(3.230.173.249) 您好!臺灣時間:2021/04/18 08:33
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:范國榮
研究生(外文):Kuo-Rung Fan
論文名稱:聚噁唑啉與聚乳酸三團聯共聚物的降解行為探討
論文名稱(外文):Enzymatic Degradation Behaviour of Poly(2-ethyl-2-oxazoline)/Poly(L-lactide) Triblock Copolymers
指導教授:薛敬和薛敬和引用關係
指導教授(外文):Ging-Ho Hsiue
學位類別:碩士
校院名稱:國立清華大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:86
中文關鍵詞:三團聯共聚物聚乳酸聚噁唑啉酵素降解
外文關鍵詞:triblock copolymerpoly(L-lactide)poly(2-ethyl-2-oxazoline)enzymatic degradationproteinase K
相關次數:
  • 被引用被引用:1
  • 點閱點閱:131
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
本研究先合成聚乳酸(poly(L-lactide), PLLA)為A,聚噁唑啉(poly(2-ethyl-2-oxazolne), PEOz)為B鏈段的ABA三團聯共聚物,藉由調整PLLA與PEOz單體的進料比例可得到各種不同親疏水性質的高分子,然後再將高分子以澆鑄方式製作成薄膜在proteinase K酵素的催化下進行降解,並分別針對薄膜與降解產生殘餘物的成分與性質詳細分析。主要的目的是對此三團聯共聚物的降解行為作一詳盡的探討,並且利用三團聯共聚物特殊的微相分離結構,加上PEOz與PLLA相異的親疏水性質,希望能夠透過降解快速移去其中一鏈段,留下具有高度規則的奈米結構。
因此,薄膜降解過程的重量與含水率皆有秤重紀錄,結果發現含水率與重量損失速率成正相關;而凝膠滲透層析儀記錄了分子量與分子量分佈的變化,顯示降解是由小分子開始;而從質子核磁共振光譜儀分析的薄膜成分組成可得知,降解初期主要流失的成分以PEOz為主,接著PEOz與PLLA再以固定的比例流失;以掃瞄式電子顯微鏡觀察薄膜表面與截面的形態變化可得知,與空氣接觸之薄膜表面以及與鐵氟龍面板接觸之底面有相異的形態變化,空氣面相較於鐵氟龍面較容易被分解,而且降解後留下許多的微米級多孔性粒子,此外,薄膜內部產生了許多孔徑相近並分佈均勻的孔洞;熱微差掃瞄卡計則是觀察到降解過程中薄膜的結晶度提升與再結晶現象,因此減緩了降解速率。另一方面,降解產生殘餘物分析的結果,主要是懸浮在溶液中由PEOz與poly(ethyleneimine) (PEI)共聚物形成的粒子,以及溶解在溶液中的乳酸寡聚物與單體。
根據以上的實驗結果推測,PLLA-PEOz-PLLA三團聯共聚物的酵素降解可分為兩階段:首先是水解造成的PEOz鏈段大量流失並在溶液中形成懸浮粒子,並使薄膜留下許多孔洞,接著酵素經由這些孔洞進入薄膜內部使得PLLA開始大量流失,形成單體與寡聚物溶解在溶液中,並在薄膜上留下許多的均勻孔洞結構。所以,本研究提供了本生分解材料在實際應用上需考慮殘餘物的觀點,以評估使用上的性質以及解決所遭遇的問題,除此之外,溶蝕後產生具有高度規則結構的薄膜,或許可為組織工程上的鷹架,或是應用在藥物制放與其他領域的光子晶體製造方面,提供一個經濟又簡便的方法。

In this study, ABA triblock copolymers consisting of poly(L-lactide) (PLLA) A block and poly(2-ethyl-2-oxazoline) (PEOz) B block are synthesized. By controlling inlet ratio of L-lactide and 2-ethyl-2-oxazoline, triblock copolymers with various amphiphilicity can be obtained. Afterward, casting polymer films are degraded in the presence of proteinase K. During degradation, the composition and properties of films and degradation residues are analyzed in detail, respectively. The purpose is to investigate the degradation behavior of these polymers thoroughly. In addition, by virtue of unique microphase separation of triblock copolymer and the distinct amphiphilicity between PEOz and PLLA, we expect one of the blocks can be removed quickly by enzymatic degradation, and left the highly-ordered nanostructure.
Therefore, on one hand the weight and water absorption change of films are weighed. The rate of weight loss is proportioned to water absorption. The molecular weight and molecular weight distribution are determined by gel permeation chromatography, and it shows degradation prefer lower molecular weight polymers in the beginning. Furthermore, according to 1H nuclear magnetic resonance analysis, the weight loss in early stage is mainly attributed to PEOz, and then PEOz and PLLA are washed away at fixed proportion. And the surface and cross section morphology are observed by scanning electronic microscope. The result shows there are different morphology changes between the film surface that contacts air and that contacts Teflon mold. The air side of films is more degradable than Teflon side, and it would generate lots of porous microspheres on the surface. Last, the increase of crystallinity and recrystallization phenomena that reduce degradation rate are observed by differential scanning calorimetry. On the other hand, the analysis of degradation residues shows it consists of particles dispersed in solution that comprise PEOz and poly(ethyleneimine) (PEI) copolymers and PLLA oligomers and monomers dissolved in solution.
Based on the results, a mechanism of enzymatic degradation is proposed that the degradation behavior of PLLA-PEOz-PLLA triblock copolymer displays as two stages. In the first stage, the loss of PEOz-dominant segments forms particles dispersed in solution, and results in porous films. And in the second stage, enzyme permeates films via these pores makes the loss of a large number PLLA of which oligomers and monomers dissolved in solution, and makes films with uniform pores. Therefore, we provide a point of view which takes degradation residues into consideration to evaluate the properties in application and to solve the encountered problems of this biodegradable polymer. Besides, the highly-ordered erosion film may provide a economic and convenient way to produce scaffold in tissue engineering and photonic crystal in drug delivery or other applications.

一、研究背景與動機……………………………………………… 1
二、文獻回顧……………………………………………………… 5
2-1. 生物可分解性高分子……………………………………... 5
2-1-1. 聚酯………………...…………….………………... 8
2-1-2. 聚酸酐………………………………….………….. 9
2-1-3. 聚醯胺………………………………………........... 11
2-2. 影響降解的因素…………………………………………... 12
2-2-1. 高分子的形態……………………………………... 13
2-2-2. 分子量與分子量分佈………………………........... 14
2-2-3. 材料尺寸…………………………………………... 15
2-3. 酵素降解………………………………….……………….. 17
2-3-1. 高分子的酵素降解…………………………........... 18
2-3-2. proteinase K催化降解………………………......... 20
2-4. 生分解團聯共聚物………………………………………... 22
2-4-1. 分類………………………………………………... 23
2-4-2. 合成方法……………………………………........... 25
2-4-3. 團聯共聚物的降解………………………………... 26
三、實驗部分……………………………………………………… 29
3-1. 實驗藥品與實驗儀器…………………...………………… 30
3-1-1. 實驗藥品……………………………………........... 30
3-1-2. 實驗儀器及裝置……………………………........... 31
3-2. 高分子合成………………………………………………... 32
3-2-1. 藥品純化…………………………………………... 32
3-2-2. Poly(2-ethyl-2-oxazoline)之合成………………….. 32
3-2-3. PLLA-PEOz-PLLA三團聯共聚物之合成…..…….. 33
3-3. 合成鑑定與特性分析……………………………………... 35
3-3-1. 1H NMR結構分析…………………………………. 35
3-3-2. FT-IR結構分析…………………………………….. 35
3-3-3. GPC分子量量測…………………………………… 35
3-3-4. DSC熱性質分析…………………………………… 35
3-4. PLLA-PEOz-PLLA之酵素降解…………………………... 36
3-4-1. 薄膜製備…………………………………………... 36
3-4-2. POM分析…………………………………………... 36
3-4-3. 酵素降解…………………………………………... 36
3-4-4. 薄膜分析…………………………………………... 37
3-4-5. 溶液分析…………………………………………... 38
四、結果與討論…………………………………………………… 40
4-1. 合成鑑定與特性分析……………………………………... 40
4-1-1. 1H NMR結構分析…………………………………. 40
4-1-2. FT-IR結構分析…………………………………….. 43
4-1-3. DSC熱性質分析…………………………………… 44
4-1-4. GPC分析…………………………………………… 45
4-2. PLLA-PEOz-PLLA酵素降解薄膜分析…………………... 47
4-2-1. 重量損失與含水率變化…………………………... 47
4-2-2. 分子量分析..................................... 51
4-2-3. 成分變化分析……………………………………... 53
4-2-4. DSC熱性質分析…………………………………… 56
4-2-5. SEM表面形態分析………………………………… 60
4-2-6. SEM截面分析……………………………………… 67
4-3. PLLA-PEOz-PLLA酵素降解溶液分析…………………... 69
4-3-1. 成分分析…………………………………………... 69
4-3-2. 形態分析…………………………………………... 71
4-3-3. 粒徑分析…………………………………………... 74
五、結論…………………………………………………………… 75
六、參考資料……………………………………………………… 81

1.L. Liu, S. Li, H. Garreau, M. Vert, Selective enzymatic degradations of poly(L-lactide) and poly(ε-caprolactone) blend films, Biomacromolecules 1 (2000) 350~359
2.G. H. Hsiue, T. Okano, U. Y. Kim, H. W. Sung, N. Yui, K. D. Park, Advances in biomaterials and drug delivery systems (2002) 263~278
3.S. Li, H. Garreau, M. Vert, Structure-property relationships in the case of the degradation of massive poly(α-hydroxy acids) in aqueous media, J. Mater. Sci.-Mater. M. 1 (1990) 198~206
4.M. S. Reeve, S. P. McCarthy, M. J. Downey, R. A. Gross, Polylactide stereochemistry: effect on enzymatic degradability, Macromolecules 27 (1994) 825~831
5.S. Li, M. Tenon, H Garreau, C. Braud, M. Vert, Enzymatic degradation of stereocopolymers derived from L-, DL- and meso-lactides, Polym. Degrad. Stabil. 67 (2000) 85~90
6.S. Li, S. McCarthy, Influence of crystallinity and stereochemistry on the enzymatic degradation of poly(lactide)s, Macromolecules 32 (1999) 4454~4456
7.R. T. MacDonald, S. P. McCarthy, R. A. Gross, Enzymatic degradability of poly(lactide): effects of chain stereochemistry and material crystallinity, Macromolecules 29 (1996) 7356~7361
8.N. Kumar, M. N.V. Ravikumar, A.J. Domb, Biodegradable block polymers, Adv. Drug Deliver. Rev. 53 (2001) 23~44
9.B. Jeong, Y.K. Choi, Y.H. Bae, G. Zentner, S.W. Kim, New biodegradable polymers for injectable drug delivery systems, J. Control. Release 62 (1999) 109~114
10.S. Li, I. Molina, M. B. Martinez, M. Vert, Hydrolytic and enzymatic degradations of physically crosslinked hydrogels prepared from PLA/PEO/PLA triblock copolymers, J. Mater. Sci.-Mater. M. 13 (2002) 81~86
11.Y. Kikkawa, H. Abe, T. Iwata, Y. Inoue, Y. Doi, Crystallization, stability, and enzymatic degradation of poly(L-lactide) thin film, Biomacromolecules 3 (2002) 350~356
12.M. Hakkarainen, A.C. Albertsson, S. Karlsson, Weight losses and molecular weight changes correlated with the evolution of hydroxyacids in simulated in vivo degradation of homo- and copolymers of PLA and PGA, Polym. Degrad. Stabil. 52 (1996) 283~291
13.M. W. Matsen, F. S. Bates, Conformationally Asymmetric Block Copolymers, J. Polym. Sci. Pol. Phys. 35 (6) 1997 945~952
14.K. Park, W. S.W. Shalaby, H. Park, Biodegradable hydrogels for drug delivery (1993) 13~34
15.R. Chandra, R. Rustgi, Biodegradable polymers, Prog. Polym. Sci. 23 (1998) 1273~1335
16.S. Li, M. Vert, Biodegradable polymers: polyesters, Global Chinese Symposium on Biomaterials and Controlled Release (1999) 332~355
17.H.R. Kricheldorf, I. Kreiser-Saunders, C. Boettcher, Polylactones: 31. Sn(Ⅱ)octoate-initiated polymerization of L-lactide: a mechanistic study, Polymer 36 (6) (1995) 1253~1259
18.S. Li, H. Garreau, B. Pauvert, J. McGrath, A. Toniolo, M. Vert, Enzymatic degradation of block copolymers prepared fromε-caprolactone and poly(ethylene glycol), Biomacromolecules 3 (2002) 525~530
19.K.E. Uhrich, S.M. Cannizzaro, R.S. Langer, K.M. Shakesheff, Polymeric Systems for Controlled Drug Release, Chem. Rev. 99 (1999) 3181~3198
20.J. O. Hollinger, Biomedical Applications of Synthetic Biodegradable Polymers (1995), 224
21.S. Li, S. Anjard, L. Rashkov, M. Vert, Hydrolytic degradation of PLA/PEO/PLA triblock copolymers prepared in the presence of Zn metal or CaH2, Polymer 39 (22) (1998) 5421~5430
22.L. Youxin, C. Volland, T. Kissel, In-vitro degradation and bovine serum albumin release of the ABA triblock copolymers consisting of poly(L(+) lactic acid), or poly(L(+) lactic acid-co-glycolic acid) A-blocks attached to central polyoxyethylene B-blocks, J. Control. Release 32 (1994) 121~128
23.D. S.G. Hu, H.J. Liu, Structural analysis and degradation behavior in polyethylene glycol/poly(L-lactide) copolymers, J. Appl. Polym. Sci. 51 (1994) 473~482
24.A. Gopferich, Mechanisms of polymer degradation and erosion, Biomaterials 17 (1996) 103~114
25.F. von Burkersroda, L. Schedl, A. Gopferich, Why degradable polymers undergo surface erosion or bulk erosion, Biomaterials 23 (2002) 4221~4231
26.T. Kissel, Y. Li, F. Unger, ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins, Adv. Drug. Deliver. Rev. 54 (2002) 99~134
27.A. Gopferich, R. Langer, The influence of microstructure and monomer properties on the erosion mechanism of a class of polyanhydrides, J. Polym. Sci. Pol. Chem. 31 (1993) 2445~2458
28.Q. Cai, G. Shi, J. Bei, S. Wang, Enzymatic degradation behavior and mechanism of poly(lactide-co-glycolide) foams by trypsin, Biomaterials 24 (2003) 629~638
29.趙世彬, 鄒煦杕, 蔡東璣, 陳河吉, 周大中, 李文齡, 生物化學 (1995) 130
30.W. Ebeling, N. Hennrich, M. Klockow, H. Metz, H.D. Orth, H. Lang, Proteinase K from Tritirachium album Limber, Eur. J. Biochem. 47 (1974) 91~97
31.H. Cai, V. Dave, R. A. Gross, S. P. McCarthy, Effects of physical aging, crystallinity, and orientation on the enzymatic degradation of poly(lactic acid), J. Polym. Sci. Pol. Phys. 34 (1996) 2701~2708
32.I. Molina, S. Li, M.B. Martinez, M. Vert, Protein release from physically crosslinked hydrogels of the PLA/PEO/PLA triblock copolymer-type, Biomaterials 22 (2001) 363~369
33.X. Zhang, J. K. Jackson, W. Wong, W. Min, T. Cruz, W. L. Hunter, H. M. Burt, Development of biodegradable polymeric paste formulations for taxol: an in vitro and in vivo study, Int. J. Pharm. 137 (1996) 199~208
34.B. Jeong, Y.H. Bae, D.S. Lee, S.W. Kim, Biodegradable block copolymers as injectable drug-delivery systems, Nature 388 (28) (1997) 860~862
35.B. Jeong, Y. K. Choi, Y. H. Bae, G. Zentner, S. W. Kim, New biodegradable polymers for injectable drug delivery systems, J. Control. Release 62 1999, 109~114
36.B. Jeong, Y. H. Bae, S. W. Kim, Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers, J. Control. Release 63 2000 155~163
37.K.W. Kwon, M.J. Park, Y.H. Bae, H.D. Kim, K. Char, Gelation behavior of PEO-PLGA-PEO triblock copolymers in water, Polymer 43 (2002) 3353~3358
38.W. P. Ye, F. S. Du, W. H. Jin, J. Y. Yang, Y. Xu, In vitro degradation of poly(caprolactone), poly(lactide) and their block copolymers: influence of composition, temperature and morphology, Reac. Func. Polym. 32 1997 161~168
39.C. Kim, S. C. Lee, S. W. Kang, I. C. Kwon, S. Y. Jeong, Phase transition characterization of amphiphilic poly(2-ethyl-2-oxazoline) /poly(ε-caprolactone) block copolymers in aqueous solutions, J. Polym. Sci. Pol. Phys. 38 (2000) 2400~2408
40.S.C. Lee, Y. Chang, J.S. Yoon, C. Kim, I.C. Kwon, Y.H. Kim, S.Y. Jeong, Synthesis and micellar characterization of amphiphilic diblock copolymers based on poly(2-ethyl-2-oxazoline) and aliphatic polyesters, Macromolecules 32 (1999) 1847~1852
41.L. Martini, D. Attwood, J. H. Collett, A. D’Emanuele, The bioadhesive properties of a triblock copolymer of ε-caprolactone and ethylene oxide, Int. J. Pharm.113 1995, 223~229
42.Y. Zhao, H. Liang, S. Wang, C. Wu, Self-assembly of poly(caprolactone-b-ethylene oxide-b-caprolactone) via a microphase inversion in water, J. Phys. Chem. B 105 (2001) 848~851
43.Q. Cai, J. Bei, S. Wang, Synthesis and properties of ABA-type triblock copolymers of poly(glycolide-co-caprolactone) (A) and poly(ethylene glycol) (B), Polymer 43 2002 3585~3591
44.A. K. Hilbert, U. Fritzsche, T. Kissel, Biodegradable microspheres containing influenza A vaccine: immune response in mice, Vaccine 17 (1999) 1065~1073
45.T. Kissel, Y.X. Li, C. Volland, S. Gorich, R. Koneberg, Parenteral protein delivery systems using biodegradable polyesters of ABA block structure, containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethylene oxide) B blocks, J. Control. Release 39 (1996) 315~326
46.C. Witt, K. Mader, T. Kissel, The degradation, swelling and erosion properties of biodegradable implants prepared by extrusion or compression moulding of poly(lactide-co-glycolide) and ABA triblock copolymers, Biomaterials 21 (2000) 931~938
47.S.S. Shah, K.J. Zhu, C.G. Pitt, Ply-DL-lactic acid: polyethylene glycol block copolymers. The influence of polyethylene glycol on the degradation of poly-DL-lactic acid, J. Biomat. Sci.-Polym. E. 5 (1994) 421~431
48.I. Rashkov, N. Manolova, S. M. Li, J. L. Espartero, M. Vert, Synthesis, characterization, and hydrolytic degradation of PLA/PEO/PLA triblock copolymers with short poly(L-lactic acid) chains, Macromolecules 29 (1996) 50~56
49.S. M. Li, I. Rashkov, J. L. Espartero, N. Manolova, M. Vert, Synthesis, characterization, and hydrolytic degradation of PLA/PEO/PLA triblock copolymers with long poly(L-lactic acid) chains, Macromolecules 29 (1996) 57~62
50.M. Penco, S. Marcioni, P. Ferruti, S. D’Antone, R. Deghenghi, Degradation behaviour of block copolymers containing poly(lactic-glycolic acid) and poly(ethylene glycol) segments, Biomaterials 17 (1996) 1583~1590
51.K. Aoi, M. Okada, Polymerization of oxazolines, Prog. Polym. Sci. 21 (1996) 151~208
52.S. Kobayashi, E. Masuda, S.I. Shoda, Synthesis of acryl- and methyl-type macromonomers and telechelics by utilizing living polymerization of 2-oxazolines, Macromolecules 22 (1989) 2878~2884
53.J. L. Espartero, I. Rashkov, S. M. Li, N. Manolova, M. Vert, NMR analysis of low molecular weight poly(lactic acid)s, Macromolecules 29 (1996) 3535~3539
54.S.O. Han, R. I. Mahato, and S. W. Kim, Water-soluble lipopolymer for gene therapy, Bioconjugate Chem. 12 (2001) 337~345
55.林哲平, 王朝暉, 薛敬和, 李世煌, Synthesis of PLA-PEOz-PLA triblock copolymers for a newly developed bioglue, 生醫材料及藥物制放研討會論文集 (2003) 245~246
56.Y.Y. Li, F. Cunin, J. R. Link, T. Gao, R. E. Betts, S. H. Reiver, V. Chin, S. N. Bhatia, M. J. Sailor, Polymer replicas of photonic porous silicon for sensing and drug delivery applications, Science 299 (2003) 2045~2047

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔