本研究目的為自製一套方便組裝且精準度高的間質內壓測量系統，除了能夠測量各種液體壓力之外，也能精準地進行小鼠腫瘤模型之間質內壓測量，使在台灣癌症研究中較少被提及的腫瘤間質液內壓測量能受到重視，並與各種治療策略、癌症診斷進行合併探討。
本研究借鑑Wick-in needle技術之原理開發，以壓力傳送器 (Pressure transducer)為主要架構考量，採用量程為0-0.1 bar之微量壓力傳送器做為感測裝置，來符合以偵測小鼠腫瘤間質液壓力為主要使用之規格，透過基本的性能測試例如: 不同密度之溶劑校準、小鼠正常組織間質壓力測量、小鼠腫瘤模型壓力測試等，透過測量證實所組裝之WIN系統之穩定性與準確性，並發現需要改善之問題，最後我們結合較不易產生型變的材質 PE (Polyethylene)用於緩衝液填充管，能夠將受壓端之壓力源以最少的分散傳達至感測端，並以24 G側孔針(O.D.= 0.559 mm, I.D.= 0.381 mm，側孔開於距尖端2 mm管身，長2 mm，寬1/3管周長)作為壓力感受端，以極細之針管刺入腫瘤組織中，維持腫瘤內部封閉性避免大氣沿針管進入平衡內壓，並減少血液與組織液滲出，增加測量數值之真實性，並在側孔針管內部填充適量Nylon fiber，以增加液體介質交換面積增加測量精度。最終本研究架構之WIN系統透過測量小鼠腫瘤模型間質內壓，得到與其他文獻中測量小鼠乳癌 (4T1)皮下腫瘤模型間質內壓相近數值，若能以其他原理之儀器比較，更能印證我們所開發WIN系統的準確度。

The purpose of this study is to develop a set of interstitial fluid pressure (IFP) measurement system that is easy to assemble and highly accurate. In addition to being able to measure various fluid pressures, it is also possible to accurately measure pressure in mouse tumor models. Tumor IFP measurement, which is rarely mentioned in cancer research in Taiwan, could be taken more seriously and combined with various treatment strategies and cancer diagnosis. This study draws on the principle of Wick-in needle technology and considers the pressure transducer as the main framework. A micro-pressure transducer with a range of 0-0.1 bar is used as a sensing device to meet the specifications for detecting the IFP in mice tumor. Through basic performance tests such as: calibration with solvent of different density, IFP measurement in mice normal tissue, IFP test of mice tumor model, etc., the stability and accuracy of assembled WIN system were confirmed by measurement, and there are some problems should be solved. Finally, we combined the sturdy material PE (Polyethylene) for the buffer-filled tube, which can transmit the pressure source from the pressure endpoint to the sensing endpoint completely, and the 24 G needle (O.D.= 0.559 mm, I.D. = 0.381 mm) with a side-hole at 2 mm from the tip. The side-hole size is 2 mm, and 0.585 mm width as a pressure-sensing endpoint, penetrating into the tumor tissue with a very thin needle to maintain the internal sealing of the tumor. With this thin needle, we could also avoid air diffusion into tumor along with track for balancing internal pressure, and reduce the leakage of blood and interstitial fluid. To maintain the measurement accuracy, we filled up the side-hole needle with nylon fibers to increase liquid exchanging surface area. At last, we found the IFP measured by WIN system was similar to the result of other researches in mice breast cancer (4T1) subcutaneous tumor model. The result could enhance the reliability of the WIN system we developed.

Abstract I
摘要 II
目錄 i
圖目錄 iv
表目錄 vii
一、研究動機 1
二、文獻回顧與理論基礎 3
2.1 惡性腫瘤 3
2.1.1 乳癌 4
2.1.2 乳癌分期 4
2.1.3 乳癌治療現況 7
2.2 腫瘤微環境 9
2.2.1 細胞外基質 (Extracellular matrix, ECM) 11
2.3 腫瘤間質內壓 (Interstitial fluid pressure)形成之原因 12
2.3.1 膠原蛋白 (Collagen) 14
2.3.2 透明質酸 (Hyaluronic acid, HA) 16
2.3.3 基底膜 (Basement membrane) 18
2.3.4 血管增生 (Angiogenesis)與淋巴管功能不全 19
2.3.5 細胞之分泌蛋白質與微胞累積 21
2.4 傳統壓力測量技術 21
2.4.1 Wick-in-needle technique (WIN) 22
2.4.2 微管系統 (Micropipette system) 27
2.4.3光纖壓力感測技術 31
三、實驗方法與步驟 35
3.1 Wick-in-needle technique (WIN) 系統建構 35
3.1.1 壓力傳送器選擇與規格 36
3.1.2 WIN各部件組合 38
3.1.3 WIN部件組合後之基本運行問題檢查與排除 39
3.1.4 緩衝液填充管 40
3.1.5 側孔針 (Side-hole needle)規格選擇 40
3.2 自製WIN系統之實際測量 40
3.2.1 WIN系統對不同密度之液體之校準 40
3.2.2 WIN系統對不同濃度之海藻酸鈉 (Sodium Alginate)液體之平衡時間測試 41
3.3 小鼠腫瘤模型建立與細胞培養 43
3.3.1 細胞來源及適合之培養環境 43
3.3.2 配置細胞培養液與磷酸鹽緩衝溶液 44
3.3.3 細胞繼代 44
3.3.4 細胞計數 45
3.3.5 動物來源 45
3.3.6 小鼠皮下腫瘤模型建立 45
3.3.7 以阿霉素 (Doxorubicin, DOX)進行小鼠腫瘤瘤內注射 46
3.4 WIN技術用於活體小鼠測量 47
3.4.1 小鼠正常組織IFP測量 47
3.4.2 不同規格之側孔針對腫瘤IFP平衡時間測試 47
3.4.3 小鼠腫瘤IFP測量 48
3.5 小鼠腫瘤之組織切片與染色 48
3.5.1腫瘤冷凍包埋及切片 48
3.5.2Picro-Sirius Red 膠原蛋白染色 49
3.6 數據統計 49
四、結果與討論 50
4.1 WIN部件組合後之基本運行檢查與常見問題排除 50
4.2 WIN系統部件之選擇 52
4.2.1緩衝液填充管 52
4.2.2壓力傳送器對不同密度液體之校準測試 54
4.2.3側孔針 (Side-hole needle)規格選擇 55
4.3 WIN系統實際應用 59
4.3.1 WIN系統測量不同粘度液體之平衡時間 59
4.3.2 WIN系統測量小鼠之皮下與肌肉組織壓力 60
4.3.3 WIN系統測量小鼠之皮下腫瘤模型 61
4.4 WIN系統與市售其他儀器比較 64
4.5 膠原蛋白染色之腫瘤切片觀測 66
五、結論 68
六、參考資料 69

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