生醫微機電系統裝置近年來已應用至分離與操控磁珠粒子，此類裝置也證實結合細胞分離和操控細胞至精確位置之可行性。在此篇文章中，敘述使用超順磁性磁珠與磁膜陣列來控制細胞陣列組成之方法，我們設計多層磁膜發展一種簡單便宜的細胞排列方法，以黃光微影技術做出鋸齒型多層磁膜結構，受限曝光系統解析度須大於3微米，因此設計線寬為5微米。利用磁化後平面式磁性微結構殘磁特性，不需持續施加磁場，當改變施加磁場之方向時，因為鋸齒型磁膜的幾何形狀因素，我們可得到有區別性地磁壁結構。然後，再利用磁力顯微鏡量測磁膜膜厚及加場磁化後磁壁之位置。
我們使用奈米磁珠標定人鼻咽癌細胞，並藉由磁泳方法定量標定上細胞之磁珠量，將標定磁珠之細胞撒入後，因磁壁造成漏磁場，我們發現對細胞有吸引力而座落在磁壁附近區域，藉由量測細胞座落位置與磁壁間距離，結果證實磁珠標定細胞會受磁壁影響並使個別細胞在二維下形成規則性排列。基於此，我們改善以往細胞磁操控排列裝置必須連續加場之缺點，我們相信此方法對於單分子操控、生醫磁性感測、與細胞間作用等數種應用上為一有效之工具，並開啟此方法於實驗室晶片應用上新的可行性。

Bio-MEMS devices have been made for separating and manipulating magnetic particles in recent years. The possibility of combining the thoughts of cell separation and accurately position of cells have been proved. In this article, an approach is described for controlling the alignment of cells by using superparamagnetic beads and patterned magnetic film arrays. We designed multilayer magnetic films to develop a simple and cheap cell patterning method. The zigzag multilayer magnetic films were made by photolithography, and the resolution of the lithography system was shown to be more than 3 µm. The line width is 5 µm. After the magnetic films are magnetized, we use the remanent states of the planar magnetic microstructures without continuously applying magnetic field. Distinct domain structures are available, when we changing the orientation of magnetic field, because of the zigzag geometry of magnetic films. Then, we measured the thickness of magnetic films and the distributions of domain walls by using magnetic force microscopy.
We labeled human nasopharyngeal carcinoma cells by using magnetic nanoparticles, and quantified the magnetic nanoparticles within cells by using magnetophoresis .After dropping the magnetic nanoparticles-labeled cells upon magnetic films, we found that the gradient of stray field which generated by domain walls results in an attractive force acting on magnetic nanoparticles-labeled cells and the cells translocated in the proximity of the domain wall location. By measuring the distance between cell location and the sites of domain walls, the results prove that the magnetic nanoparticles-labeled cells can be manipulated by domain walls, and the patterns of cells in two dimensions are formed orderly. Based on this, we improved the shortcoming of traditional cell patterning devices, which must be continuously applying magnetic field when using magnetic force. We believed that this method is a potential tool for several applications including single molecule manipulation, biomagnetic sensing and cell-cell interaction. Such a method would open up new possibility of lab-on-chip application.

[1] A. K. Vuppu, A. A. Garcia, and M. A. Hayes, "Video microscopy of dynamically aggregated paramagnetic particle chains in an applied rotating magnetic field," Langmuir, vol. 19, pp. 8646-8653, 2003.
[2] K. Ino, M. Okochi, N. Konishi, M. Nakatochi, R. Imai, M. Shikida, A. Ito, and H. Honda, "Cell culture arrays using magnetic force-based cell patterning for dynamic single cell analysis," Lab on a Chip, vol. 8, pp. 134-142, 2008.
[3] J. H. Lee, Y. M. Huh, Y. Jun, J. Seo, J. Jang, H. T. Song, S. Kim, E. J. Cho, H. G. Yoon, J. S. Suh, and J. Cheon, "Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging," Nature Medicine, vol. 13, pp. 95-99, 2007.
[4] J. A. Kim, H. J. Lee, H. J. Kang, and T. H. Park, "The targeting of endothelial progenitor cells to a specific location within a microfluidic channel using magnetic nanoparticles," Biomedical Microdevices, vol. 11, pp. 287-296, 2009.
[5] B. Polyak, I. Fishbein, M. Chorny, I. Alferiev, D. Williams, B. Yellen, G. Friedman, and R. J. Levy, "High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steed stents," Proceedings of the National Academy of Sciences of the United States of America, vol. 105, pp. 698-703, 2008.
[6] M. Veiseh, O. Veiseh, M. C. Martin, F. Asphahani, and M. Q. Zhang, "Short peptides enhance single cell adhesion and viability on microarrays," Langmuir, vol. 23, pp. 4472-4479, 2007.
[7] J. Fukuda, A. Khademhosseini, J. Yeh, G. Eng, J. J. Cheng, O. C. Farokhzad, and R. Langer, "Micropatterned cell co-cultures using layer-by-layer deposition of extracellular matrix components," Biomaterials, vol. 27, pp. 1479-1486, 2006.
[8] T. Kimura, Y. Sato, F. Kimura, M. Iwasaka, and S. Ueno, "Micropatterning of cells using modulated magnetic fields," Langmuir, vol. 21, pp. 830-832, 2005.
[9] A. Ashkin, "Optical trapping and manipulation of neutral particles using lasers," Proceedings of the National Academy of Sciences of the United States of America, vol. 94, pp. 4853-4860, 1997.
[10] G. H. Markx, P. A. Dyda, and R. Pethig, "Dielectrophoretic separation of bacteria using a conductivity gradient," Journal of Biotechnology, vol. 51, pp. 175-180, 1996.
[11] M. A. Poggi, E. D. Gadsby, L. A. Bottomley, W. P. King, E. Oroudjev, and H. Hansma, "Scanning probe microscopy," Analytical Chemistry, vol. 76, pp. 3429-3443, 2004.
[12] G. Binnig, C. F. Quate, and C. Gerber, "Atomic force microscope," Physical Review Letters, vol. 56, pp. 930-933, 1986.
[13] 嚴密,彭曉領編著。2006。磁學基礎與磁性材料。第一版, pp. 68-74。浙江大學出版社。
[14] T. Taniyama, I. Nakatani, T. Yakabe, and Y. Yamazaki, "Control of domain structures and magnetotransport properties in patterned ferromagnetic wires," Applied Physics Letters, vol. 76, pp. 613-615, 2000.
[15] N. Pamme and C. Wilhelm, "Continuous sorting of magnetic cells via on-chip free-flow magnetophoresis," Lab on a Chip, vol. 6, pp. 974-980, 2006.
[16] C. Wilhelm, F. Gazeau, and J. C. Bacri, "Magnetophoresis and ferromagnetic resonance of magnetically labeled cells," European Biophysics Journal with Biophysics Letters, vol. 31, pp. 118-125, 2002.
[17] V. S. Kalambur, E. K. Longmire, and J. C. Bischof, "Cellular level loading and heating of superparamagnetic iron oxide nanoparticles," Langmuir, vol. 23, pp. 12329-12336, 2007.
[18] G. P. Hatch and R. E. Stelter, "Magnetic design considerations for devices and particles used for biological high-gradient magnetic separation (HGMS) systems," Journal of Magnetism and Magnetic Materials, vol. 225, pp. 262-276, 2001.
[19] M. Deutsch, A. Deutsch, O. Shirihai, I. Hurevich, E. Afrimzon, Y. Shafran, and N. Zurgil, "A novel miniature cell retainer for correlative high-content analysis of individual untethered non-adherent cells," Lab on a Chip, vol. 6, pp. 995-1000, 2006.
[20] D. Di Carlo, L. Y. Wu, and L. P. Lee, "Dynamic single cell culture array," Lab on a Chip, vol. 6, pp. 1445-1449, 2006.
[21] M. Ochsner, M. R. Dusseiller, H. M. Grandin, S. Luna-Morris, M. Textor, V. Vogel, and M. L. Smith, "Micro-well arrays for 3D shape control and high resolution analysis of single cells," Lab on a Chip, vol. 7, pp. 1074-1077, 2007.
[22] S. Sekula, J. Fuchs, S. Weg-Remers, P. Nagel, S. Schuppler, J. Fragala, N. Theilacker, M. Franueb, C. Wingren, P. Ellmark, C. A. K. Borrebaeck, C. A. Mirkin, H. Fuchs, and S. Lenhert, "Multiplexed lipid dip-pen nanolithography on subcellular scales for the templating of functional proteins and cell culture," Small, vol. 4, pp. 1785-1793, 2008.
[23] S. N. Bhatia, M. L. Yarmush, and M. Toner, "Controlling cell interactions by micropatterning in co-cultures: Hepatocytes and 3T3 fibroblasts," Journal of Biomedical Materials Research, vol. 34, pp. 189-199, 1997.
[24] A. Revzin, K. Sekine, A. Sin, R. G. Tompkins, and M. Toner, "Development of a microfabricated cytometry platform for characterization and sorting of individual leukocytes," Lab on a Chip, vol. 5, pp. 30-37, 2005.
[25] C. S. Chen, M. Mrksich, S. Huang, G. M. Whitesides, and D. E. Ingber, "Geometric control of cell life and death," Science, vol. 276, pp. 1425-1428, 1997.
[26] D. S. Gray, J. L. Tan, J. Voldman, and C. S. Chen, "Dielectrophoretic registration of living cells to a microelectrode array," Biosensors & Bioelectronics, vol. 19, pp. 771-780, 2004.
[27] L. C. Hsiung, C. H. Yang, C. L. Chiu, C. L. Chen, Y. Wang, H. Lee, J. Y. Cheng, M. C. Ho, and A. M. Wo, "A planar interdigitated ring electrode array via dielectrophoresis for uniform patterning of cells," Biosensors & Bioelectronics, vol. 24, pp. 869-875, 2008.
[28] A. Ashkin, "Acceleration and trapping of particles by radiation pressure," Physical Review Letters, vol. 24, pp. 156-159, 1970.
[29] R. A. Flynn, A. L. Birkbeck, M. Gross, M. Ozkan, B. Shao, M. M. Wang, and S. C. Esener, "Parallel transport of biological cells using individually addressable VCSEL arrays as optical tweezers," Sensors and Actuators B-Chemical, vol. 87, pp. 239-243, 2002.
[30] Q. Ramadan, C. Yu, V. Samper, and D. P. Poenar, "Microcoils for transport of magnetic beads," Applied Physics Letters, vol. 88, pp.032501, 2006.
[31] K. Gunnarsson, P. E. Roy, S. Felton, J. Pihl, P. Svedlindh, S. Berner, H. Lidbaum, and S. Oscarsson, "Programmable motion and separation of single magnetic particles on patterned magnetic surfaces," Advanced Materials, vol. 17, pp. 1730-1734, 2005.
[32] R. S. Conroy, G. Zabow, J. Moreland, and A. P. Koretsky, "Controlled transport of magnetic particles using soft magnetic patterns," Applied Physics Letters, vol. 93, pp. 203901, 2008.
[33] H. Lee, A. M. Purdon, and R. M. Westervelt, "Manipulation of biological cells using a microelectromagnet matrix," Applied Physics Letters, vol. 85, pp. 1063-1065, 2004.
[34] M. Tanase, E. J. Felton, D. S. Gray, A. Hultgren, C. S. Chen, and D. H. Reich, "Assembly of multicellular constructs and microarrays of cells using magnetic nanowires," Lab on a Chip, vol. 5, pp. 598-605, 2005.
[35] H. Akiyama, A. Ito, Y. Kawabe, and M. Kamihira, "Fabrication of complex three-dimensional tissue architectures using a magnetic force-based cell patterning technique," Biomedical Microdevices, vol. 11, pp. 713-721, 2009.
[36] C. Wilhelm and F. Gazeau, "Universal cell labelling with anionic magnetic nanoparticles," Biomaterials, vol. 29, pp. 3161-3174, 2008.