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Studying 3D cell cultures in a microfluidic droplet array under multiple time-resolved conditions

Raphaël F.-X. Tomasi, View ORCID ProfileSébastien Sart, Tiphaine Champetier, View ORCID ProfileCharles N. Baroud
doi: https://doi.org/10.1101/407759
Raphaël F.-X. Tomasi
aLadHyX and Department of Mechanics, École Polytechnique, CNRS, 91128 Palaiseau, France
bPhysical Microfluidics and Bio-Engineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
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Sébastien Sart
aLadHyX and Department of Mechanics, École Polytechnique, CNRS, 91128 Palaiseau, France
bPhysical Microfluidics and Bio-Engineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
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  • ORCID record for Sébastien Sart
Tiphaine Champetier
aLadHyX and Department of Mechanics, École Polytechnique, CNRS, 91128 Palaiseau, France
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Charles N. Baroud
aLadHyX and Department of Mechanics, École Polytechnique, CNRS, 91128 Palaiseau, France
bPhysical Microfluidics and Bio-Engineering, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
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  • ORCID record for Charles N. Baroud
  • For correspondence: baroud@ladhyx.polytechnique.fr
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Abstract

The relevance of traditional cell cultures to cellular behavior in vivo is limited, since the two-dimensional (2D) format does not appropriately reproduce the microenvironment that regulates cell functions. In this context, spheroids are an appealing 3D cell culture format to complement standard techniques, by combining a high level of biological relevance with simple production protocols. However the methods for spheroid manipulation are still labor intensive, which severely limits the complexity of operations that can be performed on statistically relevant numbers of individual spheroids. Here we show how to apply hundreds of different conditions on spheroids in a single microfluidic chip, where each spheroid is produced and immobilized in an anchored droplet. By using asymmetric anchor shapes, a second drop can be merged with the spheroid-containing drop at a later time. This time-delayed merging uniquely enables two classes of applications that we demonstrate: (1) the initiation of cell-cell interactions on demand, either for building micro-tissues within the device or for observing antagonistic cell-cell interactions with applications in immuno-therapy or host-pathogen interactions, (2) a detailed dose-response curve obtained by exposing an array of hepatocyte-like spheroids to droplets containing a wide range of acetaminophen concentrations. The integrated microfluidic format allows time-resolved measurements of the response of hundreds of spheroids with a single-cell resolution. The data shows an internally regulated evolution of each spheroid, in addition to a heterogeneity of the responses to the drug that the single-cell analysis correlates with the initial presence and location of dead cells within each spheroid.

Footnotes

  • R.F.-X.T. and C.N.B. conceived the experiments, discussed the protocol optimization, as well as the results and implications, and commented the manuscript at all stages. C.N.B., S.S. and R.F.-X.T. wrote the manuscript. S.S. performed the co-culture and 2D experiments and R.F.-X.T. performed all other experiments. T.C. and R.F.-X.T. optimized the library preparation and its injection in the trapping chip. R.F.-X.T. analyzed the data.

    The results presented in this paper are covered by several patents owned by Ecole Polytechnique and CNRS

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 04, 2018.
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Studying 3D cell cultures in a microfluidic droplet array under multiple time-resolved conditions
Raphaël F.-X. Tomasi, Sébastien Sart, Tiphaine Champetier, Charles N. Baroud
bioRxiv 407759; doi: https://doi.org/10.1101/407759
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Studying 3D cell cultures in a microfluidic droplet array under multiple time-resolved conditions
Raphaël F.-X. Tomasi, Sébastien Sart, Tiphaine Champetier, Charles N. Baroud
bioRxiv 407759; doi: https://doi.org/10.1101/407759

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