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研究生： 陳則劭
Chen, Tse Shao
論文名稱： 整合式微流體晶片用於腫瘤轉移與血管新生之研究
An Integrated Microfluidic Chip for The Study of Metastasis and Angiogenesis
指導教授： 劉承賢
Liu, Cheng Hsien
口試委員: 盧向成
Lu, Shiang Cheng
李岡遠
Lee, Kang Yun
學位類別： 碩士
Master
系所名稱： 工學院 - 動力機械工程學系
Department of Power Mechanical Engineering
論文出版年： 2013
畢業學年度： 101
語文別： 中文
論文頁數： 81
中文關鍵詞： 肺癌細胞 、血管新生 、細胞圖案化定義 、血管內皮細胞 、細胞外基質
外文關鍵詞： Lung cancer, Angiogenesis, Pattern, Vascular Endothelial Cell, Extracellular Matrix (ECM)
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    • 惡性腫瘤的罹患率和致死率連年增高，其中肺癌更是所有癌症中造成死亡的絕大多數。醫學上致力於研究相關的因應對策，運用化療、放射治療、外科手術等方法治療癌症，其後遺症與治癒率都讓癌症病患為之失望。在醫學不斷進步下，近年發展出許多新的癌症治療方式，根據文獻以及臨床醫學，因腫瘤而實現新生血管的能力一直以來在癌症的生物訊息被認為是重要的標記，因此使用細胞分子作為標地的新癌症治療方法抑制腫瘤的新血管生成，可為癌症病患帶來新的契機。 　
    隨著微機電技術的蓬勃發展，組織重建以仿效真實生物體內應有組織功能的體外模型得以實現，使得這些基於細胞的檢測數據將更具生物學的意義，並且對許多病患來說，可以在體外進行細胞的藥物篩選或找尋合適的治療方式，來預期治療的效果是理想的情況，也可避免掉許多法律問題與道德爭議，因此本論文以整合微流體系統的生醫晶片，並利用生醫微機電技術與微製程技術操控細胞圖案化定義，提供精準的細胞空間定位，在體外實現腫瘤細胞微環境的重構，探討腫瘤組織與血管內皮細胞相互作用，並定義細胞外基質剛性影響新生血管的關鍵性因素，以模擬腫瘤與新生血管成形的區域，細胞遷移的情形，有助於提供腫瘤臨床用藥或治療的資訊。

    Cancer results from the uncontrolled growth of abnormal cells in the body. The death rate caused due to cancer has been rising every year. Lung cancer among all cancers has the most significant impact on death of people affected by cancer. The diagnostics are committed to develop cure strategies. Although there are many remedies to treat different kind of cancer such as surgery, radiation and chemotherapy, but the success rate is still low. With the advance in medical approach, there are many new cancer treatments which have been developed in recent years. According to the literature survey and clinical experts’ comments, the ability of a tumor to achieve vascularization is an essential hallmark of cancer biology. Recently, cell-based therapy has been getting important for the inhibition of tumor angiogenesis. It can be a ray of hope to cure cancer for patients suffering from cancer.
    With the rapid development in MEMS technology, tissue reconstruction can be realized in vitro which can mimic the biological function in vivo and enable biologically meaningful data to be extracted during cell-based assays. For some patients, predicting the outcome of a treatment by performing in vitro cellular drug screening or trying to find the other suitable therapy is desirable, as it can avoid the problem of legal and ethical controversies. In this study, we try to integrate the microfluidic bio-chip, the manipulation of cells via dielectrophoresis patterning, bio-MEMS and photolithography techniques. The spatial orientation arrangement of cells via the cell patterning technique developed in our group was used to realize the reconstruction of tumor microenvironment. We can not only use this model to study the cell interaction of the cancer cell and the vascular endothelial cell but also define the mechanical stiffness of ECM that will influence the angiogenesis. At the same time, it can mimic the area of tumor angiogenesis where the cell migration phenomenon appears. It will provide pharmaceutical information and aid in drug discovery for cancer. The development in this research will provide pharmaceutical information and aid in drug discovery for cancer treatment.

    Abstract………………………………………………………………………I 中文摘要…………………………………………………………………………III 致謝………………………………………………………………………………IV 目錄………………………………………………………………………………V 圖目錄……………………………………………………………………………VIII 表目錄……………………………………………………………………………XII I. 緒論…………………………………………………………………1 1.1. 研究背景與動機……………………………………………………1 1.1.1. 微機電技術與實驗室晶片…………………………………………1 1.1.2. 腫瘤血管新生………………………………………………………2 1.1.3. 細胞外基質(extracellular matrix ,ECM)與蛋白質……4 1.2. 研究動機與目標……………………………………………………5 1.3. 文獻回顧……………………………………………………………6 1.3.1. 微流體系統產生濃度梯度之原則…………………………………6 1.3.1.1. 結合三維空間基質的生理現象………………………6 1.3.1.2. 通過三維基質濃度梯度之微流體晶片………………7 1.3.1.3. 微流體濃度梯度產生裝置之血管新生生物應用……11 1.3.2. 組織工程……………………………………………………………13 1.3.3. 細胞排列技術………………………………………………………14 1.3.3.1. 顯影技術………………………………………………14 1.3.3.2. 微腔體與微流道圖案定義技術………………………15 1.3.3.3. 微接觸印刷技術………………………………………16 1.3.3.4. 介電泳力(Dielectrophoresis，DEP)…………18 1.4. 肺癌與腫瘤治療及其前瞻性………………………………………21 II. 研究方法、原因與元件設計 ……………………………………………22 2.1. 理論背景…………………………………………………………………22 2.1.1. 介電泳…………………………………………………………………22 2.1.2 擴散理論………………………………………………………………26 2.1.3. 微尺度下的物質傳遞…………………………………………………29 2.1.3.1 雷諾數(Reynolds number)……………………………………29 2.1.3.2. 特徵擴散長度(characteristic diffusion length)…29 2.1.4. 微流體分析……………………………………………………………30 2.1.5. 肺癌組織模型…………………………………………………………32 2.2. 設計概念…………………………………………………………………33 2.2.1. 載入細胞外基質微流道設計…………………………………………35 2.2.2. 肺癌組織模型電極設計………………………………………………38 2.2.3. 肺癌組織模型圖案化定義操作原則………………………………39 2.2.4. 肺癌組織模型電極之數值模擬……………………………………40 2.4.5. 肺癌組織釋放之血管生長因子擴散模擬……………………………42 2.4.6. 基於擴散效應濃度梯度產生裝置之設計……………………………44 III. 晶片製程…………………………………………………………………47 3.1. 製作流程……………………………………………………………47 3.1.1. 細胞與細胞基質區域定位微流道製程……………………………47 3.1.2. 肺癌組織圖形化定義電極製程……………………………………50 3.1.3. 微流道翻模與電極接合……………………………………………51 3.2. 製程結果……………………………………………………………53 3.2.1. 微流道………………………………………………………………53 3.2.2. 電極…………………………………………………………………54 IV.實驗架設與方法……………………………………………………………55 4.1. 材料準備…………………………………………………………………55 4.1.1. 細胞培養………………………………………………………………55 4.1.2. 表面改質增加細胞貼附能力之試劑…………………………………58 4.1.3. 固化膠原蛋白…………………………………………………………58 4.2. 實驗架設…………………………………………………………………59 4.2.1. 儀器架設………………………………………………………………59 4.2.2. 實驗參數設定…………………………………………………………60 V. 實驗結果與討論……………………………………………………………61 5.1. 晶片微流道呈現…………………………………………………………61 5.2. 膠原蛋白固化於目標微流道實驗結果…………………………………62 5.3. 基於擴散效應之濃度梯度實驗結果……………………………………63 5.4. 肺癌組織模型圖案化定義………………………………………………65 5.5. 細胞增生率MTT檢測……………………………………………………66 5.6. 腫瘤誘發血管新生晶片實驗……………………………………………69 5.6.1. 纖維母細胞遷移實驗…………………………………………………69 5.6.2. 人類臍帶血管內皮細胞遷移實驗……………………………………71 VI. 結論…………………………………………………………………………74 VII. 參考文獻…………………………………………………………………75

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