臺灣博碩士論文加值系統

近年來，紙基微流體裝置(µPADs)得到了廣泛的關注，因為它提供了方便、簡單、快速且低成本的檢測方法，可應用於化學與生物檢測、食安分析、環境監控等等，目前已經發展出許多不同製備紙基微流體裝置的方法，例如：ink jet printing, paper cutting, 以及 photolithography等多種方法。在本研究中，我們將展示利用微壓印法製作紙基微流體裝置，這個方法首先需要製作一個具有流道圖案的模具，再將這個模具壓在濾紙上，使濾紙變形產生厚度差，接著在濾紙上塗上一層蠟，放在加熱板加熱即可完成一片紙基晶片，根據實驗結果，使用Whatman No.3濾紙可以得到優於No.1與No.4濾紙的成果，這是因為Whatman No.3濾紙具有較小的孔徑以及較厚的厚度。加熱時間是一個很關鍵的參數，控制流體是否會漏出流道外或者是使流道阻塞，用本方法所製作的紙基微流體裝置進行葡萄糖檢測可以得到與其它紙基微流體裝置一致的結果。利用微壓印法製作一片紙基微流體裝置不需超過一分鐘。

SUMMARY
In this study, we have proposed and demonstrated a relatively simple and fast technique, i.e. microembossing to fabricate paper-based microfluidic devices. A stamp with desired pattern was constructed and used to press against the filter paper, followed by painting with a wax pen and heating it on a hot plate. The results showed that No.3 Whatman paper yielded consistent results compared to No.1 ＆ No.4 owing to its smaller pore diameter and larger film thickness. The heating time was critical in order to prevent the channel from leakage or complete blockage. The glucose detection was conducted and result was comparable to that when µPADs are fabricated by other methods. Using the proposed method, the µPADs were fabricated within 1 min and the shelf life is, at least, 2 months.

Keywords : microfluidics, microembossing, filter paper, glucose detection

Introduction
Since emerging in the beginning of the 1980s, microfluidics has been widely studied with zealous exploration of its functionalities. Owing to its unique advantages such as fast analysis, high throughput, low reagent consumption, reduced waste product, high sensitivity and great portability. The field of microfluidics is characterized by the study and manipulation of fluids at the submillimetre length scale [1]. There are many advantages by exploiting microfluidic platform technology such as fast analysis, high throughput, low rea-gent consumption, reduced waste product, high sensitivity and great portability. Moreover, different unit operations can be integrated into one microfluidic platform to perform multiple functions. The microfluidics technology has been applied to a wide range of research fields such as drug screening [2], biomedical applications [3, 4], point of care [5-7], environmental monitoring [8-10], chemical and bio-logical detection [11, 12]. Among various substrate mate-rials such as silicon, glass, polymer, etc. [13], paper (and related porous hydrophilic materials) has been receiving more and more attention owing to its many unique merits including power-free fluid transport via capillary action, a high surface area to volume ratio that improves detection limits for colorimetric methods, and the ability to store rea-gents in active form within the fiber network [14]. Since the first paper-based microfluidic device constructed via conventional photolithographic technique and demonstrated for chemical analysis in 2007 [15], different strategies have been proposed to pursue easy, fast, and reliable fabrication for potential mass production of paper-based microfluidic devices [15]. For example, the handcrafted method [16-18], utilization of masks [15, 19-21], printing [16, 22-28], flexo-graphic printing [29], direct cutting/shaping [30-32], lacquer spraying [33], vapor phase polymer deposition [35], etc. Although some other materials like photopolymers, curable inks, paraffilm, alkyl ketene dimer (AKD), methylsilsesquioxane (MSQ), fluoropolymers, etc. can be found being used to form the barrier (i.e. the microchannel wall), wax is still the commonly used material in fabrication of paper-based microfluidic devices because it is cheap, easy to use and, most importantly, convenient for printing. By using the wax, the whole process can be finished within 5-10 min [16]. Despite the attractiveness, applying wax is not without concerns. For example, applying wax onto the paper requires heating afterwards. In most of the cases, the heating temperature is over 100 ℃ and it takes more than 10 minutes to complete fabrication of paper-based microfluidic devices [14]. If wax printing technique is used, expensive wax printers are needed [36] and clogging or error in printed reagent amounts may occur. Therefore, the need of simple and low-cost fabrication technique that can produce paper-based microfluidic devices still remains. Here, we demonstrated that by applying microembossing, the paper-based microfluidic devices can be fabricated in a relatively simple, fast and low-cost manner with great reproducibility and reliability.

Experimental
Materials. The wax pen, horseradish peroxide, glucose oxidase, D-(+)-glucose and the Whatman filter papers were purchased from Sigma-Aldrich. PBS buffer solution was purchased from Invitrogen. Potassium Iodide was purchased from UniRegion Bio-Tech. All the aqueous solutions were prepared with deionized water.
Methods. First, a metallic or plastic mold was first constructed by computer numerical controlled (CNC) machining. A straight trench was milled, which connects two reservoirs at both ends. The mold was then placed on top of the filter paper, followed by embossing under the press (QC 601T, Cometech, Taiwan). The wax was applied on the embossed filter paper, which was then placed on top of the hot plate with temperature set at around 75 oC to melt the wax for certain period of time. The embossed filter paper was then removed from the hot plate for subsequent testing of glucose detection. The embossed filter paper was characterized by optical microscope (Eclipse TE 2000-S, Nikon) and scanning electron microscope (Hitachi S-3000H or JEOL JSM-6700F). The ink solution was dispensed at the reservoir for flow visualization and characterization of flow behavior.
Glucose Detection. The fabricated paper-based microfluidic device was used to detect the glucose through the enzymatic oxidation of iodide to iodine. In this study, 1.5 µL of potassium iodide solution (0.6 M) was first dropped onto the detection zone at one end of the device. After drying under ambient conditions, 1.5 µL of horseradish peroxidase–glucose oxidase enzyme mixture (1 : 5) was spotted on the same zone. 10 µL of the glucose solution (0.5 M in pH 7.4 buffer) was then dispensed on the inlet zone at the other end of the device.
Quantification of the color response was carried out by using a commercially available scanner (HP, Photosmart C4580) to capture the images of the detection zone, which were deconvoluted into red (R), green (G), and blue (B) components [Juang, et. al., 2017]. The ratio of intensity of R to (R+G+B) was taken as quantification of the color image.
Results and discussion
Figure 1 shows the µPADs fabricated by microembossing. It can be seen that the filter paper in contact with the mold was embossed, which renders the unembossed region being a protruded structure as shown in Figure 1(a). The difference between the embossed and unembossed region can be distinguished under the scanning electron microscope where the fiber structure at the embossed region was compressed nearly to be flat as shown in Figure 1(b).








Figure 1. (a) The optical images of the top view of the embossed µPAD. (b) The SEM image of the embossed channel at the boundary between the embossed and unembossed region.
The successful µPADs were made when using Whatman No. 3 as the ink solution wicked through the channel from one reservoir to the other with repetitive and consistent results. Therefore, the Whatman No. 3 filter paper was used for subsequent experiments. The 6-channel, star-shaped µPAD can also be constructed by microembossing and the shelf life of the µPADs is, at least, 2 months. The thickness ratio increased as the embossing pressure increased, which reached around 2.8 when the embossing pressure is over 50 kg/cm2 as shown in Figure 2(a). The thickness ratio was defined as the thickness of the unembossed region divided by that of the embossed region. It was also influenced by the channel width as shown in Figure 2(b). That is, the thickness ratio increased and reached around 2.8 as the channel width became equal to or larger than 2 mm. Note that, leakage was observed or inconsistent results were obtained when the embossing pressure was less than 50 kg/cm2 or the channel width less than 2 mm.
Figure 2. The influence of (a) the embossing pressure and (b) the channel width) on thickness ratio.
Figure 3(a) shows the influence of the wax heating time on the solution wicking through the channel. When the heating time is less than 15 sec, either leakage was observed or inconsistent results were obtained. As the heating time increased up to around 15 sec, the ink wicked through the channel without leakage. Figure 3(b) shows the cross sectional view and it can be seen that the ink solution was confined in the channel. This is because, with sufficient heating time, the wax was able to diffuse through the embossed area and form the barrier to prevent the ink solution from leaking out of the channel. Note that most of the unembossed region, i.e. the channel, was filled with the ink solution. Since there was no leakage through the backside of the filter paper, it was believed that there should exist a thin layer of wax at the bottom of the channel. For the heating time around 45 sec, the ink solution was also confined in the channel but with a smaller cross-sectional area. Further increase of heating time to 60 sec resulted in hydrophobization of the filter paper, i.e. a droplet was observed after dispensing the ink solution.
Figure 3. (a) Effect of wax heating time on constructing µPADs without leakage. (b) The cross sectional view of the channel fabricated by applying different wax heating time.

The channel depth of the mold that we milled also can influence the thickness ratio and wicking test results. We constructed molds with three different channel depths (600, 250, 150µm). The results showed that the wicking test was similar when using the molds with 600 ＆ 250µm depth. However, the successful rate of using the mold with 150µm depth is low (~20%).
Glucose Detection. After dispensing the glucose solution, it wicked through the channel and reached the detection zone where color change was observed. Figure 4 shows quantification of the color response for different glucose concentrations by using the µPAD as fabricated. It can be seen that a linear relationship was obtained for concentrations between 5 to 50 mM with R2 value equal to 0.97. This demonstrated that the µPAD fabricated by our proposed technique possessed the similar performance to those fabricated by other methods.
Figure 4. The relative intensity measured at different glucose concentrations using the µPADs as fabricated.
Conclusions
In this study, fabrication of µPADs was demonstrated by microembossing. It is found that, by using the Whatman No. 3 filter paper, the µPAD can be constructed within approximately 1 min with the shelf life at least 2 months. In addition, there is no need of a hydrophobic material as the backside support. The thickness ratio increases as the embossing pressure or the channel width increases, which levels off as the embossing pressure exceeds 50 kg/cm2 or the channel width 2 mm. The amount of wax heating time to form the barrier, which allows the solution to successfully wick through the channel ranges from 15 to 45 sec. The glucose detection was also demonstrated a linear relationship was obtained between 5 to 5o mM glucose concentrations. With its simplicity and rapidness, the proposed technique sheds light in potential mass production of µPADs.

中文摘要 i
Extended Abstract ii
誌謝 viii
圖目錄 xii
表目錄 xvi
第一章 緒論 1
1.1 前言 1
1.2 研究動機與方法 2
第二章 文獻回顧 3
2.1 紙基微流體 3
2.2 紙基微流體的製作 5
2.2.1 Handcrafted 6
2.2.2 Mask 9
2.2.3 Printing 11
2.2.4 Cutting/Shaping 14
2.2.5 其它方法 18
2.3 紙基微流體之檢測方法 26
2.3.1 光度檢測法 26
2.3.2 化學發光法 27
2.3.3 螢光檢測法 27
2.3.4 電化學檢測法 28
2.4 紙基微流體之應用 29
2.4.1 臨床檢測 29
2.4.2 環境監控 31
2.4.3 食安分析 33
2.5 流體在濾紙中的流動行為 35
第三章 實驗材料及方法 37
3.1 實驗藥品與材料 37
3.2 實驗儀器 40
3.3 實驗步驟 46
3.3.1 紙基晶片製作 46
3.3.2 拉曼分析 47
3.3.3 葡萄糖檢測應用 47
第四章 結果討論 48
4.1 濾紙選擇 48
4.2 流道形成機制 51
4.3 製程變數之影響 54
4.3.1 壓印壓力 54
4.3.2 加熱時間 56
4.3.3 模具印章的流道深度 62
4.4 葡萄糖檢測 66
第五章 結論 68
第六章 未來工作與展望 69
第七章 參考文獻 71











圖目錄
圖2-1光蝕刻紙基微流體製作流程[2] 4
圖2-2 各種製作紙基微流體的方法[3] 4
圖2-3 用紙製作微流體裝置的特點[18] 5
圖2-4 活字印刷法[20] 8
圖2-5 加熱金屬戳印法[21] 8
圖2-6 A、B、C分別為使用金屬戳印加熱法，壓印2、5、10秒的結果 9
圖2-7 利用Mask浸蠟法[22] 10
圖2-8 絲網印刷法[7] 11
圖2-9 Wax printing法[6] 13
圖2-10 Inject printing法[11] 13
圖2-11 AKD printing法[14] 14
圖2-12 Cutting法[16] 15
圖2-13 Renault et al.利用雷射切割法所製作的中空流道紙基微流體裝置示意圖[23] 16
圖2-14 Flexographically Printed法[24] 19
圖2-15 Laser treatment法[19] 21
圖2-16 treatment前後之比較圖[19] 22
圖2-17 塗佈前後之比較圖[19] 22
圖2-18 阻絕層的形成機制[25] 23
圖2-19 在PP不織布上施力不同的結果[25] 24
圖2-20 用五種不同的有機溶劑進行流道外漏測試[25] 25
圖2-21 DNA的檢測[33] 28
圖2-22 樣品中葡萄糖的含量檢測[41] 29
圖2-23 利用護貝的方式製作出紙基微流體裝置[42] 30
圖2-24 Nanoparticles的反應示意圖[47] 31
圖2-25 銅離子與其他金屬離子的檢測，可看出選擇性良好[47] 31
圖2-26 摺紙的方式進行硝酸鹽及亞硝酸鹽的檢測[48] 32
圖2-27 ABC分別為大腸桿菌、紗門菌及單核細胞增生李斯特氏菌的檢測[49] 33
圖2-28檢測重金屬含量[50] 34
圖2-29 流體流經紙條的模擬過程[53] 36
圖3-1熱電耦溫控加熱板 40
圖3-2 手動熱壓成形機 41
圖3-3 解剖顯微鏡 42
圖3-4倒立螢光顯微鏡 43
圖3-5 CNC雕刻機 44
圖3-6 帶鋸機 44
圖3-7 DXR顯微拉曼分析系統 45
圖3-10 紙基晶片製作過程的示意圖 46
圖3-11 壓克力板上雕刻完後的模具 46
圖4-1 不同型號濾紙的測試結果 49
圖4-2 (a)濾紙壓印過後的外觀以及顯微鏡的影像。(b)壓印處與未壓印處的顯微鏡剖面圖。(c)壓印處與未壓印處的SEM圖 52
圖4-3 紙基微晶片之截面示意圖 53
圖4-4 滴上墨水後之紙基微晶片剖面圖 53
圖4-5四片紙基晶片放置2個月後，再滴墨的測試結果 54
圖4-6利用微壓印法做出米字形流道 54
圖4-7 (a)壓力與厚度比的關係圖。 (b)壓力為120 kg/cm2的條件下，流道寬與厚度比的關係 56
圖4-8 (a)流道寬0.5mm，加熱15秒，(b)流道寬1mm，加熱15秒，(c) 流道寬1mm，加熱時間16秒後滴上墨水的結果 56
圖4-9 在75℃下測試不同加熱時間再滴上墨水的結果 57
圖4-10 紙基晶片加熱15秒與45秒流道寬度的差異 58
圖4-11 不同加熱時間的流速關係圖 59
圖4-12 純濾紙與蠟的拉曼圖譜 60
圖4-13 紙基晶片流道底部附近的拉曼圖譜 61
圖4-14 不同加熱時間相同位置的拉曼圖譜。左上角示意圖中間那一點即為偵測位置 61
圖4-15 模具的流道深度(a) 600µm，(b) 250µm，(c)150µm壓印在Whatman No.3濾紙後的結果剖面圖 63
圖4-16 壓克力模具流道溝槽處的剖面圖 63
圖4-17 流道深度(a) 600µm，(b)250µm的模具所製備的紙基晶片滴墨測試結果 65
圖4-18 (a)~(e)流道深度150µm的模具所製備的5片紙基晶片滴墨測試結果 65
圖4-19三種不同溝槽深度模具所製備的紙基晶片流速圖 66
圖4-20 在紙基微流體裝置上滴上不同濃度的葡萄糖溶液 67
圖4-21 X軸為葡萄糖溶液濃度，Y軸則是R/(R+B+G)相對紅色強度的數值 67
圖6-1 壓印後與未壓印濾紙的流速關係圖 69


表目錄
表一. 四種不同製程的比較[18] 17
表4.1 Whatman No.1、No.3、No.4濾紙(cellulose filters)的比較 50
表4.2、No.4濾紙在不同參數下做出的結果。加熱溫度65℃ 50
表4.3、No.1濾紙在不同參數下做出的結果。加熱溫度65℃ 50
表4.4、No.3濾紙在不同參數下做出的結果。加熱溫度75℃ 51

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