用于骨组织再生修复的胶原-HA复合材料的应用基础研究
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摘要
骨肿瘤和外伤等引起骨缺损发病率的逐年增加已对人类健康造成极大的威胁。目前,治疗骨缺损一般采用自体骨和异体骨移植的方法,但由于自体骨和异体骨移植存在供体有限、免疫反应和传染病的危险等。因此,急需开发人工骨修复材料用于修复骨组织的缺损。目前,用于骨组织再生修复生物材料的研究和临床应用已从第一代生物惰性材料、第二代生物活性材料及生物可降解材料发展到基于细胞和分子水平的第三代生物材料。同时,组织工程、原位组织再生等新理论和新方法的出现为骨缺损的治疗带来了新技术,生物活性与生物可降解性结合的第三代生物材料的研究使应用组织工程和原位组织再生方法修复病缺损组织成为可能。因此,研究开发新型骨诱导生物活性和生物降解性结合的骨修复材料以满足医学科学发展和临床需要是生物医学工程学领域研究的重要方向之一。
本论文模拟天然骨组织的组成和结构特征,构建胶原—羟基磷灰石(HA)复合材料并引入细胞因子骨形态发生蛋白(BMP),研制用于原位骨组织再生修复和骨组织工程的骨诱导生物活性和生物降解性结合的生物材料。主要研究结果如下:
1.胶原—HA复合骨修复材料的制备及其理化、生物安全性表征
选用生物相容性好的天然胶原、HA为主原料,通过共混、化学交联等过程制备胶原—HA复合人工骨修复材料,并对材料的结构和理化性能进行了表征,研究了材料与血浆接触后材料对血浆蛋白吸附及对血浆中钙磷影响,参照GB/T16886医疗器械生物学评价系列标准等对材料进行了系统的生物安全性评价。研究结果显示,胶原—HA复合人工骨修复材料为非致密多孔状,可见HA间的胶原纤维,HA均匀分散在胶原纤维中;复合材料的理化性能和生物安全性符合体内植入物相关标准的要求,具有良好的生物相容性;复合材料与血浆接触后,血浆溶液中血浆总蛋白(TP),纤维蛋白原(FiB)及纤维粘连蛋白(FNC)的降低表明了材料表面有各种蛋白质的吸附,材料吸附某些特异性非胶原蛋白,将益于骨组织形成和矿化;血浆溶液中Ca、P值均有增加,与材料表面离子释放有关,可参与体内代谢,对骨诱导将会起到促进作用。
2.胶原—HA/BMP复合材料异位成骨效应的研究
将BMP与胶原—HA复合材料通过物理吸附的方法复合,利用鼠股部肌袋模型,通过组织学观察、碱性磷酸酶(ALP)染色以及组织中ALP定量检测等手段研究了复合BMP后材料的异位诱导成骨效应。实验结果显示复合BMP的胶原—HA复合材料和HA材料均有异位诱导成骨作用,而未复合BMP的材料均没有表现异位诱导成骨作用。
3.胶原—HA/BMP复合材料修复节段性骨缺损及成骨效应的研究
为进一步研究和评价研制的骨修复材料对骨缺损的修复能力,将复合BMP的胶原—HA复合材料植入兔桡骨10mm骨缺损,通过血生化检测、生物力学测定、扫描电镜及组织学染色分析等手段,观察了新骨形成及材料的降解规律。实验结果显示胶原HA复合材料对骨缺损有较强的修复能力,具有良好的可降解吸收性;胶原—HA复合材料/BMP骨缺损修复能力大于胶原—HA复合材料,BMP的加入可有效地促进新骨的形成。结合异位成骨实验结果说明,胶原—HA复合材料可与BMP构成优良的承载系统,保护BMP的生物活性,使BMP能在组织局部聚集成较高的浓度,诱导成骨。
4.胶原—HA复合骨组织工程支架材料及复合蛋白药物的释放特性的研究
采用冷冻干燥法制备多孔胶原-HA复合支架材料用于骨组织工程,对材料的结构形态、性能进行了表征;以牛血清白蛋白(BSA)为模型药物,应用离子交联法制备载BSA壳聚糖胶体颗粒,并与支架材料复合,对胶原-HA骨组织工程支架材料作为生物活性因子释放载体的体内外释放特性进行了研究。现究结果显示,制备的胶原-HA骨组织工程支架材料为多孔三维结构,支架孔径平均50—150μm;胶原与HA复合后支架材料的强度得到提高;甲醛交联和碳化二亚胺交联使支架材料的降解速率明显降低,力学强度增加;支架材料具有良好的细胞相容性。
应用离子交联法制备的壳聚糖胶体颗粒粒径为200-300nm,先制备载BSA壳聚糖胶体颗粒,再和支架材料复合,可明显增强缓释作用,延长药物在植入局部存留的时间,体外释放的趋势与体内释放的基本一致。
Bone defects caused by disease, trauma, or surgery, increase with years, and threaten the human health. The traditional treatment for bone defects include autografts and allografts, though there are some restrictions, such donor site morbidity and donor shortage for autograft, immunologic response and risk of infecting disease for allografts. Artificial bone substitute materials are also used for bone repair. The biomedical materials used for bone repair and regeneration have developed from the first generation-bioinert materials, the second generation-bioactive materials and biodegradable materials, to the third generation-the biomaterials based on celuller and molecular level. At the same time, the new theories and methods of tissue engineering and in situ tissue regeneration bring the new technology for the treatment of bone defects. The research of the third generation biomedical materials, which combine the bioactivity with biodegradation, is the base for applying the methods of tissue engineering and in situ tissue regeneration for repair of bone defects. So, research and develop osteoinductive and biodegradable bone substitute materials for the need of clinic is the major aspect in the area of biomedical engineering.
In this study, simulating the composition and structure of nature bone, we prepared the collagen-hydroxyapaptite(HA) compsite, and incorporated the BMP into the material to develop the biomedical material for bone tissue engineering and in situ tissue regeneration which combine the osteoinduction with biodegradation. The paper includes four parts as following:
1.Preparation and characterization of the collagen-HA composite
Using collagen and HA as main raw material, the collagen-HA composite material was prepared by the process of blending, chemical crosslinking and so on, the structure, physical and chemical properties of the material were characterized, the biocompatibility of the material was evaluated according to GB/T16886 series standard. After the material was contacted with plasma, the capability of the material to absorb plasma protein and effect on calcium(Ca), phosphorus(P) were investigated. SEM photogragh of collagen-HA composite show the material has porous microstructure. It possesses excellent biocompatibility for its chemical, physical and biological properties accord with standards about the biomedical materials. After the material is contacted with plasma, the TP, FiB and FNC in plasma decreased. It indicate the absorption of protein on the surface of the materials, which may benefit for the formation and mineralization of bone. The increasing of Ca and P in plasma is related with the releasing of ions from the material, it may participate in metabolization and accelerate the osteoinduction.
2. The ectopic osteoinduction of collagen-HA/BMP composite
The collagen-HA composite was combined with BMP by absorption, and implanted into the muscle of rat. The ectopic osteoinduction of the material was estimated by histological observation, alkaline phosphatase(ALP) stain and measurement. The results show that Collagen-HA composite and HA which is combined with BMP have obvious ectopic osteoinduction, and the materials which is not combined with BMP have no ectopic osteoinduction.
3. New bone formation and segmental bone defects repair with collagen-HA/BMP composite in vivo
Collagen-HA/BMP composite was implanted into bone defect about 10mm in the shaft of the radius of rabbits. In order to observe the new bone formation and the degradation process of the material, a series of examination were carried out including blood biochemical test, SEM, biomechanical test and histological observation. The results show that the collagen-HA composite have the capability to repair bone defect and can be biodegraded, incorporation of BMP can accelerate the formation of new bone. The material can be used as the carrier for BMP to sustain its releasing, protect its bioactivity, improve the osteoinduction.
4.The research of collagen-HA composite scaffold for bone tissue engineering and the release properties of the scaffold incorporated protein
The porous collagen-HA scaffolds were prepared by lyophilization. Microstructure and properties of the scaffold was characterized. Chitosan colloid particle carrying model drug BSA was prepared by the method of ionic gelatin, and incorporated into the scaffold. BSA release from the system was studied in vitro and in vivo. The collagen-HA scaffolds used for bone tissue engineering are porous with three-dimension interconnected fiber microstructure, and pore sizes are 50-150μm. Compared with pure collagen, the mechanical property of collagen-HA composite improves significantly. Crosslinking by formaldehyde and EDC both decrease the degradation rate of the scaffold and increase the mechanical property. The scaffold has good biocompatibility and suitable for used as bone tissue engineering.
The size of chitosan particle prepared by ion crosslink is 200-300nm. In vivo release studies show that encapsulating BSA by chitosan particle, then incorporating the chitosan particle into the scaffold, would apparently enhance the controlled release effect to prolong the local retention of the protein after implantation. The results of in vitro release studies show good pertinency with respective in vivo results.
本论文模拟天然骨组织的组成和结构特征,构建胶原—羟基磷灰石(HA)复合材料并引入细胞因子骨形态发生蛋白(BMP),研制用于原位骨组织再生修复和骨组织工程的骨诱导生物活性和生物降解性结合的生物材料。主要研究结果如下:
1.胶原—HA复合骨修复材料的制备及其理化、生物安全性表征
选用生物相容性好的天然胶原、HA为主原料,通过共混、化学交联等过程制备胶原—HA复合人工骨修复材料,并对材料的结构和理化性能进行了表征,研究了材料与血浆接触后材料对血浆蛋白吸附及对血浆中钙磷影响,参照GB/T16886医疗器械生物学评价系列标准等对材料进行了系统的生物安全性评价。研究结果显示,胶原—HA复合人工骨修复材料为非致密多孔状,可见HA间的胶原纤维,HA均匀分散在胶原纤维中;复合材料的理化性能和生物安全性符合体内植入物相关标准的要求,具有良好的生物相容性;复合材料与血浆接触后,血浆溶液中血浆总蛋白(TP),纤维蛋白原(FiB)及纤维粘连蛋白(FNC)的降低表明了材料表面有各种蛋白质的吸附,材料吸附某些特异性非胶原蛋白,将益于骨组织形成和矿化;血浆溶液中Ca、P值均有增加,与材料表面离子释放有关,可参与体内代谢,对骨诱导将会起到促进作用。
2.胶原—HA/BMP复合材料异位成骨效应的研究
将BMP与胶原—HA复合材料通过物理吸附的方法复合,利用鼠股部肌袋模型,通过组织学观察、碱性磷酸酶(ALP)染色以及组织中ALP定量检测等手段研究了复合BMP后材料的异位诱导成骨效应。实验结果显示复合BMP的胶原—HA复合材料和HA材料均有异位诱导成骨作用,而未复合BMP的材料均没有表现异位诱导成骨作用。
3.胶原—HA/BMP复合材料修复节段性骨缺损及成骨效应的研究
为进一步研究和评价研制的骨修复材料对骨缺损的修复能力,将复合BMP的胶原—HA复合材料植入兔桡骨10mm骨缺损,通过血生化检测、生物力学测定、扫描电镜及组织学染色分析等手段,观察了新骨形成及材料的降解规律。实验结果显示胶原HA复合材料对骨缺损有较强的修复能力,具有良好的可降解吸收性;胶原—HA复合材料/BMP骨缺损修复能力大于胶原—HA复合材料,BMP的加入可有效地促进新骨的形成。结合异位成骨实验结果说明,胶原—HA复合材料可与BMP构成优良的承载系统,保护BMP的生物活性,使BMP能在组织局部聚集成较高的浓度,诱导成骨。
4.胶原—HA复合骨组织工程支架材料及复合蛋白药物的释放特性的研究
采用冷冻干燥法制备多孔胶原-HA复合支架材料用于骨组织工程,对材料的结构形态、性能进行了表征;以牛血清白蛋白(BSA)为模型药物,应用离子交联法制备载BSA壳聚糖胶体颗粒,并与支架材料复合,对胶原-HA骨组织工程支架材料作为生物活性因子释放载体的体内外释放特性进行了研究。现究结果显示,制备的胶原-HA骨组织工程支架材料为多孔三维结构,支架孔径平均50—150μm;胶原与HA复合后支架材料的强度得到提高;甲醛交联和碳化二亚胺交联使支架材料的降解速率明显降低,力学强度增加;支架材料具有良好的细胞相容性。
应用离子交联法制备的壳聚糖胶体颗粒粒径为200-300nm,先制备载BSA壳聚糖胶体颗粒,再和支架材料复合,可明显增强缓释作用,延长药物在植入局部存留的时间,体外释放的趋势与体内释放的基本一致。
Bone defects caused by disease, trauma, or surgery, increase with years, and threaten the human health. The traditional treatment for bone defects include autografts and allografts, though there are some restrictions, such donor site morbidity and donor shortage for autograft, immunologic response and risk of infecting disease for allografts. Artificial bone substitute materials are also used for bone repair. The biomedical materials used for bone repair and regeneration have developed from the first generation-bioinert materials, the second generation-bioactive materials and biodegradable materials, to the third generation-the biomaterials based on celuller and molecular level. At the same time, the new theories and methods of tissue engineering and in situ tissue regeneration bring the new technology for the treatment of bone defects. The research of the third generation biomedical materials, which combine the bioactivity with biodegradation, is the base for applying the methods of tissue engineering and in situ tissue regeneration for repair of bone defects. So, research and develop osteoinductive and biodegradable bone substitute materials for the need of clinic is the major aspect in the area of biomedical engineering.
In this study, simulating the composition and structure of nature bone, we prepared the collagen-hydroxyapaptite(HA) compsite, and incorporated the BMP into the material to develop the biomedical material for bone tissue engineering and in situ tissue regeneration which combine the osteoinduction with biodegradation. The paper includes four parts as following:
1.Preparation and characterization of the collagen-HA composite
Using collagen and HA as main raw material, the collagen-HA composite material was prepared by the process of blending, chemical crosslinking and so on, the structure, physical and chemical properties of the material were characterized, the biocompatibility of the material was evaluated according to GB/T16886 series standard. After the material was contacted with plasma, the capability of the material to absorb plasma protein and effect on calcium(Ca), phosphorus(P) were investigated. SEM photogragh of collagen-HA composite show the material has porous microstructure. It possesses excellent biocompatibility for its chemical, physical and biological properties accord with standards about the biomedical materials. After the material is contacted with plasma, the TP, FiB and FNC in plasma decreased. It indicate the absorption of protein on the surface of the materials, which may benefit for the formation and mineralization of bone. The increasing of Ca and P in plasma is related with the releasing of ions from the material, it may participate in metabolization and accelerate the osteoinduction.
2. The ectopic osteoinduction of collagen-HA/BMP composite
The collagen-HA composite was combined with BMP by absorption, and implanted into the muscle of rat. The ectopic osteoinduction of the material was estimated by histological observation, alkaline phosphatase(ALP) stain and measurement. The results show that Collagen-HA composite and HA which is combined with BMP have obvious ectopic osteoinduction, and the materials which is not combined with BMP have no ectopic osteoinduction.
3. New bone formation and segmental bone defects repair with collagen-HA/BMP composite in vivo
Collagen-HA/BMP composite was implanted into bone defect about 10mm in the shaft of the radius of rabbits. In order to observe the new bone formation and the degradation process of the material, a series of examination were carried out including blood biochemical test, SEM, biomechanical test and histological observation. The results show that the collagen-HA composite have the capability to repair bone defect and can be biodegraded, incorporation of BMP can accelerate the formation of new bone. The material can be used as the carrier for BMP to sustain its releasing, protect its bioactivity, improve the osteoinduction.
4.The research of collagen-HA composite scaffold for bone tissue engineering and the release properties of the scaffold incorporated protein
The porous collagen-HA scaffolds were prepared by lyophilization. Microstructure and properties of the scaffold was characterized. Chitosan colloid particle carrying model drug BSA was prepared by the method of ionic gelatin, and incorporated into the scaffold. BSA release from the system was studied in vitro and in vivo. The collagen-HA scaffolds used for bone tissue engineering are porous with three-dimension interconnected fiber microstructure, and pore sizes are 50-150μm. Compared with pure collagen, the mechanical property of collagen-HA composite improves significantly. Crosslinking by formaldehyde and EDC both decrease the degradation rate of the scaffold and increase the mechanical property. The scaffold has good biocompatibility and suitable for used as bone tissue engineering.
The size of chitosan particle prepared by ion crosslink is 200-300nm. In vivo release studies show that encapsulating BSA by chitosan particle, then incorporating the chitosan particle into the scaffold, would apparently enhance the controlled release effect to prolong the local retention of the protein after implantation. The results of in vitro release studies show good pertinency with respective in vivo results.
引文
1.王小红,马建标,王亦农,何炳林.骨修复材料的研究进展.生物医学工程杂志,2001,18(4):647-652
2.材料科学技术百科全书.北京:中国大百科全书出版杜,1993,927-928
3.顾双卿,徐国风.生物医学材料学.天津:科学技术出版社,1993,361-362
4.王慧明等.四种骨替代材料的人成骨细胞生物相害性研究.中国生物医学工程学报,1996,15(3):239-244
5.J.Ryhanen,E.Niemi,T.Salo,et al.Biocompatibility of nickel-titanium shape memory metal and its corrosion behavior in human cell cultures.J Biomed Mater Res,1997,35:451-457
6.M.Berger-Gorbet,B.Broxup,L.H.Yahia et al.Biocompatibility testing of NiTi screws using immunohistochemistry on sections containing metallic implants.J Biomed Mater Res,1996,32:243-248
7.S.J.Simske,R Sachdeva.Cranial bone apposition and ingrowth in a porous Nickel-Titanium implant,J Biomed Mater Res,1995,29:527-533
8.V.I.Itin et al.Mechanical properties and shape memory of porous Nitinol.Materials Characterization,1994,32:179-187
9.L.M.Rodriguez-Lorenzo,A.J.Salinas et al.Composite biomatedals based on ceramic polymers.I.Reinforced systems based on Al_2O_3/PMMA/PLLA.J Biomed Mater Res,1996,30:515-522
10.W.Sochanek et al.Processing and properties of hydroxyapatite-based biomaterial for use as hard tissue replacement implants.J.Mater.Res.Jan.,1998,13(1):94-117
11.Hench LL.Bioceramics:from concept to clinic.J Am Ceram Soc,1991,74:1487-1510
12.Heneh L L.Bioactive materials:the potential for tissue regeneration.J Biomed Mater Res,1998,41(4):511-518
13.Hench L L,Wilson J,Eds.An Introduction to Bioceramics.London:World Scientific,1993,199-221
14.L.L.Hench,J.Wilson,Eds.Clinical Performance of Skeletal Prostheses.London: Chapman & Hall,1996,chaps.13 and 15
15.Kokubo T,Kim H-M,Kawashita M.Novel bioactive materials with different mechanical properties.Biomateriais,2003,24:2161-75
16.Hench LL.Bioactive glasses and glasses-ceramics.In:Shackelford JF,editor.Bioceramics -applications of ceramic and glass materials in medicine.Switzerland:Trans Tech Publication,1999,37-64.
17.Hench LL,Kokubo T.Properties of bioactive glasses and glassceramics.In:Black J,Hastings G,editors.Handbook of biomaterial properties.London:Chapman &Hail,1998,355 - 363.
18.Chen QZ,Boccaccini AR.Poly(D,L-lactic acid) coated 45S5 Bioglass-based scaffolds for bone engineering.J Biomed Mater Res A,2006,77:445-457
19.LeGeros RZ,LeGeros JP.Dense hydroxyapatite.In:Hench LL,Wilson J,editors.An introduction to bioceramics.2nd ed.London:Word Scientific,1999,139 - 80
20.Yamamuro T,Hench L L,Wilson J,Eds.CRC Handbook of Bioactive Ceramics,Vol2,Calcium Phosphate and Hydroxylapatite Ceramics.Boca Raton:CRC Press,1990,373-377
21.杨洪,宁黔冀.生物硬组织材料羟基磷灰石-从天然到人工合成.生物学通报,2004,39(5):6-7
22.陈晓明等.α-TCP骨水泥水化产物的生物相容性研究.中国生物医学工程学报,1996,15(3):233-236
23.Guillemin G,Patat JL.The use of coral as a bone graft substitute.J Biomed Mater Res,1987,21(5):557-672
24.Soost F,Peisshauer B,Herrmann A.Natural coral calcium carbonate as alternative substitute in bone defects of the skull.Mund Kiefer Gesiehtschir,1998,2(2):96-100
25.Keaveny TM,Hayes WC.Mechanical properties of cortical and trabecular bone.In:Hall BK,editor.Bone growth.Boca Raton,FL:CRC Press,1993,285 - 344
26.Zioupos P,Currey J D.Changes in the stiffness,strength,and toughness of human cortical bone with age.Bone,1998,22:57 - 66
27.Ma Q,Mao T,Liu B,et al.Vascular osteomuscular autograft prefabrication using coral,type Ⅰ collagen and recombinant human bone morphogenetie protein-2.Br J Oral Maxillofac Surg,2000,38(5):561-564
28.Louisia S,Stmmboni M,Meunier A,et al.Coral grafting supplemented with bone marrow.J Bone Joint Surg Br,1999,81(4):719-724
29.G.Hastings,P.Ducheyne,Eds.Macromolcular Biomatedals.Boca Raton:CRC Press,1984
30.Seal BL,Otero TC,Panitch A.Polymeric biomaterials for tissue and organ regeneration.Mater Sci Eng:R:Rep,2001,34:147 - 230
31.Middleton JC,Tipton AJ.Synthetic biodegradable polymers as orthopaedic devices.Biomaterials,2000,21:2335 - 46
32.C.T.Laurencin et al.Bone resorption mechanism elicited by degradation products of orthopedic polymer.Society for Biomaterials,1998,April 22-26:309
33.Bozic KJ,Jocobs JJ.Why the bearing surface matters:the problems caused by bearing surface wear.Seminars in Arthroplasty,2003,14:578
34.Harris W H,Muratoglu O K.A review of current cross-linked polyethylene used in total joint arthroplasty.Clin Orthop,2005,430:462
35.Bradgon CR,Jasty M,M uratoglu OK,et al.Third body wear testing of a highly cross-linked acetabular liner.J Arthroplasty,2005,20:37985
36.A Wang et al.Effect of head/cup on the wear of UHMWPE in total hip replacement.Society for Biomaterials,1998,April 22-26:357
37.戴克戎等.无机骨粒骨水泥的实验研究.中国外科杂志,1989,27(5):209-213
38.黄平,董英海,张钟元.等病灶刮除骨水泥充填术治疗骨盆四肢转移性骨肿瘤.临床骨科杂志,2005,8:331-333
39.Mohanty AK,Misra M,Hinrichsen G.Biofibres,biodegradable polymers and biocomposites:an overview.Macromol Mater Eng,2000,276-277:1-24
40.Lu LC,Mikos AG.Poly(lactic acid).In:Mark JE,editor.Polymer data handbook.Oxford:Oxford Press,1999,527-633
41.Martin C,Wirier H,Bao JY.Acidity near eroding polylactide-polyglycolide in vitro and in vivo in rabbit tibial bone chambers.Biomaterials,1996,17(24):2373 -2380
42.P.Maind-Varlet et al.Local infection resistance and mechanical properties of polylactide implant after experimental contamination.Society for Biomaterials,1998,April 22-26:245
43.Bergsma EJ,Rozema FR,Bos RRM,Debruijn WC.Foreign body reaction to resorbable poly(L-lactic) bone plates and screws used for the fixation of unstable zygomatic fractures.J Oral Maxillofac Surg,1993,51:666-670
44.Groot K De.Bioceramics of calcium phosphate.CRC Press:Boca Roton,FI,1983:31-34
45.Aoki H.Science and medical application of hydroxyapatite.JAAS Press,Tokyo,1991:367
46.Ducheyne P.Bioceramics:materials characteristics versus in vivo behavior.J Biomed Mater Res,1987,21:219-236
47.候文明等.羟基磷灰石复合材料的复合作用的研究.生物医学工程杂志,1995,12(2):182-185
48.高家诚等.激光制备生物陶瓷涂层种植体的生物学行为.材料工程,1994,6:16-18
49.G P A T Klein et al.Calcium phosphate plasma-spayed coating and their stability:in vivo study.J Biomed Mater Res,1994,28:909-917
50.M Shirkazadeh.Diffraction and fourier transform infrared analysis of nanophase apatite coating by electrocrystallization.NanoStructured Materials,1994,4(6):677-684
51.胡科军等.羟基磷灰石涂层种植体的生物学行为.国外医学生物医学工程分册,1999,22(4):228-232
52.K Park et al.Characteristics of carbon fibre-reinforced calcium phosphate composite fabricated by hot pressing.J Mater Sci Lett,1997,16:985-987
53.储成林等.羟基磷灰石(HA)生物复合材料的研究进展.材料导报,1999,13(2):51-54
54.欧玉春等.刚性粒子填充聚合物的增强、增韧与界面相结构.高分子材料与 工程,1998,14(2):12-15
55.C Doyle et al.An ultra-structured study of the interface between hydroxyapatite/polymers composite and bone.Advanced in Biomaterial,1990,9:239-245
56.严永刚,李玉宝,汪建新等.聚酰胺-66/羟基磷灰石复合材料的制备和性能研究.塑料工业,2000,28(3):38-40
57.Andrew SD,Phil GC,Marra KG.The influence of polymer blend composition on the degradation of polymer/hydroxyapatite biomaterials.J Mater Sci:Mater Med,2001,12:673 - 677
58.Deng X,Hao J,Wang C.Preparation and mechanical properties of nanocomposites of poly(D,L-lactide) with Ca-deficient hydroxyapatite nanocrystals.Biomaterials,2001,22:2867 - 73.
59.Kasaga T,Yoshio O,Masayuki N,Yoshihiro A.Preparation and mechanical properties of polylactide acid composites containing hydroxyapatite fibres.Biomaterials,2001,22:9 - 23
60.M Wang et al.Hydroxyapatite-polyethylene composites for substitution effect of ceramic particle size and morphology,Biomaterials,1998,19:2357-2366
61.Liu Q et al.Nano-apatite/polymer composite I:mechanical and physiochemical characteristics.The Fifth World Biomaterials Congress,1996:435
62.L L Hench,J M Polak.Third generation biomedical materials.Science,2002,295:1014-1017
63.Langer R,Vancanti J P.Tissue engineering.Science,1993,260:920
64.Williams D.Benefit and risk in tissue engineering.Mater Today,2004,7:24 - 9
65.L G Griffith,G Naughton.Tissue engineering-current challenge and expanding opportunities.Science,2002,295:1009-1014
66.C Mauli Agrawal,Robert B Ray.Biodegradable Polymeric Scaffolds for Musculoskeletal Tissue Engineering.J Biomed Mater Res,2001,55:141-150
67.Karen J L Burg,Scott Porter,James F Kellam.Biomaterial Developments for Bone Tissue Engineering.Biomaterials,2000,21:2347-2359
68.Johnna S Temenoff,Antonios G Mikos,Injectable Biodegradable Materials For Orthopedic Tissue Engineering.Biomaterials,2000,21:2405-2412
69.Catherine M Cowan,Chia Soo,Benjamin Wu et al.Evolving Concepts in Bone Engineering.Current Topics in Developmental Biology,2005,66:239-285
70.Vassilis Karageorgiou,David Kaplan.Porosity of 3D biomatedal scaffolds and osteogensis.Biomaterials,2005,26:5474-5491
71.K Rezwan,Q Z Chen,A R Boccaccini et al.Biodegradable and bioactive porous polymer/inorganic composite scaffold for bone tissue engineering.Biomaterials,2006,27:3413-3431
72.Mironov V,Viconti R P,Markwald R R.What is regenerative medicine?Emergence of applied stem cell and developmental biology.Expert.Opin.Biol.Ther.,2004,4(6):773-781
73.齐莉萍,戈峰.再生研究与再生医学.生命的化学,2003,23(3):201-203
74.徐迎新.再生医学与外科学研究.中华实验外科杂志,2004,21(2):133-134
75.孙雪,奚廷斐.生物材料和再生医学的进展.中国修复重建外科杂志,2006,20(2):189-193
76.Mano JF,Sousa RA,Boesel LF,Neves NM,Reis RL.Bioinert,biodegradable and injectable polymeric matrix composites for hard tissue replacement:state of the art and recent developments.Compos Sci Technol,2004,64:789 - 817
77.Heungsoo Shin,Seongbong Jo.Antonios G Mikos,Biomimetic materials for tissue engineering.Biomaterials,2003,24:4353-4364
78.M J Whitaker,R A Quirk,K M Shaksheff et al.Growth factor from tissue engineering scaffolds.Journal of Pharmacy and Pharmacology,2001,53:1427
79.Zhang S G.Fabrication of novel biomaterials through molecular self-assembly.Nat.Biotechnol.,2003,21(10):1171-1178
80.沈家骢.纳米生物医用材料.中国医学科学院学报,2006,28(4):472-474
81.Kitsch T,Nickel J,Sebald W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-Ⅱ.EMBO J,2000,9:3314-3324
82.Sascha Keller,Joachim Nickel.Thomas D Mueller,Molecular recognition of BMP-2 and BMP receptor IA.Nature Structure and Molecular Biology,2004,11(5):481-488
83.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-307
84.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomaterials,2003,24:2287-2293
85.王身国,蔡晴,吕泽,贝建中.组织工程中药物控制释放技术的应用研究.中国修复重建外科杂志,2001,15(5):280-285
1.DA Wahl,JT Czernuszka.Collagen-hydroxyapatite composites for hard tissue repair.European Cells and Materials,2006,11:43
2.宁聪琴.硬组织替换用羟基磷灰石复合材料的研究进展.生物医学工程学杂志,2003,20(3):550
3.葛建华,王迎军.可吸收性骨科材料类型及发展.生物医学工程学杂志,2004,21(1):151
4.张其清,任磊,王淳等.羟基磷灰石-胶原复合人工骨材料的研究.生物医学工程通报.1994;6(1):29
5.余英,朱明华,曾怡等.生物活性陶瓷人工骨复合材料的理化性能测试.职业卫生与病伤,2003,18(2):88
6.GB/T14233医用输液、输血、注射器具检验方法
7.GB/T16886医疗器械生物学评价
8.GB/T 16175医用有机硅材料生物学评价试验方法
9.中国药典,二部.1995
10.K.Rezwan,Q.Z.Chen,J.J.Blaker,Aldo Roberto Boccaccini.Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering.Biomaterials,2006,27:3413
11.Kikuchi M,Itoh S,Tanaka J et al.Self-organization mechanism in a bone-like hydroxyapatite/collagen nanocomposite synthesized in vitro and its biological reaction in vivo.Biomaterials,2001,22(13):1705
12.段友容,陈继镛,张兴栋.胶原作为骨修复材料的研究进展.材料导报,2001,15(10):47-49
13.张阳德,乐园,赵梓屹.羟基磷灰石骨修复材料.中国现代医学杂志,2006,16(1):72-75
14.杨洪,宁黔冀.生物硬组织材料羟基磷灰石--从天然到人工合成.生物学通报,2004,39(5):6-7
15.候文明等.羟基磷灰石复合材料的复合作用的研究.生物医学工程杂志,1995,12(2):182-185
16.欧玉春等.刚性粒子填充聚合物的增强、增韧与界面相结构.高分子材料与工程,1998,14(2):12-15
17.储成林等.羟基磷灰石(HA)生物复合材料的研究进展.材料导报,1999,13(2):51-54
18.R Z Wang et al.Synthesie of Nanophase of hydroxyapatite/collagen composite.J Mater Sci Lett,1995,1141:490
19.杨勤等.纤维蛋白粘合剂和羟基磷灰石微粒复合人工骨的制备和测试.生物医学工程杂志,1993,10(1):8-12
20.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
21.Alireza R,Kevin EH.Integrin subunits responsible for adhesion for human osteoblast-like cell to biomimetic peptid surfaces.J Orth Res,1999,17(4):615
22.Germer M,Kanse SM,Kirkdgaard T,et al.Kinetic analysis of integrin-dependent cell adhesion on vitrinectin-the irthivitory potential of plasminogen activator inhibitor-1 and RGD peptides.Eur J Biochem,1998,253(3):669
23.Yoshiba N,Yoshiba K,Nakamura H,et al.Immunoelectroncroscopic study of the localization of fibrionectin in the odontoblast layer of human teeth.Arch Oral Biol,1995,40(2):83
24.Howe A,Aplin AE,Alabari SK,et al.Integrin signaling and cell growth control.Carr Opin cell Biol,1998,10(2):220
25.徐彬等.羟基磷灰石种植体动物实验研究.口腔材料口腔器械杂志,1993,2(4):20
26.杨晓芳,奚廷斐.生物材料生物相容性评价研究进展.生物医学工程学杂志,2001,18(1):123-128
27.孙皎.生物材料和医疗器械的生物学评价.中国医疗器械杂志,2003,27(1):1-3,8
28.丁婷婷,章平,孙皎.生物材料引起机体炎症反应的研究进展.国外医学生物 医学工程分册,2005,28(5):23-26
29.刘欣,史弘道.医用生物材料血液相容性评价研究概况.透析与人工器官,2003,14(1):40-44
30.张真,卢晓风.生物材料有效性和安全性评价的现状与趋势.生物医学工程学杂志,2002,19(1):117-121
31.Wang X H.Progress in the research of bone substitutes.J Biomed Eng,2001,8(4):647-652
32.Chang Q,Shi Z L,Li C G.Study on degradation calcium polyphosphate fibers.Environmental Science,1997,1(2):52
1.Kirsch T,Nickel J,Sebald W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-Ⅱ.EMBO J,2000,9:3314-3324
2.Sascha Keller,Joachim Nickel.Thomas D Mueller,Molecular recognition of BMP-2 and BMP receptor IA.Nature Structure and Molecular Biology,2004,11(5):481-488
3.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992;32(2):160
4.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molecular,celluar and tissue strategies.to engineer human bone.Biomaterials,1996;17(2):175
5.Alam MI,Asahina I,Ohmamiuda K,et al.Evaluation of ceramics composed of different hydroxyapatite to tricalcium phosphate ration as carriers for rhBMP-2.Biomaterial,2001;22(12):643
6.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-3077
.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomaterials,2003,24:2287-2293
8.Ekelund A,Brosjo O,Nilsson OS.Experimental induction of heterotopic bone.Clin Orthop Relat Res,1991,263:102-112
9.Noshi T,Yoshikawa T,Ikeuchi M et al.Enhancement of the in vivo osteogenic potential of marrow/hydroxyapatite composites by bovine bone morphogenetic protein.J Biomed Mater Res,2000,52(4):621-630
10.Wlodarshi K H.Heterotopic bone marrow formation in xenogeneic implants of insoluble bone matrix gelatin.Clin Orthop Relat Res,1982,171:210-212
11.Katz RW,Hollinger JO,Reddi AH,et al.The functional equivalence of dematerialized bone and tooth matrices in ectopic bone induction.J Biomed Res,1993;27:239
12.陈德敏,刘雪阳,钱云芳.锶磷灰石多孔陶瓷复合成骨细胞的体内异位成骨 研究.生物医学工程与临床,2007,11(5):329-332
13.朱明华,曾怡,孙涛,彭蔷,林凡.生物陶瓷与细胞外基质对成骨细胞生长及代谢影响.北京生物医学工程,2005,24(1):17-23
14.朱明华,叶长宁,余英,曾怡,孙涛,彭蔷.生物活性陶瓷与细胞外基质形成对Ca、P、ALP影响.透析与人工器官,2004,15(1):1-5
15.Boyan BD,Savain LD,Schavartz et al.Epithlail cell line that induce bone formation in vivo produce alkaline phosphatase enriched matrix vesicles in culture.Clin Orthop,1992,277:266
16.Canalis E,The hormone and local regulation of bone formation.Endocrine Reviews,1983,4(1):62
17.Kabler N,Urist R.Cell differentiation in response to partially purified osteosarcoma-derived bone morphogenetic protein in vivo and in vitro.Clin Orthorp,1993,292:321
18.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992,32(2):160
19.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molcular,cellular and tissue strategies to engineer human bone.Biomaterials,1996;17(2):175
20.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
21.胡蕴玉.骨诱导及骨愈合分子生物学研究进展.中华骨科杂志,1997,17(1):17-19
22.Eric Hay,Monique Hott,Anne-Marie Graulet,et al.Effects of bone morphogenetic protein-2 on human neonatal calvaria cell differentiation.Journal of Cellular Biochemistry,1999,72:81-93
23.Wang E A,Rosen V D,Alessandro J S et al.Recombinant human bone morpbogenetic protein induce bone formation.Proc Natl Acad Sci USA,1990,87:2220
24.Yamagiwa H,Endo N,Tokunaga K,et al.In vivo bone-forming capacity of human bone marrow-derived stromal cells is stimulated by recombinant human bone morphogenetic brotein-2. J Bone Miner Metab, 2001, 19(1):20-8
25. Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nature Biotechnology, 1998, 16:247-252
26. Carl A, Kirker H. Potential applications and delivery strategies for bone morphogenetic proteins. Advanced Drug Delivery Reviews,2000,43:65
27. Soichiro Itoh, Masanori Kikuchi, et al. The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomatenal, and its function as a carrier of rhBMP-2. J. Biomed Mater Res, 2001, 54: 445-453
28. Toshiaki Noshi, Takafumi Yoshikawa, Yoshiko Dohi, et al. Recombinant human bone morphogenetic protein-2 potentiates the in vivo osteogenic ability of marrow/hydroxyapatite composites. Artificial Organs, 2001, 25(3): 201-208
29. Hasan Uludage, Darren D'Augusta, Janet Golden, et al. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: A correlation between protein pharmacokinetics and osteoiduction in the rat ectopic model. J Biomed Mater Res, 2000, 50:227-238
30. Takaoka K, Nakahara H, et.al. Ectopic bone induction on and in porous hydroxyapatite combined with collagen and bone morphogenetic protein. Clin Orthop 1998, 234: 250-254
1.Carl A,Kirker H.Potential applications and delivery strategies for bone morphogenetic proteins.Advanced Drug Delivery Reviews,2000,43:65
2.Lind M.Growth factor stimulation of bone healing:An Effect on osteoblasts,Osteomies and implants fixation.Acta Orthop Scand Supple,1998;283:2
3.Mundy GR.Regulation of bone formation by bone morphogonic protein and other growth factors.Clin Orthop Relat Res,1996,324:24
4.徐彬.羟基磷灰石种植体的动物实验研究.口腔材料器械杂志,1993,2(4):20
5.杨志宏,郭沈波,王守彪等.甲壳质衍生物对新西兰兔骨缺损愈合相关血生化指标的影响.中国海洋药物,2003,22(6):10-13
6.朱明华,叶长宁,余英,曾怡,孙涛,彭蔷.生物活性陶瓷与细胞外基质形成对Ca、P、ALP影响.透析与人工器官,2004,15(1):1-5
7.周正新,丁锷,李保泉等.消瘀接骨散对骨折愈合相关生化指标的影响.中国骨伤,1998,11(1):19-21
8.朱明华,曾怡,孙涛,彭蔷,林凡.生物陶瓷与细胞外基质对成骨细胞生长及代谢影响.北京生物医学工程,2005,24(1):17-23
9.Boyan BD,Savain LD,Schavartz et al.Epithlail cell line that induce bone formation in vivo produce alkaline phosphatase enriched matrix vesicles in culture.Clin Orthop,1992,277:266
10.Canalis E,The hormone and local regulation of bone formation.Endocrine Reviews,1983,4(1):62
11.王华松,黄琼霞,许申明.骨碎补对骨折愈合中血生化指标及丁GF-β_1表达的影响.中医正骨,2001,13(5);6-8
12.张昌颖.生物化学.北京:人民卫生出版社,1987:589
13.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
14.胡蕴玉.骨诱导及骨愈合分子生物学研究进展.中华骨科杂志,1997,17(1):17-19
15.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992,32(2):160
16.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molecular,cellular and tissue strategies to engineer human bone.Biomaterials,1996;17(2):175
17.Eric Hay,Monique Hott,Anne-Marie Graulet,et al.Effects of bone morphogenetic protein-2 on human neonatal calvaria cell differentiation.Journal of Cellular Biochemistry,1999,72:81-93
18.Wang E A,Rosen V D,Alessandro J S et al.Recombinant human bone morphogenetic protein induce bone formation.Proc Natl Acad Sci USA,1990,87:2220
19.Yamagiwa H,Endo N,Tokunaga K,et al.In vivo bone-forming capacity of human bone marrow-derived stromal cells is stimulated by recombinant human bone morphogenetic brotein-2.J Bone Miner Metab.2001,19(1):20-8
20.李文、岑远坤.骨缺损整复中的生长因子载体材料.中国口腔种植学杂志,1998,3(4):187
21.梁戈、胡蕴玉、郑昌群等.多孔β-TCP/BMP复合人工骨的研制和动物体内的相关研究.中华骨科杂志,1995,18(2):75
22.Alam,Asahina I,Ohmamiuda K.et al.Comparative study of biphasic calcium phosphate ceramics impregnated with rhBMP-2 as bone substitutes.J Biomed Mater Res,2001,54(1):129
23.Reddi AH.Role of morphogenetic proteins in skeletal tissue engineering and regeneration.Nature Bioteclanology,1998,16:247-252
24.杨志明.生物技术的综合应用促进组织工程学发展.中国修复重建外科杂志,2007,21(2):107-109
25.边卫国,彭磊,梁芳慧,徐华梓.骨形态发生蛋白复合明胶羟基磷灰石多孔钛修复骨缺损的实验研究.中华创伤骨科杂志,2007,9(6):550-554
1.Langer R,Vancanti J P.Tissue engineering.Science,1993,260:920
2.Williams D.Benefit and risk in tissue engineering.Mater Today,2004,7:24-9
3.L G Griffith,G Naughton.Tissue engineering-current challenge and expanding opportunities.Science,2002,295:1009-1014
4.C Mauli Agrawal,Robert B Ray.Biodegradable Polymeric Scaffolds for Musculoskeletal Tissue Engineering.J Biomed Mater Res,2001,55:141-150
5.Karen J L Burg,Scott Porter,James F Kellam.Biomatedal Developments for Bone Tissue Engineering.Biomatedals,2000,21:2347-2359
6.Johnna S Temenoff,Antonios G Mikos,Injectable Biodegradable Materials For Orthopedic Tissue Engineering.Biomaterials,2000,21:2405-2412
7.Catherine M Cowan,Chia Soo,Benjamin Wu et al.Evolving Concepts in Bone Engineering.Current Topics in Developmental Biology,2005,66:239-285
8.Vassilis Karageorgiou,David Kaplan.Porosity of 3D biomaterial scaffolds and osteogensis.Biomatedals,2005,26:5474-5491
9.K Rezwan,Q Z Chen,A R Boccaccini et al.Biodegradable and bioactive porous polymer/inorganic composite scaffold for bone tissue engineering.Biomaterials,2006,27:3413-3431
10.M J Whitaker,R A Quirk,K M Shaksheff et al.Growth factor from tissue engineering scaffolds.Journal of Pharmacy and Pharmacology,2001,53:1427
11.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-307
12.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomatedals,2003,24:2287-2293
13.王身国,蔡晴,吕泽,贝建中.组织工程中药物控制释放技术的应用研究.中国修复重建外科杂志,2001,15(5):280-285
14.Kuboki Y,Takita H,Kobayashi D et al.BMP-induced osteogenesis on the surface of hydroxyapatite with geometrically feasible and nonfeasible structures:topology of osteogenesis.J Biomed Mater Res,1998,39:190-199
15.Gren D,Walsh D et al.The potential of biominesis lessons from the design and synthesis of invertebratein bone tissue engineering:skeletons.Bone,2002,30(6):810-815
16.Eggli PS,Muller W,Schenk RK.Porous hydroxyapatite and tricalcium phosphate cylinders with two different pore size ranges implanted in the cancellius bone of rabbits:A comparative histomorphometic and histologic study of bony ingrowth and implant substitution.Clin Orthop,1988,232:127-138
17.Zhang RY,Ma PX,Poly(α-hydroxyl acids)/hydroxyapatite porous composites for bone-tissue engineering:I.Preparation and morphology.J Biomed Mater Res,1999,44:446-455
18.Zhang Y,Zhang M.Synthesie and characterization of macroporous chitosan/calcium phosphate composite scaffolds for tissue engineering.J Biomed Mater Res,2001,55:304-312
19.Madihally SV,Mathew HW.Porous chitosan scaffolds for tissue engineering.Biomaterials,1999,20:1133-1142
20.Kang H W,Tabata Y,Ikata Y.Fabrication of porous gelatin scaffolds for tissue engineering.Biomaterials,1999,20:1339:1344
21.张其清;医用胶原及胶原基材料的研究,天津大学博士论文,1998
22.J S Pieper,A Oosterhof,T H van Kuppevelt,et al.Preparation and characterization of porous crosslinked collagenous matrices containing bioavailable chondroitin sulphate.Biomaterials,1999,20:847-858
23.P.B.van Wachem,J.A.Plantinga,M.J.B.Wissink,et.al.In vivo biocompatibility of carbodiimide-crosslinked collagen matrices:effects of crosslink density,heparin immobilization,and bFGF loading.J.Biomed Mater Res,2001,55(3):368-378
24.Hongyi Yang,Qiqing Zhang.Preparation and characterization of collagen-GAGs bioactive materials for tissue engineering.J Mate Sci Technol,2001;17(5):495-500
25.Yasuhiko Tabata.Tissue regeneration based on growth factor release.Tissue Engineering,2003,9(suppl,1):S5-15
26.Bodmeier,H.G.Chen,O.Paeratakul.A novel approach to the oral delivery of micro-or nanoparticles.Pharm.Res.,1989,6(5):413-7
27.K.A.Janes,P.Calvo,M.J.Alonso.Polysaccharide colloidal particles as delivery systems for macromolecules.Adv.Drug.Deliv.Rev.,2001,47:83-97
28.O.Felt,P.Buri,R.Gurny.Chitosan:A unique polysaccharide for drug delivery.Drug.Dev.Ind.Pharm.,1998,24(11):979-93
29.A.K.Singla and M.Chawla.Chitosan:some pharmaceutical and biological aspects -an update.J.Pharm.Pharmaco.,2001,53:1047-67
30.F.L.Mi,S.S.Shyu,C.T.Chen et al.Porous chitosan microsphere for controlling the antigen release of Newcastle disease vaccine:preparation of antigen-adsorbed mierosphere and in vitro release.Biomaterials,1999,20:1603-12
31.R.Fernandez-Urrusuno,P.Calvo,C.Remunan-Lopez et al.Enhancement of nasal absorption of insulin using chitosan nanoparticles.Pharm.Res.,1999,16(10):1576-81
32.A.M.Dyer,M.Hinchcliffe,P.Watts et al.Nasal delivery of instulin using novel chitosan based formulations:.A comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles.Pharm.Res.,2002,19(7):998-1008
33.R.Hejazi,M.Amiji.Stomach-specific anti-H.pylori therapy.I:preparation and characterization of tetracycline-loaded chitosan microspheres.Int.J.Pharm.,2002,235:87-94
34.A.Vila,A.Sanchez,M.Tobio et al.Design of biodegradable particles for protein delivery.J.Control.Rel.,2002,78:15-24
35.K.A.Janes,M.P.Fresneau,A.Marazuela et al.Chitosan nanoparticles as delivery systems for doxorubicin.J.Control.Rel.,2001,73:255-67
36.Z.Ma,H.H.Yeoh,L.Y.Lim.Formulation ph Modulates the Interaction of Insulin with Chitosan Nanoparticles.J.Pharm.Sci.,2002,91(6):1396-404
37.A.Fernandez,M.Jose.Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms.EP 0 860 166 A1
38.X.Z.Shu,K.J.Zhu.Controlled drug release properties of ionically cross-linked chitosan beads:the influence of anion structure.Int.J.Pharm.,2002,233:217-25
39.X.Z.Shu,K.J.Zhu.A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery.Int.J.Pharm.,2000,201:51-8
40.H.Zhang,I.Alsarra,S.H.Neau.An invitro evaluation of a chitosan-containing multiparticulate system for macromolecule delivery to the colon.Int.J.Pharm.,2002,239:197-205
41.Yongmei Xu,Yumin Du.Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles.Int.J.Pharm.,2003,250:215-26
42.A.Berthold,K.Cremer,J.Kreuter.Preparation and characterization of chitosan microspheres as drug cartier for prednisolone sodium phosphate as model for antiinflammatory drugs.J.Control.Rel.,1996,39:17-25
43.S Yokota,T Uchida,et al.Release of recombinant human bone morphogenetic protein 2 from a newly developed carrier.Int J Pharrna,2003,251(1-2):57-66
44.H Uludag,D D'Augusta,et al.Implantation of recombinant human bone morphogenetic proteins with biomatedals carriers:A correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model.J Biomed Mater Res,2000,50(2):227-38
45.W Friess,H Uludag,et al.Characterization of absorbable collagen sponges as recombinant human bone morphogenetic protein-2 carriers.Int J Pharm,1999,185(1):51-60
46.M Yamamoto,Y Tabata,Y Ikada.Ectopic bone formation induced by biodegradable hydrogels incorporating bone morphogenetic protein.J.Biomater.Sci.Polymer Ecin.1998,9(5):439-58
47.S Yokota,S Sonohara,M.Yoshida,et al.A new recombinant human bone morphogenetic protein-2 cartier for bone regeneration.Int.J.Pharm.,2001,223:69-79
48.J Ziegler,U Mayr-Wohlfart,S Kessler,et al.Adsorption and release properties of growth factors from biodegradable implants.J Biomed Mater Res.2002,59:422-8
49.H Uludag,D D'Augusta,R Palmer,et al.Characterization of rhBMP-2pharmacokinetics implanted wih biomaterial carriers in the rat ectopic model.J Biomed Mater Res, 1999,46:193-202
50. J Louis-Ugbo, HS Kim, S D Boden, et al. Retention of ~(125)I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model. J Orthopaedic Research. 2002,20:1050-9
51. R Talwar, L De Silvto, F J Hughes, et al. EfiFects of carrier release kinetics on bone morphogenetic protein-2-induced periodontal regeneration in vivo. J Clin Periodontol. 2001, 28:340-7
2.材料科学技术百科全书.北京:中国大百科全书出版杜,1993,927-928
3.顾双卿,徐国风.生物医学材料学.天津:科学技术出版社,1993,361-362
4.王慧明等.四种骨替代材料的人成骨细胞生物相害性研究.中国生物医学工程学报,1996,15(3):239-244
5.J.Ryhanen,E.Niemi,T.Salo,et al.Biocompatibility of nickel-titanium shape memory metal and its corrosion behavior in human cell cultures.J Biomed Mater Res,1997,35:451-457
6.M.Berger-Gorbet,B.Broxup,L.H.Yahia et al.Biocompatibility testing of NiTi screws using immunohistochemistry on sections containing metallic implants.J Biomed Mater Res,1996,32:243-248
7.S.J.Simske,R Sachdeva.Cranial bone apposition and ingrowth in a porous Nickel-Titanium implant,J Biomed Mater Res,1995,29:527-533
8.V.I.Itin et al.Mechanical properties and shape memory of porous Nitinol.Materials Characterization,1994,32:179-187
9.L.M.Rodriguez-Lorenzo,A.J.Salinas et al.Composite biomatedals based on ceramic polymers.I.Reinforced systems based on Al_2O_3/PMMA/PLLA.J Biomed Mater Res,1996,30:515-522
10.W.Sochanek et al.Processing and properties of hydroxyapatite-based biomaterial for use as hard tissue replacement implants.J.Mater.Res.Jan.,1998,13(1):94-117
11.Hench LL.Bioceramics:from concept to clinic.J Am Ceram Soc,1991,74:1487-1510
12.Heneh L L.Bioactive materials:the potential for tissue regeneration.J Biomed Mater Res,1998,41(4):511-518
13.Hench L L,Wilson J,Eds.An Introduction to Bioceramics.London:World Scientific,1993,199-221
14.L.L.Hench,J.Wilson,Eds.Clinical Performance of Skeletal Prostheses.London: Chapman & Hall,1996,chaps.13 and 15
15.Kokubo T,Kim H-M,Kawashita M.Novel bioactive materials with different mechanical properties.Biomateriais,2003,24:2161-75
16.Hench LL.Bioactive glasses and glasses-ceramics.In:Shackelford JF,editor.Bioceramics -applications of ceramic and glass materials in medicine.Switzerland:Trans Tech Publication,1999,37-64.
17.Hench LL,Kokubo T.Properties of bioactive glasses and glassceramics.In:Black J,Hastings G,editors.Handbook of biomaterial properties.London:Chapman &Hail,1998,355 - 363.
18.Chen QZ,Boccaccini AR.Poly(D,L-lactic acid) coated 45S5 Bioglass-based scaffolds for bone engineering.J Biomed Mater Res A,2006,77:445-457
19.LeGeros RZ,LeGeros JP.Dense hydroxyapatite.In:Hench LL,Wilson J,editors.An introduction to bioceramics.2nd ed.London:Word Scientific,1999,139 - 80
20.Yamamuro T,Hench L L,Wilson J,Eds.CRC Handbook of Bioactive Ceramics,Vol2,Calcium Phosphate and Hydroxylapatite Ceramics.Boca Raton:CRC Press,1990,373-377
21.杨洪,宁黔冀.生物硬组织材料羟基磷灰石-从天然到人工合成.生物学通报,2004,39(5):6-7
22.陈晓明等.α-TCP骨水泥水化产物的生物相容性研究.中国生物医学工程学报,1996,15(3):233-236
23.Guillemin G,Patat JL.The use of coral as a bone graft substitute.J Biomed Mater Res,1987,21(5):557-672
24.Soost F,Peisshauer B,Herrmann A.Natural coral calcium carbonate as alternative substitute in bone defects of the skull.Mund Kiefer Gesiehtschir,1998,2(2):96-100
25.Keaveny TM,Hayes WC.Mechanical properties of cortical and trabecular bone.In:Hall BK,editor.Bone growth.Boca Raton,FL:CRC Press,1993,285 - 344
26.Zioupos P,Currey J D.Changes in the stiffness,strength,and toughness of human cortical bone with age.Bone,1998,22:57 - 66
27.Ma Q,Mao T,Liu B,et al.Vascular osteomuscular autograft prefabrication using coral,type Ⅰ collagen and recombinant human bone morphogenetie protein-2.Br J Oral Maxillofac Surg,2000,38(5):561-564
28.Louisia S,Stmmboni M,Meunier A,et al.Coral grafting supplemented with bone marrow.J Bone Joint Surg Br,1999,81(4):719-724
29.G.Hastings,P.Ducheyne,Eds.Macromolcular Biomatedals.Boca Raton:CRC Press,1984
30.Seal BL,Otero TC,Panitch A.Polymeric biomaterials for tissue and organ regeneration.Mater Sci Eng:R:Rep,2001,34:147 - 230
31.Middleton JC,Tipton AJ.Synthetic biodegradable polymers as orthopaedic devices.Biomaterials,2000,21:2335 - 46
32.C.T.Laurencin et al.Bone resorption mechanism elicited by degradation products of orthopedic polymer.Society for Biomaterials,1998,April 22-26:309
33.Bozic KJ,Jocobs JJ.Why the bearing surface matters:the problems caused by bearing surface wear.Seminars in Arthroplasty,2003,14:578
34.Harris W H,Muratoglu O K.A review of current cross-linked polyethylene used in total joint arthroplasty.Clin Orthop,2005,430:462
35.Bradgon CR,Jasty M,M uratoglu OK,et al.Third body wear testing of a highly cross-linked acetabular liner.J Arthroplasty,2005,20:37985
36.A Wang et al.Effect of head/cup on the wear of UHMWPE in total hip replacement.Society for Biomaterials,1998,April 22-26:357
37.戴克戎等.无机骨粒骨水泥的实验研究.中国外科杂志,1989,27(5):209-213
38.黄平,董英海,张钟元.等病灶刮除骨水泥充填术治疗骨盆四肢转移性骨肿瘤.临床骨科杂志,2005,8:331-333
39.Mohanty AK,Misra M,Hinrichsen G.Biofibres,biodegradable polymers and biocomposites:an overview.Macromol Mater Eng,2000,276-277:1-24
40.Lu LC,Mikos AG.Poly(lactic acid).In:Mark JE,editor.Polymer data handbook.Oxford:Oxford Press,1999,527-633
41.Martin C,Wirier H,Bao JY.Acidity near eroding polylactide-polyglycolide in vitro and in vivo in rabbit tibial bone chambers.Biomaterials,1996,17(24):2373 -2380
42.P.Maind-Varlet et al.Local infection resistance and mechanical properties of polylactide implant after experimental contamination.Society for Biomaterials,1998,April 22-26:245
43.Bergsma EJ,Rozema FR,Bos RRM,Debruijn WC.Foreign body reaction to resorbable poly(L-lactic) bone plates and screws used for the fixation of unstable zygomatic fractures.J Oral Maxillofac Surg,1993,51:666-670
44.Groot K De.Bioceramics of calcium phosphate.CRC Press:Boca Roton,FI,1983:31-34
45.Aoki H.Science and medical application of hydroxyapatite.JAAS Press,Tokyo,1991:367
46.Ducheyne P.Bioceramics:materials characteristics versus in vivo behavior.J Biomed Mater Res,1987,21:219-236
47.候文明等.羟基磷灰石复合材料的复合作用的研究.生物医学工程杂志,1995,12(2):182-185
48.高家诚等.激光制备生物陶瓷涂层种植体的生物学行为.材料工程,1994,6:16-18
49.G P A T Klein et al.Calcium phosphate plasma-spayed coating and their stability:in vivo study.J Biomed Mater Res,1994,28:909-917
50.M Shirkazadeh.Diffraction and fourier transform infrared analysis of nanophase apatite coating by electrocrystallization.NanoStructured Materials,1994,4(6):677-684
51.胡科军等.羟基磷灰石涂层种植体的生物学行为.国外医学生物医学工程分册,1999,22(4):228-232
52.K Park et al.Characteristics of carbon fibre-reinforced calcium phosphate composite fabricated by hot pressing.J Mater Sci Lett,1997,16:985-987
53.储成林等.羟基磷灰石(HA)生物复合材料的研究进展.材料导报,1999,13(2):51-54
54.欧玉春等.刚性粒子填充聚合物的增强、增韧与界面相结构.高分子材料与 工程,1998,14(2):12-15
55.C Doyle et al.An ultra-structured study of the interface between hydroxyapatite/polymers composite and bone.Advanced in Biomaterial,1990,9:239-245
56.严永刚,李玉宝,汪建新等.聚酰胺-66/羟基磷灰石复合材料的制备和性能研究.塑料工业,2000,28(3):38-40
57.Andrew SD,Phil GC,Marra KG.The influence of polymer blend composition on the degradation of polymer/hydroxyapatite biomaterials.J Mater Sci:Mater Med,2001,12:673 - 677
58.Deng X,Hao J,Wang C.Preparation and mechanical properties of nanocomposites of poly(D,L-lactide) with Ca-deficient hydroxyapatite nanocrystals.Biomaterials,2001,22:2867 - 73.
59.Kasaga T,Yoshio O,Masayuki N,Yoshihiro A.Preparation and mechanical properties of polylactide acid composites containing hydroxyapatite fibres.Biomaterials,2001,22:9 - 23
60.M Wang et al.Hydroxyapatite-polyethylene composites for substitution effect of ceramic particle size and morphology,Biomaterials,1998,19:2357-2366
61.Liu Q et al.Nano-apatite/polymer composite I:mechanical and physiochemical characteristics.The Fifth World Biomaterials Congress,1996:435
62.L L Hench,J M Polak.Third generation biomedical materials.Science,2002,295:1014-1017
63.Langer R,Vancanti J P.Tissue engineering.Science,1993,260:920
64.Williams D.Benefit and risk in tissue engineering.Mater Today,2004,7:24 - 9
65.L G Griffith,G Naughton.Tissue engineering-current challenge and expanding opportunities.Science,2002,295:1009-1014
66.C Mauli Agrawal,Robert B Ray.Biodegradable Polymeric Scaffolds for Musculoskeletal Tissue Engineering.J Biomed Mater Res,2001,55:141-150
67.Karen J L Burg,Scott Porter,James F Kellam.Biomaterial Developments for Bone Tissue Engineering.Biomaterials,2000,21:2347-2359
68.Johnna S Temenoff,Antonios G Mikos,Injectable Biodegradable Materials For Orthopedic Tissue Engineering.Biomaterials,2000,21:2405-2412
69.Catherine M Cowan,Chia Soo,Benjamin Wu et al.Evolving Concepts in Bone Engineering.Current Topics in Developmental Biology,2005,66:239-285
70.Vassilis Karageorgiou,David Kaplan.Porosity of 3D biomatedal scaffolds and osteogensis.Biomaterials,2005,26:5474-5491
71.K Rezwan,Q Z Chen,A R Boccaccini et al.Biodegradable and bioactive porous polymer/inorganic composite scaffold for bone tissue engineering.Biomaterials,2006,27:3413-3431
72.Mironov V,Viconti R P,Markwald R R.What is regenerative medicine?Emergence of applied stem cell and developmental biology.Expert.Opin.Biol.Ther.,2004,4(6):773-781
73.齐莉萍,戈峰.再生研究与再生医学.生命的化学,2003,23(3):201-203
74.徐迎新.再生医学与外科学研究.中华实验外科杂志,2004,21(2):133-134
75.孙雪,奚廷斐.生物材料和再生医学的进展.中国修复重建外科杂志,2006,20(2):189-193
76.Mano JF,Sousa RA,Boesel LF,Neves NM,Reis RL.Bioinert,biodegradable and injectable polymeric matrix composites for hard tissue replacement:state of the art and recent developments.Compos Sci Technol,2004,64:789 - 817
77.Heungsoo Shin,Seongbong Jo.Antonios G Mikos,Biomimetic materials for tissue engineering.Biomaterials,2003,24:4353-4364
78.M J Whitaker,R A Quirk,K M Shaksheff et al.Growth factor from tissue engineering scaffolds.Journal of Pharmacy and Pharmacology,2001,53:1427
79.Zhang S G.Fabrication of novel biomaterials through molecular self-assembly.Nat.Biotechnol.,2003,21(10):1171-1178
80.沈家骢.纳米生物医用材料.中国医学科学院学报,2006,28(4):472-474
81.Kitsch T,Nickel J,Sebald W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-Ⅱ.EMBO J,2000,9:3314-3324
82.Sascha Keller,Joachim Nickel.Thomas D Mueller,Molecular recognition of BMP-2 and BMP receptor IA.Nature Structure and Molecular Biology,2004,11(5):481-488
83.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-307
84.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomaterials,2003,24:2287-2293
85.王身国,蔡晴,吕泽,贝建中.组织工程中药物控制释放技术的应用研究.中国修复重建外科杂志,2001,15(5):280-285
1.DA Wahl,JT Czernuszka.Collagen-hydroxyapatite composites for hard tissue repair.European Cells and Materials,2006,11:43
2.宁聪琴.硬组织替换用羟基磷灰石复合材料的研究进展.生物医学工程学杂志,2003,20(3):550
3.葛建华,王迎军.可吸收性骨科材料类型及发展.生物医学工程学杂志,2004,21(1):151
4.张其清,任磊,王淳等.羟基磷灰石-胶原复合人工骨材料的研究.生物医学工程通报.1994;6(1):29
5.余英,朱明华,曾怡等.生物活性陶瓷人工骨复合材料的理化性能测试.职业卫生与病伤,2003,18(2):88
6.GB/T14233医用输液、输血、注射器具检验方法
7.GB/T16886医疗器械生物学评价
8.GB/T 16175医用有机硅材料生物学评价试验方法
9.中国药典,二部.1995
10.K.Rezwan,Q.Z.Chen,J.J.Blaker,Aldo Roberto Boccaccini.Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering.Biomaterials,2006,27:3413
11.Kikuchi M,Itoh S,Tanaka J et al.Self-organization mechanism in a bone-like hydroxyapatite/collagen nanocomposite synthesized in vitro and its biological reaction in vivo.Biomaterials,2001,22(13):1705
12.段友容,陈继镛,张兴栋.胶原作为骨修复材料的研究进展.材料导报,2001,15(10):47-49
13.张阳德,乐园,赵梓屹.羟基磷灰石骨修复材料.中国现代医学杂志,2006,16(1):72-75
14.杨洪,宁黔冀.生物硬组织材料羟基磷灰石--从天然到人工合成.生物学通报,2004,39(5):6-7
15.候文明等.羟基磷灰石复合材料的复合作用的研究.生物医学工程杂志,1995,12(2):182-185
16.欧玉春等.刚性粒子填充聚合物的增强、增韧与界面相结构.高分子材料与工程,1998,14(2):12-15
17.储成林等.羟基磷灰石(HA)生物复合材料的研究进展.材料导报,1999,13(2):51-54
18.R Z Wang et al.Synthesie of Nanophase of hydroxyapatite/collagen composite.J Mater Sci Lett,1995,1141:490
19.杨勤等.纤维蛋白粘合剂和羟基磷灰石微粒复合人工骨的制备和测试.生物医学工程杂志,1993,10(1):8-12
20.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
21.Alireza R,Kevin EH.Integrin subunits responsible for adhesion for human osteoblast-like cell to biomimetic peptid surfaces.J Orth Res,1999,17(4):615
22.Germer M,Kanse SM,Kirkdgaard T,et al.Kinetic analysis of integrin-dependent cell adhesion on vitrinectin-the irthivitory potential of plasminogen activator inhibitor-1 and RGD peptides.Eur J Biochem,1998,253(3):669
23.Yoshiba N,Yoshiba K,Nakamura H,et al.Immunoelectroncroscopic study of the localization of fibrionectin in the odontoblast layer of human teeth.Arch Oral Biol,1995,40(2):83
24.Howe A,Aplin AE,Alabari SK,et al.Integrin signaling and cell growth control.Carr Opin cell Biol,1998,10(2):220
25.徐彬等.羟基磷灰石种植体动物实验研究.口腔材料口腔器械杂志,1993,2(4):20
26.杨晓芳,奚廷斐.生物材料生物相容性评价研究进展.生物医学工程学杂志,2001,18(1):123-128
27.孙皎.生物材料和医疗器械的生物学评价.中国医疗器械杂志,2003,27(1):1-3,8
28.丁婷婷,章平,孙皎.生物材料引起机体炎症反应的研究进展.国外医学生物 医学工程分册,2005,28(5):23-26
29.刘欣,史弘道.医用生物材料血液相容性评价研究概况.透析与人工器官,2003,14(1):40-44
30.张真,卢晓风.生物材料有效性和安全性评价的现状与趋势.生物医学工程学杂志,2002,19(1):117-121
31.Wang X H.Progress in the research of bone substitutes.J Biomed Eng,2001,8(4):647-652
32.Chang Q,Shi Z L,Li C G.Study on degradation calcium polyphosphate fibers.Environmental Science,1997,1(2):52
1.Kirsch T,Nickel J,Sebald W.BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-Ⅱ.EMBO J,2000,9:3314-3324
2.Sascha Keller,Joachim Nickel.Thomas D Mueller,Molecular recognition of BMP-2 and BMP receptor IA.Nature Structure and Molecular Biology,2004,11(5):481-488
3.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992;32(2):160
4.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molecular,celluar and tissue strategies.to engineer human bone.Biomaterials,1996;17(2):175
5.Alam MI,Asahina I,Ohmamiuda K,et al.Evaluation of ceramics composed of different hydroxyapatite to tricalcium phosphate ration as carriers for rhBMP-2.Biomaterial,2001;22(12):643
6.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-3077
.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomaterials,2003,24:2287-2293
8.Ekelund A,Brosjo O,Nilsson OS.Experimental induction of heterotopic bone.Clin Orthop Relat Res,1991,263:102-112
9.Noshi T,Yoshikawa T,Ikeuchi M et al.Enhancement of the in vivo osteogenic potential of marrow/hydroxyapatite composites by bovine bone morphogenetic protein.J Biomed Mater Res,2000,52(4):621-630
10.Wlodarshi K H.Heterotopic bone marrow formation in xenogeneic implants of insoluble bone matrix gelatin.Clin Orthop Relat Res,1982,171:210-212
11.Katz RW,Hollinger JO,Reddi AH,et al.The functional equivalence of dematerialized bone and tooth matrices in ectopic bone induction.J Biomed Res,1993;27:239
12.陈德敏,刘雪阳,钱云芳.锶磷灰石多孔陶瓷复合成骨细胞的体内异位成骨 研究.生物医学工程与临床,2007,11(5):329-332
13.朱明华,曾怡,孙涛,彭蔷,林凡.生物陶瓷与细胞外基质对成骨细胞生长及代谢影响.北京生物医学工程,2005,24(1):17-23
14.朱明华,叶长宁,余英,曾怡,孙涛,彭蔷.生物活性陶瓷与细胞外基质形成对Ca、P、ALP影响.透析与人工器官,2004,15(1):1-5
15.Boyan BD,Savain LD,Schavartz et al.Epithlail cell line that induce bone formation in vivo produce alkaline phosphatase enriched matrix vesicles in culture.Clin Orthop,1992,277:266
16.Canalis E,The hormone and local regulation of bone formation.Endocrine Reviews,1983,4(1):62
17.Kabler N,Urist R.Cell differentiation in response to partially purified osteosarcoma-derived bone morphogenetic protein in vivo and in vitro.Clin Orthorp,1993,292:321
18.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992,32(2):160
19.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molcular,cellular and tissue strategies to engineer human bone.Biomaterials,1996;17(2):175
20.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
21.胡蕴玉.骨诱导及骨愈合分子生物学研究进展.中华骨科杂志,1997,17(1):17-19
22.Eric Hay,Monique Hott,Anne-Marie Graulet,et al.Effects of bone morphogenetic protein-2 on human neonatal calvaria cell differentiation.Journal of Cellular Biochemistry,1999,72:81-93
23.Wang E A,Rosen V D,Alessandro J S et al.Recombinant human bone morpbogenetic protein induce bone formation.Proc Natl Acad Sci USA,1990,87:2220
24.Yamagiwa H,Endo N,Tokunaga K,et al.In vivo bone-forming capacity of human bone marrow-derived stromal cells is stimulated by recombinant human bone morphogenetic brotein-2. J Bone Miner Metab, 2001, 19(1):20-8
25. Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nature Biotechnology, 1998, 16:247-252
26. Carl A, Kirker H. Potential applications and delivery strategies for bone morphogenetic proteins. Advanced Drug Delivery Reviews,2000,43:65
27. Soichiro Itoh, Masanori Kikuchi, et al. The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomatenal, and its function as a carrier of rhBMP-2. J. Biomed Mater Res, 2001, 54: 445-453
28. Toshiaki Noshi, Takafumi Yoshikawa, Yoshiko Dohi, et al. Recombinant human bone morphogenetic protein-2 potentiates the in vivo osteogenic ability of marrow/hydroxyapatite composites. Artificial Organs, 2001, 25(3): 201-208
29. Hasan Uludage, Darren D'Augusta, Janet Golden, et al. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers: A correlation between protein pharmacokinetics and osteoiduction in the rat ectopic model. J Biomed Mater Res, 2000, 50:227-238
30. Takaoka K, Nakahara H, et.al. Ectopic bone induction on and in porous hydroxyapatite combined with collagen and bone morphogenetic protein. Clin Orthop 1998, 234: 250-254
1.Carl A,Kirker H.Potential applications and delivery strategies for bone morphogenetic proteins.Advanced Drug Delivery Reviews,2000,43:65
2.Lind M.Growth factor stimulation of bone healing:An Effect on osteoblasts,Osteomies and implants fixation.Acta Orthop Scand Supple,1998;283:2
3.Mundy GR.Regulation of bone formation by bone morphogonic protein and other growth factors.Clin Orthop Relat Res,1996,324:24
4.徐彬.羟基磷灰石种植体的动物实验研究.口腔材料器械杂志,1993,2(4):20
5.杨志宏,郭沈波,王守彪等.甲壳质衍生物对新西兰兔骨缺损愈合相关血生化指标的影响.中国海洋药物,2003,22(6):10-13
6.朱明华,叶长宁,余英,曾怡,孙涛,彭蔷.生物活性陶瓷与细胞外基质形成对Ca、P、ALP影响.透析与人工器官,2004,15(1):1-5
7.周正新,丁锷,李保泉等.消瘀接骨散对骨折愈合相关生化指标的影响.中国骨伤,1998,11(1):19-21
8.朱明华,曾怡,孙涛,彭蔷,林凡.生物陶瓷与细胞外基质对成骨细胞生长及代谢影响.北京生物医学工程,2005,24(1):17-23
9.Boyan BD,Savain LD,Schavartz et al.Epithlail cell line that induce bone formation in vivo produce alkaline phosphatase enriched matrix vesicles in culture.Clin Orthop,1992,277:266
10.Canalis E,The hormone and local regulation of bone formation.Endocrine Reviews,1983,4(1):62
11.王华松,黄琼霞,许申明.骨碎补对骨折愈合中血生化指标及丁GF-β_1表达的影响.中医正骨,2001,13(5);6-8
12.张昌颖.生物化学.北京:人民卫生出版社,1987:589
13.朱明华等.生物材料及细胞外基质与骨形成研究进展.北京生物医学工程,2003,22(2):155-158
14.胡蕴玉.骨诱导及骨愈合分子生物学研究进展.中华骨科杂志,1997,17(1):17-19
15.Wozery JM The bone morphogenetic protein family and osteogenesis.Mol Reprod Dev,1992,32(2):160
16.Yaszemski MJ,Payne RG,Hayes WC,et al.Evolution of bone transplantation:molecular,cellular and tissue strategies to engineer human bone.Biomaterials,1996;17(2):175
17.Eric Hay,Monique Hott,Anne-Marie Graulet,et al.Effects of bone morphogenetic protein-2 on human neonatal calvaria cell differentiation.Journal of Cellular Biochemistry,1999,72:81-93
18.Wang E A,Rosen V D,Alessandro J S et al.Recombinant human bone morphogenetic protein induce bone formation.Proc Natl Acad Sci USA,1990,87:2220
19.Yamagiwa H,Endo N,Tokunaga K,et al.In vivo bone-forming capacity of human bone marrow-derived stromal cells is stimulated by recombinant human bone morphogenetic brotein-2.J Bone Miner Metab.2001,19(1):20-8
20.李文、岑远坤.骨缺损整复中的生长因子载体材料.中国口腔种植学杂志,1998,3(4):187
21.梁戈、胡蕴玉、郑昌群等.多孔β-TCP/BMP复合人工骨的研制和动物体内的相关研究.中华骨科杂志,1995,18(2):75
22.Alam,Asahina I,Ohmamiuda K.et al.Comparative study of biphasic calcium phosphate ceramics impregnated with rhBMP-2 as bone substitutes.J Biomed Mater Res,2001,54(1):129
23.Reddi AH.Role of morphogenetic proteins in skeletal tissue engineering and regeneration.Nature Bioteclanology,1998,16:247-252
24.杨志明.生物技术的综合应用促进组织工程学发展.中国修复重建外科杂志,2007,21(2):107-109
25.边卫国,彭磊,梁芳慧,徐华梓.骨形态发生蛋白复合明胶羟基磷灰石多孔钛修复骨缺损的实验研究.中华创伤骨科杂志,2007,9(6):550-554
1.Langer R,Vancanti J P.Tissue engineering.Science,1993,260:920
2.Williams D.Benefit and risk in tissue engineering.Mater Today,2004,7:24-9
3.L G Griffith,G Naughton.Tissue engineering-current challenge and expanding opportunities.Science,2002,295:1009-1014
4.C Mauli Agrawal,Robert B Ray.Biodegradable Polymeric Scaffolds for Musculoskeletal Tissue Engineering.J Biomed Mater Res,2001,55:141-150
5.Karen J L Burg,Scott Porter,James F Kellam.Biomatedal Developments for Bone Tissue Engineering.Biomatedals,2000,21:2347-2359
6.Johnna S Temenoff,Antonios G Mikos,Injectable Biodegradable Materials For Orthopedic Tissue Engineering.Biomaterials,2000,21:2405-2412
7.Catherine M Cowan,Chia Soo,Benjamin Wu et al.Evolving Concepts in Bone Engineering.Current Topics in Developmental Biology,2005,66:239-285
8.Vassilis Karageorgiou,David Kaplan.Porosity of 3D biomaterial scaffolds and osteogensis.Biomatedals,2005,26:5474-5491
9.K Rezwan,Q Z Chen,A R Boccaccini et al.Biodegradable and bioactive porous polymer/inorganic composite scaffold for bone tissue engineering.Biomaterials,2006,27:3413-3431
10.M J Whitaker,R A Quirk,K M Shaksheff et al.Growth factor from tissue engineering scaffolds.Journal of Pharmacy and Pharmacology,2001,53:1427
11.S Kamakura,S Nakajo,O Suzuki et al.New scaffold for recombinant human bone morphogenetic protein-2.J Biomed Mater Res,2004,71A:299-307
12.Naoto Saito,Kunio Takaoka.New synthetic biodegradable polymers as BMP carriers for bone tissue engineering.Biomatedals,2003,24:2287-2293
13.王身国,蔡晴,吕泽,贝建中.组织工程中药物控制释放技术的应用研究.中国修复重建外科杂志,2001,15(5):280-285
14.Kuboki Y,Takita H,Kobayashi D et al.BMP-induced osteogenesis on the surface of hydroxyapatite with geometrically feasible and nonfeasible structures:topology of osteogenesis.J Biomed Mater Res,1998,39:190-199
15.Gren D,Walsh D et al.The potential of biominesis lessons from the design and synthesis of invertebratein bone tissue engineering:skeletons.Bone,2002,30(6):810-815
16.Eggli PS,Muller W,Schenk RK.Porous hydroxyapatite and tricalcium phosphate cylinders with two different pore size ranges implanted in the cancellius bone of rabbits:A comparative histomorphometic and histologic study of bony ingrowth and implant substitution.Clin Orthop,1988,232:127-138
17.Zhang RY,Ma PX,Poly(α-hydroxyl acids)/hydroxyapatite porous composites for bone-tissue engineering:I.Preparation and morphology.J Biomed Mater Res,1999,44:446-455
18.Zhang Y,Zhang M.Synthesie and characterization of macroporous chitosan/calcium phosphate composite scaffolds for tissue engineering.J Biomed Mater Res,2001,55:304-312
19.Madihally SV,Mathew HW.Porous chitosan scaffolds for tissue engineering.Biomaterials,1999,20:1133-1142
20.Kang H W,Tabata Y,Ikata Y.Fabrication of porous gelatin scaffolds for tissue engineering.Biomaterials,1999,20:1339:1344
21.张其清;医用胶原及胶原基材料的研究,天津大学博士论文,1998
22.J S Pieper,A Oosterhof,T H van Kuppevelt,et al.Preparation and characterization of porous crosslinked collagenous matrices containing bioavailable chondroitin sulphate.Biomaterials,1999,20:847-858
23.P.B.van Wachem,J.A.Plantinga,M.J.B.Wissink,et.al.In vivo biocompatibility of carbodiimide-crosslinked collagen matrices:effects of crosslink density,heparin immobilization,and bFGF loading.J.Biomed Mater Res,2001,55(3):368-378
24.Hongyi Yang,Qiqing Zhang.Preparation and characterization of collagen-GAGs bioactive materials for tissue engineering.J Mate Sci Technol,2001;17(5):495-500
25.Yasuhiko Tabata.Tissue regeneration based on growth factor release.Tissue Engineering,2003,9(suppl,1):S5-15
26.Bodmeier,H.G.Chen,O.Paeratakul.A novel approach to the oral delivery of micro-or nanoparticles.Pharm.Res.,1989,6(5):413-7
27.K.A.Janes,P.Calvo,M.J.Alonso.Polysaccharide colloidal particles as delivery systems for macromolecules.Adv.Drug.Deliv.Rev.,2001,47:83-97
28.O.Felt,P.Buri,R.Gurny.Chitosan:A unique polysaccharide for drug delivery.Drug.Dev.Ind.Pharm.,1998,24(11):979-93
29.A.K.Singla and M.Chawla.Chitosan:some pharmaceutical and biological aspects -an update.J.Pharm.Pharmaco.,2001,53:1047-67
30.F.L.Mi,S.S.Shyu,C.T.Chen et al.Porous chitosan microsphere for controlling the antigen release of Newcastle disease vaccine:preparation of antigen-adsorbed mierosphere and in vitro release.Biomaterials,1999,20:1603-12
31.R.Fernandez-Urrusuno,P.Calvo,C.Remunan-Lopez et al.Enhancement of nasal absorption of insulin using chitosan nanoparticles.Pharm.Res.,1999,16(10):1576-81
32.A.M.Dyer,M.Hinchcliffe,P.Watts et al.Nasal delivery of instulin using novel chitosan based formulations:.A comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles.Pharm.Res.,2002,19(7):998-1008
33.R.Hejazi,M.Amiji.Stomach-specific anti-H.pylori therapy.I:preparation and characterization of tetracycline-loaded chitosan microspheres.Int.J.Pharm.,2002,235:87-94
34.A.Vila,A.Sanchez,M.Tobio et al.Design of biodegradable particles for protein delivery.J.Control.Rel.,2002,78:15-24
35.K.A.Janes,M.P.Fresneau,A.Marazuela et al.Chitosan nanoparticles as delivery systems for doxorubicin.J.Control.Rel.,2001,73:255-67
36.Z.Ma,H.H.Yeoh,L.Y.Lim.Formulation ph Modulates the Interaction of Insulin with Chitosan Nanoparticles.J.Pharm.Sci.,2002,91(6):1396-404
37.A.Fernandez,M.Jose.Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms.EP 0 860 166 A1
38.X.Z.Shu,K.J.Zhu.Controlled drug release properties of ionically cross-linked chitosan beads:the influence of anion structure.Int.J.Pharm.,2002,233:217-25
39.X.Z.Shu,K.J.Zhu.A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery.Int.J.Pharm.,2000,201:51-8
40.H.Zhang,I.Alsarra,S.H.Neau.An invitro evaluation of a chitosan-containing multiparticulate system for macromolecule delivery to the colon.Int.J.Pharm.,2002,239:197-205
41.Yongmei Xu,Yumin Du.Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles.Int.J.Pharm.,2003,250:215-26
42.A.Berthold,K.Cremer,J.Kreuter.Preparation and characterization of chitosan microspheres as drug cartier for prednisolone sodium phosphate as model for antiinflammatory drugs.J.Control.Rel.,1996,39:17-25
43.S Yokota,T Uchida,et al.Release of recombinant human bone morphogenetic protein 2 from a newly developed carrier.Int J Pharrna,2003,251(1-2):57-66
44.H Uludag,D D'Augusta,et al.Implantation of recombinant human bone morphogenetic proteins with biomatedals carriers:A correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model.J Biomed Mater Res,2000,50(2):227-38
45.W Friess,H Uludag,et al.Characterization of absorbable collagen sponges as recombinant human bone morphogenetic protein-2 carriers.Int J Pharm,1999,185(1):51-60
46.M Yamamoto,Y Tabata,Y Ikada.Ectopic bone formation induced by biodegradable hydrogels incorporating bone morphogenetic protein.J.Biomater.Sci.Polymer Ecin.1998,9(5):439-58
47.S Yokota,S Sonohara,M.Yoshida,et al.A new recombinant human bone morphogenetic protein-2 cartier for bone regeneration.Int.J.Pharm.,2001,223:69-79
48.J Ziegler,U Mayr-Wohlfart,S Kessler,et al.Adsorption and release properties of growth factors from biodegradable implants.J Biomed Mater Res.2002,59:422-8
49.H Uludag,D D'Augusta,R Palmer,et al.Characterization of rhBMP-2pharmacokinetics implanted wih biomaterial carriers in the rat ectopic model.J Biomed Mater Res, 1999,46:193-202
50. J Louis-Ugbo, HS Kim, S D Boden, et al. Retention of ~(125)I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model. J Orthopaedic Research. 2002,20:1050-9
51. R Talwar, L De Silvto, F J Hughes, et al. EfiFects of carrier release kinetics on bone morphogenetic protein-2-induced periodontal regeneration in vivo. J Clin Periodontol. 2001, 28:340-7