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研究生:董彥廷
研究生(外文):Yen-Ting Tung
論文名稱:利用具圓柱狀分支結構之支架於體外建構符合設計結構之微血管網路
論文名稱(外文):In vitro Development of Microvascular Network through a Patterned Scaffold of Cylindrical Branches
指導教授:王國禎朱志成
口試委員:徐善慧林峯輝董國忠
口試日期:2017-07-18
學位類別:博士
校院名稱:國立中興大學
系所名稱:組織工程與再生醫學博士學位學程
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:61
中文關鍵詞:人造微血管網路軟微影人類臍帶靜脈內皮細胞聚乳酸聚甘醇酸纖維蛋白
外文關鍵詞:Microvascular engineeringSoft lithographyHUVECPLGAFibrin
相關次數:
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  • 收藏至我的研究室書目清單書目收藏:0
在體外環境下建立一個微血管網路系統不僅可作為心血管研究之實驗平台,也可作為特定組織之內循環系統。目前大多數人工微血管網絡之建立方法乃是將血管內皮細胞培養於所設計之方形管道內,然而方型管道並不同於人體微血管網絡之構造,在其四個角落易形成液體不流動之”dead zone”。此外;管狀結構之微血管網絡不僅在培養初期需要一個複雜的循環幫浦以維持管道內培養液之循環,且目前所有以管狀通道製作之微血管網路其直徑皆大於50微米,遠大於生理上微血管之最小直徑(3微米),限制其實際應用面。因此,本研究以仿生的「支架降解」方式於體外建立一個可客製化結構之微血管網絡系統。利用黃光微影製程與熱回熔(thermal reflow)技術,可製備直徑小於30微米之半圓柱狀光阻結構,再用其製備多個聚二甲基矽氧烷(PDMS)模具。本研究先選擇具生物降解特型之聚乳酸聚甘醇酸(PLGA)為材料,以PDMS為模具製造具圓柱狀分支之支架並將人類臍帶靜脈內皮細胞(HUVEC)培養於支架上,於體外形成微血管網路。實驗結果證實此仿生的「支架降解」方式可在體外環境生成微血管網路架構;接著利用纖維蛋白(Fibrin)取代PLGA做為支架材料,以達成更快速且可控制的支架降解。血小板内皮細胞黏附分子-1 (CD31;PECAM-1)與血管内皮鈣黏蛋白(VE-cadherin)為兩種血管內皮細胞特定功能性蛋白,細胞培養結果驗證此兩種蛋白皆會表現在培養於本研究所製作之支架上的內皮細胞,代表此仿生的「支架降解」方式具製備功能性微血管網絡之潛力。由於細胞培養於具柱狀結構分支之支架上,因此不需要外接循環系統,且可直接以傳統倒立式顯微觀察細胞生長狀況。又由於fibrin支架之可控與快速降解特性,本研究所開發之支架預期可用於製備具功能性微血管網絡之組織,或用以製造可客製化血管結構之微血管晶片。
The importance of generating a microvessel network in vitro lies in engineering vital tissue of a considerable size or working as a platform for biomedical or cardiovascular studies. However, most of the existing methods for generating microvessel networks with desired patterns in vitro use rectangular channels which cannot represent real vessels in vivo and has dead zones at its corners, hence hindering the circulation of culture medium. We propose a scaffold-wrapping method for fast fabrication of customized microvascular networks in vitro in a more biomimetic way. By integrating microelectromechanical techniques with thermal reflow, we designed and fabricated a microscale hemi-cylindrical photoresist template. A replica mold of polydimethylsiloxane, produced by casting, was then used to generate scaffolds with cylindrical branches of biodegradable poly(lactide-co-glycolide) (PLGA) and fibrin, respectively. Unlike PLGA, fibrin is a natural fibrous protein and has a much faster and controllable degrading property. Human umbilical vein endothelial cells were seeded on both types of scaffold and cultured without an additional circulation pump. The expression of endothelial cell marker CD31 and intercellular junction vascular endothelial cadherin on the cultured cell demonstrated the potential of generating a microvascular network with a degradable scaffold of cylindrical branches. Through seeding cells on a solid scaffold, we can monitor cell conditions in a much easier and direct manner during the early stage of vascular development. By combining the proposed cylindrical branches formed scaffold and the controllable degradation property, we hope the novel scaffold developed in this study can serve as a framework for building large tissues or can be used to develop microvascular chips for in vitro biomedical studies.
致謝 i
摘要 ii
ABSTRACT iii
TABLE OF CONTENTS iv
LIST OF SCHEMES vii
LIST OF FIGURES viii
CHAPTER 1: RESEARCH BACKGROUND AND PURPOSE 1
1.1 THE IMPORTANCE OF MICROVASCULAR NETWORK AND ITS FORMATION 1
1.2 IN VITRO DEVELOPMENT OF MICROVASCULAR SYSTEMS 4
1.2.1 Developments of Microvascular Networks with Designed Patterns 4
1.2.2 Development of a Microvascular Network with Random Patterns 8
1.3 AIM OF THE STUDY 11
CHAPTER 2: FABRICATION OF CYLINDRICAL SCAFFOLDS IN SMALL DIAMETER WITH A CUSTOMIZED PATTERN 13
2.1 EXPERIMENT SCHEME FOR THE FABRICATION OF CYLINDRICAL SCAFFOLD WITH A CUSTOMIZED PATTERN 13
CHAPTER 3: FABRICATION OF A RETICULAR POLY(LACTIDE-CO-GLYCOLIDE) CYLINDRICAL SCAFFOLD FOR THE IN VITRO DEVELOPMENT OF MICROVASCULAR NETWORKS 16
3.1 INTRODUCTION 16
3.1.1 PLGA Biomaterial 16
3.1.2 Degradation of PLGA 17
3.2 MATERIALS AND METHODS 19
3.2.1 Flowchart for the Production of Cylindrical PLGA Scaffold 19
3.2.2 Design of Mask for Photolithography 19
3.2.3 Polydimethylsiloxane (PDMS) Replica Mold Preparation 20
3.2.4 3,6-bis(1-methyl-4-vinylpyridium) Carbazole Diiodide (BMVC) Production 21
3.2.5 Fabrication of PLGA Microvascular Scaffolds with Cylindrical Branches 21
3.2.6 Cell Culture 22
3.2.7 WST-1 Assay 22
3.2.8 Immunofluorescent Staining 23
3.2.9 Statistical Analysis 23
3.3 RESULTS AND DISCUSSIONS 24
3.3.1 Thermal Reflow Treatment of AZ4620 and the Preparation of PDMS Mold 24
3.3.2 Fabrication of the PLGA Scaffold 25
3.3.3 Viability of HUVECs on PLGA50/50 26
3.3.4 Formation of a Microvascular Framework with PLGA Cylinders 27
3.3.5 Examination of the CD31 and VE-cadherin Expression on HUVECs Cultured Scaffold 30
3.4 SUMMARY 32
CHAPTER 4: DEVELOPMENT OF MICROVASCULAR NETWORKS THROUGH A CYLINDRICAL FIBRIN SCAFFOLD 34
4.1 INTRODUCTION 34
4.1.1 Fibrin Formation and Fibrinolysis 34
4.1.2 Applications of Fibrin 36
4.2 MATERIALS AND METHODS 37
4.2.1 Flowchart for the Production of Cylindrical Fibrin Scaffold 37
4.2.2 Mask Design for the Fabrication of Cylindrical Fibrin Scaffold 37
4.2.3 Preparation of PDMS replica molds 38
4.2.4 Fabrication of Cylindrical Fibrin Scaffold 39
4.2.5 Cell Culture 39
4.2.6 Plasmin Degradation 40
4.2.7 Immunofluorescent Staining 40
4.3 RESULTS AND DISCUSSIONS 41
4.3.1 Preparation of PDMS Mold for Fibrin Scaffold Production 41
4.3.2 Fabrication of fibrin scaffold 42
4.3.3 Plasmin Degradation of Fibrin Scaffold 43
4.3.4 Formation of the microvascular network with fibrin scaffold 45
4.4 SUMMARY 48
CHAPTER 5: CONCLUSIONS AND FUTURE WORKS 50
5.1 CONCLUSIONS 50
5.2 FUTURE WORKS 52
5.2.1 Development of a Microvascular Chip 52
5.2.2 Animal Studies for the Incorporation of HUVEC-Derived Microvascular Network into Rabbit Circulation System 53
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