以天然交聯劑Genipin交聯幾丁聚醣材料的體外及體內性質評估

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研究生：	譚育浚 Yu-Jung Tian
論文名稱：	以天然交聯劑Genipin交聯幾丁聚醣材料的體外及體內性質評估
指導教授：	宋信文
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程與材料工程學系 Department of Chemical & Materials Engineering
畢業學年度：	88
語文別：	中文
論文頁數：	78
中文關鍵詞：	體內實驗、體外實驗、幾丁聚醣
外文關鍵詞：	in vivo, in vitro, genipin, chitosan
相關次數：	點閱：17 下載：0
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為了使藥劑能發揮高度的療效並降低其副作用，同時又能維持較長的療效時程，近年來制放技術逐漸被應用於藥物釋放之控制上。應用在藥物制放載體的各類型生醫高分子材料，由於其不同的生物相容性及生物可分解性，故均僅侷限於某些特定之藥物控制釋放劑型之應用。幾丁聚醣為具有良好生物相容性及生物可分解性的生物高分子，因此具備了製備成口服、皮下植入、肌肉注射及皮膚貼劑等各種不同劑型之基本條件。但由於幾丁聚醣不具抗酸性且膨潤度過大，因此常須以交聯劑如glutaraldehyde來交聯，以克服上述的問題及達到控制藥物釋放速率的目的。但由於過去所採用的交聯劑如glutaraldehyde的細胞毒性過高，因此常易導致強烈且持續性的免疫反應。
為此，我們使用了由中藥梔子果實中萃取純化出來的一種細胞毒性極低的天然交聯劑genipin 來交聯幾丁聚醣，將其分別製成薄膜及微粒，並以體外及體內實驗的方式來評估其各項性質。體外實驗的部分主要是探討薄膜的最佳交聯條件、機械強度、膨潤度、抗酵素分解、抗菌性質以及細胞相容性等，實驗中的對照組為未經交聯處理的幾丁聚醣製成的薄膜，以及以glutaraldehyde交聯幾丁聚醣製成的薄膜。在體內實驗的部分，我們則評估以genipin交聯幾丁聚醣微粒，注入老鼠體內後的生物相容性與被分解性。實驗中的對照組，同樣為未經交聯處理的幾丁聚醣微粒，以及以glutaraldehyde交聯處理的幾丁聚醣微粒。
由體外動物實驗的結果顯示，在機械性質方面，Fresh薄膜的機械強度最差，斷裂伸長率與膨潤度最大；而GP薄膜的機械強度則較GA薄膜來的大，但其斷裂伸長率與膨潤度則比GA薄膜來的小。在抗酵素分解部份，Fresh薄膜被酵素分解的速度最快，GA薄膜次之，GP薄膜最慢。在抗菌性質方面，三種薄膜均具有相當良好的抑菌效果，且三種薄膜的抑菌效果，差異並不大。而在細胞相容性方面，Fresh薄膜擁有最佳的細胞相容性，而GP薄膜的細胞相容性則明顯的要比GA薄膜來的好，因此可能會有較好的生物相容性。
由體內動物實驗結果顯示，Fresh微粒載體雖然具有較佳的生物相容性，但被分解速率最快；而GA微粒載體的生物相容性最差、被分解速率次之；相對的GP微粒載體的生物相容性佳且較GA微粒載體被分解速率較慢。
由以上的體外及體內實驗結果顯示，未交聯的幾丁聚醣材料適合應用於短效型的藥物制放載體；另外GP交聯的幾丁聚醣材料較GA交聯的幾丁聚醣材料適合應用在短效型的藥物制放載體。

目錄
內容頁數
摘要……………………………………………………...………………..I
目錄………………………………………………..……………...…….III
圖索引…………………………………………………...………………V
表索引…………………………………………………………….….…Ⅸ
第一章緒論……………………………………………………………..1
1.1藥物制放……………………………………………………………..1
1.2幾丁聚醣之簡介及文獻回顧………………………………………..2
1.3免疫反應……………………………………………………………..3
1.4研究動機與目的……………………………………………………..4
第二章GP薄膜的製備與其體外性質的探討………………………….7
2.1研究目的……………………………………………………………...7
2.2實驗材料……………………………………………………………..7
2.2.1薄膜的組成成份…………………………………………7
2.2.2 薄膜的製備……………………………………………..8
2.3 實驗方法…………………………………………………………….9
2.3.1 薄膜製備條件…………………………………………9
2.3.1.1 基材濃度選擇…………………………….9
2.3.1.2 交聯劑濃度選擇………………………..10
2.3.1.3 膨潤度…………………………………..11
2.3.1.4 交聯指數……………………..…………11
2.3.2 體外抗酵素分解實驗…………………….……….13
2.3.3 抗菌性質…………………………………………...14
2.3.4 細胞相容性…………………………………………15
2.4 實驗結果與討論……………………………………………….16
2.4.1 薄膜製備條件………………………………………16
2.4.1.1 基材幾丁聚醣濃度………………..………16
2.4.1.2 交聯劑濃度……………………….………19
2.4.1.3 幾丁聚醣溶液pH值………………………25
2.4.2 體外抗酵素分解……………………………………28
2.4.3 抗菌性質…………………………………………...32
2.4.4 細胞相容性…………………………………………35
2-5結論…………………………………………………………….42
第三章GP微粒載體在動物體內的生物相容性評估…………………44
3.1研就目的………………………………………………………..44
3.2材料與方法……………………………………………………..44
3.2.1微粒載體製備……………………………………….44
3.2.2 實驗方法…………………………………………...45
3.2.2.1 SEM表面形態觀察………………………..49
3.2.2.2 病理顯微觀察……………………………….50
3.3實驗結果與討論……………………………………………………51
3.3.1 SEM表面形態觀察……………………………………51
3.3.2 病理切片觀察…………………………………………58
3.4結論…………………………………………………………….67
3.5總結論………………………………………………………….67
參考文獻…………………………………………………………...69
圖索引
圖頁數
圖1-1、理想狀況的藥物釋放速率曲線圖………………………………1
圖2-1、幾丁聚醣分子結構式………………………………………..7
圖2-2、實驗中所使用的交聯劑分子結構式…………………………..8
圖2-3、各式薄膜的製備流程……………………………….……….8
圖2-4、在機械性質測試時薄膜試片的幾何形狀………………...…….9
圖2-5、材料測試機示意圖………………………………………….10
圖2-6、Ninhydrin與自由胺基的反應機制…………………………12
圖2-7、SEM前處理步驟流程圖…………………………………13
圖2-8、薄膜抗菌性質測試流程圖………………………………….14
圖2-9、細胞相容性實驗裝置示意圖……………………………..15
圖2-10、不同濃度幾丁聚醣製成的薄膜交聯指數比較………………16
圖2-11、不同濃度幾丁聚醣製成的薄膜機械強度比較………………17
圖2-12、不同濃度幾丁聚醣製成的薄膜斷裂伸長率比較…………..18
圖2-13、幾丁聚醣濃度增加使得幾丁聚醣分子間的物理纏繞機率增
加…………………………………………………………………..18
圖2-14、不同交聯劑濃度製成的薄膜之交聯指數比較……………..19
圖2-15、交聯劑濃度增加使得幾丁聚醣分子間的交聯鏈結增加……20
圖2-16、GP薄膜假設反應機制示意圖……………………………….21
圖2-17、GA薄膜假設反應機制示意圖………………………………22
圖2-18、不同交聯劑濃度製成的薄膜之機械強度比較……………..23
圖2-19、不同交聯劑濃度製成的薄膜之斷裂伸長率比較……………24
圖2-20、不同交聯劑濃度製成的薄膜之膨潤度比較………………..24
圖2-21、幾丁聚醣溶液在不同pH值下，經不同交聯劑交聯製成薄膜後之交聯指數比較…………………………………………………..26
圖2-22、幾丁聚醣溶液在不同 pH值下，經不同交聯劑交聯製成薄膜後之機械強度比較…………………………………………………..26
圖2-23、幾丁聚醣溶液在不同pH值下，經不同交聯劑交聯製成薄膜後之斷裂伸長率比較………………………………………….…….27
圖2-24、lysozyme酵素水解幾丁聚醣示意圖……………………….28
圖2-25、每週幾丁聚醣被分解至液相中的自由胺基含量的時間柱狀
圖…………………………………………………………………..29
圖2-26、幾丁聚醣被分解至液相中的自由胺基含量的累積曲線圖....30
圖2-27a、Fresh薄膜經lysozyme酵素分解前SEM表面形態觀察….30
圖2-27b、GA薄膜經lysozyme酵素分解前SEM表面形態觀察……30
圖2-27c、GP薄膜經lysozyme酵素分解前SEM表面形態觀察…….31
圖2-28a、Fresh薄膜經lysozyme酵素分解五個月後SEM表面形態觀察…………………………………………………………………..31
圖2-28b、GA薄膜經lysozyme酵素分解五個月後SEM表面形態觀
察…………………………………………………………………..31
圖2-28c、GP薄膜經lysozyme酵素分解五個月後SEM表面形態觀
察…………………………………………………………………..32
圖2-29、各式薄膜對大腸桿菌生長的影響……………….………….34
圖2-30、各式薄膜對綠濃桿菌生長的影響……………….………….34
圖2-31、各式薄膜對金黃色葡萄球菌生長的影響……….………….35
圖2-32a、人體纖維母細胞植入3天後Fresh薄膜細胞相容性測試結
果…………………………………………………………………..36
圖2-32b、人體纖維母細胞植入3天後GA薄膜細胞相容性測試結
果…………………………………………………………………..37
圖2-32c、人體纖維母細胞植入3天後GP薄膜細胞相容性測試結
果…………………………………………………………………..37
圖2-33a、H460細胞植入3天後Fresh薄膜細胞相容性測試結果…38
圖2-33b、H460細胞植入3天後GA薄膜細胞相容性測試結果…..38
圖2-33c、H460細胞植入3天後GP薄膜細胞相容性測試結果……39
圖2-34a、3T3纖維母細胞植入3天後Fresh薄膜細胞相容性測試結
果…………………………………………………………………..39
圖2-34b、3T3纖維母細胞植入3天後GA薄膜細胞相容性測試結
果…………………………………………………………………..40
圖2-34c、3T3纖維母細胞植入3天後GP薄膜細胞相容性測試結
果…………………………………………………………………..40
圖2-35a、KB細胞植入3天後Fresh薄膜細胞相容性測試結果……41
圖2-35b、KB細胞植入3天後GA薄膜細胞相容性測試結果………41
圖2-35c、KB細胞植入3天後GP薄膜細胞相容性測試結果………42
圖3-1、微粒載體製備流程圖………………………………………45
圖3-2、動物實驗流程圖……………………………………………46
圖3-3、微粒載體注射位置示意圖…………………………….47
圖3-4、微粒載體注射於老鼠後腿骨骼肌部位照片………..48
圖3-5a、動物實驗取樣示意圖…………………………………49圖3-5b、動物實驗取樣示意圖…………………………………50
圖3-6、病理組織切片製作流程圖…………………………….50
圖3-7a、肌肉注射前Fresh微粒載體SEM表面形態觀察…………..51
圖3-7b、肌肉注射前GA微粒載體SEM表面形態觀察…………….51
圖3-7c、肌肉注射前GP微粒載體SEM表面形態觀察……………..52
圖3-8a、注入3天後Fresh微粒載體SEM表面形態觀察…………..52
圖3-8b、注入3天後GA微粒載體SEM表面形態觀察…………….52
圖3-8c、注入3天後GP微粒載體SEM表面形態觀察……………..53
圖3-9a、注入1週後Fresh微粒載體SEM表面形態觀察…………..53
圖3-9b、注入1週後GA微粒載體SEM表面形態觀察……………53
圖3-9c、注入1週後GP微粒載體SEM表面形態觀察…………….54
圖3-10a∼c、注入4週後Fresh微粒載體SEM表面形態觀察…….54
圖3-10a∼c、注入4週後GA微粒載體SEM表面形態觀察……….54
圖3-10a∼c、注入4週後GP微粒載體SEM表面形態觀察………..55
圖3-11a、注入12週後Fresh微粒載體SEM表面形態觀察………..56
圖3-11b、注入12週後GA微粒載體SEM表面形態觀察………….56
圖3-11c、注入12週後GP微粒載體SEM表面形態觀察…………..56
圖3-12a、注入12週後Fresh微粒載體SEM表面形態觀察………..57
圖3-12b、注入12週後GA微粒載體SEM表面形態觀察………….57
圖3-12c、注入12週後GP微粒載體SEM表面形態觀察…………..57
圖3-13a、注入3天後Fresh微粒載體病理切片（x200）..…………60
圖3-13b、注入3天後GA微粒載體病理切片（x200）……………60
圖3-13c、注入3天後GP微粒載體病理切片（x200）…………….61
圖3-14a、注入1週後Fresh微粒載體病理切片（x200）………….61
圖3-14b、注入1週後GA微粒載體病理切片（x200）……………62
圖3-14c、注入1週後GP微粒載體病理切片（x200）…………….62
圖3-15a、注入4週後Fresh微粒載體病理切片（x200）………….63
圖3-15b、注入4週後GA微粒載體病理切片（x200）…………….63
圖3-15c、注入4週後及GP微粒載體病理切片（x200）…………..64
圖3-16a、注入12週後GP微粒載體病理切片（x200）……………64
圖3-16b、注入12週後GA微粒載體病理切片（x200）……………65
圖3-16c、注入12週後GP微粒載體病理切片（x200）……………65
圖3-17a、注入20週後Fresh微粒載體病理切片（x200）…………66
圖3-17b、注入20週後GA微粒載體病理切片（x200）……………66
圖3-17c、注入20週後GP微粒載體病理切片（x200）…………….67
表索引
表頁數
表一、攪拌不同濃度幾丁聚醣至全溶所需時間………………………19
表二、體外實驗結果整理………………………………………………43
表三、動物實驗取樣時間表………………………………………..48

                                

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