The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Fundamentals of microfluidic cell culture in controlled microenvironments
Open accessAbstract
Microfluidics has the potential to revolutionize the way we approach cell biology research. The dimensions of microfluidic channels are well suited to the physical scale of biological cells, and the many advantages of microfluidics make it an attractive platform for new techniques in biology. One of the key benefits of microfluidics for basic biology is the ability to control parameters of the cell microenvironment at relevant length and time scales. Considerable progress has been made in the design and use of novel microfluidic devices for culturing cells and for subsequent treatment and analysis. With the recent pace of scientific discovery, it is becoming increasingly important to evaluate existing tools and techniques, and to synthesize fundamental concepts that would further improve the efficiency of biological research at the microscale. This tutorial review integrates fundamental principles from cell biology and local microenvironments with cell culture techniques and concepts in microfluidics. Culturing cells in microscale environments requires knowledge of multiple disciplines including physics, biochemistry, and engineering. We discuss basic concepts related to the physical and biochemical microenvironments of the cell, physicochemical properties of that microenvironment, cell culture techniques, and practical knowledge of microfluidic device design and operation. We also discuss the most recent advances in microfluidic cell culture and their implications on the future of the field. The goal is to guide new and interested researchers to the important areas and challenges facing the scientific community as we strive toward full integration of microfluidics with biology.
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Citations
Cites
Monolithic Microfabricated Valves and Pumps by Multilayer Soft Lithography
Unger, M., Chou, H.-P., Thorsen, T., Scherer, A., & Quake, S. R. (2000) · Science · doi:10.1126/science.288.5463.113 · Cited by 4,016
Freshney, R. I. (2005) · Wiley eBooks · doi:10.1002/9780470649367 · Cited by 3,904
Flow-mediated endothelial mechanotransduction
Davies, P. F. (1995) · Physiological Reviews · doi:10.1152/physrev.1995.75.3.519 · Cited by 2,802
Growth Factors, Matrices, and Forces Combine and Control Stem Cells
Discher, D. E., Mooney, D. J., & Zandstra, P. W. (2009) · Science · doi:10.1126/science.1171643 · Cited by 2,666
Soft Lithography in Biology and Biochemistry
Whitesides, G. M., Ostuni, E., Takayama, S., Jiang, X., & Ingber, D. E. (2001) · Annual Review of Biomedical Engineering · doi:10.1146/annurev.bioeng.3.1.335 · Cited by 2,603
El-Ali, J., Sorger, P. K., & Jensen, K. F. (2006) · Nature · doi:10.1038/nature05063 · Cited by 2,105
Physics and Applications of Microfluidics in Biology
Beebe, D. J., Mensing, G. A., & Walker, G. M. (2002) · Annual Review of Biomedical Engineering · doi:10.1146/annurev.bioeng.4.112601.125916 · Cited by 1,803
Self-citationPamme, N. (2005) · Lab on a Chip · doi:10.1039/b513005k · Cited by 1,141
Review on micro molding of thermoplastic polymers
Heckele, M., & Schomburg, W. K. (2003) · Journal of Micromechanics and Microengineering · doi:10.1088/0960-1317/14/3/r01 · Cited by 924
Biological implications of polydimethylsiloxane-based microfluidic cell culture
Regehr, K. J., Domenech, M., Koepsel, J. T., Carver, K. C., Ellison-Zelski, S. J., Murphy, W. L., Schuler, L. A., Alarid, E. T., & Beebe, D. J. (2009) · Lab on a Chip · doi:10.1039/b903043c · Cited by 719
Self-citationMicrofluidic devices for cellomics: a review
Svahn, H. A., & van den Berg, A. (2003) · Sensors and Actuators B Chemical · doi:10.1016/s0925-4005(03)00266-1 · Cited by 679
Cell Mechanics: Integrating Cell Responses to Mechanical Stimuli
Janmey, P. A., & McCulloch, C. A. (2007) · Annual Review of Biomedical Engineering · doi:10.1146/annurev.bioeng.9.060906.151927 · Cited by 650
Versatile, Fully Automated, Microfluidic Cell Culture System
Gómez-Sjöberg, R., Leyrat, A. A., Pirone, D. M., Chen, C. S., & Quake, S. R. (2007) · Analytical Chemistry · doi:10.1021/ac071311w · Cited by 619
The organizing principle: microenvironmental influences in the normal and malignant breast
Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.700907.x · Cited by 617
Biomolecular gradients in cell culture systems
Keenan, T. M., & Folch, A. (2008) · Lab Chip · doi:10.1039/b711887b · Cited by 596
Cell migration into scaffolds under co-culture conditions in a microfluidic platform
Chung, S. H., Sudo, R., Mack, P. J., Wan, C.-R., Vickerman, V., & Kamm, R. D. (2008) · Lab on a Chip · doi:10.1039/b807585a · Cited by 530
Huh, D., Fujioka, H., Tung, Y., Futai, N., Paine, R., Grotberg, J. B., & Takayama, S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610868104 · Cited by 496
Microfluidics technology for manipulation and analysis of biological cells
Yi, C., Li, C., Ji, S., & Yang, M. (2006) · Analytica Chimica Acta · doi:10.1016/j.aca.2005.12.037 · Cited by 479
A practical guide to microfluidic perfusion culture of adherent mammalian cells
Kim, L. Y., Toh, Y., Joel Voldman, B., & Yu, H. (2007) · Lab on a Chip · doi:10.1039/b704602b · Cited by 466
The organ microenvironment and cancer metastasis
Fidler, I. J. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.700904.x · Cited by 428
Computerized microfluidic cell culture using elastomeric channels and Braille displays
Gu, W., Zhu, X. A., Futai, N., Cho, B. S., & Takayama, S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404353101 · Cited by 403
Analysis of single mammalian cells on-chip
Sims, C. E., & Allbritton, N. L. (2007) · Lab on a Chip · doi:10.1039/b615235j · Cited by 400
Microenvironment design considerations for cellular scale studies
Walker, G. M., Zeringue, H. C., & Beebe, D. J. (2004) · Lab on a Chip · doi:10.1039/b311214d · Cited by 387
Self-citationEngineering microscale cellular niches for three-dimensional multicellular co-cultures
Huang, C. P., Lu, J., Seon, H., Lee, A. P., Flanagan, L. A., Kim, H.-Y., Putnam, A. J., & Jeon, N. L. (2009) · Lab on a Chip · doi:10.1039/b818401a · Cited by 384
Flow-induced deformation of shallow microfluidic channels
Gervais, T., El-Ali, J., Günther, A., & Jensen, K. F. (2006) · Lab on a Chip · doi:10.1039/b513524a · Cited by 361
Microenvironment-induced cancer metastasis
Rofstad, E. K. (2000) · International Journal of Radiation Biology · doi:10.1080/095530000138259 · Cited by 335
Microfluidic Endothelium for Studying the Intravascular Adhesion of Metastatic Breast Cancer Cells
Song, J. W., Cavnar, S. P., Walker, A. C., Luker, K. E., Gupta, M., Tung, Y.-C., Luker, G. D., & Takayama, S. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005756 · Cited by 317
Kimura, H., Yamamoto, T., Sakai, H., Sakai, Y., & Fujii, T. (2008) · Lab on a Chip · doi:10.1039/b717091b · Cited by 293
Culturing Life: How Cells Became Technologies
Landecker, H. L. (2007) · Cited by 283
Heo, Y. S., Cabrera, L. M., Song, J. W., Futai, N., Tung, Y., Smith, G. D., & Takayama, S. (2006) · Analytical Chemistry · doi:10.1021/ac061990v · Cited by 245
Paguirigan, A. L., & Beebe, D. J. (2008) · BioEssays · doi:10.1002/bies.20804 · Cited by 211
Self-citationCombinatorial Signaling Microenvironments for Studying Stem Cell Fate
Flaim, C. J., Teng, D., Chien, S., & Bhatia, S. N. (2008) · Stem Cells and Development · doi:10.1089/scd.2007.0085 · Cited by 195
Flow rate analysis of a surface tension driven passive micropump
Berthier, E., & Beebe, D. J. (2007) · Lab on a Chip · doi:10.1039/b707637a · Cited by 191
Self-citationLaBarge, M. A., Nelson, C. M., Villadsen, R., Fridriksdottir, A. J., Ruth, J. R., Stampfer, M. R., PETERSEN, O. W., & Bissell, M. J. (2008) · Integrative Biology · doi:10.1039/b816472j · Cited by 177
Automated cell culture in high density tubeless microfluidic device arrays
Meyvantsson, I., Warrick, J. W., Hayes, S. A., Skoien, A., & Beebe, D. J. (2008) · Lab on a Chip · doi:10.1039/b715375a · Cited by 173
Self-citationA gel-free 3D microfluidic cell culture system
Ong, S.-M., Zhang, C., Toh, Y.-C., Kim, S. H., Foo, H. L., Tan, C. H., van Noort, D., Park, S., & Yu, H. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2008.04.022 · Cited by 172
Shrinky-Dink microfluidics: 3D polystyrene chips
Chen, C., Breslauer, D. N., Luna, J. I., Grimes, A., Chin, W., Lee, L. P., & Khine, M. (2008) · Lab on a Chip · doi:10.1039/b719029h · Cited by 152
Diffusion dependent cell behavior in microenvironments
Yu, H., Meyvantsson, I., Shkel, I. A., & Beebe, D. J. (2005) · Lab on a Chip · doi:10.1039/b504403k · Cited by 146
Self-citationPaguirigan, A. L., & Beebe, D. J. (2009) · Integrative Biology · doi:10.1039/b814565b · Cited by 141
Self-citationA platform for assessing chemotactic migration within a spatiotemporally defined 3D microenvironment
Abhyankar, V. V., Toepke, M. W., Cortesio, C. L., Lokuta, M. A., Huttenlocher, A., & Beebe, D. J. (2008) · Lab on a Chip · doi:10.1039/b803533d · Cited by 136
Self-citationAbdelgawad, M. O., Watson, M. W. L., & Wheeler, A. R. (2009) · Lab on a Chip · doi:10.1039/b820682a · Cited by 122
Berthier, E., Warrick, J., Yu, H., & Beebe, D. J. (2008) · Lab on a Chip · doi:10.1039/b717422e · Cited by 114
Self-citationHard Top Soft Bottom Microfluidic Devices for Cell Culture and Chemical Analysis
Mehta, G., Lee, J. S.-J., Cha, W., Tung, Y., Linderman, J. J., & Takayama, S. (2009) · Analytical Chemistry · doi:10.1021/ac802178u · Cited by 111
An active bubble trap and debubbler for microfluidic systems
Skelley, A. M., & Voldman, J. (2008) · Lab on a Chip · doi:10.1039/b807037g · Cited by 110
Du, Y., Shim, J., Vidula, M. K., HANCOCK, M. J., Lo, E., Chung, B. G., Borenstein, J. T., Khabiry, M., Cropek, D. M., & Khademhosseini, A. (2008) · Lab on a Chip · doi:10.1039/b815990d · Cited by 89
Neeves, K. B., & Diamond, S. L. (2008) · Lab on a Chip · doi:10.1039/b717824g · Cited by 85
Spence, D. M., Torrence, N. J., Kovarik, M. L., & Martin, R. S. (2004) · The Analyst · doi:10.1039/b410547h · Cited by 65
Bliss, C. L., McMullin, J. N., & Backhouse, C. (2007) · Lab on a Chip · doi:10.1039/b711601b · Cited by 57
Selective and tunable gradient device for cell culture and chemotaxis study
Kim, D., Lokuta, M. A., Anna Huttenlocher, A., & Beebe, D. J. (2009) · Lab on a Chip · doi:10.1039/b901613a · Cited by 56
Self-citationA plate reader-compatible microchannel array for cell biology assays
Yu, H., Alexander, C. M., & Beebe, D. J. (2007) · Lab on a Chip · doi:10.1039/b612358a · Cited by 44
Self-citationPuccinelli, J. P., Su, X., & Beebe, D. J. (2009) · JALA Journal of the Association for Laboratory Automation · doi:10.1016/j.jala.2009.10.002 · Cited by 34
Self-citationZeng, Y., Lee, T.-S., Yu, P., Roy, P., & Low, H. T. (2005) · Journal of Biomechanical Engineering · doi:10.1115/1.2170118 · Cited by 33
Computation of transient flow rates in passive pumping micro-fluidic systems
Chen, I.-J., Eckstein, E. C., & Lindner, E. (2008) · Lab on a Chip · doi:10.1039/b808660e · Cited by 28
Microfabricated curtains for controlled cell seeding in high throughput microfluidic systems
O’Neill, A. T., Monteiro-Riviere, N. A., & Walker, G. M. (2009) · Lab on a Chip · doi:10.1039/b819622b · Cited by 13
Flagged first, then by citations
Research works printed but not linked: 1
- Cressey, 2008, Nat. Med., 14, 1292
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Sorted by citations
A practical guide to hydrogels for cell culture
Caliari, S. R., & Burdick, J. A. (2016) · Nature Methods · doi:10.1038/nmeth.3839 · Cited by 2,075
A guide to the organ-on-a-chip
Leung, C. M., de Haan, P., Ronaldson-Bouchard, K., Kim, G.-A., Ko, J., Rho, H. S., Chen, Z., Habibovic, P., Jeon, N. L., Takayama, S., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00118-6 · Cited by 1,116
Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices
Halldorsson, S., Lucumi, E., Gómez-Sjöberg, R., & Fleming, R. M. T. (2015) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2014.07.029 · Cited by 1,027
Prebiotic Systems Chemistry: New Perspectives for the Origins of Life
Ruiz-Mirazo, K., Briones, C., & de la Escosura, A. (2014) · Chemical Reviews · doi:10.1021/cr2004844 · Cited by 930
Advances in Microfluidic Materials, Functions, Integration, and Applications
Nge, P. N., Rogers, C. I., & Woolley, A. T. (2013) · Chemical Reviews · doi:10.1021/cr300337x · Cited by 989
Metadata
- Authors
- Young, E. W. K., & Beebe, D. J.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Beebe, David J.
- Venue
- Chemical Society Reviews
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2010
- Volume
- 39
- Issue
- 3
- Pages
- 1036
- ISSN
- 0306-0012 (ISSN-L)
- 1460-4744
- PMC
- PMC2967183
- OpenAlex
- W2092941484
- Cited by
- 615
- References
- 54
- Citations by year
- 2026: 30 · 2025: 35 · 2024: 29 · 2023: 32 · 2022: 39 · 2021: 35 · 2020: 42 · 2019: 38 · 2018: 60 · 2017: 38 · 2016: 41 · 2015: 29 · 2014: 45 · 2013: 44 · 2012: 35
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Society Reviews (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute (R33CA137673)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Bio-sensing Technologies
- Keywords
- microfluidic cell culture, cell microenvironment, microfluidic device design, cell culture, microfluidics
- MeSH terms
- Endothelium, Humans, Muscle, Smooth, Cell Culture Techniques, Microfluidics
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