聚乳酸类缓释型支架材料的研究与应用意义_英文__cropped

聚乳酸类缓释型支架材料的研究与应用意义_英文__cropped 9 卷 第 46 期 2005- 12- 14 出版 第 中国临床康复Chinese Journal of Clinical Rehabilitation,December 14 2005 Vol. 9 No. 46 178 ?REVIEW? Significance of the application of polylactic acid ?sustained-r elease scaffold9 Hu Ji-jie , Pe i Guo-xia n Department of Traumatic Orthopaedics, Nanfang Hospital, Southern Medi- fold and sustained-release drug carrier. PLA is the earliest scaf- cal University, Guangzhou 510515, Guangdong Province, China folds material applied in bone and cartilage tissue-engineering, and [2]Hu Ji-jie ?, Master, Physician, Department of Traumatic Orthopaedics, also the most widely used tissue-engineering material at present . Nanfang Hospital, Southern Medical University, Guangzhou 510515, PLA sustained-release scaffold is at present the interest in tissue- Guangdong Province, China engineering scaffold researches. In this article, the author reviews Suppor ted by: the National 863 Plan Program, No. 2003AA20500S1 the research progress in this domain by summarizing the related Received: 2005- 05- 20 Accepted: 2005- 08- 01 (03 /GW) articles published between 1993 and 2004 retrieved from the Med- Abstr act line database and Chinese Periodical Database. OBJ ECTIVE: Polylactic acid (PLA) is a biodegradable polymer possess- ing good biocompatibility and biodegradability, and approved as a biomate- PLA MATERIALS FOR TISSUE-ENGINEERING SCAF- rial for in vivo implantation by American Food and Drug Administration FOLD (FDA). The role of cytokines in promoting osteogenesis and vascularization Commonly used PLA products consist of poly-D, L-lactic acid for constructing tissue-engineered bones has received increasing attention. (PDLLA) and poly-L-lactide (PLLA), which are respectively syn- But exogenous cytokine has shorter half-life in vivo and can not reach and thesized by the mesomer and L-isomer of lactic acid or lactide, and maintain relatively high local level for bone repair. This article reviews the the higher the molecular weight of PLA, the better the mechanical present researches and analyzes the application prospect of PLA and its derivatives in bone tissue engineering to serve as the carrier for polypep- performance. tide and protein medicines with controlled release through its degradation. The aperture and porous rate are two main parameters for evalua- DATA SOURCES: Related articles published between 1993 and 2004 tion of bone tissue-engineering scaffold material, and also the focus were searched in Medline database with key words of “polylactic acid, of wide attentions. The manufacture technology of PLA is develop- bone morphogenetic protein, vascular endothelial growth factor, TGF- be- ing towards controllability of the aperture and porous rate. What ta”, limiting the language to Englishf meanwhile the related medical papers size of aperture is suitable is still in controversial at present. In a between 1993 and 2004 were also searched in the Chinese Periodical Database, limiting the language to Chinese. cell suspension, the diameter of an osteoblast is approximately 20 STUDY SELECTION: Related researches on PLA and its derivatives for μm and increases to 30 μm after cell attachment, so that an os- constructing bone tissue-engineering Scaffolds and study of PLA scaffolds 2teoblast occupies an area of about 700 μm, and it is generally carrying cytokines were included with the obsolete literature and repetitive held that an aperture of less than 100 μm is unfit for bone growth. researches eliminated. [3] Robinson et albelieved that the aperture of 200- 300 μm bene- DATA EXTRACTION: Altogether 96 related literatures on PLA and its fits mediated bone growth. The porous rate should be as large as derivatives for constructing bone tissue-engineering scaffolds were collect- possible on the basis of maintaining certain configuration to meet ed, 23 of which were included in this review. the need of cell implantation, and the conventional cell implanta- DATA SYNTHESIS: PLA /PLA-polyglycolic acid copolymer is a good biodegradable scaffold for controlled drug release, having the dual func- tion can be successful only with materials with porous rats of above tions as scaffolds and sustained-release drug carrier. PLA is the earliest 75%. scaffold material in bone and cartilage tissue-engineering, and also the As a tissue-engineering bone scaffold material, good mechanical most widely used tissue-engineering material at present. BMP is the most performance and structural compatibility of PLA material is far frequently adopted cytokine in bone tissue-engineering, and PLA scaffolds from being everything for actual application, and further exploration carrying sustained-release BMP is studies most thoroughly, but researches of its degradability and acidic degradation products is necessary. on PLA scaffolds carrying vascular endothelia growth factor has not been Degradability is the basic property of PLA and polyglycollide ma- conducted. CONCLUSION: Development and application of PLA scaffolds carrying terials, which relied mainly on the hydrolysis of the ester bond, but various sustained-release cytokines has become the new interest in bone less on non-specific enzyme hydrolysis. The hydrolysis rate is de- tissue-engineering researches. cided predominantly by the crystallinity and hydrophobicity of the monomer components, which also mediate the actions of other fac- Hu JJ, Pe i GX.Significa nce of the a pplica tion of polyla ctic a cid susta ine d-re le a se tors and may produce some negative effects. Degradation of thin and sca ffold.Zhongguo Linchuang Kangfu 2005B9(46):178 -90(China ) porous PLA and glycollide is obviously quicker than that of thick [www.zglckf.com] blocks of materials, but PLA-polyglycolic acid copolymer (50:50) with low porous rate shows rapid degradation rate than those with INTRODUCTION high porous rate, possibly because the local acid degradation prod- Tissue-engineering is a developing interdisciplinary subject linking [1]ucts can be rapidly removed with higher porous rate. In order to material science with biotechnology and life sciences , and pro- control the acidification of the local microenvironmental, basic salt vides a promising method for clinical repair of bone damage, bone to counter acid degradation product showed good effect as ob- tumor as well as refractory bone fracture. The role of cytokines in [4]served by Agrawal et al . tissue-engineered bone construction has received increasing atten- Good cytocompatibility is the basic requirement of tissue engi- tion. The copolymer of polylactic acid (PLA) and polyglycolic acid neering materials. Massive researches indicate that the surface is degradable material with good biocompatibility, whose degrada- physiochemical properties (such as surface energy, surface hy- tion is attributed to the unstable chemical bonds in the molecules drophilia and hydrophobicity, superficial electric charge, surface that are liable to hydrolysis or enzymolysis, therefore PLA /PLA- chemical structure and so on) and material surface topological polyglycolic acid copolymer is recognized as a better biodegradable structure remarkably affect such cell behaviors as attachment, controlled-release scaffold, possessing dual functions of both scaf- spread, and growth on the material surface. Most in vitro cultured releases by using mineralized PLA and polyglycolic acid copolymer foaming /granule filtration technology to as VEGF carrier and gas cells show wall-adhering growth behavior. Biological researches show that the adhering cells express integrin receptors on the cell produce three-dimensional porous scaffolds. membrane that specifically recognize the growth factors, adhering Researches on PLA scaffolds carrying VEGF is still in its infancy factors and hormones in the extracellular matrix, which mediate and animal experiments, especially bone damage repair experiment cell adhesion to the basal material surface for their spread and with big animals have not been reported. Recently it was reported split. Bioactive bonded substances on the surface of high polymer that subcutaneous transplantation of hydrogel matrix material con- biomaterials such as polypeptide, polysaccharide and vitamins can structed with synthesized amino acid-modified PLA carrying VEGF effectively increase cell adhesion to the biomaterial. Arginine- 121 and VEGF165 in rats was capable of releasing VEGF neces- glycine-aspartic acid peptide existing in extracellular matrix pro- sary for the growth of the local cells to promote the formation of teins is at present the most intensively studied material for promot- vascularized tissues, and this material was believed to possess the [14]ing cell adherence. The development of PLA-amino acid copolymer clinical potential for local vascularization. The interactions be- meets right the requirement of tissue engineering. On one hand, tween VEGF and other biological factors in tissue-engineering polyamino acid has good biocompatibility and biodegradability, its bone are still not clear. Some reports suggest that VEGF and degradation products is free of toxicity and the introduction of BMP4 may cooperatively participate in fracture repair and recon- amino acid side chains provides the means for regulating degener- struction through various mechanisms under appropriate density [15]ation of the PLA materiaSl On the other hand, amino acid chains proportion . contain reactive functional side group such as -NHand -COOH Tr ansfor ming gr owth factor β(TGF-β) 2 which facilitate the fixation of bioactive molecules such as pro- TGF-βis a member of the transforming growth factor-βsuperfami- teins, carbohydrates, and polypeptides to improve the interaction ly, which consists of actin, BMP, growth differentiation factor, between the material and the cells. TGF-βand so on and can modulate the growth and differentiation of various cells including osteoblasts. TGF-βis one of the major bone growth factors capable of inducing mesenchymic cell synthe- PLA SCAFFOLD MATERIAL CARRYING CYTOKINES sis of cartilage-specific protein polyose and type II collagen and mor phogenic pr otein (BMP) Bone [16]BMP is a bone growth factor in early studies, whose osteogenetic stimulating osteoblast proliferation and collagen synthesis . The [5] effect has been confirmed in many researches. Agrawal et al and chondrocytes and osteoblasts can secret TGF-βas proved by in [6] Zellin et al investigated PLA and polyglycolic acid copolymer as vitro experiment, and massive TGF-β accumulation may occur[17]BMP carrier with animal experiment for its degradation, BMP re- during cartilage osteogenesis suggesting the important role of ,TGF-βfor osteogenesis and chondrogenesis. TGF-βis mainly di- lease rate and bone damage repair and found that PLA and polyg- vided into 5 subgroups, named from TGF-β1 to TGF-β5, of which [7] lycolic acid copolymer was an effective BMP carrier. Saito pre- TGF-β1, 2, and 3 play vital roles in bone metabolism modulation. pared polymers with PLA and polyglycolic acid mixed at different TGF-β1 and TGF-β2 are secreted by osteoblasts and integrated proportions as recombinant human BMP2 carrier and found that into the bone matrix. Initially synthesized TGF-βis a long single- their osteogenetic capability varied with the molecular weight and strand polypeptide molecule without activity but can be activated proportion of PLA and polyglycolic acid, amongst which lactic acid by proteinase and acidic condition. Most of TGF-βin the bone -650 / polyglycolic acid-3000 was the best BMP sustained-release matrix exists as the inactive precursor, along with only small [8] carrier. Oldham et al also conducted in vitro studyof PLA and amount of activated TGF-β. When osteoclasts dissolve the bones polyglycolic acid copolymer and proved that recombined human the acidic environment at the brush border activates TGF-β. TheBMP2 encapsulated by PLA and polyglycolic acid copolymer can be released slowly and continuously to maintain the local effective plasminogen activation factor produced by the osteoblasts can acti- vate fibrinolysin, and fibrinoclase may activate TGF-βthrough pro- concentration and its bioactivity. In canine models of 2 cm radius [18][9] teolysis . damage, Hu et al used hydroxyl apatite /PLA scaffolds as BMP Many hormones and cytokines can affect TGF-βsecretion. In vitro carrier and believed that BMP not only accelerated bone regenera- experiment indicates that vitamin D3 and estrogen can stimulate tion, but also promoted scaffold degradation. Optimization of the rat osteoblasts to secrete TGF-β, but they both can also reduce three-dimensional structure of the scaffold material may signifi- TGF-βcontent in the bone cortex in vivoS androgen and parathy- cantly enhance the osteogenetic bioactivity. roid hormone can increase TGF-βcontent in human osteoblasts, Vascular endothelial gr owth factor (VEGF) and BMP2 may induce human osteoblasts to express TGF-β, which VEGF is a protein firstly purified from in vitro culture medium of can induce osteoblastic expression and BMP2 expression in os- bovine follicle stellate cells in 1989 by Ferrara et al, which is a teoblasts to enhance the osteogenetic capability. These two factors multi-functional cytokine mainly display two kinds of bioactivity, constitute positive feedback during bone fracture to enhance osteo- namely promoting vascularization and increasing vascular perme- genesis. TGF-βcan induce BMS differentiation into osteoblasts by ability, thereby leading to vascularization. VEGF receptor only ex- increasing ILGF- I mRNA expression. It has been reported that re- ists on vascular endothelia cells, but many cells including os- [10]combinant human BMP2 and TGF-βcan promote the proliferation .teoblasts can synthesize VEGF VEGF can be divided into 5 [19]and differentiation of rabbit BMSCs in vitro . subgroups, namely VEGF 206, VEGF 189, VEGF 165, VEGF 123 Animal experiments of incorporation of TGF-βand BMP into PLA and VEGF 121. In clinical practice, VEGF has been used for pro- scaffolds for repairing bone damage revealed that the local appli- moting wound repair and healing, as well as in treating limb is- cation of exogenous TGF-βand BMP could promote callous forma- chemia and cardiovascular diseases. VEGF and bFGF can promote [11][12] tion and enhance bone biomechanical property after healing. TGF-β the vascularization in ischemic tissues. Elcin et alattempted to proves to produce better effect than BMP, and combined applica- prepare microspheres containing VEGF to construct a sustained-re- tion is even better, suggesting their cooperation in promoting frac- lease system for implantation in rats, and proved that VEGF could [20] ture healing. Yang et alused decalcified porcine bone as scaf- obviously accelerate local vascularization, which shed light on the folds to carry TGF-β, BMP and WO-1 for animal bone damage re- promising prospect of VEGF in tissue-engineering osseous vascu- [13] pair. Earlier researches also proved TGF-βinduced ectopia osteo- larization. Murphy et alalso investigated the dynamics of VEGF ISS N 1671- 5926 CN 21- 1470 /R www.zglckf.com 中国临床康复 2005 年 12 月 14 日 第 9 卷 第 46 期 180 [21]glycol block copolymers as a BMP delivery system for inducing bone.J genesis only in the presence of BMP . Bone Joint Surg Am 2001r83-A Suppl 1(Pt 2):S92- 8 Other factor s 8 ldham JB,Lu I,Zhu X,et al.Biological activity of rhBMP-2 released from ; PLGA microspheres.J Biomech Eng 2000122(3):289- 92 There are still some other cytokines for use in PLA sustained-re- 9 Hu YY, Zhang C, Lu R, et al.Repair of radius defect with bone-morpho- genetic-protein loaded hydroxyapatite/ collagen-poly(L-lactic acid) composite. lease scaffolds. Insulin-like growth factor, including ILGF-? and Chin J Traumatol 2003r6(2):67- 74 ILGF-?, is the major cytokine with the highest content in the 10 Goad DL,Rubin J,Wang H,et al.Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts bone matrix, and the bioactivity of ILGF-? is stronger than ILGF- ; induced by insulin-like growth factor I.Endocrinology 1996137(6):2262- 8 11 Nomi M, Atala A, Coppi PD, et al. Principals of neovascularization for tis- ?. ILGF mainly influence bone growth and repair by stimulating sue engineering.Mol Aspects Med 2002r23(6):463 -83 osteoblast proliferation and can prevent collagen fiber decomposi- 12 Elcin YM, Dixit V, Gitnick G.Extensive in vivo angiogenesis following con- trolled release of human vascular endothelial cell growth factor: implica- tion by promoting collagen synthesis in the osteoblasts. Fibroblasts tions for tissue engineering and wound healing.Artif Organs 2001r25 (7): growth factor is a growth factor capable of promoting cell mitosis in 558- 65 13 Murphy WL, Peters MC, Kohn DH,et al. Sustained release of vascular en- mesoderm and neural ectoderm, which is divided into 7 subgroups, dothelial growth factor from mineralized poly (lactide-co-glycolide) scaffolds for tissue engineering.Biomaterials 2000r21(24):2521 -7 among which FGF 2 is the most important. FGF is capable of pro- 14 Zisch AH, Lutolf MP, Ehrbar M, et al. Cell-demanded release of VEGF moting vasogenesis to promote osteoblast growth by promoting from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth.FASEB J 2003r17(15):2260 -2 growth of the blood vessels into the implanted tissue in bone tissue 15 Peng H, Wright V, Usas A, et al. Synergistic enhancement of bone forma- [22]tion and healing by stem cell-expressed VEGF and bone morphogenetic engineering . bFGF can remarkably promote cell adherence and protein-4.J Clin Invest 2002r110(6):751 -9 osteoblast bonding to the scaffold materials even at very low levels 16 Centrella M, McCarthy TL, Canalis E.Skeletal tissue and transforming growth factor beta.FASEB J 1988r2(15):3066 -73 (0 - 10 g /L). It was also reported that 10 g /L bFGF could in- μμ17 Robey PG,Young MF,Flanders KC, et al.Osteoblasts synthe-size and respond [23]to transforming growth factor-βinvitro.J Cell Biol 1987r105(7):457 -63 crease endothelial cell adherence to PLA materials . Platelet-de- Bonewald LF, Dallas SL. Role of active and latent transforming growth fac- 18 riving growth factor, one of the earliest cytokines activated during tor beta in bone formation.J Cell Biochem 1994; 55:357- 67 Hu Q,Ai YF,Xong M,et al.The effect of rhBMP-2 and TGF-β on the dif- 19 bone fracture, has gained attention in tissue engineering. ferntiation and proliferation of cultured rabbit bone marrow stromal cell. Zhongguo Meirong Yixue (中国美容医学)2001r10(3):185 -8 Yang ZM,Li YB,Qin TW,et al.Ectopic Osteogenesis of Tissue Engineered 20 Bone with Slow-released Bioactive Factors.Zhongguo Yixue Kexueyuan Xue- PROSPECTS bao (中国医学科学院学报) 2003r(25)1:2- 7 Roberts AB,Sporn MB,Assoian RK,et al.Transforming growth factor type be- In summary, PLA sustained-release scaffold has promising prospect 21 ta:rapid induction of fibrosis in vitro and stimulation of collagen formation in tissue engineering due to its peculiar advantages. Although such in vitro.Proc Natl Acad Sci USA 1986r83(12):4167 Zelin G,linde A.effects of recombinant human fibroblast growth factor-2 or- materials possess disadvantages such as poor strength, acid 22 thopic osteogenesis in vivo. Bone 2000; 26:161- 8 Zheng L,Wang Q,Pei XG,et al. The influence of basic fibroblast growth metabolic products, and likeliness of inducing aseptic inflamma- 23 factor on the adhension of osteoblasts to the porous biomaterial.Xiandai tion, they have good biocompatibility and degradability and are 现代康复Kangfu () 2001r8(5):42- 3 easy to prepare. The strength of the scaffold material can be en- hanced by modifying the molecular weight. At present consensus has been reached that the cytokine release can be controlled by diffusion, and the microstructure of growth factor carrier material ?聚乳酸类缓释型支架材料的研究与应用意义 ‘(for example aperture, porous connection degree, porous straining and so on) has important influence on the stability and controlled- 胡稷杰 , 裴 国 献 ( 南 方 医 科 大 学 南 方 医 院 创 伤 骨 科 , 广 东 省 广 州 市 release of the growth factors. The aperture and porous rate of PLA 510515) 胡稷杰, 男, 年生, 江西省景德镇市人, 汉族, 年南方医科大 ?1979 2005 controlled-release scaffold material can be controlled by different 学毕业, 硕士, 医师, 助教, 主要从事骨组织工程的研究。processing techniques, and its poor hydrophilia can be managed by 国家八六三计划项目( ) 2003AA205001‘introducing amino acid side chain into the molecule. In general, 摘要PLA controlled-release scaffolds have incomparable merits over 目的: 聚乳酸是具有良好的生物相容性和生物降解特性的聚合物,是美 other inorganic scaffolds material. 国食品和药品管理局( FDA) 认可的一类可植入体内的生物材料。细胞 因子在组织工程骨构建中的促进成骨、血管化等作用越来越受到广泛 Researches on controlled-release scaffold material carrying cy- 关注。但外源性细胞因子在体内半衰期较短, 不能在骨修复局部聚集和 tokines should be intensified. In spite of the progress in researches 保持相对较高浓度。主要分析聚乳酸及其衍生化合物材料可作为多肽 of BMP and other osteogenetic factors incorporated in PLA scaf- 及蛋白质类药物的载体, 通过其自身降解来调节药物释放, 用于骨组织 工程研究的研究现状与应用前景。 folds material, most of these studies examined only single factors, 资料来源: 应用计算机检索 Medline 1993/ 2004 文章, 检索词为“polylac- and researches on VEGF and other cytokines capable of promoting tic acid, bone morphogenetic protein, vascular endothelial growth factor, vascularization of tissue-engineering bone scaffolds have been in TGF-β”, 限定语言 English; 检 索 中 国 期 刊 网 1993/ 2004 医 药 卫 生 类 文 their infancy. The composition technique of various factors and 章, 限定语言种类中文。scaffolds, appropriate cytokine concentration, examination of the 资料选择: 纳入标准: ?有关聚乳酸及其衍生物构建骨组织工程支架的 release dynamics, activity maintenance of the factors, appraisal of 研究。?聚乳酸类支架负载细胞因子研究。排除标准: ?陈旧文献。? 重复研究。material biological safety, and future clinical trials, marketing and 资料提炼: 共收集到 96 篇与聚乳酸组织工程支架相关文献, 其中 23 篇 industrialization of the research results all deserve careful consid- 纳入引用。 eration. Development and application of PLA scaffold material ca- 资料综合: ?聚乳酸 / 聚乳酸和聚羟基乙酸的共聚物是一种良好的可生 pable of sustained release of cytokines should become the hot spot 物降解的控释骨架,且具有支架和缓释的双重作用。聚乳酸是最早作为 in bone tissue-engineering. 骨、软骨组织工程的支架材料,也是目前运用最广泛的骨组织工程材。? 骨形态发生蛋白是应用于骨组织工程最多的因子, 负载、缓释骨形态发 生蛋白的聚乳酸类支架研究最为深入, 未见血管内皮生长因子负载于 REFERENCES 聚乳酸类支架材料研究。1 Langerr, Vacanti JP.Tissue engineering.Science 199; 2603:920-6 RA, Chan WC, Davies MC,et al.poly (l-lysine)-GRGDSas abiomimetics urface Quirk 2 结论: 对于可缓释多种因子的聚乳酸类支架材料的开发与应用已经成 modifier for poly(lactic acid).Biomaterials 200; 221(8):865-972 为骨组织工程支架新的热点。 Robinson BP,Hollinger JO,SzachowiczEH ,et al.Calvarial bone repair with porous D. 3 L Polylactide.OtalaryngoHl ead Neck Surg 1995n1126:707 -13 主题词 : 迟 效 制 剂 ; 聚 合 物 / 代 谢 ; 聚 羟 基 乙 酸 / 代 谢 ; 聚 乳 酸 / 代 谢 ; 支 4 Agrawal CM,Athanasoiu KA.Technique to control PH in vicinity of biodegrading 架; 生物降解; 细胞因子类 ; PLA-PGA implants.J Biomed MaterRes 199738(2):105-14 中 图 分 类 号 : 文 献 标 识 码 : 文 章 编 号 : R493 B 1671 - 5926 (2005)46 - 0178 - 035 Agrawal CM,Best J,HeckmanJD ,et al. 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