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Multi-Dimensional Nanostructures for Microfluidic Screening of Biomarkers: From Molecular Separation to Cancer Cell Detection

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Abstract

Rapid screening of biomarkers, with high specificity and accuracy, is critical for many point-of-care diagnostics. Microfluidics, the use of microscale channels to manipulate small liquid samples and carry reactions in parallel, offers tremendous opportunities to address fundamental questions in biology and provide a fast growing set of clinical tools for medicine. Emerging multi-dimensional nanostructures, when coupled with microfluidics, enable effective and efficient screening with high specificity and sensitivity, both of which are important aspects of biological detection systems. In this review, we provide an overview of current research and technologies that utilize nanostructures to facilitate biological separation in microfluidic channels. Various important physical parameters and theoretical equations that characterize and govern flow in nanostructure-integrated microfluidic channels will be introduced and discussed. The application of multi-dimensional nanostructures, including nanoparticles, nanopillars, and nanoporous layers, integrated with microfluidic channels in molecular and cellular separation will also be reviewed. Finally, we will close with insights on the future of nanostructure-integrated microfluidic platforms and their role in biological and biomedical applications.

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References

  1. Alivisatos, A. P. Semiconductor clusters, nanocrystals, and quantum dots. Science (80-) 271:933–937, 1996.

    Article  CAS  Google Scholar 

  2. Arosio, P., T. Müller, L. Mahadevan, and T. P. J. Knowles. Density-gradient-free microfluidic centrifugation for analytical and preparative separation of nanoparticles. Nano Lett. 14:2365–2371, 2014.

    Article  CAS  PubMed  Google Scholar 

  3. Bhushan, B. Springer Handbook of Nanotechnology. Springer, 2010. https://books.google.com/books?hl=en&lr=&id=me1grr_pobMC&pgis=1.

  4. Blinka, E., K. Loeffler, Y. Hu, A. Gopal, K. Hoshino, K. Lin, X. Liu, M. Ferrari, and J. X. J. Zhang. Enhanced microcontact printing of proteins on nanoporous silica surface. Nanotechnology 21:415302, 2010.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bohunicky, B., and S. A. Mousa. Biosensors: the new wave in cancer diagnosis. Nanotechnol. Sci. Appl. 4:1–10, 2010.

    PubMed  PubMed Central  Google Scholar 

  6. Burger, R., P. Reith, G. Kijanka, V. Akujobi, P. Abgrall, and J. Ducrée. Array-based capture, distribution, counting and multiplexed assaying of beads on a centrifugal microfluidic platform. Lab Chip 12:1289–1295, 2012.

    Article  CAS  PubMed  Google Scholar 

  7. Cao, Y. C., R. Jin, and C. A. Mirkin. Nanoparticles with Raman spectroscopic fingerprints for DNA and RNA detection. Science 297:1536–1540, 2002.

    Article  CAS  PubMed  Google Scholar 

  8. Chen, G. D., C. J. Alberts, W. Rodriguez, and M. Toner. Concentration and purification of human immunodeficiency virus type 1 virions by microfluidic separation of superparamagnetic nanoparticles. Anal. Chem. 82:723–728, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen, P., Y.-Y. Huang, K. Hoshino, and X. Zhang. On-chip magnetic field modulation for distributed immunomagnetic detection of circulating tumor cells. Solid-State Sens. 2013. doi:10.1109/Transducers.2013.6626989.

    Google Scholar 

  10. Chen, P., Y.-Y. Huang, K. Hoshino, and J. X. J. Zhang. Microscale magnetic field modulation for enhanced capture and distribution of rare circulating tumor cells. Sci. Rep. 5:8745, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, W., S. Weng, F. Zhang, S. Allen, X. Li, L. Bao, R. H. W. Lam, J. A. Macoska, S. D. Merajver, and J. Fu. Nanoroughened surfaces for efficient capture of circulating tumor cells without using capture antibodies. ACS Nano 7:566–575, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chikkaveeraiah, B. V., V. Mani, V. Patel, J. S. Gutkind, and J. F. Rusling. Microfluidic electrochemical immunoarray for ultrasensitive detection of two cancer biomarker proteins in serum. Biosens. Bioelectron. 26:4477–4483, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cho, B. S., T. G. Schuster, X. Zhu, D. Chang, G. D. Smith, and S. Takayama. Passively driven integrated microfluidic system for separation of motile sperm. Anal. Chem. 75:1671–1675, 2003.

    Article  CAS  PubMed  Google Scholar 

  14. Day, E. S., L. R. Bickford, J. H. Slater, N. S. Riggall, R. A. Drezek, and J. L. West. Antibody-conjugated gold-gold sulfide nanoparticles as multifunctional agents for imaging and therapy of breast cancer. Int. J. Nanomed. 5:445–454, 2010.

    Article  CAS  Google Scholar 

  15. Delamarche, E., D. Juncker, and H. Schmid. Microfluidics for processing surfaces and miniaturizing biological assays. Adv. Mater. 17:2911–2933, 2005.

    Article  CAS  Google Scholar 

  16. Desai, T. A., D. J. Hansford, L. Leoni, M. Essenpreis, and M. Ferrari. Nanoporous anti-fouling silicon membranes for biosensor applications. Biosens. Bioelectron. 15:453–462, 2000.

    Article  CAS  PubMed  Google Scholar 

  17. Di Carlo, D. Inertial microfluidics. Lab Chip 9:3038–3046, 2009.

    Article  PubMed  Google Scholar 

  18. Duncombe, T. A., and A. E. Herr. Photopatterned free-standing polyacrylamide gels for microfluidic protein electrophoresis. Lab Chip 13:2115–2123, 2013.

    Article  CAS  PubMed  Google Scholar 

  19. Eck, W., G. Craig, A. Sigdel, G. Ritter, L. J. Old, L. Tang, M. F. Brennan, P. J. Allen, and M. D. Mason. PEGylated gold nanoparticles conjugated to monoclonal F19 antibodies as targeted labeling agents for human pancreatic carcinoma tissue. ACS Nano 2:2263–2272, 2008.

    Article  CAS  PubMed  Google Scholar 

  20. Feng, P., X. Bu, and D. J. Pine. Control of pore sizes in mesoporous silica templated by liquid crystals in block copolymer–cosurfactant–water systems. Langmuir 16:5304–5310, 2000.

    Article  CAS  Google Scholar 

  21. Fu, J., R. B. Schoch, A. L. Stevens, S. R. Tannenbaum, and J. Han. A patterned anisotropic nanofluidic sieving structure for continuous-flow separation of DNA and proteins. Nat. Nanotechnol. 2:121–128, 2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gupta, A. K., and M. Gupta. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021, 2005.

    Article  CAS  PubMed  Google Scholar 

  23. Haas, F. Quantum Plasmas. New York: Springer, 2011.

    Book  Google Scholar 

  24. Hornbeck, P. Enzyme-linked immunosorbent assays. Curr. Protoc. Immunol. Chapter 2: Unit 2.1, 2001.

  25. Horsman, K. M., S. L. R. Barker, J. P. Ferrance, K. A. Forrest, K. A. Koen, and J. P. Landers. Separation of sperm and epithelial cells in a microfabricated device: potential application to forensic analysis of sexual assault evidence. Anal. Chem. 77:742–749, 2005.

    Article  CAS  PubMed  Google Scholar 

  26. Hosta-Rigau, L., I. Olmedo, J. Arbiol, L. J. Cruz, M. J. Kogan, and F. Albericio. Multifunctionalized gold nanoparticles with peptides targeted to gastrin-releasing peptide receptor of a tumor cell line. Bioconjug. Chem. 21:1070–1078, 2010.

    Article  CAS  PubMed  Google Scholar 

  27. Hou, H. W., M. E. Warkiani, B. L. Khoo, Z. R. Li, R. A. Soo, D. S.-W. Tan, W.-T. Lim, J. Han, A. A. S. Bhagat, and C. T. Lim. Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci. Rep. 3:1259, 2013.

    PubMed  PubMed Central  Google Scholar 

  28. Hu, Y., A. Bouamrani, E. Tasciotti, L. Li, X. Liu, and M. Ferrari. Tailoring of the nanotexture of mesoporous silica films and their functionalized derivatives for selectively harvesting low molecular weight protein. ACS Nano 4:439–451, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang, N.-T., W. Chen, B.-R. Oh, T. T. Cornell, T. P. Shanley, J. Fu, and K. Kurabayashi. An integrated microfluidic platform for in situ cellular cytokine secretion immunophenotyping. Lab Chip 12:4093–4101, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang, L. R., E. C. Cox, R. H. Austin, and J. C. Sturm. Continuous particle separation through deterministic lateral displacement. Science 304:987–990, 2004.

    Article  CAS  PubMed  Google Scholar 

  31. Huang, Y., K. Hoshino, P. Chen, C. Wu, N. Lane, M. Huebschman, H. Liu, K. Sokolov, J. W. Uhr, E. P. Frenkel, and J. X. J. Zhang. Immunomagnetic nanoscreening of circulating tumor cells with a motion controlled microfluidic system. Biomed. Microdevices 15:673–681, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang, Y. Y., P. Chen, K. Hoshino, C. H. Wu, N. Lane, M. Huebschman, J. Uhr, K. Sokolov, E. Frenkel, and X. Zhang. Patterned nanomagnets on-chip for screening circulating tumor cells in blood. MicroTAS, 2012.

  33. Innocenzi, P., and L. Malfatti. Mesoporous thin films: properties and applications. Chem. Soc. Rev. 42:4198–4216, 2013.

    Article  CAS  PubMed  Google Scholar 

  34. Innocenzi, P., L. Malfatti, and G. J. A. A. Soler-Illia. Hierarchical mesoporous films: from self-assembly to porosity with different length scales. Chem. Mater. 23:2501–2509, 2011.

    Article  CAS  Google Scholar 

  35. Innocenzi, P., Y. L. Zub, and V. G. Kessler. Sol-Gel Methods for Materials Processing. Dordrecht: Springer, 2008. doi:10.1007/978-1-4020-8514-7.

    Book  Google Scholar 

  36. Jha, S. K., R. Chand, D. Han, Y.-C. Jang, G.-S. Ra, J. S. Kim, B.-H. Nahm, and Y.-S. Kim. An integrated PCR microfluidic chip incorporating aseptic electrochemical cell lysis and capillary electrophoresis amperometric DNA detection for rapid and quantitative genetic analysis. Lab Chip 12:4455–4464, 2012.

    Article  CAS  PubMed  Google Scholar 

  37. Ji, J., L. Nie, L. Qiao, Y. Li, L. Guo, B. Liu, P. Yang, and H. H. Girault. Proteolysis in microfluidic droplets: an approach to interface protein separation and peptide mass spectrometry. Lab Chip 12:2625–2629, 2012.

    Article  CAS  PubMed  Google Scholar 

  38. Kamholz, A. E., B. H. Weigl, B. A. Finlayson, and P. Yager. Quantitative analysis of molecular interaction in a microfluidic channel: the T-sensor. Anal. Chem. 71:5340–5347, 1999.

    Article  CAS  PubMed  Google Scholar 

  39. Kim, M., and T. Kim. Integration of nanoporous membranes into microfluidic devices: electrokinetic bio-sample pre-concentration. Analyst 138:6007–6015, 2013.

    Article  CAS  PubMed  Google Scholar 

  40. Kim, K. S., and J.-K. Park. Magnetic force-based multiplexed immunoassay using superparamagnetic nanoparticles in microfluidic channel. Lab Chip 5:657–664, 2005.

    Article  CAS  PubMed  Google Scholar 

  41. Lagally, E. T., I. Medintz, and R. A. Mathies. Single-molecule DNA amplification and analysis in an integrated microfluidic device. Anal. Chem. 73:565–570, 2001.

    Article  CAS  PubMed  Google Scholar 

  42. Lagally, E. T., P. C. Simpson, and R. A. Mathies. Monolithic integrated microfluidic DNA amplification and capillary electrophoresis analysis system. Sens. Actuators B Chem. 63:138–146, 2000.

    Article  CAS  Google Scholar 

  43. Lai, J. J., J. M. Hoffman, M. Ebara, A. S. Hoffman, C. Estournès, A. Wattiaux, and P. S. Stayton. Dual magnetic-/temperature-responsive nanoparticles for microfluidic separations and assays. Langmuir 23:7385–7391, 2007.

    Article  CAS  PubMed  Google Scholar 

  44. Lai, G., J. Wu, H. Ju, and F. Yan. Streptavidin-functionalized silver-nanoparticle-enriched carbon nanotube tag for ultrasensitive multiplexed detection of tumor markers. Adv. Funct. Mater. 21:2938–2943, 2011.

    Article  CAS  Google Scholar 

  45. Laurent, S., D. Forge, M. Port, A. Roch, C. Robic, L. Vander Elst, and R. N. Muller. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 108:2064–2110, 2008.

    Article  CAS  PubMed  Google Scholar 

  46. Levine, R. M., C. M. Scott, and E. Kokkoli. Peptide functionalized nanoparticles for nonviral gene delivery. Soft Matter 9:985–1004, 2013.

    Article  CAS  Google Scholar 

  47. Li, J. Application of microfluidic devices to proteomics research: identification of trace-level protein digests and affinity capture of target peptides. Mol. Cell. Proteomics 1:157–168, 2002.

    Article  CAS  PubMed  Google Scholar 

  48. Liang, P., C.-J. Liu, R.-X. Zhuo, and S.-X. Cheng. Self-assembled inorganic/organic hybrid nanoparticles with multi-functionalized surfaces for active targeting drug delivery. J. Mater. Chem. B 1:4243, 2013.

    Article  CAS  Google Scholar 

  49. Lion, N., F. Reymond, H. H. Girault, and J. S. Rossier. Why the move to microfluidics for protein analysis? Curr. Opin. Biotechnol. 15:31–37, 2004.

    Article  CAS  PubMed  Google Scholar 

  50. Lu, A., E. Salabas, and F. Schüth. Magnetic nanoparticles: synthesis, protection, functionalization, and application. Chemie Int. Ed., 2007. http://onlinelibrary.wiley.com/doi/10.1002/anie.200602866/pdf.

  51. Luo, C., Q. Fu, H. Li, L. Xu, M. Sun, Q. Ouyang, Y. Chen, and H. Ji. PDMS microfludic device for optical detection of protein immunoassay using gold nanoparticles. Lab Chip 5:726–729, 2005.

    Article  CAS  PubMed  Google Scholar 

  52. Malhotra, R., V. Patel, B. V. Chikkaveeraiah, B. S. Munge, S. C. Cheong, R. B. Zain, M. T. Abraham, D. K. Dey, J. S. Gutkind, and J. F. Rusling. Ultrasensitive detection of cancer biomarkers in the clinic by use of a nanostructured microfluidic array. Anal. Chem. 84:6249–6255, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mellors, J. S., W. A. Black, A. G. Chambers, J. A. Starkey, N. A. Lacher, and J. M. Ramsey. Hybrid capillary/microfluidic system for comprehensive online liquid chromatography-capillary electrophoresis-electrospray ionization-mass spectrometry. Anal. Chem. 85:4100–4106, 2013.

    Article  CAS  PubMed  Google Scholar 

  54. Mostert, B., S. Sleijfer, J. A. Foekens, and J. W. Gratama. Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat. Rev. 35:463–474, 2009.

    Article  CAS  PubMed  Google Scholar 

  55. Mucic, R. C., J. J. Storhoff, C. A. Mirkin, and R. L. Letsinger. DNA-directed synthesis of binary nanoparticle network materials. J. Am. Chem. Soc. 120:12674–12675, 1998.

    Article  CAS  Google Scholar 

  56. Nagrath, S., L. V. Sequist, S. Maheswaran, D. W. Bell, D. Irimia, L. Ulkus, M. R. Smith, E. L. Kwak, S. Digumarthy, A. Muzikansky, P. Ryan, U. J. Balis, R. G. Tompkins, D. A. Haber, and M. Toner. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235–1239, 2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ng, E., A. Gopal, K. Hoshino, and X. Zhang. Multicolor microcontact printing of proteins on nanoporous surface for patterned immunoassay. Appl. Nanosci. 1:79–85, 2011.

    Article  CAS  Google Scholar 

  58. Ng, E., K. Hoshino, and X. Zhang. Microfluidic immunodetection of cancer cells via site-specific microcontact printing of antibodies on nanoporous surface. Methods 63:266–275, 2013.

    Article  CAS  PubMed  Google Scholar 

  59. Pumera, M., J. Wang, E. Grushka, and R. Polsky. Gold nanoparticle-enhanced microchip capillary electrophoresis. Anal. Chem. 73:5625–5628, 2001.

    Article  CAS  PubMed  Google Scholar 

  60. Punnoose, E. A., S. K. Atwal, J. M. Spoerke, H. Savage, A. Pandita, R.-F. Yeh, A. Pirzkall, B. M. Fine, L. C. Amler, D. S. Chen, and M. R. Lackner. Molecular biomarker analyses using circulating tumor cells. PLoS One 5:e12517, 2010.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rabilloud, T. Two-dimensional gel electrophoresis in proteomics: old, old fashioned, but it still climbs up the mountains. Proteomics 2:3–10, 2002.

    Article  CAS  PubMed  Google Scholar 

  62. Sackmann, E. K., A. L. Fulton, and D. J. Beebe. The present and future role of microfluidics in biomedical research. Nature 507:181–189, 2014.

    Article  CAS  PubMed  Google Scholar 

  63. Sharma, T., Y. Hu, M. Stoller, M. Feldman, R. S. Ruoff, M. Ferrari, and X. Zhang. Mesoporous silica as a membrane for ultra-thin implantable direct glucose fuel cells. Lab Chip 11:2460–2465, 2011.

    Article  CAS  PubMed  Google Scholar 

  64. Shi, J., A. P. Fang, L. Malaquin, A. Pépin, D. Decanini, J. L. Viovy, and Y. Chen. Highly parallel mix-and-match fabrication of nanopillar arrays integrated in microfluidic channels for long DNA molecule separation. Appl. Phys. Lett. 91:153114, 2007.

    Article  Google Scholar 

  65. Shih, S. C. C., H. Yang, M. J. Jebrail, R. Fobel, N. McIntosh, O. Y. Al-Dirbashi, P. Chakraborty, and A. R. Wheeler. Dried blood spot analysis by digital microfluidics coupled to nanoelectrospray ionization mass spectrometry. Anal. Chem. 84:3731–3738, 2012.

    Article  CAS  PubMed  Google Scholar 

  66. Shintaku, H., H. Nishikii, L. A. Marshall, H. Kotera, and J. G. Santiago. On-chip separation and analysis of RNA and DNA from single cells. Anal. Chem. 86:1953–1957, 2014.

    Article  CAS  PubMed  Google Scholar 

  67. Somasundaran, P. Encyclopedia of Surface and Colloid Science, Volume 1. CRC Press, 2006, https://books.google.com/books?hl=en&lr=&id=9jAHFOqyX5YC&pgis=1.

  68. Squires, T., and S. Quake. Microfluidics: fluid physics at the nanoliter scale. Rev. Mod. Phys. 77:977–1026, 2005.

    Article  CAS  Google Scholar 

  69. Stott, S. L., C.-H. Hsu, D. I. Tsukrov, M. Yu, D. T. Miyamoto, B. A. Waltman, S. M. Rothenberg, A. M. Shah, M. E. Smas, G. K. Korir, F. P. Floyd, A. J. Gilman, J. B. Lord, D. Winokur, S. Springer, D. Irimia, S. Nagrath, L. V. Sequist, R. J. Lee, K. J. Isselbacher, S. Maheswaran, D. A. Haber, and M. Toner. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc. Natl. Acad. Sci. USA 107:18392–18397, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Striemer, C. C., T. R. Gaborski, J. L. McGrath, and P. M. Fauchet. Charge- and size-based separation of macromolecules using ultrathin silicon membranes. Nature 445:749–753, 2007.

    Article  CAS  PubMed  Google Scholar 

  71. Strohmeier, O., A. Emperle, G. Roth, D. Mark, R. Zengerle, and F. von Stetten. Centrifugal gas-phase transition magnetophoresis (GTM)–a generic method for automation of magnetic bead based assays on the centrifugal microfluidic platform and application to DNA purification. Lab Chip 13:146–155, 2013.

    Article  CAS  PubMed  Google Scholar 

  72. Sun, W., C. Jia, T. Huang, W. Sheng, G. Li, H. Zhang, F. Jing, Q. Jin, J. Zhao, G. Li, and Z. Zhang. High-performance size-based microdevice for the detection of circulating tumor cells from peripheral blood in rectal cancer patients. PLoS One 8:e75865, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Taton, T. A. Scanometric DNA array detection with nanoparticle probes. Science 289:1757–1760, 2000.

    Article  CAS  PubMed  Google Scholar 

  74. Taylor, D. D., W. Zacharias, and C. Gercel-Taylor. Exosome isolation for proteomic analyses and RNA profiling. Methods Mol. Biol. 728:235–246, 2011.

    Article  CAS  PubMed  Google Scholar 

  75. Théry, C., L. Zitvogel, and S. Amigorena. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2:569–579, 2002.

    PubMed  Google Scholar 

  76. Tiwari, J. N., R. N. Tiwari, and K. S. Kim. Zero-dimensional, one-dimensional, two-dimensional and three-dimensional nanostructured materials for advanced electrochemical energy devices. Prog. Mater. Sci. 57:724–803, 2012.

    Article  CAS  Google Scholar 

  77. Tsai, C.-P., C.-Y. Chen, Y. Hung, F.-H. Chang, and C.-Y. Mou. Monoclonal antibody-functionalized mesoporous silica nanoparticles (MSN) for selective targeting breast cancer cells. J. Mater. Chem. 19:5737, 2009.

    Article  CAS  Google Scholar 

  78. Wainright, A., U. T. Nguyen, T. Bjornson, and T. D. Boone. Preconcentration and separation of double-stranded DNA fragments by electrophoresis in plastic microfluidic devices. Electrophoresis 24:3784–3792, 2003.

    Article  CAS  PubMed  Google Scholar 

  79. Wang, Z., H. Wu, D. Fine, J. Schmulen, Y. Hu, B. Godin, J. X. J. Zhang, and X. Liu. Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles. Lab Chip 13:2879–2882, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Whitesides, G. M. The origins and the future of microfluidics. Nature 442:368–373, 2006.

    Article  CAS  PubMed  Google Scholar 

  81. Wilbur, J. L., A. Kumar, H. A. Biebuyck, E. Kim, and G. M. Whitesides. Microcontact printing of self-assembled monolayers: applications in microfabrication. Nanotechnology 7:452–457, 1996.

    Article  CAS  Google Scholar 

  82. Wu, C.-H., Y.-Y. Huang, P. Chen, K. Hoshino, H. Liu, E. P. Frenkel, J. X. J. Zhang, and K. V. Sokolov. Versatile immunomagnetic nanocarrier platform for capturing cancer cells. ACS Nano 7:8816–8823, 2013.

    Article  CAS  PubMed  Google Scholar 

  83. Xia, H., X. Gao, G. Gu, Z. Liu, N. Zeng, Q. Hu, Q. Song, L. Yao, Z. Pang, X. Jiang, J. Chen, and H. Chen. Low molecular weight protamine-functionalized nanoparticles for drug delivery to the brain after intranasal administration. Biomaterials 32:9888–9898, 2011.

    Article  CAS  PubMed  Google Scholar 

  84. Xia, N., T. P. Hunt, B. T. Mayers, E. Alsberg, G. M. Whitesides, R. M. Westervelt, and D. E. Ingber. Combined microfluidic-micromagnetic separation of living cells in continuous flow. Biomed. Microdevices 8:299–308, 2006.

    Article  CAS  PubMed  Google Scholar 

  85. Xu, H., Z. P. Aguilar, L. Yang, M. Kuang, H. Duan, Y. Xiong, H. Wei, and A. Wang. Antibody conjugated magnetic iron oxide nanoparticles for cancer cell separation in fresh whole blood. Biomaterials 32:9758–9765, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yamada, M., K. Kano, Y. Tsuda, J. Kobayashi, M. Yamato, M. Seki, and T. Okano. Microfluidic devices for size-dependent separation of liver cells. Biomed. Microdevices 9:637–645, 2007.

    Article  PubMed  Google Scholar 

  87. Yamada, M., and M. Seki. Hydrodynamic filtration for on-chip particle concentration and classification utilizing microfluidics. Lab Chip 5:1233–1239, 2005.

    Article  CAS  PubMed  Google Scholar 

  88. Yang, W., Y. Cheng, T. Xu, X. Wang, and L.-P. Wen. Targeting cancer cells with biotin-dendrimer conjugates. Eur. J. Med. Chem. 44:862–868, 2009.

    Article  CAS  PubMed  Google Scholar 

  89. Yasui, T., N. Kaji, M. R. Mohamadi, Y. Okamoto, M. Tokeshi, Y. Horiike, and Y. Baba. Electroosmotic flow in microchannels with nanostructures. ACS Nano 5:7775–7780, 2011.

    Article  CAS  PubMed  Google Scholar 

  90. Yasui, T., N. Kaji, R. Ogawa, S. Hashioka, M. Tokeshi, Y. Horiike, and Y. Baba. Arrangement of a nanostructure array to control equilibrium and non-equilibrium transports of macromolecules. Nano Lett. 2015. doi:10.1021/acs.nanolett.5b00783.

    PubMed  Google Scholar 

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Acknowledgments

The research is partially sponsored by National Institute of Health (NIH) National Cancer Institute (NCI) Cancer Diagnosis Program under grant 1R01CA139070. We would like to gratefully thank the National Science Foundation Graduate Research Fellowship (Elaine Ng) and the Dartmouth Women in Science Programs scholarship (Kaina Chen, Annie Hang) for the generous support.

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Correspondence to Elaine Ng or John X. J. Zhang.

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Associate Editor Jennifer West oversaw the review of this article.

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Ng, E., Chen, K., Hang, A. et al. Multi-Dimensional Nanostructures for Microfluidic Screening of Biomarkers: From Molecular Separation to Cancer Cell Detection. Ann Biomed Eng 44, 847–862 (2016). https://doi.org/10.1007/s10439-015-1521-2

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