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研究生:鄭芷菱
研究生(外文):Chih-Ling Cheng
論文名稱:蠶絲蛋白水膠於生醫領域:(1) 蠶絲/透明質酸/聚多巴胺摻合N-乙醯-L-半胱氨酸複合水膠鼻腔藥物遞送 (2)傷口癒合之應用
論文名稱(外文):Silk Fibroin hydrogel in biomedical field : (1) SF/ hyaluronic acid/polydopamine with NAC composite hydrogel for nasal drug delivery, (2) Application in wound healing
指導教授:鍾次文
指導教授(外文):Tze-Wen Chung
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物醫學工程學系
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:2020
畢業學年度:108
語文別:中文
論文頁數:90
中文關鍵詞:蠶絲蛋白聚多巴胺鼻腔遞送至腦緊密連接褐藻醣膠水膠傷口敷料
外文關鍵詞:Silk fibroinPolydopaminenose-to-brain delieverytight junctionfucoidanhydrogel wound dressing
相關次數:
  • 被引用被引用:0
  • 點閱點閱:261
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誌謝 I
中文摘要 II
Abstract III
目錄 V
圖目錄 X
表目錄 XIII
縮寫表 XIV
第一章 緒論 1
1.1 HDS hydrogel 的反應機制介紹 1
1.2 生物材料的簡介 3
1.2.1 蠶絲蛋白 (Silk fibroin, SF, S) 3
1.2.2 透明質酸 (Hyaluronic acid, HA, H) 6
1.2.3 聚多巴胺 (Polydopamine, PDA) 7
1.2.4 褐藻醣膠 (Fucoidan, FC) 9
1.2.5 聚賴氨酸 (Poly-L-lysine, PL, P) 10
1.3 水膠的應用 11
1.3.1 水膠於藥物釋放的應用 11
1.3.2 水膠於組織工程的應用 11
緒論 (I) 蠶絲/透明質酸/聚多巴胺摻合N-乙醯-L-半胱氨酸複合水膠鼻腔藥物遞送 13
1.4 鼻腔藥物遞送至大腦運輸途徑簡介 13
1.4.1 神經途徑 14
1.4.2 跨細胞和細胞旁運輸途徑 14
1.5 藥物從鼻腔遞送之模擬 17
1.5.1 RPMI 2650 細胞培養之體外模式 17
1.5.2 動物鼻腔遞送模式 17
1.6 水膠於鼻腔藥物遞送應用 19
1.7 N-乙醯-L-半胱氨酸 (N-Acetyl-L-cysteine, NAC) 21
緒論 (II) 傷口癒合之應用 22
1.8 傷口癒合機制 22
1.9 理想的傷口敷料 23
1.10 水膠於傷口癒合應用 24
1.11 研究動機與目的 26
第二章 材料與方法 28
2.1 實驗材料與藥品 28
2.2 實驗設備 30
2.3 實驗流程 31
2.4 材料製備 32
2.4.1 蠶絲蛋白溶液製備 32
2.4.2 HDS hydrogel 製備 32
2.4.3 SF/NAC NP製備 33
2.4.4 SDP/FC hydrogel 製備 33
2.4.5 SDP hydrogel 製備 33
2.4.6 SF hydrogel 製備 33
2.5 材料性質分析 34
2.5.1 全反射傅立葉轉換紅外線光譜儀 (ATR-FTIR) 34
2.5.2 核磁共振儀 (NMR) 34
2.5.3 流變儀 (Rheometer) 34
2.5.4 原子力顯微鏡 (AFM) 35
2.5.5 光熱效應分析 35
2.5.6 水膠體外降解試驗 35
2.5.7 水膠過氧化氫濃度的量測 36
2.5.8 粒徑與表面電位量測 36
2.5.9 高場發掃描式電子顯微鏡 (SEM) 37
2.5.10 水膠凍乾之孔隙率 37
2.5.11 水膠含水量 37
2.5.12 水膠膨潤性測試 37
2.5.13 奈米粒子 NAC 包覆率及載藥率 38
2.5.14 NAC 體外藥物釋放 38
2.5.15 材料抗凝血實驗 38
2.6 體外細胞培養實驗 39
2.6.1 細胞培養 39
2.6.2 細胞相容性測試 39
2.6.3 Live/Dead 染色 40
2.6.4 跨上皮電阻儀量測 (Transepithelial electrical resistance, TEER) 40
2.6.5 含 NAC 水膠和奈米粒子的滲透性 40
2.6.6 Tight junction 蛋白的免疫螢光染色 41
2.6.7 體外細胞增殖實驗 41
2.6.8 體外傷口癒合實驗 41
2.6.9 Vimentin 蛋白的免疫螢光染色 42
2.7 活體即時影像檢測系統 (In Vivo Imaging System, IVIS) 42
2.8 統計分析方法 42
第三章 研究結果與討論 43
3.1 HDS hydrogel 特性分析及功能鑑定 43
3.1.1 ATR-FTIR 結構分析 43
3.1.2 NMR 結構分析 43
3.1.3 黏彈性質分析 45
3.1.4 黏著力分析 45
3.1.5 光熱性質分析 47
3.1.6 水膠體外降解 48
3.1.7 抗氧化能力測試 49
3.1.8 細胞相容性測試 51
3.1.9 Live/Dead 染色 52
3.2 SF/NAC NP特性分析 54
3.2.1 FTIR官能基分析 54
3.2.2 粒徑及表面電位分析 54
3.3 HDS hydrogel 結合NAC & SF/NAC NP之應用 55
3.3.1 體外 NAC 釋放實驗 55
3.3.2 Heating effects對 RPMI 2650 細胞的 TEER 57
3.3.3 Heating effects對 RPMI 2650 細胞的滲透 59
3.3.4 Heating effects對 RPMI 2650 細胞的tight junction 影響 60
3.3.5 活體即時影像檢測系統 (IVIS) 62
3.4 SDP/FC hydrogel 特性分析 65
3.4.1 官能基分析 65
3.4.2 孔隙率及SEM圖 66
3.4.3 含水量及膨潤率 67
3.4.4 表面電位分析 68
3.4.5 Live/Dead 染色 68
3.4.6 材料抗凝血實驗 69
3.5 SDP/FC hydrogel 之應用 70
3.5.1 體外細胞增生實驗 70
3.5.2 體外傷口癒合實驗 72
3.5.3 Vimentin染色 73
第四章 結論 74
第五章 未來工作 75
參考文獻 76
附錄 87
1. 水膠的ATR-FTIR圖譜 87
2. DA-BDDE反應對DA聚合的影響 87
3. 水膠的黏彈性質 88
4. 水膠的黏附強度測試 89
5. 奈米粒子的FTIR圖譜 89
6. 奈米粒子的粒徑及電位分析 90
7. Live/Dead 染色 90


圖目錄
圖1. 1本研究中HDS hydrogel 的分子反應機制示意圖 2
圖1. 2 SF透過NF-ΚB signaling 促進細胞增生的機制 5
圖1. 3透明質酸化學結構式 6
圖1. 4 PDA 聚合分子結構示意圖 8
圖1. 5 Fucoidan 化學結構式 9
圖1. 6聚賴氨酸化學結構式 10
圖1. 7鼻內藥物運輸途徑 14
圖1. 8鼻內藥物轉運至中樞神經系統的跨細胞和細胞旁機制的初始過程 15
圖1. 9緊密連接的結構組成 16
圖1. 10 NAC化學結構式 21
圖1. 11傷口癒合組織變化過程 22
圖1. 12理想的傷口敷料設計 23
圖1. 13水膠敷料促進傷口癒合機制 24
圖1. 14實驗設計示意圖 27

圖 2. 1 HA利用Carbazole 定量的反應機制 35
圖 2. 2 Amplex Red經反應轉為Resorufin 36
圖 2. 3表面電位量測 (A) 表面電位量測裝置示意圖, (B) 表面電位量測示意圖 36

圖 3. 1 1H-NMR 圖譜 44
圖 3. 2水膠用AFM 量測重力-距離曲線圖 46
圖 3. 3不同DA濃度的水膠黏著力 46
圖 3. 4不同DA濃度的水膠NIR照射光熱實驗 47
圖 3. 5 HDS hydrogel 隨著時間 (A) SF (B) HA (C)重量維持的百分比 48
圖 3. 6 HDS hydrogel 與Amplex Red reagent 反應 (A)UV-VIS 吸收光譜圖 50
圖 3. 7 HDS hydrogel 的H2O2 濃度 50
圖 3. 8 HDS5 hydrogel 的細胞相容性 51
圖 3. 9 RPMI 2650細胞於 HDS hydrogel 培養之 Live/Dead 染色 53
圖 3. 10體外 NAC 累積釋放曲線 56
圖 3. 11 RPMI 2650 細胞經 (A) HDS/NAC hydrogels (B) HDS/NP hydrogels 加熱處理後 TEER 變化 58
圖 3. 12去除 (A) HDS/NAC hydrogels (B) HDS/NP hydrogels 經加熱處理後 RPMI 2650 細胞 TEER 的恢復率 58
圖 3. 13 NAC 通過RPMI 2650細胞的滲透量 (μg) 59
圖 3. 14 HDS/NAC hydrogels-NIR、HDS/NAC hydrogels及 SF/NAC NP 對RPMI 2650細胞的tight junction表現 60
圖 3. 15 RPMI 2650 細胞於HDS hydrogel 染 tight junction 蛋白 61
圖 3. 16不同組別於大鼠鼻腔給藥的體內螢光系統影像 63
圖 3. 17鼻腔給藥後NAC-FITC隨時間於(A)鼻腔停留(B)輸送至大腦的量測值 64
圖 3. 18 SDP/FC hydrogel 之ATR-FTIR 圖譜 65
圖 3. 19 SDP/FC hydrogel 之SEM圖 66
圖 3. 20 SDP/FC hydrogel 的膨潤率 67
圖 3. 21不同成分水膠的表面電位 68
圖 3. 22 (A) 血液於材料上的凝塊示意圖, (B)用PBS將材料上的血液沖洗量hemoglobin 69
圖 3. 23 L929細胞生長情形 70
圖 3. 24 L929細胞的增殖率 71
圖 3. 25 L929體外刮傷試驗 (A)細胞癒合圖 (B)細胞癒合比率 72
圖 3. 26 SDP/FC hydrogel 於hUMSC 生長情形 73

圖 S. 1 HDS hydrogel 之 ATR-FTIR 圖譜 76
圖 S. 2 (A) DA 在鹼性下聚合 (B) DA-BDDE 在鹼性下聚合 76
圖 S. 3黏附夾具設計圖 78
圖 S. 4 SF/NAC NP 之FTIR 分析 78
圖 S. 5 SF NP 和 SF/NAC NP 之粒徑與表面電位分析 79
圖 S. 6 L929於SDP/FC hydrogel 培養之 Live/Dead 染色 79

表目錄
表 3. 1 NAC 通過RPMI 2650細胞的滲透量 59

表 S1. 水膠的黏彈性質分析 77



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