[9]Aoki H. Science and medical applications of hydroxyapatite [M]. Ishiyaku Euroamerica, 1991.
[10]Swetha M, Sahithi K, Moorthi A, et al. Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering [J]. International journal of biological macromolecules, 2010,47(1):1-4.
[11]Bhumiratana S, Grayson W L, Castaneda A, et al. Nucleation and growth of mineralized bone matrix on silk-hydroxyapatite composite scaffolds [J]. Biomaterials,2011,32(11):2812-2820.
[12]Magin M N, Delling G. Improved lumbar vertebral interbody fusion using rhOP-1:a comparison of autogenous bone graft, bovine hydroxylapatite (Bio-Oss), and BMP-7 (rhOP-1) in sheep [J]. Spine,2001,26(5):469-478.
[13]Liang G Yang Y, Oh S, et al. Ectopic osteoinduction and early degradation of recombinant human bone morphogenetic protein-2-loaded porous< i>β-tricalcium phosphate in mice [J]. Biomaterials,2005,26(20):4265-4271.
[14]Motskin M, Wright D, Muller K, et al. Hydroxyapatite nano and microparticles:correlation of particle properties with cytotoxicity and biostability [J]. Biomaterials,2009,30(19):3307-3317.
[15]Kamegai A, Shimamura N, Naitou K, et al. Bone formation under the influence of bone morphogenetic protein/self-setting apatite cement composite as a delivery system [J]. Bio-medical materials and engineering.1994,4(4):291-307.
[16]Bais M. Wigner N, Young M, et al. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells [J]. Bone,2009,45(2):254-266.
[17]Arosarena O A, Collins W L. Bone regeneration in the rat mandible with bone morphogenetic protein-2:a comparison of two carriers [J]. Otolaryngology-Head and Neck Surgery,2005,132(4): 592-597.
[18]Jones A A, Buser D, Schenk R, et al. The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model [J]. Journal of periodontology,2006,77(7): 1184-1193.
[19]Akamaru-T, Suh D, Boden S D, et al. Simple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion [J]. Spine,2003,28(5):429.
[20]Murakami N, Saito N, Horiuchi H, et al. Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer [J]. Journal of biomedical materials research,2002,62(2): 169-174.
[21]Seeherman H J, Bouxsein M, Kim H, et al. Recombinant human bone morphogenetic protein-2 delivered in an injectable calcium phosphate paste accelerates osteotomy-site healing in a nonhuman primate model [J]. The Journal of Bone and Joint Surgery (American),2004,86(9): 1961-1972.
[22]刘通方,刘建,孟国林,等注射型磷酸钙骨水泥／纤维蛋白胶作为BMP注射性载体的可行性研究[J].第四军医大学学报,2006,27(14)：1296-1299.
[23]李亚非,胡蕴玉.四种可溶性载体对骨形态发生蛋白在小鼠体内诱导成骨活性的影响[J].中华骨科杂志,1997,17(2)：117-119.
[24]Erbe E M, Clineff T D, Bagga C S, et al. Bone restorative carrier mediums [M]. Google Patents.2009.
[25]王玮,尹庆水,张余.重组人骨形态发生蛋白2壳聚糖纳米微球的制备及体外细胞毒性[J].中国组织工程研究与临床康复,2011,15(25)：46114614.
[26]Park J, Ries J, Gelse K, et al. Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer:a comparison of adenoviral vectors and liposomes [J]. Gene therapy,2003, 10(13):1089-1098.