臺灣博碩士論文加值系統

界面相互作用是醫療設備和生物系統之間的首要連結，科學家們認為生物醫學設備的應用性取決於它們的表面特性，設計優良的物化性表面可以增強細胞與表面的附著或抗污能力，例如紋理性質，淨電荷以及親水性。表面性質廣泛被認為是決定生物醫學設備成功的關鍵，包含植入式醫療設備到細胞培養工具與診斷設備，目前已經開發許多表面改質的方式來修飾生物醫學設備的表面，然而只有少數方法可以在基質材料間轉移，甚至有更少數的方法將導致複雜的幾何結構。
儘管脂肪族聚酯類已經被廣泛的使用於生物醫學應用，例如聚乳酸(Poly L-lactic acid, PLLA)及聚己內酯(Polycaprolactone, PCL)，這些材料由於疏水性質及缺乏能夠改質的官能基團而受到諸多限制。目前已經開發許多改善材料表面潤濕性的方法，而功能化的表面為細胞創造良好的界面。本研究提供了一種簡單的水相表面改質方法，這種方法能夠改變任何基質材料的表面性質。這種改質的方式具有環保的特性，過程中不使用任何有機溶劑、起始劑和催化劑。在研究中將介孔生物活性玻璃(Mesoporous bioactive glasses, MBG)嵌入PCL薄膜內，並且透過氨基丙二腈(aminomalonitrile, AMN)與3,4,5-三羥基苯甲醛(3,4,5-trihydroxybenzaldehyde, THBA)的聚合進行改質，結果顯示AMN/THBA共聚物均勻塗佈在PCL和MBG的表面上。此外，改質後的PCL、M-PCL薄膜親水性有顯著的提升。最後在細胞實驗結果顯示，經由AMN/THBA改質後之M-PCL薄膜上的細胞延展性與骨母細胞分化明顯比未處理的組別高。總而言之，我們的研究表明AMN/THBA的表面改質方法具有應用於複合材料和複雜結構的潛力。

nterfacial interaction is the first contact between a medical device and a biological system. Scientists agree that the success of biomedical devices depends on their surface properties. Well-designed surface physical and chemical properties, such as the texture, net charge, and hydrophilicity, can enhance cell attachment to the surface or antifouling. Today there is worldwide agreement that the major factor determines successful of biomedical devices, ranging from implantable medical devices to cell culture tools and diagnostic devices, depends on their surface properties. A broad range of surface modification methods have been developed to modify the surface of biomedical devices. However, only few of methods can be transferred between substrate materials and even less will result in complex geometries. The present study describes a simple, water-based surface modification method that has the ability to alter any substrate materials. Despite the widely use of aliphatic polyesters, such as poly(L-lactic acid) (PLLA), and poly(3-caprolactone) (PCL), for biomedical application, however, these materials are limited due to their hydrophobic property and lack of functional groups for modification. Numerous of approaches have been developed to improve their wettability, to create a friendly interface for cells and to functionalize surface. The present modified process is a green process because no any organic solvents, initiators and catalysts be used. In this work, mesoporous bioglass (MBG) nanoparticles embedding in PCL films were modified by polymerisation of aminomalonitrile (AMN) with 3,4,5-trihydroxybenzaldehyde (THBA). Results demonstrated that AMN/THBA copolymer was homogeneously coating on PCL and MBGs surfaces. Moreover, the hydrophilicity of PCL-based membranes significantly improved after modification. Finally, cell culture test showed that the extension level of cells and mineralization of osteoblast cells were higher on AMN/THBA coating PCL/MBG films than on untreated ones. Overall, our study suggested that the AMN/THBA surface modification method could potentially use in composite materials and complex constructs.

目錄
指導教授推薦書
口試委員審定書
致謝 iii
摘要 iv
Abstract vi
目錄 viii
圖目錄 xi
表目錄 xvi
第一章 緒論 1
1-1 聚己内酯(Polycaprolacton, PCL)的特性與應用 1
1-2材料改質 3
第二章 文獻回顧 5
2-1 Blending 5
2-2表面沉積法 7
2-3 正負電荷相吸附法 10
2-4 共價結合法 13
2-5 電漿表面改質 17
2-6 實驗目的 23
第三章 實驗藥品與儀器 24
3-1 實驗藥品 24
3-2 儀器設備 26
第四章 實驗方法與原理 27
4-1 聚己内酯薄膜的製備 27
4-2 氨基丙二腈塗層 27
4-3 介孔生物活性玻璃製備 27
4-4 孔隙結構分析 28
4-5 骨傳導性化合物-PCL複合材料之表面改質 29
4-6 薄膜之特性分析 30
4-7 體外生物活性測試 30
4-8 類骨母細胞MG63之培養與分化 32
4-9 細胞骨架之螢光染色 32
4-10 MTT細胞活性分析 33
4-12 統計分析 35
第五章 結果與討論 36
5-1 孔隙結構分析 36
5-2薄膜之特性分析 38
5-2-1 表面型態觀察 38
5-2-2 表面元素分析 40
5-2-3 表面電位 42
5-2-4 表面濕潤性分析 43
5-3體外生物活性測試 45
5-3-1 場發射掃描式電子顯微鏡與能量散射X-射線光譜分析 45
5-3-2 X-射線繞射分析 48
5-3-3傅立葉轉換紅外線光譜儀進行分析 52
5-4 薄膜對類骨母細胞之細胞活性測定 56
5-4-1 細胞骨架之螢光染色 56
5-4-2 細胞貼附與增生 59
5-4-3 鹼性磷酸酶之活性 61
第六章 結論 63
參考資料 65

 
圖目錄
圖1-1. PCL的水解機制[6]。 2
圖1-2.生物材料改質技術。 3
圖2-1.含有30% 生物玻璃顆粒（Bioactive Glass Particles, BGP)以及不同生物玻璃微球(Bioactive Glass Microsphere, BGM)含量(0, 10, 20及30 wt.%)的PCL複合材料之吸水率與(A)重量損失率(B)。(C)為含有不同MP含量(0, 20及40 wt.%)的PCL複合材料之重量損失率。含有不同Mg2SiO4含量(0, 10, 20, 30,40及50 wt.%) PCL複合材料的(D)重量損失率與(E)吸水率[44]。 6
圖2-2. 氨基丙二腈生成原理示意圖[12]。 8
圖2-3. 不同材料以AMN改質24小時後(A)contact angle與(B)XPS分析結果[12]。 8
圖2-4. L929纖維母細胞培養24小時後，貼附於(A)TCPS、(B)ULA以及(C)ULA-AMN基材上的細胞生長情形(D)透過MTT進行細胞相對的定量分析(E)透過micro-contact printer技術證實細胞的生長受限於AMN-ULA上(F)AMN萃取液對細胞的毒性影響[12]。 9
圖2-5. 聚酯表面經過NaOH處理後與蛋白質間的離子相互作用。 10
探討三種PCLP支架組別(Control、Coll I coated, and Coll I/CS)材料表面對hMSC人類間葉幹細胞粘附的影響。hMSC(人類間葉幹細胞)細胞貼附能力在所有組別都會隨著培養時間的增加。而支架經過NaOH的處理後，確實比未處理的支架有更多的細胞貼附量，支架表面如果再coated一層膠原蛋白，細胞貼附能力更加顯著(圖2-6)。 10
圖2-6. PLCL材料表面改質前後對hMSC人類間葉幹細胞粘附的影響[53]。 11
圖2-7. hMSC人類間葉幹細胞分別在不同組別支架上(A)ALP活性(B)鈣沉積的結果[53]。 12
圖2-8. 使用Ligand 11改質材料以提高內皮細胞貼附能力[54]。 13
圖2-9.兩種交聯劑固定於PCL表面的機制[55]。 14
圖2-10. 細胞於PCL、PCL-NH2、DGR、DEGE以及GA材料上之貼附能力[55]。 15
圖2-11. SEM影像圖為植入物在血液中2小時後血小板貼附情形，(A) PCL植入物；(B) PCL-RGD植入物。植入3天後血小板與單核細胞在(C)PCL和(D)PCL-RGD植入物上的貼附情形。(E) 暴露於血液2小時後附著血小板的定量分析[56]。(n=3) 16
圖2-12. CAP處理PLA支架的表面粗糙度與化學結構的機制[10]。 17
圖2-13. 奈米表面材料在骨再生材料中的優勢示意圖[57]。 19
圖2-14. (A)未改質的3D-printed支架，CAP電漿改質(B)1分鐘、(C)3分鐘以及(D)5分鐘的SEM影像圖[10]。 20
圖2-15. 3D printed PLA支架在不同CAP改質時間後的(A)AFM與(B)contact angle結果[10]。 21
圖4-5-1. (A)吸脫附等溫曲線(adsorption isotherm)、 (B) 遲滯現象(hysteresis loops)在IUPAC的規範中的分類。 29
圖4-10-1. MTT的反應機制。 33
圖4-11-1. 鹼性磷酸脢(ALP)的反應機制。 34
圖5-1-1. 多孔材料的孔徑分佈。 37
圖5-1-2. MBG之吸脫附曲線圖。 37
圖5-2-1. (A)PCL、(B)APCL、(C)M-PCL及(D)M-APCL之SEM影像圖，放大倍率為300倍。 39
圖5-2-2. (A)MPCL及(B)M-APCL之FE-SEM影像圖，箭頭所指處為MBG。放大倍率為7000倍。 39
表5-2-1. PCL及APCL之XPS定量分析結果。 41
圖5-2-3. PCL及APCL之XPS光譜圖。 41
圖5-2-4. PCL及APCL之表面電位分析定量結果。(樣品檢測溶液: NaCl(aq)，pH =7) 42
圖5-2-5. PCL、APCL、M-PCL及M-APCL之材料表面濕潤性定量分析結果圖。 44
圖5-2-6. PCL、APCL、M-PCL及M-APCL之材料表面濕潤性結果影像圖。 44
圖5-3-1. (A、B、C) PCL、(D、E、F) APCL、(G、H、I) M-PCL及(J、K、L) M-APCL浸泡於1.5倍SBF模擬體液中反應(A、D、G、I) 7天、(B、E、H、K) 14天及(C、F、I、L) 21天後之FE-SEM影像圖，放大倍率為300倍。 46
圖5-3-2. M-APCL浸泡於1.5倍SBF模擬體液中反應21天後之能量散射X-射線光譜分析結果圖。 47
49
圖5-3-3. (A、B、C、D) PCL、(E、F、G、H) APCL、(I、J、K、L) M-PCL及(M、N、O，P) M-APCL浸泡於1.5倍SBF模擬體液中反應(A、E、I、M) 0天、(B、F、J、N) 7天、(C、G、K、O) 14天及(D、H、L、P) 21天後之廣角X-射線繞射分析圖譜。 51
圖5-3-4. (A、B、C、D) PCL、(E、F、G、H) APCL、(I、J、K、L) M-PCL及(M、N、O，P) M-APCL浸泡於1.5倍SBF模擬體液中反應(A、E、I、M) 0天、(B、F、J、N) 7天、(C、G、K、O) 14天及(D、H、L、P) 21天後之傅立葉轉換紅外線分析光譜。 55
圖5-4-1. 類骨母細胞MG63培養於(A、B、C) PCL、(D、E、F) APCL、(G、H、I) M-PCL及(J、K、L) M-APCL薄膜上4小時之螢光染色圖。Reagent: Alexa Fluor 488 phalloidin (λex: 495 nm; λem: 518 nm)、DAPI (λex: 364 nm; λem: 454 nm)，放大倍率為200倍，比例尺為100 μm。 57
圖5-4-2. 類骨母細胞MG63培養於(A、B、C) PCL、(D、E、F) APCL、(G、H、I) M-PCL及(J、K、L) M-APCL薄膜上3天之螢光染色圖。Reagent: Alexa Fluor 488 phalloidin (λex: 495 nm; λem: 518 nm)、DAPI (λex: 364 nm; λem: 454 nm)，放大倍率為200倍，比例尺為100 μm。 58
圖5-4-3. 類骨母細胞MG63培養於PCL、APCL、M-PCL及M-APCL薄膜上(A)細胞貼附與(B)細胞增生能力之測試。(p<0.05具有顯著性差異。) 60
圖5-4-4. 類骨母細胞MG63培養於PCL、APCL、M-PCL及M-APCL薄膜上細胞鹼性磷酸脢活性之測試。(p<0.05具有顯著性差異。) 62
表目錄
表1-1. 常見聚酯類的之熔點與玻璃轉化溫度的比較。 1
表5-1-1. 以BET測量生物活性玻璃比表面積、孔體積與孔徑大小。 37

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