臺灣博碩士論文加值系統

隨著民眾對口腔健康的日益重視以及牙科醫療技術的不斷演進，目前缺牙區域的贋復主流已從牙橋、活動假牙等難以清潔或是功能受限的傳統方式，逐漸轉變為將鈦合金人工牙根植入顎骨後等待骨整合，再於其上製作單顆固定式贋復物的植牙療程。也因為人工牙根需植入顎骨，因此在缺牙過久或因外傷、疾病等因素導致顎骨質量不佳的狀況必須預先處理，是故顎骨組織修補及再生手術的需求與日俱增。
目前牙科補骨手術主要是以骨粉填補缺陷，上覆再生膜以維持骨粉穩定並防止軟組織長入骨缺損區域，此術式名稱為引導骨再生手術（guided bone regeneration, GBR）。但此術式的主要缺點在於粉末顆粒狀的補骨材料僅有維持空間的骨傳導性（osteoconductivity），與再生膜的搭配操作也具有高度技術敏感性。因此，研發兼具骨傳導性及骨誘導性（osteoinductivity），並且易於操作的口腔植骨材料的重要性不言可喻。
以鈣矽陶瓷為基底的生醫材料因其良好的生物相容性以及機械強度，作為外科的補骨材料以及牙科齒質的修復材料已有多年歷史。近來的新製程則可將矽酸鈣生醫陶瓷粉末進階製備為具有介孔洞的奈米微粒，賦予矽酸鈣作為控制藥物釋放的載體潛能。因此本研究導入三維列印技術（3D-printing）的熔融沉積法（fused deposition modeling, FDM），研發出含骨塑型蛋白二（bone morphogenetic protein-2, BMP-2）的介孔洞矽酸鈣三維支架（mesoporous calcium silicate, MesoCS），搭配患者的電腦斷層影像，可客製化為具備骨誘導性且易於操作的植骨材料。而本研究的主要目的在於評估此新式三維陶瓷支架所添加的BMP-2是否能成功釋放而展現誘導成齒（odontogenesis）及成骨（osteogenesis）分化的能力，以及BMP-2載入支架的方式是否影響其釋放效能。
本研究的第一階段，以FDM列印而成的含BMP-2的MesoCS三維支架，首先以光學顯微鏡、電子顯微鏡以及萬用試驗機檢測其基本性質，再以模擬體液（simulated body fluid, SBF）試驗、人類牙髓細胞（human dental pulp cells, hDPCs）的培養實驗，以及鹼性磷酸酶活性測試，證實含BMP-2的MesoCS三維支架的誘導成齒及成骨分化的能力。第二階段則對臨床上可能的兩種BMP-2載入支架方式執行進一步的分析，包括將BMP-2預先與MesoCS粉末混合作為列印原料的預先承載（pre-loading, PL）方式，以及將列印完成的MesoCS支架直接浸泡於BMP-2溶液中的直接承載（direct-loading, DL）方式。
第一階段實驗結果，在SBF測試的部分，MesoCS支架與CS支架在鈣離子與矽酸根離子的釋放能力相似，然而在BMP-2的部分，CS支架呈現的是傳統的爆發釋放（burst release）模式，在實驗的前48小時大量釋放，而後迅速衰減，而MesoCS支架至7日後仍能呈現平緩上升的釋放曲線（p < 0.05）。同時，hDPCs的貼附、增殖與分化，以及鹼性磷酸酶活性，也都是含有BMP-2的MesoCS支架有明顯較好的表現（p < 0.05）。第二階段的研究結果則顯示，預先載入BMP-2的MesoCS支架的平緩上升釋放曲線較符合臨床需求，直接載入的支架則仍呈現出爆發釋放的模式，未能達到控制釋放的效果。
新研發的MesoCS三維孔洞支架在本研究中成功地製造並且進行測試。實驗結果亦證實本支架具有良好的生物相容性以及控制BMP-2釋放的能力，能夠誘導細胞進行成骨分化或成齒分化，因此具有作為骨組織再生手術中的骨誘導材料，或是牙髓再生術中的修復材料的極大潛能。

中文摘要 I
ABSTRACT III
目錄 VI
圖次 IX
第一章 緒論
1 骨組織再生於牙科醫療的重要性 1
2 現今引導骨再生手術的缺點 1
3 牙髓及牙根組織再生於根管治療的發展 2
4 引導組織再生材料的理想特性 3
5 三維列印技術的醫療應用 3
6 三維結構支架的熔融沉積成型 4
7 鈣矽生醫陶瓷的發展與特性 5
8 介孔洞矽酸鈣奈米微粒 6
9 聚己內酯 6
10 骨塑型蛋白二 7
11 研究動機與目的 9
12 具體目標 9
13 論文架構 10
第二章 含BMP-2介孔洞矽酸鈣三維列印支架誘導人類牙髓幹細胞成齒分化的能力
1 研究背景與目的 11
2 研究材料與方法 14
2.1 介孔洞矽酸鈣奈米微粒的製備與定性 14
2.2 BMP-2的承載 14
2.3 支架的製備 14
2.4 支架的機械性質 15
2.5 體外試驗 15
2.6 BMP-2的釋放動力學 16
2.7 人類牙髓細胞的分離與培養 16
2.8 細胞的貼附與增殖 16
2.9 螢光染色 17
2.10 西方墨點法 17
2.11 細胞的成齒分化 18
2.12 鈣質沉積 18
2.13 統計方法 18
3 研究結果 19
3.1 物化性質 19
3.2 離子及藥物釋放 19
3.3 細胞的貼附與增殖 20
3.4 訊息傳遞路徑分析 21
3.5 成齒分化 21
4 討論 23
5 結論 25
第三章 介孔洞矽酸鈣三維列印支架的BMP-2承載方式對誘導人類瓦頓氏凝膠間質幹細胞成骨分化的影響
1 研究背景與目的 40
2 研究材料與方法 43
2.1 介孔洞矽酸鈣奈米微粒的製備與定性 43
2.2 支架的製備 43
2.3 BMP-2的乘載 44
2.4 支架的機械性質 44
2.5 體外試驗 44
2.6 BMP-2的釋放動力學 44
2.7 細胞的貼附與增殖 45
2.8 螢光染色 45
2.9 西方墨點法 46
2.10 細胞的骨性分化 46
2.11 鈣質沉積 46
2.12 統計方法 47
3 研究結果 48
3.1 物化性質 48
3.2 藥物釋放 48
3.3 支架上的磷灰石沉積 48
3.4 細胞的貼附與增殖 49
3.5 BMP-2受體的表現 49
3.6 成骨分化 50
4 討論 51
5 結論 53
第四章 總結 65
參考文獻 66

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