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研究生:蔣祖搴
研究生(外文):Chiang, Zu-Chian
論文名稱:第三代骨組織-生醫材料之設計與研究
論文名稱(外文):Design and Research of Third-Generation Biomedical Materials for Bone Tissue Engineering
指導教授:趙恩中董國忠董國忠引用關係
指導教授(外文):Chao, An-ChongDong, Guo-Chung
口試委員:徐新興糜福龍黃淑玲趙恩中董國忠
口試日期:2014-05-07
學位類別:博士
校院名稱:國立聯合大學
系所名稱:材化博士學位學程
學門:工程學門
學類:材料工程學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:168
中文關鍵詞:殼聚醣支架、地賽米松、骨型態形成蛋白-2、固定化、第三代生醫材料
外文關鍵詞:Chitosan scaffold,Dexamethasone,Bone Morphogenetic Protein-2,Immobilization,Third-Generation Biomedical Materials.
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近半個世紀以來,在已開發的國家中,由於人口年齡層結構不斷向上攀升、邁向人口高齡化,導致骨骼方面的疾病日益趨重。關於骨骼方面之疾病的治療,例如由骨質疏鬆症所引起的骨折或骨缺損,或是關節方面之疾病,已有許多的專家、學者已經開始嘗試使用骨組織工程的方法來完成各自的使命;因此本博士論文著重在骨組織工程方面之第三代生醫材料的設計與研究。骨組織工程是由支架、細胞、刺激因子等三大要素所構成,而支架也就是所謂的生醫材料。本博士論文主要分成三大部分作陳述,其包括有: I. 殼聚醣篇、II. 固定化篇和 III. 地賽米松和骨型態形成蛋白篇。
由於殼聚醣對於製備支架而言,它是相當具有吸引力的生物材料,特別是用於骨骼再生之支架;它是由不規則的β-(1-4)-D-葡萄糖胺 [β-(1-4)-linked D-glucosamine] 和 N-乙醯-D-葡萄糖胺 (N-acetyl-D-glucosamine) 所組成,而一般市面上藥局所販售關於骨骼方面之保養、修復、補充治療的藥物其最主要的成分就是葡萄糖胺 (Glucosamine),所以我們選用殼聚醣作為我們製備支架的對象。殼聚醣篇主要是針對殼聚醣/咖啡酸雜合支架之形態、對水之親和性進行特性分析,並進一步探討該支架對細胞貼覆生長之影響。固定化篇主要是將刺激因子-地賽米松固定作用至殼聚醣支架上,企圖使該支架具有第三代生醫材料的生物誘導性。地賽米松和骨型態形成蛋白篇是在探討不同刺激因子的結合並用(如地賽米松的固定化和骨型態形成蛋白-2) 對於誘導成肌細胞分化至造骨細胞的影響。
鑑于殼聚醣篇的研究結果,我們發現當我們對殼聚醣支架進行越多的處理程序時,其對水的親和性就會越低,而且殼聚醣的胺基也會被用去越多;前者不利於細胞的貼覆,而後者則不利於我們的固定化作用;因此,在固定化篇我們將多孔網狀結構的三維-殼聚醣雜合支架改成薄膜結構的二維-殼聚醣支架,一則方便於研究、再則有利於我們進行固定化程序。固定化篇的研究結果我們發現我們所設計的地賽米松-殼聚醣支架能夠有效的誘導人類脂肪衍生-間葉幹細胞分化至造骨細胞世系;因此我們將其應用在地賽米松和骨型態形成蛋白篇。地賽米松和骨型態形成蛋白篇的研究結果我們發現地賽米松-殼聚醣支架並結合骨型態形成蛋白-2 的作用能夠較有利於誘使成肌細胞 C2C12 分化至造骨細胞世系。
未來我們可以將二維薄膜結構之地賽米松-殼聚醣支架發展成三維多孔網狀結構之地賽米松-殼聚醣支架並結合骨型態形成蛋白-2 的作用,以老鼠作為活體試驗的對象作進一步的研究,並用以發展出最理想的第三代骨組織-生醫材料。

Over the past half a century, the bone diseases have growing rapidly due to the aging population in many developed countries. Many therapies have attempted to use bone tissue engineering approach to treat bone disease such as bone fracture or bone defect derived from osteoporosis and osteoarthritis. Therefore, this study focused on third-generation biomedical material for bone tissue engineering to design and research. The backbone of bone tissue engineering contains Scaffolds, Cells and Stimuli-Factors, and the scaffolds are so-called the biomaterials. This paper is divided into three parts to make the statement, which includes I. Chitosan article, II Immobilization article, III Dexamethasone and Bone Morphogenetic Protein article.
Chitosan is a biopolymer and an attractive biomaterial for preparation of scaffolds, especially for bone regeneration. It is composed of randomly distributed β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine. The drugs that are used to maintain, repair and treat skeletal are sold by pharmacies, which main ingredient is Glucosamine, so we chose chitosan as the object of our preparation of scaffolds. Part I was concentrated on characterizing the morphology and hydrophilicity of chitosan/caffeic acid hybrid scaffolds, and analyzing the cell attachment on that scaffolds. Part II was focused on immobilizing dexamethasone of stimuli-factors onto chitosan scaffolds to attempt having the bioindutive property of third-generation biomedical materials on that scaffolds. Part III was regarded on investigating effect of combination of different stimuli-factors (such as dexamethasone immobilization and bone morphogenetic protein-2, BMP-2) for the induction of myoblasts differentiation into osteoblast lineage.
Given the results of Part I, we found when chitosan scaffolds were treated by increasing process procedures, the affinity to water was lower and amine of chitosan was decreasing; the former is not conducive to cell attachment and the latter is not conducive to our immobilization. Therefore, we changed chitosan scaffolds from three- to two-dimension on immobilization for a convenient research. In the results of Part II, we evidenced that DEX-CSF scaffold we designed can effectively induce the differentiation of human adipose-derived mesenchymal stem cells into the osteoblast lineage; therefore, we applied it in Part III. In the results of Part III, we demonstrated the effect of combination of BMP-2 with DEX-CSF scaffold, which can be more beneficial to induce the progression of C2C12 myoblasts toward osteoblast lineage.
In the future, we can develop DEX-CSF scaffold from two- dimensional film to three-dimensional porous structure, and combined BMP-2 effect to induce bone formation in mice as an in vivo model for development of the third-generation bone tissue biomedical materials.

謝誌 …………………………………………………………I
中文摘要 ……………………………………………………IV
英文摘要 ……………………………………………………VI
目錄 ………………………………………………………VIII
表目錄 ………………………………………………………XIV
圖目錄 ………………………………………………………XV
學術著作 ……………………………………………………XX
第一部 (Part I):殼聚醣篇 …………………………………1
中文摘要………………………………………………………2
英文摘要………………………………………………………3
第一章 緒 論…………………………………………………4
第二章 材料和方法 …………………………………………7
2-1 材 料 ……………………………………………………7
2-2 殼聚醣雜合支架之製備…………………………………7
2-3 支架之形態及親和性 …………………………………10
2-4 生物分析 ………………………………………………11
2-4-1 細胞培養於殼聚醣雜合支架 ………………………11
2-4-2 細胞的貼覆分析 ……………………………………11
2-4-3 支架之鈣化作用 ……………………………………12
第三章 技術原理……………………………………………13
3-1 掃瞄式電子顯微鏡 ……………………………………13
3-1-1 電子顯微鏡之歷史沿革 ……………………………13
3-1-2 電子顯微鏡之原理及架構 …………………………14
3-1-2-1 電子鎗 ……………………………………………17
3-1-2-2 電磁透鏡組 ………………………………………17
3-1-2-3 掃瞄線圈 …………………………………………19
3-1-3 二次電子 ……………………………………………19
3-1-4 能量散射分析儀:特徵 X 光 ……………………20
3-2 示差掃描熱量計 ………………………………………23
3-2-1 示差掃描熱量分析測定法之原理 …………………23
3-2-2 熱流式示差掃描熱量計 ……………………………24
3-2-3 功率補償式示差掃描熱量計 ………………………26
3-2-4 示差掃描熱量分計 (DSC) 技術應用………………27
第四章 結果與討論…………………………………………29
結 論…………………………………………………………41
參考文獻 ……………………………………………………42
第二部 (Part II):固定化篇…………………………………44
中文摘要 ……………………………………………………45
英文摘要 ……………………………………………………46
第一章 緒 論 ………………………………………………47
第二章 材料和方法…………………………………………51
2-1 材 料……………………………………………………51
2-2 殼聚醣薄膜之製備 ……………………………………51
2-3 地塞米松之固定法 ……………………………………52
2-4 地賽米松固定化之定量 ………………………………52
2-5 衰減全反射傅立葉轉換紅外光譜分析 ………………53
2-6 細胞培養於殼聚醣薄膜表面 …………………………53
2-7 細胞影像分析 …………………………………………55
2-8 鹼性磷酸酶之活性測定 ………………………………55
第三章 技術原理……………………………………………57
3-1 高效液相層析法 ………………………………………57
3-1-1 高效液相層析法之進展 ……………………………57
3-1-2 高效液相層析法之原理 ……………………………59
3-1-3 高效液相層析法之應用 ……………………………61
3-2 衰減全反射-傅立葉轉換紅外光譜儀…………………63
3-2-1 衰減全反射-傅立葉轉換紅外光譜儀之進展………63
3-2-2 穿透式/衰減全反射式傅立葉轉換紅外光譜儀之技
術 ……………………………………………………64
3-2-3 衰减全反射法 ………………………………………66
3-2-4 衰減全反射-傅立葉轉換紅外光譜儀之應用………70
第四章 結果與討論…………………………………………72
4-1 地賽米松-殼聚醣支架之製備和特性描述……………72
4-2 地賽米松-殼聚醣支架之鑑定…………………………75
4-3 地塞米松-殼聚醣支架之定量…………………………77
4-4 地塞米松-殼聚醣支架之生物分析……………………79
4-4-1 細胞影像分析 ………………………………………80
4-4-2 鹼性磷酸酶之活性測試 ……………………………83
結 論…………………………………………………………86
參考文獻 ……………………………………………………87
第三部 (Part III):地賽米松和骨型態形成蛋白篇 ………92
中文摘要 ……………………………………………………93
英文摘要 ……………………………………………………94
第一章 緒 論 ………………………………………………95
第二章 材料和方法…………………………………………98
2-1 材 料……………………………………………………98
2-2 二維-殼聚醣薄膜之製備………………………………98
2-3 地塞米松之固定法 ……………………………………99
2-4 地賽米松-殼聚醣支架之定量…………………………99
2-5 衰減全反射-傅立葉轉換紅外光譜分析………………100
2-6 膨潤行為之研究 ………………………………………100
2-7 細胞培養於各種不同條件之殼聚醣支架 ……………101
2-8 細胞影像分析 …………………………………………103
2-9 鹼性磷酸酶之活性測定 ………………………………104
2-10 相對基因表現分析……………………………………105
第三章 技術原理……………………………………………108
3-1 聚合酶鏈鎖反應 ………………………………………108
3-1-1 聚合酶鏈鎖反應技術之發展 ………………………108
3-1-2 聚合酶鏈鎖反應技術之原理 ………………………109
3-2 逆轉錄-聚合酶鏈鎖反應………………………………113
3-3 即時偵測-聚合酶鏈鎖反應……………………………115
3-3-1 即時偵測-聚合酶鏈鎖反應之偵測原理……………115
3-3-2 螢光系統:TaqMan MGB probe……………………118
3-3-3 即時偵測-聚合酶鏈鎖反應之應用…………………121
第四章 結果與討論 ………………………………………123
4-1 地塞米松固定化之殼聚醣支架………………………123
4-2 細胞影像分析…………………………………………128
4-3 鹼性磷酸酶活性測試…………………………………131
4-4 相對基因表現分析……………………………………134
結 論 ………………………………………………………139
參考文獻……………………………………………………140
總 結 ………………………………………………………145







表 目 錄
第一部 (Part I):殼聚醣篇
表 3-1 電子槍之特性比較表………………………………17
表 3-2 能量散射分析儀之優、缺點………………………22
第三部 (Part III):地賽米松和骨型態形成蛋白篇
表 2-1 各種不同條件之殼聚醣支架 ……………………103
表 3-1 聚合酶鏈鎖反應之各組成與其相應之功用 ……110
表 3-2 依據螢光系統在偵測時的特性區分 ……………116
表 4-1 地賽米松固定至殼聚醣支架之單位表面積的質
量 …………………………………………………124








圖 目 錄
第一部 (Part I):殼聚醣篇
圖 2-1 熱縮合-交錯連結法製備殼聚醣雜合支架…………8
圖 2-2 自由基催化作用將咖啡酸接枝於殼聚醣雜
合支架 ………………………………………………9
圖 3-1 顯微鏡光學原理示意圖……………………………15
圖 3-2 掃描式電子顯微鏡立體示意圖……………………18
圖 3-3 電磁透鏡組示意圖…………………………………18
圖 3-4 二次電子偵測器示意圖……………………………20
圖 3-5 能量射散光譜儀示意圖……………………………21
圖 3-6 示差掃描熱量測定法示意圖………………………24
圖 3-7 熱流式 DSC 示意圖………………………………25
圖 3-8 偵測溫度變化示意圖………………………………25
圖 3-9 功率補償式 DSC 示意圖…………………………27
圖 4-1 殼聚醣雜合支架之 SEM 影像……………………30
圖 4-2 各種支架之咖啡酸接枝重量百分率………………31
圖 4-3 四種不同咖啡酸接枝量的殼聚醣雜合支架
之 SEM 影像………………………………………33
圖 4-4 四種殼聚醣雜合支架之能量散射 X 射線
之能譜圖……………………………………………34
圖 4-5 各種支架之孔隙度百分比…………………………35
圖 4-6 各種支架之膨潤行為百分比和不同咖啡酸接枝量
的支架之關係………………………………………36
圖 4-7 各種支架之 DSC 曲線圖…………………………37
圖 4-8 骨瘤細胞 UMR-106 在支架 CA1.25 (a) 與鈣化
作用之支架 CA1.25 (b) 上貼覆生長的情形 ……40
第二部 (Part II):固定化篇
圖 3-1 高效液相色譜儀工作原理示意圖…………………60
圖 3-2 光路比較圖:(a) FTIR 與 (b) ATR-FTIR 裝置
之差異………………………………………………65
圖 3-3 紅外光在介面處發生全反射………………………67
圖 3-4 入射角與穿透深度之關係…………………………69
圖 3-5 多次內反射的形成…………………………………70
圖 4-1 有 (a, b) 與沒有 (c, d) 固定地賽米松的殼聚醣
支架之影像…………………………………………73
圖 4-2 地塞米松固定於殼聚醣支架的反應機制…………74
圖 4-3 (a) 殼聚醣支架和 (b) 地塞米松-殼聚醣支架之
衰減全反射-傅立葉轉換紅外光譜圖 ……………76
圖 4-4 地塞米松在反應前之初始濃度的積分面積 (a)
與在反應後之殘餘濃度的積分面積 (b)……………78
圖 4-5 利用重量和高效液相層析儀積分面積法所測得之
地塞米松的固定量 …………………………………79
圖 4-6 脂肪衍生-間葉幹細胞培養在不同條件的殼聚醣支
架上 7 天 (a, c, e) 和 14 天 (b, d, f),所呈現出
不同的細胞形態 ……………………………………82
圖 4-7 脂肪衍生-間葉幹細胞培養在各種不同條件的支架
上 14 天後,所呈現之鹼性磷酸酶的活性表現 …85
第三部 (Part III):地賽米松和骨型態形成蛋白篇
圖 2-1 地賽米松 (DEX) 與殼聚醣支架 (CSF) 之固定化
反應流程……………………………………………100
圖 2-2 細胞培養程序示意圖………………………………102
圖 2-3 鹼性磷酸酶將 p-硝基苯基磷酸酯降解成 p-硝基
酚……………………………………………………105
圖 2-4 製備 cDNA 之流程 ………………………………106
圖 2-5 進行即時偵測-聚合酶鏈鎖反應之流程 …………107
圖 3-1 在進行 DNA 複製時,DNA 聚合酶將複製需擴
增的區域 …………………………………………109
圖 3-2 聚合酶鏈鎖反應示意圖……………………………112
圖 3-3 (a) 在接合步驟中,引子、TaqMan BMG probe
與 DNA 聚合酶依序黏合至 DNA 模板上 ……119
圖 3-3 (b) DNA 聚合酶沿著模板 3'  5' 方向進行延長
遇到 5' 端的標記螢光基團 ………………………120
圖 3-3 (c) DNA 聚合酶在遇到 5' 端的標記螢光基團時
就將其切下;被切下的 5' 端標記螢光基團隨即
遇到激發光束並與之作用放出螢光………………120
圖 3-3 (d) DNA 模板上殘餘的 TaqMan BMG probe
部分被 DNA 聚合酶切下,但其不發螢光………121
圖 4-1 衰減全反射-傅立葉轉換紅外光譜圖;其分別表
示為 (a) 殼聚醣支架、(b) 地塞米松和 (c) 地塞
米松-殼聚醣支架 …………………………………125
圖 4-2 殼聚醣支架的水合作用百分率,其包括地塞米松
-殼聚醣支架和殼聚醣支架 ………………………127
圖 4-3 成肌細胞 C2C12 培養在各種不同條件的支架上
7 天後,所呈現的細胞影像 ……………………130
圖 4-4 成肌細胞 C2C12 培養在各種不同條件的支架上
7 天後,所呈現之鹼性磷酸酶的活性表現 ……133
圖 4-5 成肌細胞 C2C12 培養在各種不同條件的支架上
7 天後,所呈現之相對基因表現 ………………137

殼聚醣篇:
參考文獻
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