在本篇研究中，我們首先研究鏈反應(chain growth reaction)傳播時間(propagating time)對圖案化明膠甲基丙烯(gelatin methacrylate, GelMA)水凝膠交聯程度的影響，以及人類間質幹細胞(mesenchymal stem cells, MSCs)在不同交聯條件的水凝膠中生長的情形。接著，我們選擇能幫助MSCs伸展較好的兩種鏈反應交聯時間，應用在體內血管組織新生的小鼠實驗中。在2層工程化血管組織的實驗中，鏈反應傳播時間較長的組別能夠減少植體被免疫細胞浸潤的情形，同時增加血管組織的面積和植體厚度；與此同時，我們也成功在正常小鼠與糖尿病小鼠體內生成>1 mm厚的工程化血管組織，生成的血管組織也都證實擁有相當優異的工程化血管組織能力以及均勻的血管分布。而在4層工程化血管組織的實驗中，我們發現，若改變植體中材料的交聯分布，則能夠增加植體的厚度、植體中血管的分布厚度以及血管的密度。植入後7天的結果顯示，我們成功在正常小鼠與糖尿病小鼠體內生成>2 mm厚的工程化血管組織，且血管皆能夠分布至植體中>30%厚度的位置。最後，我們將血管組織應用在移植胰島的實驗中，結果顯示，我們的移植物能夠增進胰島細胞在體內的存活率，進而治療糖尿病小鼠體內第一型糖尿病的症狀，並擁有22%的成功率。

Propagating time, different from exposure time, can control chain growth reaction on photo-crosslinking process of hydrogels in a subtler way. Here, we investigated the cell spreading behavior of mesenchymal stem cells (MSCs) in hydrogels crosslinked under different propagating time. In addition, we applied two different propagating time on engineering vascularized tissues in vivo. For engineering 2-layered vascularized tissues, results showed that longer propagating time can decrease the numbers of infiltrating immune cells, which increase area of vascularized tissues and thickness of the implants. We also successfully engineered vascularized tissues not only with >1 mm thickness, but with excellent vascularizing ability and uniform distribution of vessels. For engineering 4-layered vascularized tissues, we found that we can increase the implant thickness, vascularized thickness and vessel density in implants by altering crosslinking distribution in implants. After 7-day-implantation, results show that we successfully engineered vascularized tissues with >2 mm thickness, and with vascular networks growing to 30% of implants’ thickness. Finally, engineered vascularized tissues were integrated with transplanted islets at subcutaneous site, which had a 22% success rate for supporting and increasing viability and functionality of transplanted islets to achieve correction of chemically induced diabetes in mouse.

摘要-i
Abstract-ii
誌謝-iii
目次-v
圖目次-x
壹、緒論-1
貳、文獻回顧-3
2.1 血管組織工程介紹-3
2.1.1 血管組織工程的需求與瓶頸-3
2.1.2 比較不同生成血管組織的方法-3
2.1.3 厚血管組織工程的發展現況與瓶頸-5
2.2 糖尿病-7
2.2.1 糖尿病的介紹與分類-7
2.2.2 第一型糖尿病小鼠模型-9
2.2.3 胰島移植的現況-10
2.2.4 糖尿病症狀對於生成血管組織的不利影響-13
2.3 明膠基水凝膠材料特性-15
2.3.1 明膠的結構與特性-15
2.3.2 明膠甲基丙烯的應用-16
2.3.3 調控明膠水凝膠機械性質的方式：藉由曝光的劑量控制自由基的數量-18
2.3.4 明膠水凝膠機械性質與體內異物反應/材料降解特性的關聯-18
2.4 研究動機-20
參、材料和實驗方法-22
3.1 GelMA合成-22
3.2 氫原子核磁共振儀(1H-NMR)-22
3.3 紫外光汞燈光源與強度-23
3.4 微影圖案化GelMA水凝膠製程-23
3.5 圖案化的光罩設計-26
3.6 圖案化GelMA水凝膠的圖案線寬與周長的分析-26
3.7 細胞來源與培養-27
3.8 圖案化GelMA水凝膠的3D細胞培養-28
3.9 細胞免疫螢光染色(Immunofluorescent staining)-29
3.10 利用流變儀和原子力顯微鏡量測圖案化GelMA水凝膠的機械性質-29
3.11 圖案化GelMA水凝膠的孔徑分析-31
3.12 工程化血管組織小鼠模型-32
3.13 鏈脲佐菌素(Streptozotocin, STZ)誘導糖尿病小鼠模型-32
3.14 小尺寸血管化組織-32
3.15 大尺寸血管化組織-33
3.16 工程化血管組織分析模型-34
3.17 胰島細胞的萃取與鑑定-35
3.18 胰島移植小鼠模型-37
3.19 腹腔葡萄糖耐受試驗(Intraperitoneal glucose tolerance test, IPGTT)-38
3.20 組織學分析-39
3.21 統計分析-39
肆、實驗結果-40
4.1 鏈脲佐菌素(Streptozotocin, STZ)誘導糖尿病小鼠模型-40
4.1.1 糖尿病小鼠模型的誘導成功率-40
4.1.2 胰島素治療對於糖尿病小鼠模型體重變化的影響-41
4.1.3 正常飼料餵食的糖尿病小鼠模型誘導時的體重對於體重變化的影響-43
4.1.4 腸系黏膜組織的組織學分析-44
4.1.5 確立糖尿病小鼠模型-47
4.1.6 糖尿病小鼠模型連續24小時的血糖變化-47
4.2 GelMA官能基取代度的測定-48
4.3 鏈反應傳播時間的影響-49
4.3.1 圖案化GelMA水凝膠的成膠特性-49
4.3.2 圖案化GelMA水凝膠中的細胞行為表現-53
4.3.3 圖案化GelMA水凝膠的結構穩定性-57
4.3.4 圖案化GelMA水凝膠的機械性質-59
4.3.5 圖案化GelMA水凝膠的微觀結構-62
4.4 工程化血管組織動物實驗(2層)-65
4.4.1 正常小鼠體內的2層工程化血管組織-65
4.4.2 糖尿病小鼠體內的2層工程化血管組織-75
4.5 工程化血管組織動物實驗(4層)-83
4.5.1 正常小鼠體內的4層工程化血管組織-84
4.5.2 糖尿病小鼠體內的4層工程化血管組織-90
4.6 胰島移植動物實驗-96
伍、討論-105
5.1 STZ誘導的糖尿病小鼠模型-105
5.2 鏈反應傳播時間對交聯程度的影響-105
5.3 鏈反應傳播時間對不同小鼠模型體內的2層工程化血管組織的影響-106
5.4 鏈反應傳播時間對不同小鼠模型體內的4層工程化血管組織的影響-110
5.5 胰島移植實驗-112
陸、結論-113
柒、參考資料-115

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