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研究生： 黃柏翰
Huang, Po-Han
論文名稱： 以自製可調速之滾筒式生物反應器誘導脂肪幹細胞於聚己內酯多孔支架上分化成平滑肌細胞
Induced Smooth Muscle Cell Differentiation from Adipose-Derived Stem Cells on Polycaprolactone Porous Scaffold with a Rotating Wall Vessel Bioreactor
指導教授： 葉明龍
Yeh, Ming-Long
學位類別： 碩士
Master
系所名稱： 工學院 - 生物醫學工程學系
Department of BioMedical Engineering
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 57
中文關鍵詞： 血管組織工程 、小管徑人工血管 、聚己內酯血管支架 、鹽析法 、脂肪幹細胞 、平滑肌細胞 、幹細胞分化 、滾筒式生物反應器
外文關鍵詞： Vascular tissue engineering, small-diameter vascular graft, PCL scaffold, salt-leaching technique, adipose-derived stem cells, smooth muscle cells, stem cell differentiation, rotating wall vessels bioreactor
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    • 根據世界衛生組織(WHO)的統計，缺血性心臟病(ischemic heart disease, IHD)為全球人口十大死因之中排名第一位，並在2016年導致全球約九百多萬人喪命，且於過去15年中始終居高不下，是全體人類須共同面臨之一大醫療挑戰。
    當前臨床上所採用之醫療手段，視病情嚴重性可依序分為藥物治療、血管修復手術、血管支架植入及血管取代手術。在血管取代手術方面，過去常見的自體血管移植常採用患者自身腿部的隱靜脈進行冠狀動脈繞道手術，但研究指出由於靜脈與動脈間力學性質差異所導致的應力不匹配，往往容易引起內膜增生與血管硬化而降低癒後品質，甚至必須進行二次手術。有鑑於此，血管組織工程領域開始注重小管徑血管支架的研究與開發，以期能開發出具有良好生物相容性與力學強度之血管支架用於血管取代手術。
    現行之小管徑血管製備技術眾多，包含使用去細胞技術的天然血管支架，或以高分子材料所合成的可降解與不可降解之血管支架，甚至結合生長因子(growth factor)來促進細胞貼附生長，或利用幹細胞分化技術加速血管重建。
    本研究採用聚己內酯(polycaprolactone, PCL)作為基材，並以加熱塑型的方式加上鹽析法(salt-leaching technique)來製備多孔性血管支架，並以環狀拉伸試驗評估其力學性質；另外也採用了傅立葉轉換紅外光譜(Fourier-transform infrared spectroscopy, FTIR)及接觸角測量等方式，檢驗結合了聚多巴胺(polydopamine, PDA)與明膠(gelatin, GE)塗層的表面改質。此外本研究亦自製可調速之滾筒式生物反應器(rotating wall vessel bioreactor, RWV bioreactor)，搭配自紐西蘭大白兔背部脂肪組織萃取出的脂肪幹細胞(adipose-derived stem cell, ADSC)進行動態培養，以期能以動態培養的方式帶動流體對細胞進行力學性刺激，取代以生長因子誘導的方式來促進幹細胞進行分化，並以冷凍切片與免疫螢光染色的方式，對脂肪幹細胞與平滑肌細胞(smooth muscle cell, SMC)所攜帶的特定蛋白進行辨識與標記。
    本研究最後分別成功製備出具有良好力學性質之聚己內酯多孔性支架及品質穩定之製程；成功確認表面改質所改善之材料親疏水性；建構出低成本且可運作之滾筒式生物反應器，並提供無菌且可氣體交換之培養腔室來對幹細胞進行動態培養；以免疫螢光染色觀察到增量的肌原蛋白(myogenic protein)表現量，藉此確認脂肪幹細胞於生物反應器內的分化潛力與此方法之可行性。本研究作為一個前驅性研究，建立了一套可行的血管支架製備流程與策略，為後續更深入的研究奠定了良好的基礎。

    According to the statistics reported by the World Health Organization (WHO), ischaemic heart disease (IHD) was the number 1 cause of deaths among the top 10 global causes. IHD claimed over 9 million lives in 2016 and has remained the leading cause of death for the last 15 years. This disease is an excellent challenge to all mankind.
    The current clinical treatments are medical treatment, angioplasty, stent implantation and surgical intervention, depending on the stage of vascular disease. For surgical intervention, the saphenous vein was once the standard choice for coronary artery bypass surgery (CABG). However, researches showed that the compliance mismatch caused by different mechanical properties between arteries and veins tended to lead to intimal hyperplasia and atherosclerosis, which gave a poor prognosis and sometimes even required a secondary surgical intervention. As a result, the development of small-diameter vascular graft draws more and more attention in vascular tissue engineering. The final goal is to fabricate a vascular graft with good biocompatibility and adequate mechanical properties for vascular replacement.
    There are now various techniques for fabricating a vascular graft, including decellularized native scaffold, degradable/non-degradable synthetic polymeric scaffold, a combination of growth factors to promote cell adhesion and proliferation, and vascular reconstruction using stem cell differentiation.
    This study used polycaprolactone (PCL) as the base material to fabricate a porous scaffold with heating process and salt-leaching technique. We also measured the mechanical properties of the scaffold with ring tensile test. Fourier transform infrared spectroscopy (FTIR) and contact angle measurement were employed to verify the surface modification of polydopamine and gelatin-coating layers. Also, we combined a self-made rotating wall vessel (RWV) bioreactor with adipose-derived stem cells (ADSCs) from the back adipose tissue of New Zealand White Rabbit to perform dynamic culture, presuming the fluid flow could stimulate the differentiation of stem cell instead of growth factors. After giving a one-week dynamic culture, we performed cryo-sectioning and immunofluorescence staining to identify certain cell markers that were reported to be specific to ADSCs and smooth muscle cells.
    This study successfully developed a PCL porous scaffold with good mechanical properties and a stable manufacturing process; we verified the improved hydrophilicity that came from surface modification; we built a cheap and functional RWV bioreactor with sterilized culture chambers that free gas exchanged was allowed; the differentiation potential of ADSC in a bioreactor was confirmed through the increased expression of myogenic protein. In conclusion, this study built a feasible protocol for PCL vascular scaffold and laid a foundation for the following studies.

    中文摘要 I Abstract III 誌謝 V Table of Contents VII List of Figures XI List of Tables XII Abbreviations XIII Chapter 1 Introduction 1 1.1 Cardiovascular diseases (CVDs) 1 1.1.1 Physiological structure and functions of blood vessels 1 1.1.2 Ischemic heart disease (IHD) 2 1.1.3Available therapeutic strategies 3 1.2 Small-diameter vascular tissue engineering 4 1.2.1 History and development of vascular engineering 4 1.2.2 Current state of vascular tissue engineering 5 1.2.3 Rising interest in small-diameter tissue engineering 6 1.3 Synthetic scaffold 6 1.3.1 Materials used in tissue engineering 6 1.3.2 Polycaprolactone (PCL) 7 1.3.3 Bioreactor 8 1.4 Objective of this study 10 1.4.1 Motivation 10 1.4.2 Aims 11 Chapter 2 Materials and Methods 12 2.1 Flow Chart 12 2.2 Fabrication of PCL Porous Scaffold 13 2.3 Surface Modification 14 2.4 Fourier-transform Infrared Spectra Analysis 14 2.5 Contact Angle Measurement 14 2.6 Cell Adhesion Test by WST-1 Assay 14 2.7 Ring Tensile Test 15 2.8 Evaluation of Young’s Modulus 16 2.9 Evaluation of Burst Pressure 17 2.10 Degradation Test 17 2.11 SEM Observation and EDS Analysis 18 2.12 Establishment of Adipose-derived Stem Cells Culture 18 2.13 Fabrication of Self-made RWV Bioreactor 19 2.14 Immunofluorescence Staining 21 2.15 Cryo-sectioning 22 Chapter 3 Results 23 3.1 PCL material properties 23 3.1.1 Formation of PCL membrane 23 3.1.2 Characterization of gelatin coating layer by EDS analysis 25 3.1.3 Cell adhesion test by fluorescence microscopy 26 3.1.4 Verification of coating layer by FTIR spectroscopy 28 3.1.5 Wettability analysis 30 3.1.6 Cell adhesion test by WST-1 assay 31 3.1.7 Degradation test of porous PCL specimen 33 3.2 Porous PCL scaffold 34 3.2.1 Fabrication of porous PCL scaffold 34 3.2.2 Evaluation of porous PCL scaffold quality 35 3.2.3 Observation of microstructure by SEM 36 3.2.4 Mechanical properties 37 3.3 Evaluation of cell differentiation induced by RWV bioreactor 38 3.3.1 Self-made RWV bioreactor 38 3.3.2 Immunohistochemical staining of cell markers 39 Chapter 4 Discussion 42 4.1 Porous PCL scaffold 42 4.1.1 Fabrication of PCL scaffold 42 4.1.2 Surface modification 43 4.1.3 Mechanical properties of porous scaffold 44 4.1.4 Degradation of PCL 45 4.2 ADSCs differentiation induced by RWV bioreactor 45 4.2.1 Immunofluorescence staining of cell markers 45 4.2.2 RWV bioreactor 47 Chapter 5 Conclusion 48 References 50

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