本研究目的為利用自行合成的聚 (氮-異丙基丙烯醯胺-co-丙烯酸) 共聚物 (Poly(N-isopropylacrylamide-co-acrylate acid), P(NI-co-AA)) 及明膠 (Gelatin)，藉由 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC)/ N-hydroxylsuccinimide (NHS) 作為交聯劑，製備出雙重環境敏感微球，並將其用作藥物載體，包覆鹽酸四環素 (Tetracycline Hydrochloride, TC) 作為模型藥物，為使微球能應用於傷口部位，將其嵌入到石蓴多醣 (Ulvan) 與 Pluronic F127 (PF127) 物理混合的水凝膠中，形成雙重釋放 (Dual release) 的藥物載體。藉由核磁共振光譜儀 (Nuclear Magnetic Resonance, NMR) 鑑定自行合成的 P(NI-co-AA)，鏈段結構中羧基所佔比例為9.07 mol%，並在 35 ℃ 具有低臨界溶液溫度 (Lower critical solution temperature, LCST)。以化學交聯的環境敏感微球 LCST 值約為 32 ℃，以雷射粒徑分析儀測量粒徑分布，當 Gelatin/P(NI-co-AA) 重量比例為 5/2 時，微球有最佳的型態、粒徑分布 並且每毫克微球中含有 TC 為 6.45 μg。不同比例的 Ulvan/Pluronic F127 複合水凝膠透過流變儀及倒置法，評估水凝膠流變性質，其中 1% Ulvan 及 20 % Pluronic F127 的混合水凝膠具有合適的膠凝轉變溫度 (sol-gel transition temperature, Tsol-gel) 及膠凝時間，因此選擇該組別與微球進行配合。微球水凝膠濃度在 2.5% 以下具有良好的細胞相容性，並在 34 ℃、pH 5.5 環境下顯示出較慢的藥物釋放速率，此外所釋放的藥物能有效的抑制多種菌株生長。綜上所述本研究製備的微球水凝膠具有穩定的型態、流變性質及細胞相容性且負載藥物的微球水凝膠可利用溫度及酸鹼值的變化來達到藥物的釋放，可作為傷口敷料之應用。

The purpose of this study was to use self-synthesized (Poly(N-isopropylacrylamide-co-acrylate acid), P(NI-co-AA)) copolymer and gelatin, through 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC)/ N-hydroxylsuccinimide (NHS) as a cross-linking agent to prepare dual environmentally sensitive microspheres. Which were used as drug carriers and loaded Tetracycline hydrochloride (TC). The microspheres was embedded in Ulvan and Pluronic F127 (PF127) hydrogel, which physically mixed with to form a dual release drug carrier. P(NI-co-AA) was identified by Nuclear Magnetic Resonance (NMR), the proportion of carboxyl groups in the segment structure was 9.07 mol%, and it had a low critical solution temperature, LCST) at 35 ℃. The LCST value of chemically cross-linked environmentally sensitive microspheres is about 32 ℃, and the particle size distribution is measured by laser particle size analyzer. When the weight ratio of Gelatin/P(NI-co-AA) is 5/2, the microspheres had the best morphology, particle size distribution and 6.45 μg TC per milligram of microspheres. Different ratios of Ulvan/PF127 hydrogels were evaluated by rheometer and inversion method to evaluate the rheological properties. The mixed hydrogels of 1% Ulvan and 20% PF127 had suitable sol-gel transition temperature (Tsol-gel) and gelation time, so this group is selected to cooperate with the microspheres. The microsphere hydrogel has good cell compatibility below 2.5 %, and shows a slow drug release rate at 34 °C and pH 5.5. In addition, the released drugs can effectively inhibit the growth of various strains. In summary, the microsphere hydrogel prepared in this study has stable morphology, rheological properties and cytocompatibility, and the drug-loaded microsphere hydrogel can use the changes of temperature and pH value to achieve drug release control, can be used as wound dressing application.

摘要 II
Abstact III
目錄 IV
圖目錄 V
表目錄 VII
第一章、前言 8
第二章、文獻回顧 9
2.1 傷口修復 9
2.2 藥物釋放系統 11
2.3 刺激敏感聚合物 (Stimuli-Responsive Polymers) 15
2.4 海藻 17
2.5 交聯劑 20
2.6 鹽酸四環素 (Tetracycline HCl, TC) 22
第三章、實驗動機與目的 23
第四章、實驗流程 24
第五章、材料與方法 25
5.1 實驗材料 25
5.2 實驗藥品 25
5.3 實驗儀器 26
5.4 實驗溶液配置 29
5.5 實驗步驟 30
第六章、結果與討論 36
6.1 P(NI-co-AA) 性質分析 36
6.2 石蓴多醣 (Ulvan) 成分分析 39
6.3 微球 (Microspheres, MS) 性質分析 40
6.4水凝膠性質分析 49
6.5 微球水凝膠 59
6.6 細胞相容性 63
6.7 藥物釋放分析 64
6.8 抗菌試驗 68
第七章、結論 70
第八章、參考文獻 71

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