控制具有生物相容性之抗沾黏表面對於醫療需求是重要的環節。於本研究中，我們利用物理吸附方式將具有疏水-親水的三團聯共聚物聚氧乙烯-聚氧丙烯-聚氧乙烯(PEO-PPO-PEO)，吸附於自組裝單層膜的表面CH3-SAM上。研究系統以兩種不同系列的PEO-PPO-PEO來改變基材表面的親疏水特性。第一個系統為具有相同的PPO分子量(~2 k)，但不同的PEO/PPO的比例(~20/80, 40/60以及80/20, w/w)；第二個系統為具有不同的總分子量(~9, 11和 15 k)，但具有相同的PEO/PPO比例(80/20, w/w)。以表面電漿共振儀來即時量測共聚物於疏水表面CH3-SAM的吸附量及蛋白質吸附於共聚物表面的吸附量。本研究將系統地探討PEO-PPO-PEO分子量、PEO/PPO比例與不同的鹽離子強度對於單一蛋白(Fibrinogen和BSA)和混合蛋白吸附行為的影響。實驗發現經由PluronicTM F108所處理的表面於最佳條件下(分子量~15 k和PEO/PPO比例為80/20)具有高度的抗非特定蛋白吸附的能力。本研究中發現經由PEO-PPO-PEO共聚物所改質的表面，可以藉由控制共聚物於的表面堆疊密度來達到超低生物沾黏的表面，如透過控制共聚物之分子量、親疏水的比例和親水基團的覆蓋程度。

A well-controlled biocompatible nonfouling surface is significant for biomedical requirements, especially for the improvement of biocompatibility. We demonstrate the low or nonfouling surface by coating hydrophobic-hydrophilic triblock copolymer of poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) (PEO-PPO-PEO) on the CH3-terminated self-assembled monolayer (SAM). Two types of copolymers are used to modify the surface, one with different PEO/PPO ratio (~20/80, 40/60, and 80/20, w/w) but the same ppo molecular weight (~2 k), the other with different copolymer MWs (~9, 11, and 15 k) but the same PEO/PPO ratio (80/20, w/w). In situ surface plasmon resonance (SPR) sensor is used to evaluate polymer adsorption on the SAMs and subsequent protein adsorption on the copolymer-treated surface. The effect of PEO-PPO-PEO molecular weight, PPO-to-PEO ratio, and ionic strength on protein adsorption from single protein solution of Fibrinogen, BSA, and complex mixed proteins are systematically investigated. A PluronicTM F108 treated surface is highly resistant to non-specific protein adsorption under the optimized conditions (MW of 15 k and PEO/PPO ratio of 80/20). This work demonstrates that the PEO-PPO-PEO polymer is able to achieve ultra low fouling surface modification by controlling surface packing density of polymers (molecular weight, hydrophobic/hydrophilic ratio, and hydrophilic group coverage).

目錄
中文摘要 I
英文摘要 II
誌謝 III
目錄 IV
圖目錄 VII
表目錄 XI
第一章 緒論 1
1.1 研究背景 1
1.2 聚乙烯乙二醇之簡介與發展 4
1.3 研究動機與目的 6
第二章 文獻回顧 8
2.1 生物材料發展背景 8
2.1.1 生物材料的分類及基本性質 11
2.1.2 生物材料的使用性能 16
2.1.3 生物材料的未來發展 20
2.2 生物分子與材料表面之交互作用 23
2.2.1 血液之組成 23
2.2.2 血液組成與表面的交互作用 24
2.2.3 水與表面的交互作用 24
2.2.4 蛋白質與表面的交互作用 25
2.2.5 細胞與表面的交互作用 27
2.2.6 血栓的形成 28
2.3 三團聯共聚物PluronicTM介紹 30
2.3.1 PluronicTM命名方式 34
2.3.2 臨界微胞濃度(Critical Micelle Concentration ) 36
2.4 表面電漿共振(Surface Plasmon Resonance, SPR) 39
2.4.1 表面電漿共振原理 39
2.4.2 表面電漿共振感測類型 42
2.4.3 表面電漿共振的應用 43
第三章 實驗藥品、設備及實驗方法 53
3.1 實驗藥品 53
3.2 實驗設備 57
3.3 實驗方法 58
3.3.1 緩衝溶液的製備 58
3.3.2 蛋白質溶液的製備 59
3.3.3 血漿溶液的分離與稀釋 59
3.3.4 金表面改質 60
3.3.5 表面電漿共振感測儀之實驗 62
3.3.6 晶片表面親疏水性量測：液相接觸角 63
第四章 結果與討論 64
4.1 自組裝三團聯共聚物PEO-PPO-PEO表面 66
4.2 PEO-PPO-PEO表面之親疏水性量測：液相接觸角 71
4.3 蛋白質吸附測試 74
4.3.1 單一蛋白質於PEO-PPO-PEO表面之吸附測試 75
4.3.2 表面PEO鏈段分佈密度與蛋白吸附之關聯性 80
4.4 PEO-PPO-PEO表面之血液相容性 83
4.5 最適化表面堆疊密度之PEO-PPO-PEO表面其抗蛋白質吸附特性的探討 87
4.5.1蛋白質三重複吸附測試 87
4.5.2溶液離子強度對於抗蛋白質吸附的影響 88
第五章 結論 93
參考文獻 94
附錄 102


圖目錄
第二章
圖 2- 1 人工關節替換手術中各種失敗因素與植入時間的關係。表示因感染所致失敗的作用逐漸減弱，其他因素作用日益增強。 20
圖 2- 2 血栓形成過程示意圖。 29
圖 2- 3 由乙烯、丙烯所衍生的界面活性劑及其原料之合成途徑。 30
圖 2- 4 三團聯共聚物合成示意圖。 31
圖 2- 5 三團聯共聚物PEO-PPO-PEO圖表“ pluronic grid ”。縱線上的共聚物具有相同的PPO/PEO比例，橫線上具有相同的PPO分子量。 35
圖 2- 6 界面活性劑分子在水溶液中安定化之方向。 36
圖 2- 7 表面張力─濃度曲線與界面活性劑之溶解狀態。 37
圖 2- 8 表面電漿波示意圖。 40
圖 2- 9 色散關係曲線圖。SP：系統之表面電漿波色散曲線。 41
圖 2- 10 (a)Otto組態示意圖；(b)Kretshmann組態示意圖。 42
圖 2- 11 抗原決定部位定位研究。 46
圖 2- 12 蛋白質在自組裝單分子膜層上的吸附。 48
圖 2- 13 不同蛋白質在血漿中於聚苯乙烯表面的吸附。用相應的抗體檢測浸泡在0.1%的血漿溶液中的聚苯乙烯表面上吸附的血清白蛋白、免疫球蛋白G和纖維蛋白原的量隨浸泡時間的變化。 49
圖 2- 14 血清白蛋白在不同改值聚苯乙烯表面上的吸附。 51
圖 2- 15 親和素在PLA-PEG聚合和經過生物素修飾PLA-PEG-biotin 52

第三章
圖 3- 1 自組裝之表面電漿共振感測儀。(1)蠕動幫浦，(2)白光光源，(3)偏極裝置，(4)晶片載具裝置組(含flow cell、夾具、耦合稜鏡)，(5)訊號偵測裝置，(6)訊號處理器，(7)溫控裝置。 62
第四章
圖 4- 1 圖示說明實驗流程步驟。PEO-PPO-PEO先吸附於生物晶片上，然後再通入血漿蛋白進行吸附測試。 64
圖 4- 2 基本的表面電漿共振儀(SPR)的訊號圖。PluronicTM F108先吸附於表面上，接著直接通入人體纖維蛋白進行吸附測試。於SPR上蛋白質的吸附量，約等於共振訊號波長偏移1nm，轉換為15ng/cm2蛋白質的吸附量。 65
圖 4- 3 利用表面電漿共振儀(SPR)量測五個不同的三團聯共聚物(PluronicTM L62, L64, F68, F88 和F108)於CH3-SAM表面在不同濃度下之吸附量。於SPR上三團聯共聚物的吸附量，可藉由共振訊號波長偏移1nm，轉換約等於22ng/cm2三團聯共聚物的吸附量。 69
圖 4- 4 圖示說明靜態液相接觸角實驗的操作步驟。 71
圖 4- 5 不同Pluronic溶液於四個不同濃度下的表面親疏水性測試，於液相操作的接觸角數據。 73
圖 4- 6 利用SPR於23℃下進行人類纖維蛋白原(Fibrinogen)吸附於三團聯共聚物 PEO-b-PPO-b-PEO(L62 , L64 , F68 , F88和F108)於不同濃度CPEO-PPO-PEO下所形成表面。 77
圖 4- 7 利用SPR於23℃下進行牛血清蛋白(BSA)吸附於三團聯共聚物 PEO-b-PPO-b-PEO(L62 , L64 , F68 , F88和F108)於不同濃度CPEO-PPO-PEO下所形成表面。 78
圖 4- 8 圖示說明高分子不同的堆疊程度所造成的蛋白質吸附於疏水表面(CH3-SAM)上。 79
圖 4- 9 利用SPR於23℃下，牛血清蛋白(BSA)和纖維蛋白原(Fibrinogen)吸附於三團聯共聚物F68 , F88和F108對應表面PEO鏈堆疊密度(個PEO鏈/100 nm2單位面積上)。 81
圖 4- 10 血漿蛋白吸附於CH3-SAM、OEG-SAM、F108-L和F108-H表面於37oC下進行吸附測試。於SPR上共振訊號波長偏移1nm，約等於15ng/cm2蛋白的吸附量。 85
圖 4- 11 於23oC，人類纖維蛋白原(Fibrinogen) 1.0mg/mL三循環的吸附於三團聯共聚物F108表面。 88
圖 4- 12 於23oC下以SPR進行三種不同鹽類和濃度變化下，Fibrinogen 三重複不可逆之吸附測試於F108-H表面，以三種不同顏色分別代表三種不同的鹽類。 90
圖 4- 13 (A)溶質優先從蛋白質鄰近鍵結水區域排出，(B)具有優先排出性的溶質，其表面能夠抵抗蛋白質吸附。 92


表目錄
第二章
表2- 1生物材料的應用 8
表2- 2金屬材料、有機高分子、無機非金屬材料的性能比較。 13
表2- 3生物陶瓷材料的臨床應用範圍。 15
表2- 4生物材料在器官中的應用。 17
表2- 5應用於人體系統的生物材料。 17
表2- 6各種生物材料優缺點比較。 18
表2- 7血液組成比例。 23
表2- 8 HLB値與用途的對應關係與水溶性的關係。 32
表2- 9 三團聯共聚物PluronicTM(PEO-PPO-PPO)的特性。 33
第三章
表3- 1 實驗設備列表 57
第四章
表4- 1 三團聯共聚物PluronicTM PEO-PPO-PEO分子量組成表a。 67

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