臺灣博碩士論文加值系統

可降解形狀記憶高分子材料為生醫器材和組織工程支架的最佳候選材料，超順磁氧化鐵奈米粒子 (Superparamagnetic iron oxide nanoparticles, SPIO NPs) 在近年被報導可以促進人類間葉幹細胞的硬骨化。在本篇研究我們合成生物可降解形狀記憶水性聚胺酯 (shape memory polyurethane, 簡稱PU) 作為三維列印 (Three-dimensional printing, 3D printing) 墨水之主要成分製造3D列印支架，並包覆500 ppm之SPIO NPs以促進間葉幹細胞之硬骨誘導以及支架之形狀固定。此外，3D列印墨水包含聚乙二醇 (polyethylene oxide, PEO) 或gelatin作為增黏劑增加墨水之列印性，支架製作以低溫熔融沉積製造 (low-temperature fuse deposition manufacturing, LFDM) 平台列印，並進行24小時之真空乾燥。形狀記憶性質評估於50C空氣以及37C水浴，PU-PEO支架較PU-gelatin支架有更好的形狀固定與回復，且水中之形狀記憶性質優於空氣。人類間葉幹細胞培養於3D列印支架以評估硬骨化能力：以膠原蛋白含量分析，細胞在PU/PEO/SPIO支架上之硬骨沉積為PU/PEO支架的2.7倍；PU/gelatin/SPIO支架上之硬骨沉積為PU/gelatin支架的1.5倍。因此，本篇製作的3D列印可降解形狀記憶支架可作為客製化硬骨組織填充物，以微創手術方式應用於硬骨組織工程。

The biodegradable shape memory polymers are candidate materials for making biomedical devices and scaffolds for tissue engineering. Superparamagnetic iron oxide nanoparticles (SPIO NPs) have been reported to promote the osteogenesis of human mesenchymal stem cells (hMSCs). In this study, we synthesize water-based biodegradable shape memory polyurethane (PU) as the main component of the 3D printing ink for fabricating bone scaffolds. The 3D printing ink contains 500 ppm SPIO NPs to promote osteogenic induction and shape fixity, and it also contains polyethylene oxide (PEO) or gelatin for the improvement of printability. Scaffolds are printed by the microextrusion-based low-temperature fuse deposition manufacturing platform. Shape memory properties are evaluated in 50C air and 37C water. PU-PEO scaffolds show better shape fixity and recovery than PU-gelatin scaffolds, while the shape memory properties in water are better than those in air. hMSCs are seeded for evaluation of bone regeneration. With SPIO in the scaffolds, the osteogenesis increases 2.7 times for PU/PEO and 1.5 times for PU/gelatin scaffolds based on the collagen content. We conclude that 3D printed PU scaffolds with shape memory properties, biodegradability and osteogenic effect may be employed as customized-bone substitutes for bone tissue engineering.

口試委員審定書 I
誌謝 II
摘要 III
Abstract IV
圖目錄.......................................................................................................................X
表目錄..........................................................................................................................XI
第一章　文獻回顧 1
1.1. 形狀記憶效應 1
1.1.1. 形狀記憶效應簡介 1
1.1.2. 形狀記憶高分子應用在生醫器材 2
1.2. 聚胺酯奈米複合材料 4
1.2.1. 無機奈米粒子於生醫應用 4
1.2.2. 聚胺酯奈米金屬複合材料於生醫應用 6
1.3. 聚胺酯奈米複合材料與形狀記憶 8
1.3.1. 聚胺酯─金奈米複合材料的形狀記憶性質 8
1.3.2. 聚胺酯─氧化鐵奈米複合材料的形狀記憶性質 9
1.4. 形狀記憶聚胺酯奈米複合材料與硬骨組織工程 9
1.4.1. 硬骨組織工程簡介 9
1.4.2. 氧化鐵奈米粒子對硬骨誘導的影響 11
1.4.3. 誘導硬骨分化之因子 12
1.4.4. 形狀記憶聚胺酯在硬骨組織工程的應用 13
1.5. 研究動機 13
第二章 研究方法 15
2.1. 研究架構 15
2.2. 形狀記憶聚胺酯 (Shape memory polyurethane, PU) 之原料與合成 17
2.2.1. L-聚乳酸二元醇之製備 17
2.2.2. L-聚乳酸二元醇之分子量鑑定 17
2.3.3. 形狀記憶聚胺酯之合成 18
2.3. 超順磁奈米氧化鐵粒子 (SPIO NPs) 之製備 22
2.3.1. 超順磁奈米氧化鐵粒子合成 22
2.3.2. 超順磁氧化鐵奈米粒子表面改質 22
2.3.3. 超順磁氧化鐵奈米粒子之鐵含量定量 23
2.4. 形狀記憶聚胺酯薄膜與聚胺酯/氧化鐵複合薄膜之製備 23
2.4.1. 形狀記憶聚胺酯薄膜製備 23
2.4.2. 形狀記憶聚胺酯/氧化鐵複合薄膜製備 23
2.5. 形狀記憶聚胺酯支架與聚胺酯/氧化鐵複合支架之製備 24
2.5.1. 形狀記憶聚胺酯支架原料 24
2.5.2. 形狀記憶聚胺酯支架製備 24
2.6. 形狀記憶聚胺酯薄膜與支架之物化性質分析 26
2.6.1. 形狀記憶聚胺酯支架表面性質分析 26
2.6.2. 差示掃描量熱 26
2.6.3. 廣角X光繞射分析儀 26
2.6.4. 形狀記憶聚胺酯薄膜機械性質測試 27
2.6.5. 形狀記憶聚胺酯支架機械性質測試 27
2.6.6. 體外降解實驗 27
2.6.7. 形狀記憶聚胺酯支架小角度X光散射分析 28
2.7. 形狀記憶測試 28
2.7.1. 聚胺酯薄膜空氣形狀記憶測試 28
2.7.2. 聚胺酯薄膜水中形狀記憶測試 28
2.7.3. 支架空氣形狀記憶測試 29
2.7.4. 支架水中形狀記憶測試 29
2.8. 人類骨髓間葉幹細胞硬骨分化誘導及分析 30
2.8.1. 人類骨髓間葉幹細胞培養 30
2.8.2. hBMSCs於支架之型態分析 30
2.8.3. hBMSCs增生測試 30
2.8.4. SPIO奈米粒子對hBMSCs硬骨誘導之評估 31
2.8.5. 基因表現評估 31
2.8.6. 茜素紅染色 (Alizarin red S staining) 34
2.8.7. 鈣質與膠原蛋白(collagen)定量分析 34
2.9. 統計學分析 34
第三章 實驗結果 35
3.1. SPIO奈米粒子之粒徑分析 35
3.2. PU與PU/SPIO薄膜與支架物化性質分析 35
3.2.1. PU 3D列印支架外觀與孔洞分析 35
3.2.2. 薄膜差示掃描量熱儀分析 36
3.2.3. 直接凍乾支架與3D列印支架之差示掃描量熱儀分析 36
3.2.4. 薄膜廣角X光繞射分析 36
3.2.5. 凍乾支架與3D列印支架廣角X光繞射分析 37
3.2.6. 小角度X光散射分析 38
3.2.7. 薄膜機械性質分析 39
3.2.8. 3D列印支架機械性質分析 40
3.2.9. 3D列印支架體外降解測試 40
3.3. PU及PU/SPIO薄膜與支架形狀記憶分析 41
3.3.1. 薄膜空氣中形狀記憶測試 41
3.3.2. 薄膜水中形狀記憶測試 42
3.3.3. 3D列印支架空氣中形狀記憶測試 42
3.3.4. 3D列印支架水中形狀記憶測試 43
3.4. 細胞培養與細胞分化誘導分析 44
3.4.1. 人類骨髓間葉幹細胞於3D列印支架上型態分析 44
3.4.2. hBMSCs於3D列印支架培養之增生評估 44
3.4.3. hBMSCs於3D列印支架培養之硬骨基因表現評估 44
3.4.4. SPIO奈米粒子對hBMSCs硬骨化之誘導 45
3.4.5. hBMSCs於3D列印支架培養之茜素紅染色分析 45
3.4.6. hBMSCs於3D列印支架培養之鈣質與膠原蛋白定量分析 45
第四章 討論 47
4.1. 3D列印支架之製備 47
4.2. SPIO奈米粒子粒徑分析 47
4.3. PU支架外觀與孔洞分析 48
4.4. PU在50C空氣之形狀記憶效應分析 48
4.4.1. 結晶度分析 48
4.4.2. 分子結構分析 49
4.5. PU在37C水中之形狀記憶效應分析 50
4.6. hBMSCs體外培養硬骨誘導分析 51
4.6.1. 3D列印支架親疏水性測試 51
4.6.2. 3D列印支架浸泡二次水後之動態機械性質測試 52
4.6.3. SPIO於培養液濃度對hBMSCs硬骨化誘導之分析 52
4.7. 3D列印形狀記憶支架於硬骨組織工程之展望 53
第五章 結論 55
參考文獻 56

圖目錄
圖2.1. 研究架構圖。 16
圖2.2. 形狀記憶聚胺酯合成示意圖。 21
圖2.3. 3D列印機示意圖。 25
圖3.1. SPIO NPs之(A)製備與(B) TEM、(C) TGA分析。……………………….66
圖3.2. (A-D) 3D列印支架經冷凍乾燥處理之成品。 67
圖3.3. (A) PU/PEO、(B) PU/PEO/SPIO、(C) PU/gelatin、(D) PU/gelatin SPIO 3DP 支架支SEM圖。比例尺為200 m。 68
圖3.4. PU各組薄膜之DSC圖譜。 69
圖3.5. PU各組支架之DSC圖譜。 70
圖3.6. PU各組薄膜之XRD圖譜。 71
圖3.7. PU各組支架之XRD圖譜。 72
圖3.8. 各組支架之SAXS圖譜分析。 73
圖3.9. (A) 各組3D列印支架隻重量剩餘百分比；(B) 含SPIO支架之SPIO奈米粒子釋放量。 74
圖3.10. PU薄膜與3D列印支架於 (A) 50C空氣與 (B) 37C水中形狀記憶表現之評估。 75
圖3.11. PU 3D列印支架於50C烘箱之形狀記憶 (A) 固定率、回復率與 (B) 回復速度之評估。 76
圖3.12. PU 3D列印支架於37C水浴之形狀記憶 (A) 固定率、回復率與 (B) 回復速度之評估。 77
圖3.13. hBMSCs種植於3D列印支架。(A) 細胞種植示意圖。(B) 以PKH26螢光染劑標註細胞 (培養24小時)。 78
圖3.14. hBMSCs培養於各組3D列印支架於72小時內之細胞數量。 79
圖3.15. hBMSCs培養於3D列印支架誘導7天與14天之 (A) ALP、(B) RUNX2、(C) COL 與 (D) OCN之基因表現。 80
圖3.16. hBMSCs培養於不同濃度SPIO奈米粒子培養液7天之 (A) ALP、(B) RUNX2、(C) COL 與 (D) OCN基因表現。OS組別為細胞培養於硬骨誘導培養液中。 81
圖3.17. hBMSCs培養於3D列印支架中以茜素紅染色觀察支架之礦物沉積。 82
圖3.18. hBMSCs培養於3D列印支架14天後之 (A) 細胞數量、(B) 支架膠原蛋白沉積量、(C) 支架鈣質沉積量、(D) 每個細胞分泌之膠原蛋白量與 (E) 每個細胞分泌之鈣質量。 83
圖3.19. 以3D列印支架在37oC水浴進行原位瑕疵填充。 (A) 原始支架、(B) 支架於-10C 冰箱固定後、(C) 回復75 s (D) 回復180 s。 84


表目錄
表2.1. 水性聚胺酯詳細配方.....................................................................................20
表2.2. 引子序列.........................................................................................................33
表3.1. DSC圖譜分析之結晶度.................................................................................85
表3.2. XRD圖譜分析之結晶度................................................................................86
表3.3. 各組PU薄膜之楊氏模數、100%模數、抗拉強度與拉伸率。.................87
表3.4. 3D列印支架DMA動態測試於37C下之機械性質。..............................88
表3.5. 各組聚胺酯薄膜於50C空氣形變、空氣固定與空氣回復之測試形狀記憶測試。...........................................................................................................................89
表3.6. 各組聚胺酯薄膜於37C水中形變、空氣固定與水中回復之測試形狀記憶測試。...........................................................................................................................90
表3.7. 各組3D列印支架之接觸角、浸泡水後在37C下之機械性質。............91

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