臺灣博碩士論文加值系統

近年微機電技術日漸成熟，利用微機電製程技術製作微流體晶片基礎研究已經有相當多的成果，而本文研究目的在於利用微機電技術製作微流體晶片，將複雜的微血管網絡簡化為兩種類型的幾何形狀(直管、彎管)，於其上加上奈米孔隙，來分析微流道幾何設計對於奈米顆粒陷入奈米流道的比例影響的基礎研究。
本實驗利用微質點影像測速法(μPIV)觀測微流道其速度分布情況，並且利用套裝模擬軟體CFD-ACE+，結合Flow Module與Spray Module來模擬求解奈米顆粒在微流道中的運動。
由目前的實驗結果顯示，當奈米粒子在微流道運動時，其受到布朗運動的力量最為顯著，並且和奈米粒子的大小有著一關係式。在陷入比例方面，在彎管前段部分，奈米粒子陷入內側的比例高於外側，而彎管後段部分，奈米粒子陷入外側的比例則是高於內側。並且當固定奈米粒子大小時，曲率半徑越大的設計所擁有的陷入比例越高，而在相同曲率半徑的設計，當奈米粒子尺寸縮小，可得較高的陷入比例。應用在腫瘤治療方面，我們希望可透過陷入比例的結果以提高癌症標靶治療的投藥效率。

In this paper, we have (1) built a micro flow network that mimics micro vessels and visualized the flow inside utilizing both experimental and CFD approaches, (2) developed a model, which considering both the inertial forces caused by flow convection and the diffusion resulting from Brownian motion, to evaluate the entrapment probability of nanoparticles with various particle sizes and channel geometries from micro flow field into nanochannels..
The micro flow network was fabricated by photolithography process and Deep Reactive Ion Etching (DRIE) process. Hundreds nanometer wide nano-gaps located around curved silicon micro-channels were arranged for simulating the geometry of leaky blood vessels in tumors. The nano-gap was about 600 nm in both width and depth, and fabricated by focus ion beam (FIB) process. Finally, the chip was sealed with a Pyrex glass substrate by anodic bonding technique. Micro particle image velocimetry (μPIV) is then employed to visualize the particle-laden flow inside the microfluidic channels. By dual pulse μPIV, the particle images are recorded at two specific moments with continuous illumination.
In the experimental results, the spatial resolution of about 2 μm is employed to resolve the near-wall flow field with 50% interrogation spot overlapping by using μPIV. The most significant deviation is about 5% between the experimental and simulation results, which implies excellent agreement and brings out the evidence in utilizing simulation for more detailed study on the flow behaviors of nano- particles. We found that the working fluid passing through the inner side of the curved channel was apparently accelerated. The distortion in velocity profile could potentially lead to the increase of particle concentration, and facilitate the entrapment of particles into the nano-gap. And finally we used Stokes-Einstein equation to estimate the entrapment probability of nanoparticles with various particle sizes and channel geometries.

目錄
中文摘要 ...................................................................................................................... i
英文摘要 ……………………………………………………………………………..ii
誌謝 ............................................................................................................................ iii
目錄 ............................................................................................................................. v
表目錄 ........................................................................................................................ viii
圖目錄 .......................................................................................................................... ix
第一章 緒論 ................................................................................................................. 1
1.1研究背景.......................................................................................................... 1
1.2研究動機.......................................................................................................... 4
第二章 文獻回顧.......................................................................................................... 7
2.1 治療惡性腫瘤之奈米顆粒介紹..................................................................... 7
2.2.1磁性氧化鐵粒子……………………………………………………7
2.2.2 微脂體……………………………………………………………...8
2.2 奈微米顆粒於流道之觀測........................................................................... 14
2.3 微質點影像測速系統................................................................................... 26
第三章 實驗設計與CFD數值模擬 .......................................................................... 30
3.1 實驗設計....................................................................................................... 30
3.2 晶片製程....................................................................................................... 33
vi
3.3 實驗儀器架設............................................................................................... 39
3.4 數值模擬....................................................................................................... 42
3.4.1 Flow Module Theory………………………………………………42
3.4.2 Spray Module Theory..........................................………………….43
3.5 網格建構與邊界設定................................................................................... 45
第四章 初步設計結果與討論 ................................................................................... 48
4.1 初步設計實驗結果....................................................................................... 48
4.1.1 直管微流道…………………………………………………..…...48
4.1.2 彎管微流道…………………………………………………….....49
4.2 初步設計模擬結果…………........ ………………………………………...53
4.2.1 直管微流道……………………………………………………......53
4.2.2 彎管微流道……………………………………………………......55
4.3 初步設計結論............................................................................................... 57
第五章 二代實驗設計與結果 ................................................................................... 58
5.1 二代實驗設計……………………………………………………………..58
5.2 二代設計結果……………………………………………………………...59
5.2.1 模擬結果………………………………………………………......59
5.2.2 實驗結果………………………………………………………......61
第六章 未來工作 ....................................................................................................... 63
vii
參考文獻……………………………………………………………………………..64
viii
表目錄
表3-2 實驗設備 ......................................................................................................... 41
表5-1 模擬結果討論 ............................................................................................... 60
ix
圖目錄
圖1-1 2004至2008年手機之MEMS市場銷售值趨勢 ............................................... 2
圖1-2全球醫用微機電市場趨勢……………….…………..………………………..3
圖1-3台灣地區十大死因人數統計 ........................................................................ …5
圖1-4鼻腔腫瘤 ............................................................................................................ 6
圖1-5 大腦惡性腫瘤 ................................................................................................... 6
圗1-6眼睛惡性腫瘤………………………………………………………………….6
圖2-1微血管TEM圖…………………………………….…...……………………….7
圖2-2 USPIO注射前(圖a)與注射後(圖b)影像差別 ............................................... 8
圗2-3微脂體示意圖.................................................................................................... 9
圗2-4微脂體搭配熱療法治療腫瘤示意圖.............................................................. 10
圖2-5 HCa-1:老鼠肝癌，LS174T:人類結腸癌，ST-8:老鼠纖維肉瘤，MCa IV:老鼠乳癌，U87:一種人類惡性腦瘤.............................................................................. 10
圖2-6不同居禮溫度的奈米鎳銅合金 ...................................................................... 11
圖2-7 liposome的累積以確認腫瘤位置……..……………………………………11
圖2-8三種不同種類的liposome其釋放藥物的時間與溫度 ................................ 12
圖2-9 FLUENT軟體模擬肺部支氣管微粒沉積結果 ................................................ 13
圖2-10 模擬腫瘤微血管滲漏現象…………………………………………………..14
圖2-11 Micro-PIV設備架設圖 .............................................................................. ..14
圖2-12 實驗結果與模擬比較 ................................................................................... 15
圖2-13 具螢光效果liposome .................................................................................. 16
x
圖2-14 μ-PIV的設備架構圖………………………...……………………………16
圖2-15 血管中的速度分佈圖………..……………………..……..………............17
圖2-16 KLF2轉錄因子在雞胚胎心臟分布情況.................................................... 17
圖2-17 Confocal micro-PIV系統……………………….…………………….…...18
圖2-18 Spinning disc共焦顯微鏡原理................................................................ 19
圖2-19 Confocal micro-PIV三維切片.................................................................. 19
圖2-20 實驗架設圖………………………………………………………………...20
圖2-21 渦流大小與在不同雷諾數下之變化(a) Re=100 (b)Re=300 (c)Re=500 (d)Re=1000 (e)Re=1500............................................................................................ 21
圖2-22 LIFPA實驗架設圖........................................................................................ 21
圖2-23 FIFPA量測之速度profile ……………………………………………..22
圖2-24 兩工作流道速度profile比較圖............................................................... 22
圖2-25 大尺度下流道速度profile ........................................................................ 23
圖2-26 PTV量測階梯式微流道晶片……………………………………………………............23
圖2-27 LDV實驗架設圖............................................................................ …………24
圖2-28 LDV量測不同雷諾數速度分佈圖 .............................................................. 24
圖2-29二次流現象………..………………………………………………………..25
圖2-30微分類器架設圖............................................................................................ 25
圖2-31 Dean=40 分類結果…………………………………………………...........25
圖2-32 interrogation spot內粒子分析圖.......................................................... 27
圖2-33 μ-PIV架構圖.............................................................................................. 28
xi
圖2-34 高解析測速技術之比較............................................................................... 29
圖3-1 微流道光罩設計圖R100: 曲率半徑100μm 45、90、135、180分別為旋轉角度………………………………………………………………………………..31
圖3-2 微流道大小尺寸............................................................................................. 32
圖3-3奈米開口大小尺寸 .......................................................................................... 32
圖3-4 微流道製程流程圖......................................................................................... 35
圖3-5 步驟13 BOE蝕刻後....................................................................................... 35
圖3-6 直管SEM圖…………………………………………………………………..36
圖3-7 45度SEM圖…………………………………………………………………...36
圖3-8 90度SEM圖………………………………….………………………………..37
圖3-9 135度SEM圖…….………………….…………….........................................37
圖3-10 180度SEM圖………………………….……...……………………………...38
圖3-11 FIB製作nanochannel SEM圖……………….……………………………...38
圖3-12封裝後晶片圖……………… ………...…………………………………….39
圖3-13 Micro-PIV流場觀測架設圖……….………………..……………………...40
圖3-14 微流道網格設定……………………….…………………………………..45
圖3-15 奈米孔隙放大圖…………………………………………………………...46
圖3-16 奈米顆粒散佈位置………………………………………………………...47
圖4-1 直管PIV分析圖............................................................................................. 48
圖4-2 直管模擬圖..................................................................................................... 48
xii
圖4-3 直管實驗與模擬比較圖………………...…………………………………..48
圖4-4 45°微流道PIV分析圖………..……………………..………….....................49
圖4-5 45°微流道模擬圖........................................................................................... 49
圖4-6 45°微流道實驗與模擬比較圖………….…………………………...............50
圖4-7 90°微流道PIV分析圖................................................................................... 51
圖4-8 90°微流道模擬圖……………………………………………………………51
圖4-9 90°微流道實驗與模擬比較圖....................................................................... 52
圖4-10 不同疏密網格比較圖(a) 殊網格 (b)密網格........................................... 54
圖4-11 直管微流道模擬結果………………...……………………………………54
圖4-12 奈米流道及直管主流道流場變化…..………………….............................55
圖4-13 45°微流道模擬結果..................................................................................... 55
圖4-14奈米流道及45°主流道流場變化………….………………………............55
圖4-15 180°微流道模擬結果………………………………………………………56
圖4-16奈米流道及180°主流道流場變化…………………………………………56
圖5-1 二代晶片設計……………………………………………………………….58
圖5-2不同曲率半徑不同粒子大小陷入比例.......................................................... 59
圖5-3奈米粒子在微流道中受力圖…………...……………………….…………...59
圖5-4奈米顆粒陷入奈米流道圖………..………..…………...................................59
圖5-5 R150 200nm粒子實驗模擬比較圖............................................................ …60

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