簡易檢索 / 詳目顯示

研究生: 何承恩
Ho, Cheng-En
論文名稱: 批次填充與平行蓋印蛋白質溶液之微陣列壓印晶片系統
Micro Array Stamping System for Passive Batch-filling and In-Parallel-Printing Protein Solutions
指導教授: 曾繁根
Tseng, Fan-Gang
錢景常
Chieng Ching-Chang
口試委員:
學位類別: 博士
Doctor
系所名稱: 原子科學院 - 工程與系統科學系
Department of Engineering and System Science
論文出版年: 2008
畢業學年度: 96
語文別: 中文
論文頁數: 159
中文關鍵詞: 微陣列微壓印蛋白質微陣列
外文關鍵詞: Micro Array, Micro contact printing, Protein microarray
相關次數: 點閱:61下載:0
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 本論文研發新式之微陣列壓印晶片系統, 能一次同時填充數十種蛋白質溶液, 並將此數十種檢體同時平行蓋印出來. 藉由微陣列填充晶片與微陣列壓印晶片之結合, 數十種蛋白質溶液以毛細力平行傳入到微壓印晶片上方; 而各檢體溶液間, 彼此區隔良好. 各檢體溶液流到填入其相對應的導棒及微流道內, 並流入微壓印章. 將微陣列壓印晶片與底材接觸, 數十種蛋白質溶液平行同時蓋印出來形成蛋白質微陣列.
    改善背後填充式微陣列壓印晶片之Su8製程, 作出通的背後填充式微陣列壓印晶片. 可同時蓋印出四種檢體, 蓋印出的液珠尺寸為50μm, 且蓋印尺寸差異性小於10%, 均勻性良好. 此外, 並進一步探討蓋印在不同親水程度表面上, 以及不同黏滯性的檢體溶液對蓋印尺寸結果的影響. 實驗結果顯示蓋印在越親水的表面時, 液珠尺寸越大. 而且當所用的檢體溶液黏滯性較大時, 蓋出的液珠尺寸較小. 所得數據可供壓印晶片設計及蓋印蛋白質微陣列點能有最小間距最大密度之設計參考.
    再者, 設計新式的導棒式微陣列壓印晶片, 可與微陣列填充晶片成功整合, 能平行填充及蓋印36種檢體. 利用微轉印法或微流道法製作Teflon 疏水區隔層於晶片表面, 能有效區隔各檢體溶液在填充時, 使其各自填入相對應的導棒, 不與鄰近的檢體混流, 使微陣列填充晶片與微壓印晶片能順利整合在一起, 達到快速批次填充的目的. 並用PDMS微壓印端直接與微填充晶片接合, 沾取檢體後蓋印. 可同時蓋出36種不同的蛋白質檢體溶液, 改善傳統PDMS壓印一次只能轉印一種或幾種的缺點, 且製程容易. 並且研發出新式排針式微陣列壓印晶片, 檢體一次吸取填充後, 可連續蓋印一百次. 蓋印出來各點尺寸及螢光強度均勻性良好, 差異性均小於10%, 且晶片製作簡單.


    This work develops a novel micro contact printing system for printing tens of protein solutions into an array with batch filling and parallel printing. This printing system consists of a micro filling chip and a micro stamp chip. The micro filling chip can simultaneously transfer numerous protein solutions into the micro stamp chip in seconds by capillary force without cross-contamination, while preserving the functionality of proteins. Different proteins can be dispensed into the corresponding channels and driven into the tips of the micro stamps. The micro stamp can be then brought to contact with the substrate to produce bio-fluid spot arrays. Teflon patterns are applied on both the micro filling chip and the micro stamp chip to prevent cross-contamination during filling. Thirty-six proteins can be printed in parallel with a spot size variation of less than 5%. This device has a potential to be expanded to a passive and high throughput system for simultaneously printing hundreds of bio-fluid spots to form dense arrays for diagnosing disease or screening for drugs.

    摘要 i 誌謝 iii 目錄 iv 圖目 vii 表目 xiii 第一章 簡介 1 第二章 文獻回顧 4 2-1 點針法 4 2-1-1 機械手臂鋼針點針 4 2-1-2 矽針點針法 6 2-2 沾水筆微影法 7 2-3 噴墨法 9 2-3-1 熱氣泡式噴墨法 9 2-3-2 壓電式噴墨法 9 2-3-3 氣動式噴墨法 11 2-3-4 生物溶液雷射噴墨法 13 2-3-5 電噴灑法 14 2-4微影法 15 2-4-1 光罩微影法 15 2-4-2微鏡片微影法 16 2-5 微壓印法 18 2-5-1 壓印法應用與發展 18 2-5-2 用兩個微壓印章晶片轉向製作檢測兩種 21 2-5-3 蝕穿Si晶片作檢體儲槽 以沾濕PDMS微壓印章 23 2-5-4 利用Si晶片移去檢體 24 2-5-5 微流道轉印法 25 2-5-6 背後填充式微陣列壓印晶片 28 2-6 微陣列檢體佈置技術的比較 30 2-7 蓋印點尺寸大小的控制 31 第三章 背後填充式微陣列壓印晶片之改進與蓋印結果 35 3-1 前言 35 3-2改善後之晶片製程 36 3-3改善前後的晶片製程參數之比較 40 3-4晶片製作時的注意事項 45 3-5蓋印結果與討論 48 3-6 本章小結 59 第四章 表面親水性及檢體溶液黏滯性對蓋印尺寸之影響 60 4-1 簡介 60 4-2 實驗材料之準備 61 4-3 在不同親疏水表面上的蓋印結果與討論 62 4-4 溶液黏滯性對蓋印液珠尺寸大小之影響 73 4-5本章小結 75 第五章 平行填充與蓋印多種之導棒式微陣列壓印晶片Type A 77 5-1簡介 77 5-2系統運作 80 5-3填充時需防止溶液橫向擴散 82 5-4微填充晶片及底部塗佈Teflon之製程及結果 83 5-5用微影製程製作導棒式壓印晶片之Teflon 疏水區隔層84 5-5-1 簡介 84 5-5-2 製作流程 85 5-5-3製作及實驗結果 86 5-6 用Soft-lithography 製作導棒式壓印晶片之Teflon 疏水區隔層 88 5-6-1 簡介 88 5-6-2 製作流程 89 5-6-3 Teflon沾印設備及晶片結合填充之操作平台 90 5-6-4初步驗證Teflon疏水區隔功效 92 5-6-5 填充蓋印結果與討論 93 5-7 以微流道方式製作Teflon疏水區隔層 100 5-7-1簡介 100 5-7-2製作流程 101 5-7-3製作結果 102 5-7-4 Teflon溶液流入後區隔實驗 103 5-7-5 填充測試 104 5-7-6 蓋印結果 107 5-8結果與討論 108 第六章 以PDMS壓印端承接檢體之微陣列壓印晶片Type B 110 6-1 簡介 110 6-2 操作流程 111 6-3 晶片製作流程 114 6-4 製作結果 115 6-5 Teflon微流道實驗 116 6-6 填充測試實驗 117 6-7 蓋印結果與討論 118 第七章 排針式微陣列壓印晶片 124 7-1 簡介 124 7-2 晶片系統運作流程 128 7-3 晶片製作流程 131 7-4 排針式微壓印晶片製作結果 132 7-5 Type C排針式微壓印晶片填充及蓋印測試觀察 133 7-6 Type C排針式微壓印晶片蓋印結果 135 7-7 Type D排針式微壓印晶片製作結果 138 7-8 Type D排針式微壓印晶片蓋印結果 139 7-9 壓印端改善以使液面流出 140 7-10 改善後蓋印結果 142 7-11本章小結 145 第八章 結論 146 參考文獻 148 附錄 154 1. Type A 導棒式微壓印晶片製程參數 154 2. Type B 沾取式微壓印晶片製程參數 157 3. Type C D 排針式微壓印晶片製程參數 159

    [1] Roger Ekins “Ligand assays: from electrophoresis to miniaturized micro arrays.” Clinical Chemistry, 1998, v44, n9, p2015-2030
    [2] Gavin Macbeath and Stuart L. Schreiber; “Printing proteins as microarrays for high-throughput function determination”; Science, 2000, v289, p1760-1763.
    [3] Paul Bertone and Michael Snyder; “Advances in functional protein microarray technology”; FEBS Journal, 2005, v272, p5400-5411.
    [4] Yoonsuk Lee, Eun Kyoung Lee, Yong Wan Cho, Takuya Matsui, In-Cheol Kang, Tai-Sun Kim, Moon Hi Han, “ProteoChip: A highly sensitive protein microarray prepared by a novel method of protein immobilization for application of protein immobilization for application of protein-protein interaction studies”; Proteomics, 2003, v3, p2289-2304
    [5] C. Garrison Fathman, Luis Soares, Steven M. Chan and Paul J. Utz; “An array of possibilities for the study of autoimmunity”; Nature, 2005, v435, 2 June, p605-611.
    [6] Heng Zhu and Michael Snyder “Protein chip technology” Current opinion in chemical biology 2003, v7, p55-63
    [7] Claus Hultschig, Jurgen Kreutzberger, Harald Seitz, Zoltan Konthur, Konrad Bussow and Nans Lehrach; “Recent advances of protein microarrays”; Current Opinion in Chemical Biology, 2006, v10, p4-10
    [8] Ann Hoeben, Bart Landuyt, Gehan Botrus, Gert De Boeck, Gunther Guetens, Martin Highly, Allan T. van Oosterom, Ernst A. de Bruijn; “Proteomics in cancer research: Methods and application of array-based protein profiling technologies” Analytica Chimica Acta , 2006, v564, p19-33
    [9] Brian B Haab, Maitreya J Dunham and Patrick O Brown “Protein microarray for highly parallel detection and quantization of specific proteins and antibodies in complex solutions” Genome Biology, 2001, v2, p1-13
    [10] Jane Gin Fai Tsai, Zugen Chen, Stanley F. Nelson and Chang-Jin Kim, “A Silicon-micromachined pin for contact droplet printing“ Proceedings of the 16th IEEE Micro Electro Mechanical System, Kyoto, Japan, January 2003, p295-298
    [11] Jane Gin Fai Tsai, Zugen Chen, Stanley F. Nelson and Chang-Jin Kim “Selective surface treatment of micro printing pin and its performance” Applied Physics Letters, 2006, v89, p083901-1~083901-3
    [12] Ki-Bum Lee, So-Jung Park, Chad A. Mirkin, Jennifer C. Smith, Milan Mrksich; “Protein nanoarrays generated by dip-pen nanolithography.” Science, 2002, v295, p1702-1705
    [13] Kee Suk Ryu, Xuefeng Wang, Kashan Shaikh, David Bullen, Edgar Goluch, Jun Zou, and Chang Liu; “Integrated microfluidic inking chip for scanning probe nanolithography” Applied Physics Letters, 2004, v85, n1 p136-139
    [14] Jennifer R. Hampton, Arrelaine A. Dameron, and Paul S. Weiss; “Transport rates vary with deposition time in dip-pen nanolithography” the Journal of Physical Chemistry B , 2005, v109 p23118-23120.
    [15] Amit Kumar and George M. Whitesides; “Features of gold having micrometer to centimeter dimensions can be formed through a combination of stamping with an elastomeric stamp and an alanethiol “ink” followed by chemical etching” Applied Physics Letters, 1993, v64, n14, p2002-2004
    [16] Younan Xia, Milan Mrksich, Enoch Kim, and George M. Whitesides; “Microcontact printing of octadecylsiloxane on the surface of silicon dioxide and its application in microfabrication” Journal of American Chemical Society, 1995, v117, p9576-9577
    [17] Andre Bernard, Emmanuel Delamarche, Heinz Schmid, Bruno Michel, Hans Rudolf Bosshard, and Hans Biebuyck; “Printing patterns of proteins”, Langmuir, 1998, v14, n9, p2225-2229
    [18] Andre Bernard, Jean Philippe Renault, Bruno Michel, Hans Rudolf Bosshard, and Emmanuel Delamarche; “Microcontact printing of proteins”, Advanced Materials, 2000, v12, p1067-1070
    [19] Andre Bernard, Dora Fitzli, Peter Sonderegger, Emmanuel Delamarche, Bruno Michel, Hans Rudolf Bosshard, and Hans Biebuyck; “Affinity capture of proteins from solution and their dissociation by contact printing”; Nature biotechnology, 2001, v19; p866-869
    [20] S. C. Lin, F.G. Tseng, H. M. Huang, Yu-Feng Chen, Y. C. Tsai, C. E. Ho, C. C. Chieng; “Simultaneous immobilization of protein microarrays by a microstamper with back-filling reservoir”; Sensors and Actuators B, 2004, v99, p174-185.
    [21] Mark J. Feldstein, Joel P. Golden, Chris A. Rowe, Brian D. MacCraith, and Frances S. Ligler “Array biosensor: optical and fluidics systems” Journal of Biomedical Microdevices, 1999, v1, p139-153
    [22] Dan M. Leatzow, James M. Dodson, Joel P. Golden, Frances S. Ligler “Attachement of plastic fluidic components to glass sensing surfaces” Biosensors and Bioelectronics, 2002, v17, p105-110
    [23] C. Crozatier, M. Le Berre, Y. Chen “Multi-colour micro-contact printing based on microfluidic network inking” Microelectronic Engineering, 2006, v83, p910-913
    [24] David A. Chang-Yen, David G. Myszka, and Bruce K. Gale “A novel PDMS microfluidic spotter for fabrication of protein chips and microarrays” Journal of Microeletromechanical systems, 2006, v15, p1145-1151
    [25] A. Roda, M. Guardigli, C. Russo, P. Pasini, M. Baraldini “Protein microdeposition using a conventional ink-jet printer.” Biotechniques 2000, v28, p492-496
    [26] Laura Pardo, W. Cris Wilson, Jr., and Thomas Boland; “Characterization of patterned self-assembled monolayers and protein arrays generated by the ink-jet method”; Langmuir 2003, v19, p1462-1466.
    [27] Gary M. Nishioka, Andrea A. Markey, and Charles K. Holloway; “Protein damage in drop-on-demand printers”; Journal of the American Chemical Society communications 2004, v126, p16320-16321
    [28] Patrick Cooley, David Wallace, Bogdan Antohe; “Applications of ink-jet printing technology to bioMEMS and microfluidic systems” Proceedings, SPIE conference on microfluidics and BioMEMS, October, 2001, p1-12
    [29] Zhigang Wang, Hao Shang, and Gil U. Lee; “Nanoliter-scale reactor arrays for biochemical sensing”; Langmuir, 2006, v22, p6723-6726
    [30] Peter Koltay, Reinhard Steger, Benjamin Bohl, Roland Zengerle “ The dispensing well plate: a novel nanodispenser for the multiparallel delivery of liquids” Peter Koltay, Reinhard Steger, Benjamin Bohl, Roland Zengerle; Sensors and Actuators A, 2004, v116, p483-491
    [31] Chris P. Steinert, Ingo Goutier, Oliver Gutmann, Hermann Sandmaier, Martina Daub, Bas de Heij, Roland Zengerle “A highly parallel picoliter dispenser with an integraged novel capillary channel structure”; Sensors and Actuators A, 2004, v116, p171-177.
    [32] Oliver Gutmann, Ruben Kuehlewein, Stefanie Reinbold, Remigius Niekrawietz, Chris P. Steinert, Bas de Heij, Roland Zengerle, and Martina Daub “ A highly parallel nanoliter dispenser for microarray fabrication”; Biomedical Microdevices, 2004, v6, n2, p131-137.
    [33] Oliver Gutmann, Ruben Kuehlewein, Stefanie Reinbold, Remigius Niekrawietz, Chris P. Steinert, Bas de Heij, Roland Zengerle and Martina Daub; “Fast and reliable protein microarray production by a new drop-in-drop technique” Lab on a chip, 2005, v5 p675-681
    [34] Baojian Xu, Yi-Kuen Lee, Qinghui Jin, Jianlong Zhao, Chih-Ming Ho “Multilayer SU-8 based microdispenser for microarray assay” Sensors and Actuators A, 2006, v132, n2, p714-725
    [35] J. A. Barron, H. D. oung, D. D. Dltt, M. M. Darfler, D.B. Krizman and B. R. Ringeisen; “Printing of protein microarrays via a capillary-free fluid jetting mechanism”; Proteomics, 2005, v5, p4138-4144.
    [36] Natalya V. Avseerko, Tamara Ya. Morozova, Fasoil I. Ataullakhanov, and Victor N. Morozov ; “Immunoassay with multicomponent protein microarrays fabricated by electrospray deposition.” Analytical Chemistry , 2002, v74, p927-933.
    [37] Victor N. Morozov and Tamara Ya. Morozova; ”Electrospray deposition as a method for mass fabrication of mono- and multicomponent microarrays of biological and biologically active substances.” Analytical Chemistry, 1999, v71, p3110-3117
    [38] B. Lee, J. Kim, K. Ishimoto, Y. Yamagata, A. Tanioka, T. Nagamune; “Fabrication of protein microarrays for immunoassay using the electrospray deposition(ESD) method”, Journal of Chemical Engineering of Japan, 2003, v36, n11, p1370-1375
    [39] Blawas, A. S., and Reichert, W. M., “Review: Protein Patterning”, Biomaterials, v19, p595-609, 1998.
    [40] Kook-Nyung Lee, Dong-Sik Shin, Yoon-Sik Lee and Yong-Kweon Kim “Protein patterning by virtual mask photolithography using a micromirror array” Journal of Micromechanics and Microengineering, 2003, v13, p18-25
    [41] Kook-Nyung Lee, Dong-Sik Shin, Yoon-Sik Lee and Yong-Kweon Kim; “Micromirror array for protein micro array fabrication” Journal of Micromechanics and Microengineering, 2003, v13, p474-481
    [42] www.ArrayIt.com
    [43] ArrayJet company ; www.arrayjet.com.uk
    [44] TopSpot ; www.biofluidix.com
    [45] Aiping Fang, Erik Dujardin, and Thierry Ondarcuhu; “Control of droplet size in liquid nanodispensing” Nano Letters; v6, p2368-2374, 2006
    [46] F.-G. Tseng, S.-C. Lin, H.M. Huang, C.-Y. Huang and C.-C. Chieng “Protein micro arrays immobilized by μ-stamps and -protein wells on PhastGel pad. Sensors and Actuators B 2002, v83, p22-29.
    [47] Yaakov Levy and Jose N. Onuchic; “Water mediation in protein folding and molecular recognition”, Annual Review of Biophysics and Biomolecular Structure, 2006, v35, p389-415
    [48] Hua Zhang, Ki-Bum Lee, Zhi Li and Chad A Mirkin; “Biofunctionalized nanoarrays of inorganic structures prepared by dip-pen nanolithography”, Nanotechnology, 2003, v14, p1113-1117
    [49] H. D. Inerowicz, S. Howell, F.E. Reginer, and R. Reifenberger; ”Multiprotein immunoassay arrays fabricated by microcontact printing” Langmuir, 2002,v18, p5263-5268
    [50] Likai Wang, Xizeng Feng, Sen Hou, Qilin Chan and Ming Qin; “Microcontact printing of multiproteins on the modified mica substrate and study of immunoassays” Surface and Interface Analysis, 2006, v38, p44-50
    [51] Jean Philippe Renault, Andre Bernard, David Juncker, Bruno Michel, Hans Rudolf Bosshard and Emmanuel Delamarche; “Fabricating microarrays of functional proteins using affinity contact printing.” Angewandte Chemie International Edition, 2002, v41, p2320-2323.
    [52] Brett D. Martin, Bruce P. Gaber, Charles H. Patterson, and David C. Turner “Direct protein microarray fabrication using a hydrogel stamper” Langmuir, 1998, v14, p3971-3975
    [53] Stephen Y. Chou, Peter R. Krauss, and Preston J. Renstrom “Nanoimprint lithography” Journal of Vac. Sci. Technology. B 1996, v14, p4129-4133
    [54] Jason T. Smith, Benjamin L. Viglianti, and W. Monty Reichert “Spreading diagrams for the optimization of quill pin printed microarray density”. Langmuir, 2002, v18, p6289-6293.
    [55] 林世章, “微陣列壓印晶片之研發”, 清華大學工程與系統科學所博士論文 , 2002
    [56] 蔡逸勤, “蛋白質微陣列晶片之壓印機構設計與其影像檢測 ” 清華大學工程與系統科學所碩士論文, 2002
    [57] 蘇群傑, “應用於癌症篩檢之蛋白質晶片系統整合與改良” 清華大學工程與系統科學所碩士論文, 2004
    [58] MicroChem company, “Su8 photoresists datasheets” www.microchem.com; 2003.
    [59] L.G. Mendoza, P. McQuary, A. Mongan, R. Gangardharan, S. Brignac and M. Eggers. “ High-Throughput Microarray-Based Enzyme-Linked Immunosorbent Assay (ELISA) ” BioTechniques; v27, p778-788, 1999
    [60] 古燕華, “蛋白質微陣列反應晶片材質與自我組裝單層分子” 清華大學工程與系統科學所碩士論文, 2002
    [61] Deniz Armani, Chang Liu, Narayan Aluru; “Re-configurable fluid circuits by PDMS elastomer micromachining” Proceedings of the IEEE Micro Electro Mechanical Systems, 1999, p222-227
    [62] Cheng-En Ho, Fan-Gang Tseng, Shih-Chang Lin, Chiun-Jie Su, Zheng-Yan Liu, Ru-Ji Yu, Yu-Feng Chen, Haimei Huang, Ching-Chang Chieng; “Characterization of the surface tension and viscosity effects on the formation of nano-liter droplet arrays by an instant protein micro stamper” Journal of Micromechanics and Microengineering, 2005, v5, p2317-2325
    [63] 陳明宏, “應用多層高分子微機電製程之單石化蛋白質微陣列填充晶片” 清華大學工程與系統科學所碩士論文, 2003
    [64] Jane Gin Fai Tsai, Zugen Chen, Stanley Nelson, and Chang-Jin ”CJ” Kim; “A silicon-micromachined pin for contact droplet printing”; IEEE MEMS conference Kyoto Japan, 2003 , p295-298

    無法下載圖示 全文公開日期 本全文未授權公開 (校內網路)
    全文公開日期 本全文未授權公開 (校外網路)

    QR CODE