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研究生:賴郁婷
研究生(外文):Yu Ting Lai
論文名稱:以電紡技術製備聚乳酸-聚甘醇酸/薑黃素/肝素複合奈米纖維膜做為創傷敷料之研究
論文名稱(外文):Composite electrospun PLGA/curcumin /heparin nanofibrous membranes for wound dressing applications
指導教授:陳志平陳志平引用關係
指導教授(外文):J. P. Chen
學位類別:碩士
校院名稱:長庚大學
系所名稱:生化與生醫工程研究所
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:2014
畢業學年度:102
論文頁數:147
中文關鍵詞:創傷敷材電紡技術聚乳酸-聚甘醇酸薑黃素肝素
外文關鍵詞:Wound dressingElectrospinningPLGACurcuminHeparin
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傷口癒合是一個涉及許多相互影響和重疊的複雜生理過程。理想的傷口敷料可暫時代替原生皮膚並加速全皮層創傷的傷口癒合率及減少疤痕的產生。許多文獻上指出薑黃素具有抗氧化與抗發炎之特性,以及肝素對於各種生長因子具有良好的親和力,兩者皆有助於傷口癒合之特性。因此,本研究我們利用電紡技術製備順向性聚乳酸-聚甘醇酸奈米纖維膜 (PLGA),含薑黃素的順向性聚乳酸-聚甘醇酸奈米纖維膜 (PC),及表面固定有肝素含薑黃素的順向性聚乳酸-聚甘醇酸奈米纖維膜 (PCH)。由實驗結果得知,在適當的參數下,能成功的製備出奈米直徑範圍為 456-479 nm ,電紡絲垂直角度為 89.6-90.5° 具有良好順向性的奈米纖維膜。其具有適當的機械強度及良好的吸水性,孔徑測量結果顯示其具有適當的孔徑大小提供營養物及代謝物的交換。由體外細胞傷口癒合結果顯示,PCH 相較 PLGA 和 PC 兩組具有較好的促進細胞遷移能力。在糖尿病大鼠背部全皮層創傷實驗中,利用三種奈米纖維膜進行治療,並用紗布作為陰性對照組。在傷口癒合 14 天後,PCH 具有 86% 的傷口修復率,相較其他組別傷口癒合率有統計上明顯差異。在組織切片結果可見 PCH 在術後 21 天皮膚結構已類似正常皮膚組織,由 α-smooth muscle actin 組織切片染色可看有較多的血管腔體形成,在新生皮膚中有較多的 collagen
v
type III (65.8 %) 和較少的 collagen type I (3.5%) 在傷口癒合後疤痕產生較少。由 Western blot 結果可知 PCH 上的肝素對於生長因子有良好親和力可增加 TGF-β 及 FGF-2 於傷口上的表現量,具有加速傷口癒合能力。總括而言,PCH 奈米纖維膜為最佳傷口癒合之敷材,在臨床應用上可能極具潛力。
Wound healing is a complex process involving many interdependent and overlapping sequences of physiological actions. Ideal wound dressings can replace native skin functions in full thickness skin wounds through faster healing rate and also by reducing scar formation. Curcumin has been shown to inhibit enzymes associated with inflammations. Heparin has binding affinities to various growth factors. Both features could contribute to wound healing and could be incorporated into a composite wound dressing. In this work, we use elctrospinning to prepare curcumin-loaded aligned poly(lactide-co-glycolide) (PLGA) nanofibrous membranes (PC NFMs). PC NFMs was further surfaced grafted with heparin to prepare PCH NFMs. The nanofibrous membranes could act as three-dimensional scaffolds to reduce inflammation, attract fibroblast migration and increase wound-healing related growth factors concentrations at wound sites to promote wound healing. From scanning electron microscopy analysis, the nanofibers in each NFM are with diameters ranging from 456 to 479 nm and with alignment angles from 89.6 to 90.5°. The NFMs show high tensile strength and good water absorptivity and provide suitable pore size for nutrients/wastes transport. In-vitro wound healing assay showed that the extraction medium of PCH NFMs provided better migration ability toward fibroblasts than PLGA and PC NFMs. The in-vivo healing efficiency of the NFMs was further evaluated by a full thickness excisional wound healing diabetic rat model. After 14 days, PCH NFMs exhibits 86% wound closure rate, which is significantly
vii
different from other groups. From histology, the wound area treated with PCH NFMs also showed more vascular lumen formation from immunohistochemistry of α-smooth muscle actin; more collagen type III (65.8%) expression and less collagen type I (3.5%) expression, indicating scar-less wound healing. From Western blot analysis, the PCH NFM showed good affinity toward growth factors from increased concentration of TGF-β and FGF-2 at the wound site to accelerate wound healing. From the results, we suggest PCH NFM as a promising candidate for wound dressing applications.
總目錄
指導教授推薦書
論文口試委員會審定書
致謝................................................................................ iii
中文摘要............................................................................. iv
英文摘要 ............................................................................ vi
總目錄 .............................................................................. viii
圖目錄 .............................................................................. xiv
表目錄 .............................................................................. xviii
第一章 導論 .......................................................................... 1
1.1 研究動機與目的..................................................................... 1
1.2 實驗設計與架構..................................................................... 3
第二章 原理及文獻回顧................................................................... 4
2.1 皮膚的生理結構..................................................................... 4
2.2 傷口癒合.......................................................................... 6
2.3 創傷敷材.......................................................................... 11
2.4 電紡技術.......................................................................... 15
2.4.1 電紡原理 ....................................................................... 15
2.4.2 影響電紡絲的因素 ................................................................ 16
2.4.3 電紡絲於人工敷料上的應用 .......................................................... 17
2.4.4 順向性電紡絲於敷材上的應用.......................................................... 18
2.5 生醫材料.......................................................................... 19
2.5.1 生醫材料簡介 .................................................................. 19
2.5.2 聚乳酸-聚甘醇酸 (Poly(lactide-co-glycolide),PLGA).............................. 20
2.6 薑黃素 (Curcumin)............................................................... 21
2.7 肝素 (Heparin).................................................................. 23
第三章 實驗材料與方法.................................................................. 24
3.1 實驗藥品 ........................................................................ 24
3.1.1 化學藥品及試劑 ................................................................. 24
3.1.2 抗體 ......................................................................... 25
3.1.3 商業試劑套組 .................................................................. 26
3.2 實驗儀器 ....................................................................... 26
3.3 實驗步驟與方法 .................................................................. 28
3.3.1 電紡膜的製備與物性分析 .......................................................... 28
3.3.1.1 電紡高分子溶液製備 ........................................................... 28
3.3.1.2 電紡裝置與參數 ............................................................... 28
3.3.1.3 電紡纖維膜的表面型態分析 (SEM) ................................................. 29
3.3.1.4 電紡纖維膜之電漿改質 .......................................................... 29
3.3.1.5 聚乳酸-聚甘醇酸/薑黃素電紡纖維膜的表面修飾.........................................30
3.3.1.6 電紡纖維膜表面自由羧基定量...................................................... 32
3.3.1.7 電紡纖維膜表面自由胺基定量 ..................................................... 32
3.3.1.8 電紡纖維膜表面肝素定量 ......................................................... 34
3.3.1.9 ESCA 表面元素分析 ............................................................ 35
3.3.1.10 孔徑大小測定 (Pore size) .................................................... 35
3.3.1.11 親疏水性分析 (Water contact angle) .......................................... 36
3.3.1.12 機械強度測量 (Mechanical tensile test) ...................................... 36
3.3.1.13 紅外線光譜圖 (IR Spectroscopy) .............................................. 36
3.3.1.14 熱重分析儀分析 (TGA) ......................................................... 37
3.3.1.15 吸水能力試驗 (water sorption) ............................................... 37
3.3.1.16 奈米纖維敷材的水蒸氣穿透速率 (Water vapor transmission rate,WVTR)............... 37
3.3.1.17 奈米纖維膜體外降解測試 ........................................................ 38
3.3.2 體外與細胞實驗 ................................................................. 39
3.3.2.1 薑黃素體外釋放測試 ............................................................ 39
3.3.2.2 體外細胞毒性測試 .............................................................. 39
3.3.2.3 利用螢光染色法進行 Live/Dead 測試 .............................................. 40
3.3.2.4 細胞之SEM 樣品前處理 .......................................................... 40
3.3.2.5 細胞傷口癒合測試 (wound healing assay) ........................................ 41
3.3.3 體內動物實驗 ................................................................... 41
3.3.3.1 糖尿病鼠誘導 ................................................................. 41
3.3.3.2 活體動物創傷癒合實驗 ........................................................... 42
3.3.3.3 組織病理切片 ................................................................. 43
3.3.3.4 病理切片之免疫組織染色 (Immunochistochemistry,IHC).............................. 43
3.3.3.5 細胞RNA之萃取(RNA Extraction) ................................................ 44
3.3.3.6 即時定量PCR (Quantitative real-time PCR,qPCR).................................45
3.3.3.7 組織蛋白質萃取與定量 .......................................................... 46
3.3.3.8 西方墨點法 (Western blot) .....................................................47
3.3.4統計方法 ....................................................................... 49
第四章 結果與討論...................................................................... 50
4.1 電紡纖維膜製備 .................................................................... 50
4.1.1 電紡纖維膜製備及電紡參數 .......................................................... 50
4.1.2 電紡纖維膜直徑與角度分布 .......................................................... 50
4.2 電紡纖維膜表面改質 ................................................................. 53
4.2.1 電紡纖維膜電漿改質 ............................................................... 53
4.2.2 電紡纖維膜表面胺基修飾 ............................................................ 54
4.2.3 電紡纖維膜表面肝素修飾 ............................................................ 56
4.2.4 修飾前後電紡纖維膜之能量分散光譜儀 (EDS) 分析 .........................................58
4.2.5 修飾前後電紡纖維膜之 ESCA 元素及碳鍵結比例分析.........................................59
4.2.6 修飾前後電紡纖維膜型態之比較 ....................................................... 63
4.3 電紡纖維膜物性分析 ..................................................................64
4.3.1 電紡纖維膜孔徑大小分析 ............................................................ 64
4.3.2 電紡纖維膜親疏水性分析 ............................................................ 66
4.3.3 電紡纖維膜紅外線光譜圖 ............................................................ 70
4.3.4 電紡纖維膜熱重分析 ............................................................... 71
4.3.5 電紡纖維膜機械強度測量 ............................................................ 73
4.3.6 電紡纖維膜吸水能力試驗結果 ......................................................... 75
4.3.7 電紡纖維膜水蒸氣穿透率試驗 ......................................................... 76
4.3.8 電紡纖維膜體外降解試驗結果 ......................................................... 78
4.4 體外及細胞實驗 ..................................................................... 80
4.4.1 薑黃素釋放 ...................................................................... 80
4.4.2 細胞毒性測試 .................................................................... 81
4.4.3 細胞於電紡纖維膜上之 Live/Dead 螢光染色以及 SEM 型態.................................. 82
4.4.4 體外細胞傷口癒合測試 .............................................................. 85
4.5 體內動物實驗........................................................................ 88
4.5.1 糖尿病動物模式建立 ................................................................ 88
4.5.2 糖尿病鼠的創傷癒合實驗 ............................................................. 89
4.5.3 SD rat皮膚創傷癒合率 ............................................................. 91
4.5.4 創傷癒合組織切片染色 .............................................................. 93
4.4.5 膠原蛋白纖維表現情形 .............................................................. 104
4.4.6 α-smooth muscle actin (α-SMA)之免疫組織染色 ...................................... 107
4.4.7 組織中轉化生長因子 β1 的蛋白表現量 .................................................. 110
4.4.8 組織中成纖維細胞生長因子的蛋白表現量 ................................................. 112
4.4.9 組織中抗氧化酵素的基因表現 ......................................................... 114
4.4.10 組織中 IκBα 的基因表現 .......................................................... 116
第五章 結論............................................................................ 117
第六章 參考文獻........................................................................ 119

圖目錄
圖2-1 皮膚結構........................................................................ 4
圖2-2 表皮層結構圖..................................................................... 5
圖2-3 真皮層主要細胞分布圖 ............................................................. 6
圖2-4 傷口癒合的分期:止血期 ........................................................... 7
圖2-5 傷口癒合的分期:發炎期 ........................................................... 8
圖2-6 傷口癒合的分期:增生期 ........................................................... 8
圖2.7 傷口癒合的分期:重塑期 ............................................................ 9
圖2.8 傷口癒合中所參與的生長因子 .................................................. 10
圖2.9 電紡設備示意圖.................................................................. 16
圖2.10 聚乳酸-聚甘醇酸化學結構式 .................................................. 20
圖2.11 發炎反應中薑黃素調節 PI3K/AKT/NFκB 傳遞路徑的分子機制示意圖................... 22
圖2.12 薑黃素化學結構式 ........................................................ 22
圖2.13 肝素化學結構式 .......................................................... 23
圖3.1 電漿反應器裝置圖............................................................ 30
圖3.2聚乳酸-聚甘醇酸/薑黃素電紡纖維膜的表面修飾示意圖 ........ 30
圖3.3 OPA 檢測法之化學反應機制 ..................................................... 34
圖3.4 孔徑大小測試裝置示意圖 .......................................................... 36
圖4.1 奈米纖維膜之 SEM 圖、纖維直徑分佈圖、纖維角度分佈圖。 ................................ 52
圖4.2 以不同電漿反應時間改質後表面的羧基定量 .......................... 53
圖4.3 探討不同 pH 值進行 PEG-di-amine 接枝後表面殘餘羧基含量 (a) 與自由胺基含量 (b)。 ....... 55
圖4.4 探討不同 pH 值 (a) 及不同 Heparin 濃度 (b) 對 Heparin 表面接枝量的影響 ............. 57
圖4.5 奈米纖維薄膜EDS示意圖: .................................................... 58
圖4.6 以XPS分析分析奈米纖維膜表面元素 .................................... 60
圖4.7 以電子能譜化學分析進行檢測分析進行檢測分析 C1s 的圖譜結果。 ............................ 62
圖4.8 表面接枝前後的 SEM 電紡纖維膜型態圖。 ......................... 63
圖4.9 Pore size之孔徑分布圖 ...................................................... 65
圖4.10 電紡纖維膜之接觸角 ................................................................ 68
圖4.11 電紡纖維膜之不同時間接觸角 ................................................ 69
圖4.12 FT-IR 譜圖 ................................................................... 71
圖4.13 電紡纖維膜 TGA 曲線圖 ........................................................ 72
圖4.14 電紡纖維膜之變-應力曲線圖 .................................................. 74
圖4.15 電紡纖維膜的吸水能力 ............................................................ 75
圖4.16 單位面積水份散失和時間的關係圖 ........................................ 76
圖4.17 電紡纖維膜體外降解試驗 ........................................................ 79
圖4.18 體外電紡纖維膜薑黃素釋放 .................................................... 80
圖4.19 電紡纖維膜的細胞毒性測試 .................................................... 81
圖4.20 Live&;Dead 螢光染色分析皮膚纖維母細胞於奈米纖維材料第 3 天之貼附生長情形.............. 83
圖4.21 以 SEM 觀察皮膚纖維母細胞於奈米纖維材料第 3 天之型態............................. 84
圖4.22 體外傷口癒合測試 ........................................................... 86
圖4.23 不同電紡纖維膜體外傷口癒合面積定量之比較........................................ 87
圖4.24 STZ 給藥後 SD rat 的血糖變化 ............................................. 88
圖4.25 SD rat 開創傷口過程 ...................................................... 89
圖4.26 SD rat 創傷癒合試驗 ....................................................... 90
圖4.27 不同敷材於 SD rat 皮膚創傷癒合面積之比較 ..................................... 92
圖4.28 糖尿病SD rat正常皮膚組織切片圖 .............................................. 93
圖4.29 H&;E 染色第 3 天 .......................................................... 96
圖4.30 Masson’s trichrome染色第 3 天 .............................................. 97
圖4.31 H&;E 染色第 7 天 .......................................................... 98
圖4.32 Masson’s trichrome 染色第 7 天 ............................................. 99
圖4.33 H&;E 染色第 14 天 ........................................................... 100
圖4.34 Masson’s trichrome 染色第 14 天 ........................................ 101
圖4.35 H&;E 染色第 21 天 ........................................................ 102
圖4.36 Masson’s trichrome 染色第 21 天 ......................................... 103
圖4.36 第14天 collagen type I 和 collagen type III 染色 ......................... 106
圖4.38 α-smooth muscle actin 染色示意圖 ........................................ 108
圖4.39 α-smooth muscle actin 面積比 ........................................... 108
圖4.40 第14 天 α-smooth muscle actin染色 .......................................... 109
圖4.41 糖尿病大鼠創傷組織中TGF-1 蛋白表現量在不同組別與天數以 Western blot 測試之結果........ 111
圖4.42 生長因子 TGF-β1 於 3、7 及 14 天糖尿病大鼠創傷組織中的蛋白表現定量結果................ 111
圖4.43 糖尿病大鼠創傷組織中 FGF-2 蛋白表現量在不同組別與天數以 Western blot 測試之結果........ 113
圖4.44 生長因子 FGF-2 於 3、7 及 14 天糖尿病大鼠創傷組織中的蛋白表現定量結果................. 113
圖4.45 抗氧化酵素 GPx (a)、SOD (b) 於 3 天及 14 天糖尿病大鼠創傷組織中的基因表現結果......... 115
圖4.46 IκBα於3、7及14天糖尿病大鼠創傷組織中的基因表現結果.................................116

表目錄
表2.1 傷口癒合中主要參與修復的 cytokines 及生長因子 .............. 10
表2.2 為創傷敷材的種類 ..................................................... 13
表2.3 本實驗室歷屆來以高分子聚合物製備創傷敷材之應用 ......... 14
表2.4 電紡參數對纖維型態的影響 ...................................................... 17
表3-1 電紡配方濃度及使用參數 ......................................................... 29
表3.2 即時定量 PCR (Q-PCR) primer ................................................. 46
表4.1 XPS分析奈米纖維膜表面元素含量比例 .................................. 61
表4.2 C-H 鍵結、C-O 鍵結、O-C=O 鍵結、NH-C=O 之峰值面積比 .............. 61
表4.3 電紡纖維膜直徑與孔徑大小表 .................................................. 65
表4.4 電紡纖維膜之接觸角 ......................................................... 67
表4.5 官能基與波數對照表 ......................................................... 70
表4.6 電紡纖維膜的楊氏係數和應變-應力 ........................................ 74
表4.7 奈米纖維薄膜之水蒸氣穿透速率與滲透度 .............................. 77
表4.8 collagen type I 和 collagen type III 面積比 ............................ 105

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