臺灣博碩士論文加值系統

多孔性支架可提供細胞貼附、生長、遷移與分化，且其孔洞結構與連通性扮演著重要關鍵。本論文利用7 mg/mL濃度之膠原蛋白支架並添加0.5%透明質酸，來仿生細胞外基質成分，並將膠原蛋白/透明質酸多孔性支架培養幹細胞，探討幹細胞之細胞行為及分化能力表現。透明質酸具有CD44與RHAMM特殊細胞結合位，兩者皆會激活血管增生之訊息傳遞路徑，而LIPUS刺激有研究指出會透過PI3K-Akt-eNOS訊息傳遞路徑引發血管增生的機制。論文亦利用透明質酸與LIPUS刺激為訊號因子來誘導人類脂肪幹細胞分化並將之應用於肝修復。SEM與H&E染色結果顯示添加0.5%透明質酸於膠原蛋白支架後，其細胞貼附、生長及遷移之狀況較佳，輔以LIPUS刺激，則有更佳之生長效果，免疫螢光染色結果也顯示，人類脂肪幹細胞與肝細胞或HUVEC共培養於膠原蛋白/透明質酸支架且經LIPUS刺激之，其CD45蛋白表現量明顯高於白蛋白表現量，在血管增生動物實驗結果顯示，免疫組織染色CD31表現量亦有增加。

Porous scaffold can provide space for cell adhesion, migration, growth and differentiation, and the pore geometry and interconnection play an important role on the cellular behaviors. In this present study, we prepared a collagen scaffold with concentration of 7 mg/mL and 0.5 w% hyaluronan (HA) to mimetic natural ECM to evaluate the growth and differentiation of ADSCs. As known, HA molecules have binging cites for CD44 and RHAMM, can activate the signal transduction of angiogenesis. Furthermore, low intensity pulsed ultrasound stimulus (LIPUS) can stimulate angiogenesis by path of PI3K-Akt-eNOS signal transduction. In this study, we utilized HA and LIPUS simulative factors to induce the differentiation of ADSCs and evaluate their effects on the live repairs. From SEM and H&E stains observations, ADSCs grew, proliferate well on the collagen scaffold containing 0.5% HA. The cellular growth significantly improved after extra LIPUS stimulus. From immunofluorescence stains, co-cultured ADSCs with live cells or HUVECs and LIPUS stimulus, the ADSCs expressed higher CD45 expression, however, the ADSCS expressed lower albumin expression. Higher CD31 expressions were observed from immunofluorescence stains in animal angiogenetic study, indicated that the angiogenesis of ADSCs on the collagen scaffolds.

誌謝 I
中文摘要 II
Abstract III
目錄IV
圖目錄IX
表目錄XVI
第一章 緒論1
1-1. 三維培養優點1
1-2. 三維培養方式2
1-3. 組織工程4
1-4. 多孔性支架5
1-5. 成體幹細胞（Adult Stem Cells）9
1-5-1. 骨間質幹細胞（rMSC）10
1-5-2. 人類脂肪幹細胞（human adipose-derived stem cells, hADSC）11
1-6. 血管增生13
1-7. 透明質酸對血管增生之交互作用15
1-7-1. RHAMM（Receptor for HA-mediated motility）17
1-7-2. CD4418
1-8. 低強度脈衝超音波刺激（Low-intensity pulsed ultrasound）19
1-9. 肝損傷22
1-10. 研究目的23
第二章 實驗藥品、材料與設備24
2-1. 實驗藥品24
2-2. 儀器設備27
第三章 材料與方法28
3-1. 研究架構28
3-2. 膠原蛋白/透明質酸支架製備與性質分析29
3-2-1. 第一型膠原蛋白萃取29
3-2-2. 第一型膠原蛋白濃度測定30
3-2-3. 膠原蛋白/透明質酸支架製備31
3-2-4. 含水量測試32
3-2-5. 膨潤度測試32
3-2-6. 孔隙率測試33
3-2-7. 降解率測試33
3-2-8. 性質測試34
3-2-9. 結構觀察34
3-3. 幹細胞萃取及細胞培養35
3-3-1. 間質幹細胞（MSC）萃取及培養.35
3-3-2. 人類脂肪幹細胞（hADSC）萃取及培養36
3-3-3. 幹細胞純度分析—流式細胞儀37
3-3-4. 人類臍靜脈內皮細胞（HUVEC）與肝臟細胞培養38
3-4. 細胞於膠原蛋白/透明質酸支架共培養並以LIPUS 刺激.........39
3-4-1. 細胞培養於膠原蛋白/透明質酸支架39
3-4-2. 低強度脈衝超音波（Low-intensity pulsed ultrasound）刺激40
3-4-3. Cell Counting Kit-8（CCK-8）分析41
3-4-4. Hematoxylin and Eosin Y stain（H&E stain） 41
3-4-5. 免疫螢光染色.42
3-4-6. 白蛋白含量測定43
3-4-7. real time RT-PCR44
3-4-8. 細胞於膠原蛋白/透明質酸支架型態觀察46
3-4-9. 統計分析46
3-5. 血管增生及肝纖維化動物模型分析47
3-5-1. 血管增生動物模型47
3-5-2. 肝纖維化動物模型建立48
3-5-3. 膠原蛋白/透明質酸支架植入肝臟50
3-5-4. 低強度脈衝超音波刺激51
3-5-5. 肝組織生理功能評估52
3-5-6. Hematoxylin and Eosin Y stain（H&E stain） 54
3-5-7. 免疫組織組化染色（Immunohistochemistry）55
第四章 結果與討論56
4-1. 膠原蛋白/透明質酸支架製備與性質分析56
4-1-1. 降解率測試56
4-1-2. 孔隙率測試57
4-1-3. 含水量測試58
4-1-4. 膨潤度測試59
4-1-5. 結構觀察60
4-1-6. 機械性質測試62
4-2. 幹細胞萃取及細胞培養63
4-2-1. 間質幹細胞（MSC）萃取及培養63
4-2-2. 人類脂肪幹細胞（hADSC）萃取級培養63
4-2-3. 幹細胞純度分析64
4-2-4. 人類臍靜脈內皮細胞（HUVEC）與肝臟細胞培養66
4-3. 細胞於膠原蛋白/透明質酸支架共培養並以LIPUS 刺激67
4-3-1. 細胞培養於膠原蛋白/透明質酸支架之型態觀察67
4-3-1-1. 單獨培養hADSC 68
4-3-1-2. hADSC/AML12 共培養69
4-3-1-3. hADSC/HUVEC 共培養70
4-3-1-4. hADSC/HUVEC/AML12 共培養71
4-3-2. 低強度脈衝超音波（LIPUS）刺激之型態觀察72
4-3-2-1. 單獨培養hADSC 73
4-3-2-2. hADSC/AML12 共培養74
4-3-2-3. hADSC/HUVEC 共培養76
4-3-2-4. hADSC/HUVEC/AML12 共培養77
4-3-3. Cell Counting Kit-8（CCK-8）分析78
4-3-4. Hematoxylin and Eosin Y stain（H&E stain） 83
4-3-5. 免疫螢光染色92
4-3-6. 白蛋白含量測定96
4-3-7. real time RT-PCR97
4-4. 血管增生及肝纖維化動物模型分析100
4-4-1. 血管增生動物模型100
4-4-2. 肝纖維化動物模型建立104
4-4-3. 肝組織生理功能評估106
第五章 結論113
第六章 參考資料115
第七章 附錄123

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