Abstract
The emerging field of micro-technology has opened up new possibilities for exploring cellular chemotaxis in real space and time, and at single cell resolution. Chemotactic cells sense and move in response to chemical gradients and play important roles in a number of physiological and pathological processes, including development, immune responses, and tumor cell invasions. Due to the size proximity of the microfluidic device to cells, microfluidic chemotaxis devices advance the traditional macro-scale chemotaxis assays in two major directions: one is to build well defined and stable chemical gradients at cellular length scales, and the other is to provide a platform for quantifying cellular responses at both cellular and molecular levels using advanced optical imaging systems. Here, we present a critical review on the designing principles, recent development, and potential capabilities of the microfluidic chemotaxis assay for solving problems that are of importance in the biomedical engineering field.
Similar content being viewed by others
References
Abhyankar, V. V., et al. Characterization of a membrane-based gradient generator for use in cell-signaling studies. Lab Chip 6(3):389–393, 2006.
Abhyankar, V. V., et al. A platform for assessing chemotactic migration within a spatiotemporally defined 3D microenvironment. Lab Chip 8(9):1507–1515, 2008.
Ahmed, T., T. S. Shimizu, and R. Stocker. Microfluidics for bacterial chemotaxis. Integr. Biol. 2(11–12):604–629, 2010.
Alberts, B., et al., Molecular Biology of the Cell (5th ed.). New York, NY: Garland Science, Taylor and Francis Froup, L.L.C., 2007.
Ambrosi, D., A. Gamba, and G. Serini. Cell directional and chemotaxis in vascular morphogenesis. Bull. Math. Biol. 66(6):1851–1873, 2004.
Boyden, S. The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J. Exp. Med. 115:453–466, 1962.
Carmeliet, P., and R. K. Jain. Angiogenesis in cancer and other diseases. Nature 407(6801):249–257, 2000.
Chambers, A. F., A. C. Groom, and I. C. MacDonald. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2(8):563–572, 2002.
Chary, S. R., and R. K. Jain. Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. Proc. Natl Acad. Sci. USA 86(14):5385–5389, 1989.
Cheng, S.-Y., et al. A hydrogel-based microfluidic device for the studies of directed cell migration. Lab Chip 7:763–769, 2007.
Choi, N. W., et al. Microfluidic scaffolds for tissue engineering. Nat. Mater. 6(11):908–915, 2007.
Choi, N. W., et al. Phosphorescent nanoparticles for quantitative measurements of oxygen profiles in vitro and in vivo. Biomaterials, 2011. doi:10.1016/j.biomaterials.2011.11.048.
Chrobak, K. M., D. R. Potter, and J. Tien. Formation of perfused, functional microvascular tubes in vitro. Microvasc. Res. 71(3):185–196, 2006.
Chung, S., et al. Cell migration into scaffolds under co-culture conditions in a microfluidic platform. Lab Chip 9(2):269–275, 2009.
Clague, M. J., S. Urbe, and J. de Lartigue. Phosphoinositides and the endocytic pathway. Exp. Cell Res. 315(9):1627–1631, 2009.
Condeelis, J., and J. E. Segall. Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 3(12):921–930, 2003.
Condeelis, J., R. H. Singer, and J. E. Segall. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu. Rev. Cell Dev. Biol. 21:695–718, 2005.
Coussens, L. M., B. Fingleton, and L. M. Matrisian. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392, 2002.
Cross, V. L., et al. Dense type I collagen matrices that support cellular remodeling and microfabrication for studies of tumor angiogenesis and vasculogenesis in vitro. Biomaterials 31(33):8596–8607, 2010.
Cukierman, E., et al. Taking cell-matrix adhesions to the third dimension. Science 294(5547):1708–1712, 2001.
De Bruyn, P. P. The amoeboid movement of the mammalian leukocyte in tissue culture. Anat. Rec. 95:177–191, 1946.
Diao, J., L. Young, S. Kim, E. A. Fogarty, S. M. Heilman, P. Zhou, M. L. Shuler, M. Wu, and M. P. DeLisa. A three-channel microfluidic device for generating static linear gradients and its application to the quantitative analysis of bacterial chemotaxis. Lab Chip 6:381–388, 2006.
Discher, D. E., P. Janmey, and Y. L. Wang. Tissue cells feel and respond to the stiffness of their substrate. Science 310(5751):1139–1143, 2005.
Domansky, K., et al. Perfused multiwell plate for 3D liver tissue engineering. Lab Chip 10(1):51–58, 2010.
Ehrbar, M., et al. Elucidating the role of matrix stiffness in 3D cell migration and remodeling. Biophys. J. 100(2):284–293, 2011.
Eisenbach, M. Chemotaxis. London: Imperial College Press, 2004.
Fleury, M. E., K. C. Boardman, and M. A. Swartz. Autologous morphogen gradients by subtle interstitial flow and matrix interactions. Biophys. J. 91(1):113–121, 2006.
Folkman, J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29(6):15–18, 2002.
Fournier, R. L. Basic Transport Phenomena in Biomedical Engineering (1st ed.). London: Taylor & Francis, 1999.
Friedl, P., and K. Wolf. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188(1):11–19, 2010.
Gamba, A., et al. Percolation, morphogenesis, and Burgers dynamics in blood vessels formation. Phys. Rev. Lett. 90(11):118101, 2003.
Golden, A. P., and J. Tien. Fabrication of microfluidic hydrogels using molded gelatin as a sacrificial element. Lab Chip 7(6):720–725, 2007.
Griffith, L. G., and M. A. Swartz. Capturing complex 3D tissue physiology in vitro. Natl Rev. Mol. Cell Biol. 7(3):211–224, 2006.
Haessler, U., et al. An agarose-based microfluidic platform with a gradient buffer for 3D chemotaxis studies. Biomed. Microdevices 11(4):827–835, 2009.
Haessler, U., et al. Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19. Proc. Natl Acad. Sci. USA 108(14):5614–5619, 2011.
Hanahan, D., and R. A. Weinberg. Hallmarks of cancer: the next generation. Cell 144(5):646–674, 2011.
Helm, C. L. E., et al. Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc. Natl Acad. Sci. USA 102(44):15779–15784, 2005.
Helmlinger, G., et al. Interstitial pH and pO(2) gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 3(2):177–182, 1997.
Herzmark, P., et al. Bound attractant at the leading vs. the trailing edge determines chemotactic prowess. Proc. Natl Acad. Sci. USA 104(33):13349–13354, 2007.
Jannat, R. A., M. Dembo, and D. A. Hammer. Traction forces of neutrophils migrating on compliant substrates. Biophys. J. 101(3):575–584, 2011.
Jeon, N. L., et al. Generation of solution and surface gradients using microfluidic systems. Langmuir 16(22):8311–8316, 2000.
Jeon, N. L., et al. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat. Biotechnol. 20(8):826–830, 2002.
Kay, R. R., et al. Changing directions in the study of chemotaxis. Nat. Rev. Mol. Cell Biol. 9(6):455–463, 2008.
Kim, S., H. J. Kim, and N. L. Jeon. Biological applications of microfluidic gradient devices. Integr. Biol. 2(11–12):584–603, 2010.
Kunze, A., et al. Micropatterning neural cell cultures in 3D with a multi-layered scaffold. Biomaterials 32(8):2088–2098, 2011.
Lammermann, T., et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453(7191):51–55, 2008.
Lebrun, L., and G. A. Junter. Diffusion of sucrose and dextran through agar gel membranes. Enzyme Microb. Technol. 15(12):1057–1062, 1993.
Lee, P., et al. Microfluidic alignment of collagen fibers for in vitro cell culture. Biomed. Microdevices 8(1):35–41, 2006.
Lin, F. A microfluidics-based method for analyzing leukocyte migration to chemoattractant gradients. In: Methods in Enzymology, Vol. 461: Chemokines, Part B, edited by T. M. Handel, and D. J. Hamel. New York: Academic Press, 2009, pp. 333–347.
Lin, F., and E. C. Butcher. T cell chemotaxis in a simple microfluidic device. Lab Chip 6(11):1462–1469, 2006.
Lin, F., et al. Effective neutrophil chemotaxis is strongly influenced by mean IL-8 concentration. Biochem. Biophys. Res. Commun. 319(2):576–581, 2004.
Lin, F., et al. Neutrophil migration in opposing chemoattractant gradients using microfluidic chemotaxis devices. Ann. Biomed. Eng. 33(4):475–482, 2005.
Maheshwari, G., H. S. Wiley, and D. A. Lauffenburger. Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration. J. Cell Biol. 155(7):1123–1128, 2001.
Mao, H. B., P. S. Cremer, and M. D. Manson. A sensitive, versatile microfluidic assay for bacterial chemotaxis. Proc. Natl Acad. Sci. USA 100(9):5449–5454, 2003.
Meier, B., et al. Chemotactic cell trapping in controlled alternating gradient fields. Proc. Natl Acad. Sci. USA 108(28):11417–11422, 2011.
Mello, B. A., and Y. Tu. Perfect and near-perfect adaptation in a model of bacterial chemotaxis. Biophys. J. 84(5):2943–2956, 2003.
Mosadegh, B., et al. Epidermal growth factor promotes breast cancer cell chemotaxis in CXCL12 gradients. Biotechnol. Bioeng. 100(6):1205–1213, 2008.
Ng, C. P., C. L. Helm, and M. A. Swartz. Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. Microvasc. Res. 68(3):258–264, 2004.
Ng, C. P., B. Hinz, and M. A. Swartz. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell Sci. 118(20):4731–4739, 2005.
Paguirigan, A. L., and D. J. Beebe. Protocol for the fabrication of enzymatically crosslinked gelatin microchannels for microfluidic cell culture. Nat. Protoc. 2(7):1782–1788, 2007.
Palecek, S. P., et al. Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness. Nature 385(6616):537–540, 1997.
Pedersen, J. A., and M. A. Swartz. Mechanobiology in the third dimension. Ann. Biomed. Eng. 33(11):1–22, 2005.
Pelham, R. J., Jr., and Y. Wang. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94(25):13661–13665, 1997.
Pluen, A., et al. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys. J. 77(1):542–552, 1999.
Polacheck, W. J., J. L. Charest, and R. D. Kamm. Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc. Natl Acad. Sci. USA 108(27):11115–11120, 2011.
Regehr, K. J., et al. Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip 9(15):2132–2139, 2009.
Renkawitz, J., and M. Sixt. Mechanisms of force generation and force transmission during interstitial leukocyte migration. EMBO Rep. 11(10):744–750, 2010.
Ricart, B. G., et al. Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4. J. Immunol. 186(1):53–61, 2011.
Roussos, E. T., J. S. Condeelis, and A. Patsialou. Chemotaxis in cancer. Nat. Rev. Cancer 11(8):573–587, 2011.
Saadi, W., et al. Generation of stable concentration gradients in 2D and 3D environments using a microfluidic ladder chamber. Biomed. Microdevices 9(5):627–635, 2007.
Serini, G., et al. Modeling the early stages of vascular network assembly. EMBO J. 22(8):1771–1779, 2003.
Servant, G., et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287(5455):1037–1040, 2000.
Shamloo, A., and S. C. Heilshorn. Matrix density mediates polarization and lumen formation of endothelial sprouts in VEGF gradients. Lab Chip 10(22):3061–3068, 2010.
Shamloo, A., et al. Endothelial cell polarization and chemotaxis in a microfluidic device. Lab Chip 8(8):1292–1299, 2008.
Shields, J. D., et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11(6):526–538, 2007.
Song, L., et al. Dicyostelium discoideum chemotaxis: threshold for directed motion. Eur. J. Cell Biol. 85(9–10):981–989, 2006.
Squires, T. M., and S. R. Quake. Microfluidics: fluid physics at the nanoliter scale. Rev. Mod. Phys. 77(3):977–1026, 2005.
Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nat. Med. 12(8):895–904, 2006.
Swartz, M. A. The physiology of the lymphatic system. Adv. Drug Deliv. Rev. 50(1–2):3–20, 2001.
Tayalia, P., E. Mazur, and D. J. Mooney. Controlled architectural and chemotactic studies of 3D cell migration. Biomaterials 32(10):2634–2641, 2011.
Verbridge, S. S., et al. Oxygen-controlled three-dimensional cultures to analyze tumor angiogenesis. Tissue Eng. Part A 16:2133–2141, 2010.
Vickerman, V., et al. Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging. Lab Chip 8(9):1468–1477, 2008.
Walker, G. M., H. C. Zeringue, and D. J. Beebe. Microenvironment design considerations for cellular scale studies. Lab Chip 4(2):91–97, 2004.
Wang, S. J., et al. Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. Exp. Cell Res. 300(1):180–189, 2004.
Wolf, K., et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160(2):267–277, 2003.
Wong, K., et al. Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. Proc. Natl Acad. Sci. USA 103(10):3639–3644, 2006.
Xia, Y. N., and G. M. Whitesides. Soft lithography. Annu. Rev. Mater. Sci. 28:153–184, 1998.
Zheng, Y., et al. Microstructured templates for directed growth and vascularization of soft tissue in vivo. Biomaterials 32(23):5391–5401, 2011.
Zicha, D., G. A. Dunn, and A. F. Brown. A new direct-viewing chemotaxis chamber. J. Cell Sci. 99(Pt 4):769–775, 1991.
Zigmond, S. H. Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors. J. Cell Biol. 75(2 Pt 1):606–616, 1977.
Acknowledgments
MW thanks insightful discussions with Abraham Stroock and Melody Swartz. Both authors thank the anonymous reviewers for their careful readings and very useful suggestions. The work was supported by the National Cancer Institute through award number R21CA138366, and through the Cornell Center on the Microenvironment & Metastasis with Award Number U54CA143876, and the Cornell Nanobiotechnology Center.
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Jong Hwan Sung oversaw the review of this article.
Rights and permissions
About this article
Cite this article
Kim, B.J., Wu, M. Microfluidics for Mammalian Cell Chemotaxis. Ann Biomed Eng 40, 1316–1327 (2012). https://doi.org/10.1007/s10439-011-0489-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-011-0489-9