Abstract

The rapid growth of microfluidic cell culturing in biological and biomedical research and industry calls for fast, non-invasive and reliable methods of evaluating conditions such as pH inside a microfluidic system. We show that by careful calibration it is possible to measure pH within microfluidic chambers with high accuracy and precision, using a direct single-pass measurement of light absorption in a commercially available phenol-red-containing cell culture medium. The measurement is carried out using a standard laboratory microscope and, contrary to previously reported methods, requires no modification of the microfluidic device design. We demonstrate the validity of this method by measuring absorption of light transmitted through 30-micrometer thick microfluidic chambers, using an inverted microscope fitted with a scientific-grade digital camera and two bandpass filters. In the pH range of 7–8, our measurements have a standard deviation and absolute error below 0.05 for a measurement volume smaller than 4 nL.

© 2013 OSA

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    [CrossRef] [PubMed]

2012

T. Verch and R. Bakhtiar, “Miniaturized immunoassays: moving beyond the microplate,” Bioanalysis4, 177–188 (2012).
[CrossRef] [PubMed]

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

2011

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

C. Zhang and D. van Noort, “Cells in microfluidics,” Top Curr Chem304, 295–321 (2011).
[CrossRef] [PubMed]

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

2010

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

M.-H. Wu, S.-B. Huang, and G.-B. Lee, “Microfluidic cell culture systems for drug research,” Lab Chip10, 939–956 (2010).
[CrossRef] [PubMed]

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

2009

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

2008

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

2007

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

2006

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

M. W. Toepke and D. J. Beebe, “Pdms absorption of small molecules and consequences in microfluidic applications,” Lab Chip6, 1484–1486 (2006).
[CrossRef]

Abou-Hassan, A.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Alberty, R.

R. Alberty, Thermodynamics of Biochemical Reactions (Wiley, 2005).

Bakhtiar, R.

T. Verch and R. Bakhtiar, “Miniaturized immunoassays: moving beyond the microplate,” Bioanalysis4, 177–188 (2012).
[CrossRef] [PubMed]

Beebe, D. J.

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

M. W. Toepke and D. J. Beebe, “Pdms absorption of small molecules and consequences in microfluidic applications,” Lab Chip6, 1484–1486 (2006).
[CrossRef]

Bernard, O.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Bowden, W.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Cabral, J. T.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Cabuil, V.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Carlborg, C. F.

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

Chan, P. P.

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

Chang, H. C.

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

Chen, C. S.

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Chou, T.-C.

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Copley, M. R.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Cote, G. L.

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

Covert, M. W.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Davies, J.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Dolan, P. R.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Dufreche, J.-F.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Eaves, C. J.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Falconnet, D.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Freshney, R.

R. Freshney, Culture of Animal Cells (Wiley, 2010).
[CrossRef]

Friend, J. R.

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

Gomez-Sjoberg, R.

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Hansen, C. L.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Haraldsson, T.

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

Huang, S.-B.

M.-H. Wu, S.-B. Huang, and G.-B. Lee, “Microfluidic cell culture systems for drug research,” Lab Chip10, 939–956 (2010).
[CrossRef] [PubMed]

Hughey, J. J.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Humphries, R. K.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Ibey, B. L.

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

Irimia, D.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Jarandehei, A.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Jayaraman, A.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Jeong-Yeol Yoon, R. L. G.

R. L. G. Jeong-Yeol Yoon, Encyclopedia of Microfluidics and Nanofluidics (Springer, 2008).

Kent, D. G.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

King, K. R.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Knapp, D. J. H. F.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Lecault, V.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Lee, G.-B.

M.-H. Wu, S.-B. Huang, and G.-B. Lee, “Microfluidic cell culture systems for drug research,” Lab Chip10, 939–956 (2010).
[CrossRef] [PubMed]

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Lee, H.-H.

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Lee, S.

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

Lee, T. K.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Leyrat, A. A.

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Liao, W.-Y.

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Lin, C.-F.

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Lipniacki, T.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Malkoch, M.

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

McLaughlin, T.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Meriguet, G.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Miller, M.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Oberg, K.

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

Paguirigan, A. L.

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

Piret, J. M.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Pirone, D. M.

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Pishko, M. V.

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

Puccinelli, J. P.

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

Quake, S. R.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Rushworth, C. M.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Sandre, O.

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Sekulovic, S.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Smith, J. M.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Su, X.

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

Taghipour, F.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Tay, S.

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Toepke, M. W.

M. W. Toepke and D. J. Beebe, “Pdms absorption of small molecules and consequences in microfluidic applications,” Lab Chip6, 1484–1486 (2006).
[CrossRef]

Toner, M.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Vallance, C.

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

van der Wijngaart, W.

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

van Noort, D.

C. Zhang and D. van Noort, “Cells in microfluidics,” Top Curr Chem304, 295–321 (2011).
[CrossRef] [PubMed]

Vaninsberghe, M.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Verch, T.

T. Verch and R. Bakhtiar, “Miniaturized immunoassays: moving beyond the microplate,” Bioanalysis4, 177–188 (2012).
[CrossRef] [PubMed]

Viel, F.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Wang, C.-H.

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Wang, S.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Webster, J.

J. Webster, The Measurement, Instrumentation, and Sensors: Handbook, The electrical engineering handbook series (CRC Press published, 1999).

White, A. K.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Wohrer, S.

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Wu, M.-H.

M.-H. Wu, S.-B. Huang, and G.-B. Lee, “Microfluidic cell culture systems for drug research,” Lab Chip10, 939–956 (2010).
[CrossRef] [PubMed]

Yarmush, M. L.

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

Yeo, L. Y.

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

Zhang, C.

C. Zhang and D. van Noort, “Cells in microfluidics,” Top Curr Chem304, 295–321 (2011).
[CrossRef] [PubMed]

Anal Chem

R. Gomez-Sjoberg, A. A. Leyrat, D. M. Pirone, C. S. Chen, and S. R. Quake, “Versatile, fully automated, microfluidic cell culture system,” Anal Chem79, 8557–8563 (2007).
[CrossRef] [PubMed]

Assay Drug Dev Technol

A. L. Paguirigan, J. P. Puccinelli, X. Su, and D. J. Beebe, “Expanding the available assays: adapting and validating in-cell westerns in microfluidic devices for cell-based assays,” Assay Drug Dev Technol8, 591–601 (2010).
[CrossRef] [PubMed]

Bioanalysis

T. Verch and R. Bakhtiar, “Miniaturized immunoassays: moving beyond the microplate,” Bioanalysis4, 177–188 (2012).
[CrossRef] [PubMed]

Biosens Bioelectron

C.-F. Lin, G.-B. Lee, C.-H. Wang, H.-H. Lee, W.-Y. Liao, and T.-C. Chou, “Microfluidic ph-sensing chips integrated with pneumatic fluid-control devices,” Biosens Bioelectron21, 1468–1475 (2006).
[CrossRef]

Chemical Physics Letters

C. M. Rushworth, J. Davies, J. T. Cabral, P. R. Dolan, J. M. Smith, and C. Vallance, “Cavity-enhanced optical methods for online microfluidic analysis,” Chemical Physics Letters554, 1–14 (2012).
[CrossRef]

Lab Chip

M. W. Toepke and D. J. Beebe, “Pdms absorption of small molecules and consequences in microfluidic applications,” Lab Chip6, 1484–1486 (2006).
[CrossRef]

C. F. Carlborg, T. Haraldsson, K. Oberg, M. Malkoch, and W. van der Wijngaart, “Beyond pdms: off-stoichiometry thiol-ene (oste) based soft lithography for rapid prototyping of microfluidic devices,” Lab Chip11, 3136–3147 (2011).
[CrossRef] [PubMed]

K. R. King, S. Wang, D. Irimia, A. Jayaraman, M. Toner, and M. L. Yarmush, “A high-throughput microfluidic real-time gene expression living cell array,” Lab Chip7, 77–85 (2007).
[CrossRef]

M.-H. Wu, S.-B. Huang, and G.-B. Lee, “Microfluidic cell culture systems for drug research,” Lab Chip10, 939–956 (2010).
[CrossRef] [PubMed]

Nat Methods

V. Lecault, M. Vaninsberghe, S. Sekulovic, D. J. H. F. Knapp, S. Wohrer, W. Bowden, F. Viel, T. McLaughlin, A. Jarandehei, M. Miller, D. Falconnet, A. K. White, D. G. Kent, M. R. Copley, F. Taghipour, C. J. Eaves, R. K. Humphries, J. M. Piret, and C. L. Hansen, “High-throughput analysis of single hematopoietic stem cell proliferation in microfluidic cell culture arrays,” Nat Methods8, 581–586 (2011).
[CrossRef] [PubMed]

Nature

S. Tay, J. J. Hughey, T. K. Lee, T. Lipniacki, S. R. Quake, and M. W. Covert, “Single-cell nf-kappab dynamics reveal digital activation and analogue information processing,” Nature466, 267–271 (2010).
[CrossRef] [PubMed]

Sensors and Actuators B: Chemical

S. Lee, B. L. Ibey, G. L. Cote, and M. V. Pishko, “Measurement of ph and dissolved oxygen within cell culture media using a hydrogel microarray sensor,” Sensors and Actuators B: Chemical128, 388–398 (2008).
[CrossRef]

Small

L. Y. Yeo, H. C. Chang, P. P. Chan, and J. R. Friend, “Microfluidic devices for bioapplications,” Small7, 12–48 (2011).
[CrossRef]

The Journal of Physical Chemistry C

A. Abou-Hassan, J.-F. Dufreche, O. Sandre, G. Meriguet, O. Bernard, and V. Cabuil, “Fluorescence confocal laser scanning microscopy for ph mapping in a coaxial flow microreactor: Application in the synthesis of super-paramagnetic nanoparticles,” The Journal of Physical Chemistry C113, 18097–18105 (2009).
[CrossRef]

Top Curr Chem

C. Zhang and D. van Noort, “Cells in microfluidics,” Top Curr Chem304, 295–321 (2011).
[CrossRef] [PubMed]

Other

R. Freshney, Culture of Animal Cells (Wiley, 2010).
[CrossRef]

J. Webster, The Measurement, Instrumentation, and Sensors: Handbook, The electrical engineering handbook series (CRC Press published, 1999).

R. Alberty, Thermodynamics of Biochemical Reactions (Wiley, 2005).

R. L. G. Jeong-Yeol Yoon, Encyclopedia of Microfluidics and Nanofluidics (Springer, 2008).

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Figures (5)

Fig. 1
Fig. 1

Schematic layout of a live-cell microfluidic measurement system. Incubator box for temperature control not shown.

Fig. 2
Fig. 2

Close-up of a microfluidic chamber, design by Gomez-Sjoberg et al. [11]. The inset shows the typical image frame and the areas used for reference measurement (top) and the different rectangle sizes used pH measurements (bottom).

Fig. 3
Fig. 3

pH values determined with optical absorption measurements, against pre-calibrated values. Error bars represent the standard deviation of 108 individual measurements (12 chambers, 9 individual measurements taken at time intervals of several minutes). The standard deviation and absolute error are also shown in Fig. 4.

Fig. 4
Fig. 4

Standard deviation of the pH value determined with absorption measurements (symbols, top panel) and deviation from predetermined pH value (symbols, bottom panel). Different liquid volumes correspond to the measurement areas shown in the inset of Fig. 2. Solid lines are guides to the eye. The increased uncertainty at low and high pH values is related to low absorption by the acid and base forms of phenol red. The minimum uncertainty is shifted from pKa due to a difference in absorption strength of the acid and base forms.

Fig. 5
Fig. 5

Evolution of pH with changing CO2 concentration in the environment surrounding a PDMS microfluidic chip containing DMEM/F12 medium with phenol red and either a bicarbonate buffer or a HEPES buffer. The figure shows measurements from five separate microfluidic chambers (solid gray lines) as well as their average (solid black lines). Atmospheric CO2 levels were equilibrated at 10% at the beginning of measurements. After 60 minutes (dashed line), the CO2 levels surrounding the chip were reduced to 0.04%. CO2 reduction results in increasing pH in all chambers. The increase is more pronounced in the chambers containing DMEM/F12 with a bicarbonate buffer.

Equations (7)

Equations on this page are rendered with MathJax. Learn more.

I = I lamp ( t ) f ( x , y , λ )
pH = p K a + log ( [ X ] [ H X ] ) ,
I i = I lamp ( t ) f ( x , y , λ i ) e α i ρ d ,
I i ( x , y , λ i , t 1 ) / I ( x , y , λ i , t 0 ) = I lamp ( t 1 ) I lamp ( t 0 ) e α λ i ρ d
ln ( T λ 1 ) / ln ( T λ 2 ) = α λ 1 / α λ 2 .
A λ = α λ ρ d = α H X λ [ H X ] d + α X λ [ X ] d
A λ 1 / A λ 2 = α H X λ 1 [ H X ] + α X λ 1 [ X ] α H X λ 2 [ H X ] + α X λ 2 [ X ] = α H X λ 1 + α X λ 1 [ X ] / [ H X ] α H X λ 2 + α X λ 2 [ X ] / [ H X ] .

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