根據研究發現，HER1及HER2在很多種類的癌症常有過度表達(over-expression)情形產生。因此，檢測her1及 her2基因為目前廣泛應用於臨床上癌症病變預測的指標，特別是指乳癌與胃癌細胞。例如研究發現胃癌約有5-10%是由於her2基因過度表現進而引發癌變。最新研究發現此類病人可使用標靶藥物Herceptin治療，以提高其長期存活率，而標靶藥物所需要的費用相當高昂，因此需要一個準確度高的檢測方法。目前偵測HER2過度表現之標準方法是使用螢光原位雜交法(FISH)，不過此方法試劑過於昂貴且過程繁複耗時更需要專業人員的操作。更甚者，一位專業人員完成整個FISH的檢測得花上一到兩天的時間。因此，我們發展出一個新型整合性的微流體FISH晶片可以於自動化完成整個FISH流程。本研究的微流體FISH晶片結合了用於傳輸少量流體的流體控制模組和溫控模組以及穩定的雜交平台。藉由整合這幾個系統，這次研究中的新型微流體晶片可以在二十個小時內完成檢測。我們使用四種不同的cell line和兩種臨床組織來驗證整個系統與晶片的穩定性，四種cell line裡分別為兩種陰性反應與兩種陽性反應，兩種臨床組織則是一種陰性檢體與一種陽性檢體。實驗結果顯示晶片上與傳統的檢測並無顯著差異。再者，利用微流體的優點減少了大約70%的試劑用量特別是探針試劑的大幅減少至2-3 μl。整個系統僅用微量的試劑和樣本即能快速且自動化診斷her2基因的相關疾病，並在未來可優化延伸至不同的病理應用。

[1] B. Courtois and R. D. Blanton “MEMs-Introduction”, IEEE Design & Test of Computers, 1999, 16, 16-17.
[2] T. Velten, H. H. Ruf, D. Barrow, N. Aspragathos, P. Lazarou, E. Jung, C. K. Malek, M. Richter, J. Kruckow and M. Wackerle, “Packaging of Bio-MEMS: Strategies, Technologies, and Applications”, IEEE Transactions on Advanced Packaging, 2005, 28, 533-546.
[3] I. Byun, J. Yang and S. Park, “Fabrication of a new micro bio chip and flow cell cytometry system using Bio-MEMS technology”, Microelectronics Journal, 2008, 39, 717-722.
[4] D. R. Reyes, D. Lossifidis, P. A. Auroux and A. Manz, “Micro total analysis system Ι: introduction, theory and technology”, Analytical Chemistry, 2002, 74, 2623-2636.
[5] P. A. Auroux, D. Iossifidis, D. R. Reyes and A. Manz, “Micro total analysis systems II: analytical standard operations and applications”, Analytical Chemistry, 2002, 74, 2637-2652.
[6] A. Manz, N. Graber and H. M. Widmer, “Miniaturized total chemical analysis systems: a novel concept for chemical sensing”, Sensors and Actuators B, 1990, 1, 244-248.
[7] D. J. Slamon, V. Paton and J. Wolter, “Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2”, The New England Journal of Medicine, 2001, 344, 783.
[8] J. T. Hsu, T. C. Chen, J. H. Tseng, C. T. Chiu, K. H. Liu, C. N. Yeh, T. L. Hwang, Y. Y. Jan and T. S. Yeh, “Impact of HER-2 overexpression/amplification on the prognosis of gastric cancer patients undergoing resection: a single-center study of 1,036 patients”, The Oncologist, 2011, 16, 1706-1713.
[9] V. Roy and E. A. Perez, “Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer”, The Oncologist, 2009, 14, 1061-1069.
[10] M. A. Olayioye, “Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members”, Breast Cancer Research, 2001, 3, 385–389.
[11] F. Puglisi F, A. M. Minisini and C. De Angelis, “Overcoming treatment resistance in HER2-positive breast cancer: potential strategies”, Drugs, 2012, 72, 1175-1193.
[12] X. F. Le, F. Pruefer and R. Bast, “HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways”, Cell Cycle, 2005, 4, 87-95.
[13] P. Lichter, S. A. Ledbetter, D. H. Ledbetter and D. C. Ward, “Fluorescence in situ hybridization with Alu and L1 polymerase chain reaction probes for rapid characterization of human chromosomes in hybrid cell lines”, Proceedings of the National Academy of Science of the United States of America, 1990, 87, 6634-6638.
[14] D. Pinkel, J. Landegent, C. Collins, J. Fuscoe, R. Segraves, J. Lucas and J. Gray, “Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4”, Proceedings of the National Academy of Science of the United States of America, 1988, 85, 9138-9142.
[15] E. Vanneste, C. Melotte, S. Debrock, T. D’Hooghe, H. Brems, J. P. Fryns, E. Legius and J. R. Vermeesch, “Preimplantation genetic diagnosis using fluorescent in situ hybridization for cancer predisposition syndromes caused by microdeletions”, Human Reproduction, 2009, 24, 1522-1528.
[16] J. L. Fox, P. H. Hsu, M. S. Legator, L. E. Morrison and S. A. Seeling, “Fluorescence in situ hybridization: powerful molecular tool for cancer prognosis”, Clinical Chemistry, 1995, 41, 1554-1559.
[17] M. A. Leversha, J. Han, Z. Asgari, D. C. Danila, O. Lin, R. G. Espinoza, A. Anand, H. Lilja, G. Heller, M. Fleisher and H. L. Scher, “Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer”, Clinical Cancer Research, 2009, 15, 2091-2097.
[18] J. Nath and K. L. Johnson, “A review of fluorescence in situ hybridization (FISH): current status and future prospects”, Biotechnic and Histochemistry, 2000, 75, 54-78.
[19] P. R. Langer-Safer, M. Levine and D. C. Ward, “Immunological method for mapping genes on Drosophila polytene chromosomes”, Proceedings of the National Academy of Science of the United States of America, 1982, 79, 4381-4385.
[20] M. Andreeff and D. Pinkel (eds.), “Introduction to Fluorescence in situ Hybridization: Principles and Clinical Applications”, Wiley, New York, 1999.
[21] C. J. Ye, J. B. Stevens, G. Liu, K. J. Ye, F. Yang F, S. W. Bremer and H. H. Q. Heng, “Combined multicolor-FISH and immunostaining”, Cytogenetic and Genome Research, 2006, 114, 227-234.
[22] R. Amann and B. M. Fuchs, “Single-cell identification in microbial communities by improved fluorescence in situ hybridization techniques”, Nature, 2008, 6, 339-348.
[23] Z. Mitri, T. Constantine and R. O'Regan, “The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy”, Chemotherapy Research and Practice, 2012, 2012.
[24] C. H. Weng, K. Y. Lien, S. Y. Yang and G. B. Lee, “A suction-type, pneumatic microfluidic device for liquid transport and mixing”, Microfluidics and Nanofluidics, 2011, 10, 301-310.
[25] C. W. Huang, S. B. Huang and G. B. Lee, “Pneumatic micropumps with serially connected actuation chambers”, Journal of Micromechanics and Microengineering, 2006, 16 2265–2272.
[26] W. K. Schomburg and C. Goll, “Design optimization of bistable microdiaphragm valves”, Sensor and Actuators A, 1998, 64, 259-264.
[27] I. Vedarethinam, P. Shah, M. Dimaki, Z. Tumer, N. Tommerup and W. E. Svendsen, “Metaphase FISH on a Chip: Miniaturized Microfluidic Device for Fluorescence in situ Hybridization”, Sensors, 2010, 10, 9831-9846.
[28] C. H. Tai, C. L. Ho, Y. L. Chen, W. L. Chen and G. B. Lee, “A novel integrated microfluidic platform to perform fluorescence in situ hybridization for chromosomal analysis”, Microfluidics and Nanofluidics, 2013, 15, 745–752.
[29] D. C. Duffy, J. C. McDonald, O. J. A. Schueller and George M. Whitesides, “Rapid prototyping of microfluidic systems in poly (dimethylsiloxane)”, Analytical Chemistry, 1998, 70, 4974-4984.
[30] Y. N. Yang, S. K. Hsiung and G. B. Lee, “A pneumatic micropump incorporated with a normally closed valve capable of generating a high pumping rate and a high back pressure”, Microfluidics and Nanofluidics, 2009, 6, 823-833.