A Versatile and Modular Microfluidic System for Dynamic Cell Culture and Cellular Interactions

Overview

Journal Micromachines (Basel)

Publisher MDPI

Date 2025 Mar 6

PMID 40047680

Authors

Qasem Ramadan

Rana Hazaymeh

Mohammed Zourob

Affiliations

Soon will be listed here.

Abstract

A versatile and modular microfluidic system for cell co-culture has been developed. Microfluidic chips, each featuring dual compartments separated by a porous membrane, have been fabricated and assembled within the system to facilitate fluidic interconnection and cell-cell communication through the chip assembly. A set of fluidic valves has been successfully integrated to regulate the flow through the chip assembly. The system allows for chip assembly in various arrangements, including in parallel, in series, and complex connections. Individual chips can be interconnected or disconnected within the system at any time. Moreover, the spatial order and orientation of the chips can be adjusted as needed, enabling the study of different cell-cell arrangements and the impact of the presence or absence of specific cell types. The utility of the system has been evaluated by culturing and interconnecting multi-monolayers of intestinal epithelial cells as a model of the complex cellular system. Epithelial monolayers were grown in multiple chips and interconnected in various configurations. The transepithelial electrical resistance and permeability profiles were investigated in detail for these configurations upon treatment of the cells with dextran sulfate sodium. Immune cells were stimulated through the epithelial layers and the expression of inflammatory cytokines was detected. This miniaturized platform offers controlled conditions for co-culturing key cellular components and assessing potential therapeutic agents in a physiologically relevant setting.

References

Sung J . Pharmacokinetic-based multi-organ chip for recapitulating organ interactions. Methods Cell Biol. 2018; 146:183-197. DOI: 10.1016/bs.mcb.2018.05.008. View

Ronaldson-Bouchard K, Teles D, Yeager K, Tavakol D, Zhao Y, Chramiec A . A multi-organ chip with matured tissue niches linked by vascular flow. Nat Biomed Eng. 2022; 6(4):351-371. PMC: 9250010. DOI: 10.1038/s41551-022-00882-6. View

Skardal A, Shupe T, Atala A . Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. Drug Discov Today. 2016; 21(9):1399-1411. PMC: 9039871. DOI: 10.1016/j.drudis.2016.07.003. View

Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H . Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids. Cell Metab. 2019; 30(2):374-384.e6. PMC: 6687537. DOI: 10.1016/j.cmet.2019.05.007. View

Ramadan Q, Jafarpoorchekab H, Huang C, Silacci P, Carrara S, Koklu G . NutriChip: nutrition analysis meets microfluidics. Lab Chip. 2012; 13(2):196-203. DOI: 10.1039/c2lc40845g. View

Orliaguet L, Dalmas E, Drareni K, Venteclef N, Alzaid F . Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity. Front Endocrinol (Lausanne). 2020; 11:62. PMC: 7042402. DOI: 10.3389/fendo.2020.00062. View

Esch M, Ueno H, Applegate D, Shuler M . Modular, pumpless body-on-a-chip platform for the co-culture of GI tract epithelium and 3D primary liver tissue. Lab Chip. 2016; 16(14):2719-29. DOI: 10.1039/c6lc00461j. View

Chelakkot C, Ghim J, Rajasekaran N, Choi J, Kim J, Jang M . Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin. Sci Rep. 2017; 7(1):1573. PMC: 5431506. DOI: 10.1038/s41598-017-01797-y. View

Bazzoun D, Lelievre S, Talhouk R . Polarity proteins as regulators of cell junction complexes: implications for breast cancer. Pharmacol Ther. 2013; 138(3):418-27. PMC: 3648792. DOI: 10.1016/j.pharmthera.2013.02.004. View

10.

Co J, Margalef-Catala M, Monack D, Amieva M . Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases. Nat Protoc. 2021; 16(11):5171-5192. PMC: 8841224. DOI: 10.1038/s41596-021-00607-0. View

11.

Vatine G, Barrile R, Workman M, Sances S, Barriga B, Rahnama M . Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Cell Stem Cell. 2019; 24(6):995-1005.e6. DOI: 10.1016/j.stem.2019.05.011. View

12.

Kiesler P, Fuss I, Strober W . Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015; 1(2):154-170. PMC: 4435576. DOI: 10.1016/j.jcmgh.2015.01.006. View

13.

Chassaing B, Aitken J, Malleshappa M, Vijay-Kumar M . Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014; 104:15.25.1-15.25.14. PMC: 3980572. DOI: 10.1002/0471142735.im1525s104. View

14.

Ramadan Q, Hazaymeh R, Zourob M . Immunity-on-a-Chip: Integration of Immune Components into the Scheme of Organ-on-a-Chip Systems. Adv Biol (Weinh). 2023; 7(12):e2200312. DOI: 10.1002/adbi.202200312. View

15.

Perestrelo A, Aguas A, Rainer A, Forte G . Microfluidic Organ/Body-on-a-Chip Devices at the Convergence of Biology and Microengineering. Sensors (Basel). 2015; 15(12):31142-70. PMC: 4721768. DOI: 10.3390/s151229848. View

16.

Maurer M, Gresnigt M, Last A, Wollny T, Berlinghof F, Pospich R . A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies. Biomaterials. 2019; 220:119396. DOI: 10.1016/j.biomaterials.2019.119396. View

17.

Otani T, Furuse M . Tight Junction Structure and Function Revisited. Trends Cell Biol. 2020; 30(10):805-817. DOI: 10.1016/j.tcb.2020.08.004. View

18.

Fatehullah A, Tan S, Barker N . Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016; 18(3):246-54. DOI: 10.1038/ncb3312. View

19.

Bryant D, Mostov K . From cells to organs: building polarized tissue. Nat Rev Mol Cell Biol. 2008; 9(11):887-901. PMC: 2921794. DOI: 10.1038/nrm2523. View

20.

Shin W, Hinojosa C, Ingber D, Kim H . Human Intestinal Morphogenesis Controlled by Transepithelial Morphogen Gradient and Flow-Dependent Physical Cues in a Microengineered Gut-on-a-Chip. iScience. 2019; 15:391-406. PMC: 6526295. DOI: 10.1016/j.isci.2019.04.037. View