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研究生:林佳妏
研究生(外文):Chia-Wen Lin
論文名稱:氰基丙烯酸酯與幾丁聚醣衍生物之凝血性質及應用
論文名稱(外文):The hemostatic property and biomedical applications of cyanoacrylates and the derivatives of chitosan
指導教授:林睿哲
指導教授(外文):Jui-Che Lin
學位類別:博士
校院名稱:國立成功大學
系所名稱:化學工程學系碩博士班
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:92
語文別:中文
論文頁數:104
中文關鍵詞:氰基丙烯酸酯幾丁聚醣
外文關鍵詞:cyanoacrylatechitosan
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氰基丙烯酸酯(cyanoacrylates)與組織或血液接觸時會快速地引發聚合反應而達到凝結的效果,所以其商業化的產品如Histoacryl�� (N-butyl cyanoacrylate)可用於內視鏡血管栓塞劑之醫療應用上;但其價格昂貴,且一般的氰基丙烯酸酯本身的黏度低,當用於血管栓塞有時會因流動性高而影響操作上的定位準確性。
本研究則探討應用氰基丙烯酸乙酯(ethyl cyanoacrylate, ECA) 加入聚合調節劑後其作為血管栓塞劑的可行性。Ethyl cyanoacrylate又稱為三秒膠,在傳統接著上的應用十分廣泛,且價格較Histoacryl�市K宜,ECA中加入聚合起始劑– 咖啡鹼(caffeine)以增加其聚合速率及黏度;另外,Lipiodol�筍h為常用的X光顯影劑,其本身的黏度高,並且可隔絕硬化劑注射前導管管壁上的水分以防止氰基丙烯酸酯單體在導管中產生聚合反應而阻塞,經由加入Lipiodol�等蟡i觀察硬化劑在血管中隨血液的移動情形以及栓塞發生的位置。實驗試劑分別經由體外實驗及體內之動物實驗探討其作為血管栓塞劑的可行性。
但因為氰基丙烯酸酯聚合後通常形成較硬且脆的固體,而且其在生物體中水解後會產生氰基乙醯酯及甲醛等對生物組織具有毒性的物質。本研究便進一步以具有生物可分解性及促凝血活性的材料 – 幾丁聚醣(chitosan)進行化學改質並探討其應用於血管栓塞之可行性。本實驗以二種不同乙醯度之幾丁聚醣進行丁醯化及降解反應,以提高此幾丁聚醣衍生物在X光顯影劑(Lipiodol��)中之溶解度,並測定其物理及化學性質以及在血液中之凝血特性。
另外,本研究中以此二種不同乙醯度之幾丁聚醣進行亞硝酸降解以製備幾丁寡醣(chitooligosaccharides),並提出一方法以不同組成比例的水/甲醇之溶液進行幾丁寡醣之分段分離。幾丁寡醣不僅可溶於中性的水溶液中更具有多樣化之生物活性,近年來,有關幾丁寡醣生理功能之研究便持續引起食品與醫藥界之重視,但經過降解反應後所得之幾丁寡醣有各種分子量,故需經過分離程序才能得到一定分子量分佈的產物,之前常用之分離及純化程序往往需要長時間,而且設備成本也相對較高,因此本實驗提出一方法以分離出不同分子量分佈範圍之幾丁寡醣。本實驗以此分段分離方法所得之幾丁聚醣進行化學及物理性質分析並測試其血液相容性。
Cyanoacrylates have known for their ability to polymerize rapidly in the presence of traces of weakly basic moieties such as water. The tissue adhesive, Histoacryl (N-butyl 2-cyanoacrylate), has been reported to control bleeding through endoscopic sclerotherapy. But the commercially available Histoacryl is expensive and it has the problem like other cyanoacrylates that the glue tends to flow/run away from the point of application, which is inherent to the low viscosity, making precise application difficult.
In this study, ethyl cyanoacrylate (ECA) was employed instead of Histoacryl due to its lower cost. The aim of the research is to modify the compositions of ECA regimen with caffeine and Lipiodol which would allow the roentegenologic monitoring in situ, and evaluate its feasibility for sclerosant application through both in vitro flow circuit model and in vivo animal tests. It was noted that the ECA setting rate was greatly increased by adding few dosage of caffeine, which is acting as a polymerization initiator. This would lead to far better injection precision during sclerotherapy. Furthermore, in vivo histological examination for the occluded lumen of the rat's inferior vena cava and a clinical piglet portal vein occlusion experiment have suggested this new sclerosant regimen, caffeine/ECA, was of great promise in endoscopic sclerotherapy.
Because the polymerized product of cyanoacrylates was hard and stiff, in addition, they would be degradated in the physiological milieu and cyanoacetate and formaldehyde were then yielded, both of which are tissue toxic. A biodegradable and blood coagulant material– chitosan was used for the further study.
Butyrylation and degradation were performed on two different chitosan samples with different degree of acetylation to prompt the chitosan derivatives dissolve in Lipiodol. The chemical and physical characteristics, blood coagulation properties were also measured to evaluate the feasibility of the chitosan derivatives for the hemostatic agent application.
In addition, the chitosan samples with different degree of acetylation were used separately to prepare chitooligosaccharide (COS) and highly deacetylated chitooligosaccharide (HDCOS) through the nitrous acid depolymerization. Water-soluble chitooligosaccharides have been reported to have specific biological activities. Rather than using the conventional fractionation schemes commonly employed, such as dialysis and ultrafiltration which require a large amount of deionized water as well as a fair long dwell time, an unique fractionation scheme is explored to recover and desalt these nitrous-acid depolymerized chitosan with different molecular weights. It was noted that chitosan with different molecular weight can be successfully recovered and fractionated with methanol added sequentially.
The chemical characterization of the fractionated water-soluble COS and HDCOS were measured by 1H NMR spectroscopy and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Moreover, the modified whole blood clotting time assay and the platelet coagulation test were also performed to evaluate the preliminary blood compatibility of the fractionated water-soluble COS and HDCOS.
中文摘要----- I
Abstract- -----III
誌謝-----------V
目錄-----------VII
圖目錄--- -----X
表目錄--- -----XII

第一章 緒論------- 1

第二章 實驗藥品及儀器簡介---4
2-1 藥品-----4
2-2 儀器-----6
2-3 分析儀器簡介------7

第三章 含聚合調節劑暨添加劑之氰基丙烯酸酯應用於血管栓塞劑之探討----9
3-1 前言 -------9
3-1-1 血管栓塞劑的應用---------9
3-1-2 氰基丙烯酸酯應用於血管栓塞劑之原理----- 13
3-1-3 氰基丙烯酸酯應用於血管栓塞劑之特性----- 15
3-1-4 聚合調節劑對氰基丙烯酸酯應用於血液栓塞之探討----15
3-2實驗內容------- 22
3-2-1 膠化時間(Gel time)--- 22
3-2-2 體外流動場實驗------- 22
3-2-3 體內(in vivo)動物測試-24
3-3 結果與討論-------26
3-3-1 膠化時間---- ----26
3-3-2 體外流動場實驗------- 27
3-3-3 體內動物測試-----31

第四章 丁醯化幾丁聚醣之凝血性質-----35
4-1 前言------------35
4-1-1 幾丁聚醣之特性------- 37
4-1-2 幾丁聚醣之促凝血特性及應用---- 42
4-1-3 醯化反應(acylation)-- 43
4-2 實驗內容------ 45
4-2-1 幾丁聚醣之純化------- --45
4-2-2 幾丁聚醣之去乙醯化------45
4-2-3 幾丁聚醣之降解--------46
4-2-4 幾丁聚醣以及降解後幾丁聚醣之丁醯化-----46
4-2-5 物理及化學性質分析------47
4-2-6 全血之凝固時間測試------47
4-3 結果與討論------------- 49
4-3-1 幾丁聚醣及高度去乙醯化幾丁聚醣之乙醯度分析-------49
4-3-2 幾丁聚醣及高度去乙醯化幾丁聚醣之分子量測定-------52
4-3-3 丁醯化幾丁聚醣之溶解性質測試---54
4-3-4 丁醯化幾丁聚醣之1H核磁共振光譜分析------56
4-3-5 丁醯化幾丁聚醣之分子量測定-------62
4-3-6 全血之凝固時間測試(Whole blood clotting time test)--------63


第五章 水溶性幾丁寡醣之製備、性質分析以及血液相容性測試---------64
5-1 前言-------64
5-1-1 幾丁寡糖---- 64
5-1-2 幾丁聚醣的降解------- 66
5-1-3 幾丁寡醣之製備及分段分離-------68
5-2 實驗內容------ 71
5-2-1 幾丁聚醣之純化------- --71
5-2-2 幾丁聚醣之去乙醯化------71
5-2-3 幾丁聚醣之降解與分段分離------72
5-2-4 物理及化學性質分析------73
5-2-5 全血之凝固時間測試------74
5-2-6 血小板凝集測試(Platelet aggregation test)--------75
5-3 結果與討論----76
5-3-1 降解產物之分段分離----76
5-3-2 水溶性幾丁寡醣之分子量分佈----78
5-3-3 紅外線光譜分析------- 82
5-3-4 1H核磁共振光譜分析-- 85
5-3-5 初步之凝血特性測試------88

第六章 結論與未來展望---------92

著作----- 103

自述----- 104
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