開發具有骨引導性之仿生凝膠應用於固定永久性硬骨植入物

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林峻宇(Chun-Yu Lin) 查詢紙本館藏

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生物醫學工程研究所

論文名稱

開發具有骨引導性之仿生凝膠應用於固定永久性硬骨植入物
(Development of Biomimetic Gel with Osteoconductivity for Fixation of Permanent Bone Implants)

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★ 開發人工利基應用於常溫細胞儲存和運輸

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摘要(中)

身體老化引起的骨質疏鬆（Osteoporosis）常導致骨折（Bone fracture），目前臨床上常使用骨水泥（Bone cement）固定螺釘型植體（Bone screw）以防止鬆脫。然而，骨水泥存在脆性（Brittleness）、高溫聚合（Heat of polymerization）、應力屏蔽（Stress shielding）及骨整合（Osteointegration）不良等問題，不適合用於骨質疏鬆患者。本研究開發了一種凝膠填補物，旨在替代傳統骨水泥，作為骨質疏鬆患者固定植體的選擇。凝膠材料由聚丙烯酸鈉（ASAP）、明膠（Gelatin）、β-三磷酸鈣（β-TCP）和生理食鹽水（Normal saline）以雙針筒（Syringe）混合而成。研究方法包括討論仿生凝膠的β-TCP含量，凝膠生物相容性（Biocompatibility）測試，凝膠物理和化學特性分析，以及功能性測試，功能性測試包括力學特性、生物工程應用特性、動物實驗功效性和架儲期測試。首先，仿生凝膠組ㄉ被定義為對照組Gel與實驗組Gel-6B兩組，結果顯示，仿生凝膠具有生物相容性；物理和化學特性中，透過掃描式電子顯微鏡（SEM）觀察到仿生凝膠具有多孔結構（Porous structure）且Gel-6B中含有β-TCP，X光繞射儀（XRD）和傅立葉轉換紅外光譜儀（FTIR）揭示了Gel和Gel-6B的主要成分，仿生凝膠的聚合（Polymerization）溫度低於30℃，凝膠浸泡於1x PBS中28天無明顯酸鹼稀出，流變儀（Rheometer）驗證了Gel和Gel-6B在擠出後開始成膠的時間，崩解測試顯示Gel在2小時內出現凝膠結構崩解，而Gel-6B則無明顯崩解；功能性測試中，仿生凝膠能夠承受50%形變量（Strain）並恢復至接近原形，萬用試驗機（UTM）的測試結果中顯示仿生凝膠的機械強度（Mechanical strength）與骨質疏鬆患者鬆質骨（Cancellous bone）硬度相近；體外測試證實了凝膠的骨引導性（Osteoconduction）和骨整合性（Osteointegration）；動物實驗中，使用電腦斷層掃描（Computed tomography, CT）照影和組織切片（Tissue section）觀察到Gel-6B有助於骨缺損癒合。因此，本研究認為Gel-6B對於骨質疏鬆患者在固定植體方面是具有潛力的，即幫助螺釘型植體與原生骨組織整合，使螺釘型植體達成永久固定之目的。

摘要(英)

Age-related osteoporosis often leads to bone fracture. Currently, in clinical practice, bone cement is commonly used to fix screw implants and prevent loosening. However, bone cement has issues, such as brittleness, high-temperature polymerization, stress shielding, and poor osteointegration, making it unsuitable for patients with osteoporosis. In this study, we developed a gel graft to replace traditional bone cement as an option for fixing implants in patients with osteoporosis. The gel material was composed of sodium polyacrylate, gelatin, β-tricalcium phosphate (β-TCP), and normal saline, mixed using a double-barreled syringe. The research methods include discussing the β-TCP content of the biomimetic gel, gel biocompatibility testing, analysis of the physical and chemical properties of the gel, and functional testing. Functional testing includes evaluation of mechanical properties, bioengineering application characteristics, efficacy in animal studies, and shelf life. The biomimetic gel group was defined as the control group (gel) and experimental group (Gel-6B). The results showed that the biomimetic gel was biocompatible. Scanning electron microscopy revealed that the biomimetic gel had a porous structure and that Gel-6B contained β-TCP. X-ray diffraction and Fourier transform infrared spectroscopy were used to identify the main components of the Gel and Gel-6B. The gel had a polymerization temperature below 30°C, and immersion of the gel in 1x PBS for 28 days did not result in significant acid-base leaching. Rheometer tests confirmed the gelation time after extrusion for Gel and Gel-6B, and disintegration tests showed gel structural breakdown within 2 h for Gel, but not for Gel-6B. In functional testing, the biomimetic gel was able to withstand 50% strain and recover close to its original shape. The results of the universal testing machine indicated that the mechanical strength of the biomimetic gel was similar to that of the osteoporotic bone. In vitro testing demonstrated osteoconduction and osteointegration of the gel. In animal experiments, computed tomography scans and tissue section observations revealed that Gel-6B facilitates the healing of bone defects. Therefore, this study suggests that Gel-6B has the potential to fix implants in osteoporosis patients.

關鍵字(中)

★ 骨質疏鬆
★ 植體
★ 骨整合
★ 骨引導
★ 仿生

關鍵字(英)

★ Osteoporosis
★ Implant
★ Osteointegration
★ Osteoconduction
★ Biomimetic

論文目次

摘要 I
ABSTRACT II
致謝 IV
目錄 VI
圖目錄 X
表目錄 XV
符號縮寫說明 XVI
一、研究背景暨文獻回顧 1
1-1 人類的骨骼 1
1-1-1 骨骼結構 1
1-1-2 硬骨內的細胞 3
1-1-3 骨重塑 6
1-2 骨質疏鬆症 9
1-2-1 骨質疏鬆成因 10
1-2-2 骨質疏鬆性骨折 12
1-3骨折內固定 14
1-3-1 老年人及骨質疏鬆性骨折內固定物窘境 15
1-3-2 內固定植體鬆脫 15
1-3-3 骨科植入物市場 18
1-4 競品比較 19
1-4-1 骨水泥 20
1-5 骨骼內固定之剛性植體穩固條件 23
1-5-1 骨整合 23
1-5-2 應力屏蔽 24
1-6 材料選用 25
1-6-1 聚丙烯酸鈉 25
1-6-2 明膠 28
1-6-3 β-三磷酸鈣 31
1-6-4 成膠原理 35
二、研究動機與目的 38
三、材料與方法 39
3-1 使用儀器與耗材 39
3-1-1 藥品清單 39
3-1-2 耗材清單 41
3-1-3 設備及器材清單 42
3-1-4 細胞種類使用 43
3-2 實驗架構 44
3-3 凝膠製備及Β-TCP含量測試 46
3-4 凝膠物理/化學特性分析 47
3-4-1 掃描式電子顯微鏡（Scanning Electron Microscope, SEM） 47
3-4-2 流變儀（Rheometer） 48
3-4-3 崩解測試（Disintegration test） 49
3-4-4 彈性測試（Elastic properties） 50
3-4-5 X光繞射儀（X-ray diffractometer, XRD） 51
3-4-6 傅立葉轉換紅外線光譜儀（Fourier transform infrared, FTIR） 52
3-4-7 電熱偶式溫度計（Thermocouple Temperature Thermometer ） 53
3-4-8 廣用試劑/廣用試紙（Universal indicator） 54
3-4-9 萬用試驗機（Universal testing machine, UTM） 55
3-5 細胞及體外實驗 57
3-5-1 細胞及組織實驗之必要試劑 57
3-5-2 細胞培養 58
3-5-3 生物相容性（Biocompatibility）試驗 59
3-5-4 小鼠初代成骨細胞（mOB）提取 62
3-5-5 凝膠細胞試驗（Proliferation of mOB） 63
3-5-6 凝膠原生組織試驗（Primary bone tissue culture） 65
3-6 動物實驗 66
3-6-1 凝膠填補測試 66
3-6-2 電腦斷層掃描（Computed Tomography, CT） 66
3-6-3 組織切片（Tissue section） 66
3-7 老化測試機（ACCELERATED AGING） 67
四、結果與討論 68
4-1 凝膠Β-TCP含量 68
4-2 生物相容性測試 69
4-3凝膠結構影像 71
4-4 主成分分析 72
4-4-1 XRD分析 72
4-4-2 FTIR分析 74
4-5 PH改變測試 76
4-6 凝膠聚合溫度 77
4-7 凝膠物理特性 78
4-7-1 凝膠流變特性 78
4-7-2 崩解定性測試 80
4-7-3 凝膠彈性 82
4-7-4 擠壓試驗 84
4-8 凝膠細胞培養試驗 87
4-9 凝膠原生組織試驗 89
4-10 動物實驗 91
4-10-1 凝膠填補性測試 91
4-10-2 組織照影 92
4-10-2 組織切片 93
4-11 架儲期測試 95
4-12 結果彙整 96
五、結論 98
參考資料 99

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指導教授

陳靖昀柯承志(Ching-Yun Chen Cherng-Jyh Ke)

審核日期

2023-7-27

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