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研究生:郭仲帆
研究生(外文):Chung-Gan Kuo
論文名稱:透明質酸之改質以製備水膠
論文名稱(外文):Modifications of Hyaluronic Acid for Hydrogel Formation
指導教授:王盈錦
指導教授(外文):Yng-Jiin Wang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學工程研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:96
中文關鍵詞:透明質酸改質水膠
外文關鍵詞:Hyaluronic acidModificationHydrogel
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透明質酸為D-glucuronic acid和 N-acetyl-D-glucosamine所組成的線性不帶支鏈之負電聚醣高分子。透明質酸可經由物理糾結或化學鍵結形成網狀的水膠結構且在生醫領域上具有很好的潛力。因此,本研究的目的為建立一個以化學交聯的方法合成水膠的技術平台。
本實驗以N, N’-carbonyldiimidazole(CDI)來改質(分子量4700)短鏈透明質酸上的羧酸根,且發現可能是由於分子間和分子內的交聯反應,會造成有反應時間增加其CDI的接枝率較低的結果。藉由控制sHA/CDI莫爾比為1/4與2小時的反應時間在25oC下可以得到接枝率為56%的sHA-CDI分子。此外,長鏈透明質酸分子(分子量900000)可藉由1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC)於羧酸根上與adipic dihydrazide (ADH)反應進而胺基化。調整HA/ADH莫爾比為1/10在25oC下反應3小時,可得56%接枝量的HA-ADH。
透明質酸(HAX)水膠其19%到70%的交聯程度可藉由HA-CDI與HA-ADH混合反應而合成。由於交聯比例的增加,膨潤度會由48%減少到30%,而含水量維持約96%至98%。機械性質測試的結果顯示增加交聯比例其壓縮模數會由0.007MPa上升至0.23MPa。各膠體在第七天擁有大約55%~60%的體外降解比例。本實驗所合成的HAX膠體較先前研究的HAX凝膠其穩定度較佳。
Hyaluronic acid (HA) is a linear unbranched negatively charged polysaccharide comprised of N-acetylglucosamine and D-glucuronic acid. HA is capable of forming a network of hydrogel by physical entanglements or chemical crosslinks with great potential in biomedical application. Therefore, the aim of this study was to develop a new technology platform for fabricating HA hydrogel via chemical crosslinking process.
We have used N, N’-carbonyldiimidazole(CDI) to modify the carboxyl groups of short-chain hyaluronic acid (sHA, MW of 4.7k) and found that longer reaction time resulted in a lower grafting ratio of CDI probably due to undesired intra- and inter-molecular crosslinkings. The sHA-CDI molecules of 56% grafting ratio could be obtained by controlling the molar ratio of sHA/CDI at 1/4 and reacted for 2 hours at 25oC. In addition, the hyaluronic acid was aminated by reacting long-chain hyaluronic acid (MW of 900K) molecules with adipic dihydrazide (ADH) via the activation of carboxylic acids by 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). By adjusting the molar ratio of HA/ADH at 1/10, HA-ADH of 56% grafting ratio could be obtained after 3 hours reaction at 25℃.
A hydrogel network of HA (HAX) with crosslinking extent of 19% to 70% could be fabricated by mixing HA-CDI and HA-ADH in a series of combination. The swelling ratio decreased from 48% to 30% by increasing the extent of crosslinking, whereas the water content remained in the range of 96%-98%. The results of mechanical testing showed that the compression modulus increased from 0.007 MPa to 0.23 MPa with increasing crosslinking ratio. All HAX gels had about the same in vitro degradation rate with 55%~60% degraded in 7 days. The more stable HAX gel synthesized in this study is better than the HAX gel previous documented.
中文摘要 I
英文摘要 II
目錄 III
圖目錄 V
表目錄 VIII
第一章 緒論 1
1-1 前言 1
1-2 透明質酸介紹 2
1-2-1透明質酸 2
1-2-2 透明質酸的結構 3
1-2-3透明質酸的性質 4
1-2-4透明質酸在醫學上的應用 7
1-3 透明質酸改質介紹 9
1-3-1 羧酸根(carboxyl groups)改質與應用 10
1-3-2 氫氧根(hydroxyl groups)改質與應用 15
1-3-3環原端(reducing end)改質與應用 16
1-3-4化學修飾交聯與應用 16
1-4透明質酸水膠 21
1-5 可注射透明質酸水膠(HAX HYDROGEL)介紹與應用 23
1-6 反應試劑 26
1-6-1 N, N’-carbonyldiimidazole (CDI)的介紹 26
1-6-2 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC)的介紹 29
1-7 研究動機 31

第二章 實驗藥品與儀器 32
2-1 實驗藥品 32
2-2 實驗儀器 34

第三章 實驗方法 35
3-1 透明質酸的改質製備 35
3-1-1 透明質酸以CDI活化羧酸根 (HA-CDI) 35
3-1-2 透明質酸以羧酸根做胺基化之改質 (HA-ADH) 37
3-2 透明質酸水膠(HAX HYDROGEL)的製備 39
3-3 透明質酸水膠(HAX HYDROGEL)的鑑定 40
3-3-1 成膠時間(Gelation time) 40
3-3-2 交聯指數分析(Cross-linked degree) 40
3-3-3 膠體膨潤度測試(Swilling ratio) 43
3-3-4 膠體含水量測試(Water content measurements) 44
3-3-5機械強度與模數的測定(Mechanical testing: compression test) 44
3-3-6 體外降解測定(In vitro degradation) 45

第四章 結果與討論 47
4-1 HA-CDI 定性與定量結果 47
4-1-1 HA-CDI之定性分析結果 47
4-1-2 純化方式對接枝量的影響 51
4-1-3 溫度對接枝量的影響 53
4-1-4 改變CDI的量做定量分析的結果 54
4-2 HA-ADH 定性與定量結果 55
4-2-1 HA-ADH之定性分析結果 55
4-2-2 改變ADH的量做定量分析的結果 58
4-3 HAX HYDROGEL 材料鑑定 59
4-3-1 成膠時間(Gelation time) 59
4-3-2交聯指數分析(Cross-linked degree) 66
4-3-3 膠體膨潤度(Swilling ratio) 70
4-3-4 膠體含水量(Water content measurements) 72
4-3-5 機械強度與模數(Mechanical testing: compression test) 73
4-3-6 體外降解(In vitro degradation) 75

第五章 結論 78

參考文獻 80
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