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研究生:林璟暉
研究生(外文):Ching-Hui Lin
論文名稱:天然來源氫氧基磷灰石之萃取及膠原蛋白/氫氧基磷灰石複合支架之製備及支架特性與生物相容性之研究
論文名稱(外文):Extraction of natural hydroxyapatite, characterization and biocompatibility of collagen/hydroxyapatite composite scaffold
指導教授:劉登城
口試委員:林高塚吳勇初
口試日期:2011-07-08
學位類別:碩士
校院名稱:國立中興大學
系所名稱:動物科學系所
學門:農業科學學門
學類:畜牧學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:87
中文關鍵詞:氫氧基磷灰石膠原蛋白複合支架硬骨
外文關鍵詞:hydroxyapatitecollagencomposite scaffoldbone
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氫氧基磷灰石(hydroxyapatite, HAp) 為哺乳動物硬骨中主要無機鹽類,因其生物相容性(biocompatibility)、生物活性及骨引導性 (osteoconduction) 良好,故可廣泛運用於硬骨醫療材料中,而由於牛骨之骨粉因狂牛症的問題已廣泛被許多國家限制進口或使用,如何尋找可替代的安全醫學用骨粉為近年來的重要研究方向,若能有效利用台灣每年所產大量豬骨中之氫氧基磷灰石以取代牛骨,便可解決牛骨所帶來的安全性疑慮。故本研究使用不同溶劑(去離子水及 25 % 氫氧化鈉)與高溫鍛燒(800℃及900℃),純化豬及牛股骨之氫氧基磷灰石並分析其特性,再與第一型膠原蛋白混合製作成不同 Col 比例(1.0 %、1.1 % 及1.2 %)之 Col/HAp 複合支架,評估支架之物化特性及生物相容性。
結果顯示:氫氧基磷灰石特性分析部分,加入氫氧化鈉之豬骨及牛骨經高溫高壓滅菌釜蒸煮後會導致內部之有機成分分解,使其外觀呈現白色,而去離子水處理組外觀則呈現黃色;鍛燒溫度方面,800℃或900℃處理組間並無顯著差異;顯微觀察結果顯示,與氫氧化鈉共同蒸煮之處理組其 HAp 表面會被侵蝕而呈現較光滑或碎裂狀,然去離子水處理組則無此現象並呈現多孔性結構。
複合支架特性分析部分,掃描式電子顯微鏡觀察結果顯示,Col/HAp 複合支架內部呈現多孔性結構,其孔洞直徑介於80.90 – 92.13 μm,適合成骨細胞生長,且孔洞直徑大小皆隨膠原蛋白濃度提高而降低;支架膨潤度方面,在加入磷酸緩衝液1分鐘後,所有處理組皆可迅速吸收液體且達到本身重量之22.96 – 27.93倍,而 Col 濃度提高其膨潤度會有降低的趨勢;抗壓強度方面,複合支架所能承受之應力大小隨 Col 濃度增加而提升;支架降解度方面,各組 Col/HAp 複合支架在酵素作用第3天後即被部分降解,且至第7天時各組 Col/HAp 複合支架已被完全分解,但 Col 濃度較高之處理組其被降解速率較低濃度處理組慢。複合支架生物相容性部分,細胞活性測定結果顯示,各組 Col/HAp 複合支架之細胞存活率均大於對照組,且隨膠原蛋白濃度提高,各複合支架處理組之細胞存活率均有上升之趨勢;細胞毒性觀測方面,各組 Col/HAp 複合支架與7F2細胞共培養後,細胞外觀呈現正常之不規則多角形並貼附孔盤底部,並無出現空泡化、破裂或變形等現象,與未植入支架之對照組相同;細胞植入支架試驗方面,各組 Col/HAp 複合支架與細胞共培養期間,可誘導細胞進入支架中生長,且不會產生細胞毒性。在上述各項支架物化特性及生物相容性分析中,豬股骨與牛股骨來源之 HAp 處理組間並無顯著差異。
綜觀上述,使用去離子水前處理及800℃鍛燒之豬股骨 HAp 其物化特性與牛股骨 HAp 相似,而以豬 HAp 所製備之 Col/HAp 複合支架之孔洞直徑適合成骨細胞生長且具有極佳的膨潤能力。然而,所有複合支架處理組因其結構較鬆散導致其會被膠原蛋白酶快速分解,因此,豬骨來源之 HAp 可替代牛骨以降低狂牛症等風險,但需再加強其結構安定性,為未來硬骨組織工程領域提供一新的研究方向。


Hydroxyapatite (HAp) is major inorganic mineral in animal bone tissue, and it had been used in bone medical materials widely due to its excellent biocompatibility, bioactivity and osteoconduction. Since bovine spongiform encephalopathy (BSE) was a very serious healthy problem when medical bone powder from bovine was used to cure for human and resulted that those bone materials were forbidden to import by many countries. Therefore, how to get a safe bone powder resource for medical purpose is an important research topic in recent years. Hydroxyapatite from porcine bone may be able to replace that of bovine because of an abundant apply in Taiwan. The aim of this study, thus, was to purify hydroxyapatite from porcine bone femur by two solvents (deionized water and 25 % NaOH) and two calcination temperatures (800℃ and 900℃), then to determine their physicochemical profiles and to evaluate the physicochemical characteristics and biocompatibility of bird collagen/hydroxyapatite composite scaffolds with various collagen concentrations (1.0, 1.1 and 1.2%).
The results showed the color of hydroxyapatite from porcine and bovine femur treated with 25% NaOH were white, but treated with deionized water were yellow. There was not significant difference in color at 800 and 900℃. For microstructure, the smooth surface on hydroxyapatite from both bone resources with 25% NaOH treatment were observed by SEM, but porous surface were saw on those with deionized water treatment .
All Col/HAp composite scaffolds demonstrated porous microstructure in frame, and the average diameter of pores were ranged from 80.90 to 92.13 μm, which was suitable for osteoblast to grow. Moreover, the average diameter of the pore was decreased with collagen concentration. In swelling fold, all Col/HAp composite scaffolds could absorb phosphate-buffered saline buffer (PBS) and quickly reach 22.96 - 27.93 fold for 1 minute. Nevertheless, the swelling fold decreased while the collagen concentration was increased. In compressive strength, the compressive stress of Col/HAp composite scaffolds increased with collagen concentration. In scaffold degradation, all Col/HAp composite scaffolds were degraded partially by collagenase at 3rd day, and were degraded completely at 7th day. Noteworthy, the collagen concentration in scaffold was higher the degraded condition was slower. In the biocompatibility of Col/HAp composite scaffolds, all Col/HAp composite scaffolds had higher cell viability than the control, and the cell viability increased with higher collagen concentration. In the cell cytotoxic test, osteoblast showed irregular polygon-like and attached on the bottom in all Col/HAp composite scaffolds. Furthermore, 7F2 cells also didn’t present hollow-, fracture-like and deformed, as well as the control. In the cell planting condition, all Col/HAp composite scaffolds could induce 7F2 cells into scaffold and grew well.
In conclusion, HAp from porcine femur purified by deionized water and calcination at 800℃ had similar physiochemical profiles when compared to those of bovine. The pore sizes of all Col/HAp composite scaffolds were prepared with HAp from porcine in this study were suited for osteoblast growth and had excellent swelling ability. However, all scaffolds were degraded easily by collagenase and resulted in a weaken microstructure for biomedical application. Thereby, HAp purified from porcine bone should be used to replace bovine bone but need to improve the structural stability of scaffolds for the bone tissue engineering in the further.


壹、 前言 1
貳、 文獻探討 2
一、 硬骨結構組成及功能 2
(一) 硬骨成分及結構 2
(二) 硬骨功能 6
(三) 硬骨的細胞種類 7
(四) 硬骨受損之修復與重建 8
二、 氫氧基磷灰石 (hydroxyapatite) 9
(一) 氫氧基磷灰石之結構及特性 9
(二) 氫氧基磷灰石於組織領域之應用 13
三、 膠原蛋白 (collagen) 15
(一) 膠原蛋白之結構 15
(二) 膠原蛋白之一般特性 19
(三) 膠原蛋白於組織工程領域之應用 21
四、 硬骨組織工程支架設計要點 24
(一) 生物相容性 24
(二) 支架外型 24
(三) 支架結構及強度 24
(四) 支架表面特性 24
(五) 支架孔隙度 25
(六) 支架降解速率 25
參、 材料與方法 26
一、 天然來源氫氧基磷灰石之鍛燒前處理 26
(一) 試驗材料 26
(二) 鍛燒前處理 26
二、 氫氧基磷灰石分析項目 27
(一) 製成率 (yield, %) 27
(二) 顯微結構 (microstructure) 及表面特性 (surface properties) 之觀察 27
三、 膠原蛋白/氫氧基磷灰石複合支架之製備 28
(一) 試驗材料 28
(二) Col/HAp 複合支架製作流程 28
(三) Col/HAp 複合支架交聯處理 29
四、 Col/HAp 複合支架分析 30
(一) Col/HAp複合支架之物化特性分析 30
1. 顯微結構 (microstructure) 及孔徑大小 (pore size) 之觀察與測定 30
2. 膨潤度測定 (swelling fold) 30
3. 抗壓強度測定 (compressive strength) 30
4. 支架降解測定 (scaffold degradation) 31
(二) Col/HAp 複合生物相容性測定 33
1. 細胞培養、繼代、計數、冷凍保存及支架殺菌處理 33
2. 細胞活性檢測 36
3. 細胞毒性觀測 36
4. 細胞植入支架試驗 37
五、 統計分析 38
肆、 結果與討論 39
一、 氫氧基磷灰石特性分析 39
(一) 氫氧基磷灰石之外觀 39
(二) 氫氧基磷灰石之製成率 39
(三) 氫氧基磷灰石之顯微結構及表面特性之觀察 40
二、 Col/HAp 複合支架之物化特性分析 48
(一) Col/HAp 複合支架之外觀 48
(二) Col/HAp 複合支架顯微結構及孔洞大小之觀察與測定 48
(三) Col/HAp 複合支架膨潤度測定 54
1. Col/HAp 複合支架膨潤後之外觀 54
2. Col/HAp 複合支架之膨潤度比較 54
(一) Col/HAp 複合支架抗壓強度測定 59
(二) Col/HAp 複合支架降解測定 61
三、 Col/HAp 複合支架之生物相容性分析 65
(一) 細胞活性測定 65
(二) 細胞毒性觀測 65
(三) 細胞植入支架後之觀察 71
伍、 結論 75
陸、 參考文獻 76

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