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研究生:張稚敏
研究生(外文):Chih Min Chang
論文名稱:攜帶TGF-β1的可注射型玻尿酸/肝素/羧甲基纖維素凍膠應用於軟骨組織工程
論文名稱(外文):TGF-β1 loaded injectable hyaluronic acid/heparin/carboxymethylcellulose cryogels for cartilage tissue engineering
指導教授:陳志平陳志平引用關係
指導教授(外文):J. P. Chen
口試委員:陳志豪蔡曉雯陳志平
口試委員(外文):C. H. ChenS. W. TsaiJ. P. Chen
口試日期:2024-01-12
學位類別:碩士
校院名稱:長庚大學
系所名稱:化工與材料工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2024
畢業學年度:112
語文別:中文
論文頁數:110
中文關鍵詞:軟骨組織工程注射型凍膠轉化生長因子1脂肪幹細胞
外文關鍵詞:Cartilage tissue engineeringInjectableCryogelTGF-β1Adipose-derived stem cells
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本研究使用玻尿酸、肝素及羧甲基纖維素製備可注射型凍膠,應用於軟骨組織工程,並結合訊息因子TGF-β1(transforming growth factor-β1)促進脂肪幹細胞分化成軟骨細胞,並於體內形成軟骨組織。對支架進行物化性實驗分析,凍膠具有多孔(平均孔洞大小約43 μm)、高孔隙率(97 %)、快速吸水、高水含量(97 %)、可生物降解、可注射性及良好機械性質,同時可藉肝素吸附TGF-β1進行持續釋放。以脂肪幹細胞進行體外細胞培養實驗,藉由DNA、GAG及collagenⅡ定量分析探討細胞增生及細胞外基質分泌,PCR分析軟骨形成階段之基因表現,免疫螢光染色分析細胞存活、細胞骨架及指標蛋白表現,證實支架攜帶TGF-β1可促進脂肪幹細胞分化成軟骨細胞。體內動物實驗,透過可注射型玻尿酸/肝素/羧甲基纖維素凍膠經注入裸鼠皮下,探討凍膠於體內之生物相容性;將支架接上螢光染劑Cy5.5進行裸鼠皮下注射,以IVIS探討凍膠於體內之降解性;最後將攜帶TGF-β1的支架接種脂肪幹細胞注入裸鼠皮下,以組織切片探討軟骨細胞生長情況,證實凍膠攜帶TGF-β1將有助於軟骨組織形成,具軟骨組織工程應用的可行性。
This research develops an injectable cryogel composed of hyaluronic acid, heparin, and carboxymethyl cellulose. The cryogel is designed for application in cartilage tissue engineering and is augmented with the transforming growth factor-β1 (TGF-β1) to facilitate the differentiation of adipose-derived stem cells into chondrocytes for effective cartilage tissue formation. Physico-chemical analyses of the scaffold demonstrate its macroporous nature with high porosity, rapid water absorption rate, high water content, biodegradability, injectability, and favorable mechanical properties. Furthermore, the cryogel exhibits the ability to adsorb TGF-β1 through biaffinity interation with heparin and provide controlled release of this growth factor for inducing chondrogenic differentiation.
In vitro experiments involve the cultivation of adipose-derived stem cells on the scaffold, with quantitative analyses of DNA, glycosaminoglycans (GAG), and collagen II employed to assess cell proliferation and extracellular matrix secretion. PCR analysis is conducted to investigate gene expression during various stages of chondrogenesis. Immunofluorescent staining is utilized to evaluate cell viability, cytoskeletal structure, and the expression of key marker proteins, thereby confirming the scaffold's capacity to promote the differentiation of adipose-derived stem cells into chondrocytes.
In vivo assessments include subcutaneous injection of the injectable hyaluronic acid/heparin/carboxymethyl cellulose cryogel into nude mice to evaluate biocompatibility. The cryogel is labeled with the fluorescent dye Cy5.5 for in vivo degradation analysis using in vivo imaging system (IVIS). Finally, the TGF-β1-loaded scaffold, along with adipose-derived stem cells, is subcutaneously implanted, and tissue sections are examined to assess cell growth and chondrogenesis, providing conclusive evidence of the cryogel's potential in promoting ectopic cartilage tissues.
目錄
中文摘要 i
Abstract iii
目錄 v
圖目綠 xiii
表目錄 xvii
第一章 緒論 1
1.1 前言 1
1.2 研究動機 1
第二章 文獻回顧 3
2.1 組織工程 3
2.1.1 介紹 3
2.1.2 組織工程三要素-細胞(Cell) 4
2.1.2.1 細胞(Cell) 4
2.1.2.2 脂肪幹細胞(ADSC) 4
2.1.3 組織工程三要素-支架(Scaffold) 5
2.1.3.1 支架(Scaffold) 5
2.1.3.2 可注射型支架(Injectable scaffold) 6
2.1.3.3 交聯反應 6
2.1.3.4 凍膠(Cryogel) 7
2.1.3.5 1,4-丁二醇二縮水甘油醚(BDDE) 8
2.1.3.6 肝素(Heparin) 9
2.1.3.7 玻尿酸(Hyaluronic acid, HA) 10
2.1.3.8 羧甲基纖維素(Carboxymethyl Cellulose, CMC) 10
2.1.4 組織工程三要素-訊息因子(Signal) 11
2.2 軟骨組織 12
2.2.1 軟骨分類 12
2.2.2 透明軟骨組成及結構 12
第三章 實驗設備、藥品及步驟 14
3.1 實驗設備 14
3.2 實驗藥品與試劑 15
3.3 實驗架構 18
3.4 實驗步驟 18
3.4.1 支架製備 18
3.4.1.1 支架滅菌 19
3.4.2 HHC cryogel 物化性分析 20
3.4.2.1 表面型態分析/能量散射分析儀 (SEM /EDS) 20
3.4.2.2 孔徑大小分析 20
3.4.2.3 水含量動力學與膨潤率 20
3.4.2.4 體外降解測試 21
3.4.2.5 熱重分析(TGA) 21
3.4.2.6 X-射線繞射分析(XRD) 21
3.4.2.7 傅立葉轉換紅外光譜(FTIR) 21
3.4.2.8 機械性質分析 22
3.4.2.8.1 壓縮機械力學分析 22
3.4.2.8.2 應力鬆弛測試(Relaxation) 22
3.4.2.8.3 循環壓縮分析(Cyclic compression) 23
3.4.2.8.4 動態力學分析(dynamic mechanical analysis, DMA) 23
3.4.2.9 TGF-β1吸附與釋放 24
3.4.2.9.1 HHC cryogel之TGF-β1吸附 24
3.4.2.9.2 TGF-β1釋放分析 24
3.4.2.10 BDDE殘留定量分析 25
3.4.3 體外細胞培養(in vitro) 25
3.4.3.1 脂肪幹細胞分離 25
3.4.3.2 脂肪幹細胞之繼代培養 26
3.4.3.3 支架毒性分析(Cytotoxicity) 26
3.4.3.4 體外3D培養 27
3.4.3.5 脂肪幹細胞分化軟骨細胞之細胞增生分析(DNA content) 28
3.4.3.6 體外細胞培養GAGs定量分析(GAGs content) 28
3.4.3.7 脂肪幹細胞分化軟骨細胞之基因表現-mRNA萃取即反轉錄cDNA 28
3.4.3.8 脂肪幹細胞分化軟骨細胞之基因表現-及時定量PCR(qPCR) 29
3.4.3.9 支架體外細胞培養影像分析(in vitro) 31
3.4.3.9.1 細胞表面型態分析(SEM) 31
3.4.3.9.2 Collagen II 免疫螢光染色分析(IF) 31
3.4.3.9.3 Aggrecan免疫螢光染色分析(IF) 32
3.4.3.9.4 螢光染色細胞核/細胞骨架分析(Nucleus/Cytoskeleton) 32
3.4.3.9.5 細胞死活染色分析(Live & Dead) 33
3.4.4 體內動物實驗 34
3.4.4.1 裸鼠皮下材料注射實驗 34
3.4.4.2 裸鼠皮下樣品採取與gross view 34
3.4.4.3 凍膠螢光接枝與螢光支架降解分析(IVIS imaging) 35
3.4.4.4 組織學切片染色 (Histology) 35
3.4.4.4.1 蘇木素-伊紅染色 (Hematoxylin & Eosin staining) 35
3.4.4.4.2 阿爾新藍染色 (Alcian blue staining) 35
3.4.4.4.3 Safranin O染色 (Safranin O staining) 36
3.4.4.4.4 第二型膠原蛋白及蛋白聚醣免疫組織染色(Col Ⅱ、Aggrecan IHC staining) 36
3.4.5 統計方法 36
第四章 結果與討論 38
4.1 HHC cryogel 物化性分析 38
4.1.1 HHC cryogel材料比例測試 38
4.1.2 HHC cryogel 表面型態分析(SEM) 39
4.1.3 能量散射分析儀(EDS/Mapping) 41
4.1.4 孔隙度(Porosity)分析 41
4.1.5 水含量動力學與膨潤率 42
4.1.6 凍膠的可注射性 42
4.1.7 體外降解 43
4.1.8 熱重分析(TGA) 44
4.1.9 X-射線繞射分析(XRD) 45
4.1.10 傅立葉轉換紅外光譜(FTIR) 46
4.1.11 機械性質分析 47
4.1.11.1 壓縮機械力學 47
4.1.11.2 循環壓縮分析 49
4.1.11.3 應力鬆弛測試(Relaxation) 50
4.1.11.4 動態力學分析(DMA) 50
4.1.12 TGF-β1釋放 51
4.1.13 BDDE釋放殘留定量分析 52
4.2 支架體外細胞培養生化分析(in vitro) 53
4.2.1 支架毒性分析(Cytotoxicity) 53
4.2.2 脂肪幹細胞分化軟骨細胞之細胞增生分析(DNA content) 54
4.2.3 體外細胞培養GAGs定量分析(GAGs content) 55
4.2.4 脂肪幹細胞分化軟骨細胞之基因表現分析 56
4.2.5 支架體外細胞培養影像分析(in vitro) 58
4.2.5.1 細胞表面型態分析(SEM) 58
4.2.5.2 Collagen II免疫螢光染色分析(IF)及定量分析 59
4.2.5.3 Aggrecan免疫螢光染色分析(IF)及定量分析 61
4.2.5.4 螢光染色細胞核/細胞骨架分析(Nucleus/Cytoskeleton) 63
4.2.5.5 細胞死活染色分析(Live & Dead) 65
4.2.6 支架體外細胞培養動態力學分析(DMA) 67
4.3 支架體內動物實驗 67
4.3.1 螢光支架降解分析(IVIS) 67
4.3.2 體內生物相容性 69
4.3.3 裸鼠皮下注射實驗之巨視圖(Gross view) 70
4.3.4 組織切片染色 70
4.3.4.1 蘇木精-伊紅(Hematoxylin Eosin)組織切片染色(H&E) 70
4.3.4.2 阿爾辛藍(Alcian blue)組織切片染色 71
4.3.4.3 番紅(Safranin O)組織切片染色 72
4.3.4.4 第二型膠原蛋白及聚集蛋白聚醣免疫染色(Collagen II、Aggrecan IHC)組織切片 72
第五章 討論 75
第六章 結論 79
第七章 參考文獻 80


圖目綠
圖2- 1 組織工程組成三要素 3
圖2- 2 交聯反應示意圖 7
圖2- 3 凍膠製備示意圖 8
圖2- 4 HA與BDDE交聯反應示意圖[26] 9
圖2- 5 肝素之結構圖(R1, R2=H or SO3 −; R3=H, COCH3 or SO3 −)[30] 10
圖2- 6 玻尿酸之結構圖[19] 10
圖2- 7 縮甲基纖維素之結構圖[36] 11
圖2- 8 透明軟骨結構組成示意圖[43] 13
圖3- 1 實驗架構圖 18
圖3- 2 支架製備流程圖 19
圖3- 3 模具圖 19
圖3- 4 裸鼠皮下材料注射實驗設計圖 34
圖4- 1 材料測試 39
圖4- 2 材料注射性測試 39
圖4- 3 表面型態圖(SEM) 40
圖4- 4 孔洞大小分布 40
圖4- 5 Mapping分析圖 41
圖4- 6 HHC cryogel之(a)膨潤率(b)水含量 42
圖4-7 凍膠於顯微鏡下注射圖 43
圖4- 8 凍膠注射過程 43
圖4- 9 HHC cryogel於Hyaluronidase降解百分率 44
圖4- 10 HHC cryogel之TGA分析(a)熱重百分比(b)微分熱重圖 45
圖4- 11 XRD圖譜 45
圖4-12 FTIR光譜 47
圖4- 13 壓縮測試後復水之凍膠 48
圖4- 14 Unconfined壓縮測試 48
圖4- 15 循環壓縮分析 49
圖4- 16 HHC cryogel之應力鬆弛測試 50
圖4- 17 HHC cryogel之動態力學分析圖 51
圖4- 18 HHC cryogel之TGF-β1釋放 52
圖4- 19 (a) BDDE檢量線(b)交聯反應各時間點之BDDE定量 53
圖4- 20 細胞毒性分析 54
圖4- 21 DNA定量分析 55
圖4- 22 GAG定量分析 56
圖4- 23 基因表現(a) Sox9, (b) Aggrecan, (c) Collagen Ⅱ, (d) Collagen Ⅹ. 58
圖4- 24 體外培養細胞表面型態SEM圖(bar=30 μm) 59
圖4- 25 Collagen Ⅱ免疫螢光染色(bar=75μm) 60
圖4- 26 Collagen Ⅱ免疫螢光染色定量分析圖 61
圖4- 27 Aggrecan免疫螢光染色(bar=75μm) 62
圖4- 28 Aggrecan免疫螢光染色定量分析 63
圖4- 29 Cytoskeleton免疫螢光染色(bar=25μm) 64
圖4- 30 細胞死活染色分析圖(bar=100μm) 66
圖4- 31 經脂肪幹細胞培養之支架動態力學分析(a)ADSC/HHC及ADSC/HHC/TGF-β1之儲存模量及損耗模量(b) ADSC/HHC及ADSC/HHC/TGF-β1之tan δ 67
圖4-32裸鼠皮下支架降解IVIS分析圖(a)純螢光染劑(b)螢光支架 68
圖4-33 裸鼠IVIS螢光BLI百分比 69
圖4- 34 生物相容性H&E組織染色圖(bar=200μm) 70
圖4- 35 植入裸鼠皮下不同天數後HHC cryogel(a) 及含脂肪幹細胞HHC/TGF-β1 cryogel (b)之gross view 70
圖4-36 H&E組織染色圖(bar=20μm) 71
圖4- 37 Alcian blue染色圖(bar=20μm) 72
圖4- 38 Safranin O染色圖(bar=20μm) 72
圖4- 39 Collagen II組織切片染色圖(bar=20 μm) 73
圖4- 40 Aggrecan組織切片染色圖(bar=20 μm) 74


表目錄
表3 - 1基因引子序列 30
表3 - 2 Collagen II免疫螢光染色染劑之激發與吸收波長 32
表3 - 3螢光染色細胞核/細胞骨架染劑之激發與吸收波長 33
表3 - 4 Live & Dead染劑之激發與吸收波長 33
表4- 1 材料成分特徵峰 47
表4- 2 彈性模數 48
表4- 3 循環壓縮面積百分比 50
表4- 4 裸鼠IVIS螢光定量值 69
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