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研究生:吳懿君
研究生(外文):Yi-Chung Wu
論文名稱:膠原蛋白/三鈣矽酸鹽複合骨膠之研究
論文名稱(外文):Study of collagen/tricalcium silicate bone glue
指導教授:鍾仁傑鍾仁傑引用關係
口試委員:葉祖德游佳欣方旭偉
口試日期:2012-07-10
學位類別:碩士
校院名稱:國立臺北科技大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:87
中文關鍵詞:骨膠三鈣矽酸鹽第一型膠原蛋白羧甲基纖維素骨填補物
外文關鍵詞:Bone glueTricalcium silicateType I CollagenCarboxymethyl celluloseBone Graft
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本研究旨在開發一新式複合骨膠,其以三鈣矽酸鹽 (C3S) 為主體並含有高比例第一型膠原蛋白,於初期具有塑性,後期可水合硬化提供強度。
三鈣矽酸鹽是波特蘭水泥中的主要成分,具有快速水合的能力使其在短時間內硬化。過去研究指出其能誘導類骨磷灰石的生成,有良好的骨質結合能力。第一型膠原蛋白,主要分布於皮膚、硬骨及血管等多數結締組織,在組織重建、傷口癒合便演種要角色。羧甲基纖維素( CMC )是纖維素基環上氫氧基被甲基取代之衍生物。根據不同的取代度產生不同程度的黏稠性質,近年來廣泛被應用於生醫產品中。
本實驗選用中取代度羧甲基纖維素鈉以增加材料的黏附力,並進行機械性質測試、表面型態與晶相分析、pH值變化、離子濃度測試,並以人類骨母細胞( MG 63 Cell ) 進行生物相容性測試以及四環素與雙氯芬酸鈉之制放。試驗結果顯示含有40%膠原蛋白的複合骨膠 (Glue 40) 有較短的工作與固化時間,分別為11分鐘與150分鐘。在體外黏附測試中有較佳黏附性質,剪切黏力亦較其他材料高,約為416 Kpa,正向黏力為167 KPa。而在人工模擬體液浸泡養護七天後,材料明顯膠結成塊。pH 值維持在7 ~ 9之間。綜合上述結果,我們選擇Glue 40為較佳比例繼續進行後續抗壓強度、生物相容性與藥物制放等測試。經過飽和水蒸汽壓養護七天,可看到抗壓強度隨著養護時間增加而增強,於第7天達到500 KPa。此外,添加羧甲基纖維素鈉不僅增強材料的黏性,對MG 63 ell增生之效果。四環素的釋放結果顯示,材料於初期具有突釋效果,自4%上升至13%;後期則可穩定的持續釋放藥物,穩定維持在20 %。而在雙氯芬酸鈉釋放2天後,釋放率自46 % 上升至53 % ,且後續釋放穩定維持在 53 % 左右。
由材料機械性質、體外黏附測試、生物相容性測試與藥物制放等實驗結果顯示,Glue 40為一具有潛力的可攜載藥物新式複合骨膠。


In this study, the aim is to develop a novel bone glue composed of tricalcium silicate and high proportion of type I collagen. The bone glue has plasticity in the early stage and will self-set after hydration to provide mechanical strength.
Tricalcium silicate (C3S) is one of the main components of Portland cement, with the ability of rapid hydration to harden in a short period of time. It was reported to induce the formation of bone-like apatite and with excellent bone binding capacity in vitro and in vivo. Type I collagen, the main distribution of the majority of connective tissue in the skin, hard bone and blood vessels, plays important roles in tissue remodeling, wound healing and bone reconstruction. Carboxymethyl cellulose (CMC) is a cellulose-based ring hydroxyl methyl substituted derivative. Depending on the degree of substitution, CMC provides different levels of the sticky property and has been widely used in biomedical products in the recent years.
In this experiment, sodium carboxymethyl cellulose with medium degree of substitution was applied to increase the adhesion property of the bone glue. Mechanical property test, surface morphology observation, crystalline phase analysis, in vitro pH value measurement, ions releasing, cytotoxicity test with MG 63 cell line and the drug releasing test including antibiotics and nonsteroidal anti-inflammatory were carried out.
The results indicated that bone glue containing 40% collagen, Glue 40, had the following advantages, including shorter working time and setting time, about 11 and 150 minutes, respectively; better adhesion ability in vitro; higher adhesive strength about 416 Kpa; higher tensile strength about 167 Kpa. After seven days curing in the simulated body fluid, Glue 40 was cemented to be block and the changes of pH value was controlled between 7~9. Furthermore, Glue 40 was selected for advanced investigations.
After seven days of curing in the saturated vapor of water, the compressive strength of Glue 40 increased with time and reached the maximum value of 500 Kpa. In addition, the additive of CMC not only enhanced the viscosity of the material, but also promoted the proliferation of MG 63 cells. Results of tetracycline releasing test showed that Glue 40 had the ability of initial burst, from 4% to 13%, and then maintained about 20%. Results of diclofenac sodium releasing test showed that after two days the release increased from 46% to 53%, and then maintained about 53%. Concluding the results of tests, Glue 40 has great potential to be a novel bone glue carrying with drugs.


目錄
摘要 I
Abstract III
誌謝 V
第一章 緒論 1
1-1 前言 1
1-2 研究動機與目的 2
第二章 文獻回顧 3
2-1 骨骼系統 3
2-1-1骨組織構造與成分 4
2-1-2 骨骼生理 6
2-1-3 骨細胞 6
2-1-4 骨骼修復重建機制 7
2-1-5 骨折種類與治療方法 8
2-2 生醫材料介紹 10
2-2-1生醫材料分類 11
2-2-2三鈣矽酸鹽 14
2-3 組織膠介紹 16
2-3-1 骨膠的發展與應用 16
2-3-2 膠原蛋白 19
2-3-3 羧甲基纖維素鈉 21
2-4 藥物制放 23
2-4-1四環素 23
2-4-2 非類固醇抗發炎藥物 24
2-5 體外生物相容性測試 26
2-5-1 細胞毒性測試 28
第三章 材料與方法 29
3-1 實驗藥品 29
3-2 實驗儀器 30
3-3 材料製備 32
3-3-1 Zn0.075Ca2.925SiO5粉末製備流程 33
3-3-2去免疫端膠原蛋白製備流程 36
3-3-3 2wt%羧甲基纖維塑膠體溶液製備流程 38
3-4 材料性質分析 39
3-4-1 工作與固化時間量測 39
3-4-2 抗稀散性質測試 40
3-4-3 體外黏附測試 41
3-4-4酸鹼值變化及離子濃度量測 42
3-4-4.1酸鹼值變化 42
3-4-4.2離子濃度量測 43
3-4-5材料機械性質測試-正向黏力、剪切黏力與抗壓強度 44
3-4-6 材料表面型態及晶格分析 46
3-4-6.1掃描式電子顯微鏡 46
3-4-6.2 X光繞射儀 47
3-4-7生物相容性測試 ( MTT assay ) 48
3-4-8藥物制放測試 49
3-4-9抑菌圈測試 50
3-4-10藥品溶液配製表 51
第四章 結果與討論 53
4-1 工作與固化時間量測 53
4-2 材料性質測試 55
4-2-1 抗稀散性質測試 55
4-2-2 體外黏附測試 57
4-3 酸鹼值變化及離子濃度量測 59
4-3-1 酸鹼值變化 59
4-3-2 離子濃度量測 61
4-4 材料機械性質測試 64
4-4-1剪切黏力測試 64
4-4-2正向黏力測試 65
4-4-3抗壓強度測試 66
4-5 材料表面型態觀察與晶相分析 67
4-5-1材料表面型態觀察 67
4-5-2晶相分析 69
4-6 生物相容性測試 ( MTT assay ) 73
4-7 藥物制放測試 74
4-7-1 四環素 74
4-7-2 抑菌圈 75
4-7-3 非類固醇抗發炎藥–雙氯芬酸鈉 77
第五章 結論 78
第六章 參考資料 81



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