Design, simulation and application of multichannel microfluidic chip for cell migration_Journal of Biomedical Engineering

Authors：

LI Huilai ^1,2 , YANG Xiao ³ , WU Xiaosong ^1,2 , LI Zhigang ^1,2 , HONG Chenggang ⁴ , LIU Yong ¹ , ZHU Ling ¹ ,  YANG Ke ¹

1. Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, P. R. China;
2. University of Science and Technology of China, Hefei 230026, P. R. China;
3. School of Biomedical Engineering, Anhui Medical University, Hefei 230032, P. R. China;
4. Hefei Zhongke Yikangda Biomedical Co., Ltd., Hefei 230031, P. R. China;

Corresponding author：

YANG Ke, Email: keyang@aiofm.ac.cn

Keywords：

Microfluidic concentration gradient chip; Neutrophils; Chemotaxis; Advanced glycation end products; Inhibition

DOI：

10.7507/1001-5515.202105002

Video：

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Cell migration is defined as the directional movement of cells toward a specific chemical concentration gradient, which plays a crucial role in embryo development, wound healing and tumor metastasis. However, current research methods showed low flux and are only suitable for single-factor assessment, and it was difficult to comprehensively consider the effects of other parameters such as different concentration gradients on cell migration behavior. In this paper, a four-channel microfluidic chip was designed. Its characteristics were as follows: it relied on laminar flow and diffusion mechanisms to establish and maintain a concentration gradient; it was suitable for observation of cell migration in different concentration gradient environment under a single microscope field; four cell isolation zones (20 μm width) were integrated into the microfluidic device to calibrate the initial cell position, which ensured the accuracy of the experimental results. In particular, we used COMSOL Multiphysics software to simulate the structure of the chip, which demonstrated the necessity of designing S-shaped microchannel and horizontal pressure balance channel to maintain concentration gradient. Finally, neutrophils were incubated with advanced glycation end products (AGEs, 0, 0.2, 0.5, 1.0 μmol·L⁻¹), which were closely related to diabetes mellitus and its complications. The migration behavior of incubated neutrophils was studied in the 100 nmol·L⁻¹ of chemokine (N-formylmethionyl-leucyl-phenyl-alanine) concentration gradient. The results prove the reliability and practicability of the microfluidic chip.

Citation： LI Huilai, YANG Xiao, WU Xiaosong, LI Zhigang, HONG Chenggang, LIU Yong, ZHU Ling, YANG Ke. Design, simulation and application of multichannel microfluidic chip for cell migration. Journal of Biomedical Engineering, 2022, 39(1): 128-138. doi: 10.7507/1001-5515.202105002 Copy

1.	Miskolci V, Klemm L C, Huttenlocher A. Cell migration guided by cell–cell contacts in innate immunity. Trends Cell Biol, 2021, 31(2): 86-94.
2.	Kameritsch P, Renkawitz J. Principles of leukocyte migration strategies. Trends Cell Biol, 2020, 30(10): 818-832.
3.	Vasudevan J, Lim C T, Fernandez J G. Cell migration and breast cancer metastasis in biomimetic extracellular matrices with independently tunable stiffness. Adv Funct Mater, 2020, 30(49): 2005383.
4.	Hopke A, Scherer A, Kreuzburg S, et al. Neutrophil swarming delays the growth of clusters of pathogenic fungi. Nat Commun, 2020, 11(1): 2031.
5.	Garcia-Seyda N, Aoun L, Tishkova V, et al. Microfluidic device to study flow-free chemotaxis of swimming cells. Lab Chip, 2020, 20(9): 1639-1647.
6.	Ren X, Getschman A E, Hwang S, et al. Investigations on T cell transmigration in a human skin-on-chip (SoC) model. Lab Chip, 2021, 21(8): 1527-1539.
7.	Zheng L, Wang B, Sun Y, et al. An oxygen-concentration-controllable multiorgan microfluidic platform for studying hypoxia-induced lung cancer-liver metastasis and screening drugs. ACS Sensors, 2021, 6(3): 823-832.
8.	Ge Y, An Q, Gao Y, et al. A microfluidic device for generation of chemical gradients. Micosyst Technol, 2015, 21(8): 1797-1804.
9.	Wu J, Hillier C, Komenda P, et al. A microfluidic platform for evaluating neutrophil chemotaxis induced by sputum from COPD patients. Plos One, 2015, 10(5): e0126523.
10.	Satti S, Deng P, Matthews K, et al. Multiplexed end-point microfluidic chemotaxis assay using centrifugal alignment. Lab Chip, 2020, 20(17): 3096-3103.
11.	Yang K, Peretz-soroka H, Wu J D, et al. Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices. Sci Rep, 2017, 7: 3100.
12.	Yang K, Wu J, Peretz-soroka H, et al. M-kit: A cell migration assay based on microfluidic device and smartphone. Biosens Bioelectron, 2018, 99: 259-267.
13.	Yang K, Wu J, Santos S, et al. Recent development of portable imaging platforms for cell-based assays. Biosens Bioelectron, 2019, 124: 150-160.
14.	Yan Y, Zhang B, Fu Q, et al. A fully integrated biomimetic microfluidic device for evaluation of sperm response to thermotaxis and chemotaxis. Lab Chip, 2021, 21(2): 310-318.
15.	Ellett F, Jalali F, Marand A L, et al. Microfluidic arenas for war games between neutrophils and microbes. Lab Chip, 2019, 19(7): 1205-1216.
16.	Arriodupont M, Cribier S, Foucauly G, et al. Diffusion of fluorescently labeled macromolecules in cultured muscle cells. Biophys J, 1996, 70(5): 2327-2332.
17.	Grigolato F, Egholm C, Impellizzieri D, et al. Establishment of a scalable microfluidic assay for characterization of population-based neutrophil chemotaxis. Allergy, 2020, 75(6): 1382-1393.
18.	Collison K S, ParharR S, Saleh S S, et al. RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukocyte Biol, 2002, 71(3): 433-444.
19.	Makita Z, Vlassara H, Cerami A, et al. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem, 1992, 267(8): 5133-5138.
20.	Gao Y, Sun J, Lin W H, et al. A compact microfluidic gradient generator using passive pumping. Microfluid Nanofluid, 2012, 12(6): 887-895.
21.	Davies P F. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med, 2009, 6(1): 16-26.
22.	Dewey C F, Bussolari S R, Gimbrone M A, et al. The dynamic-response of vascular endothelial-cells to fluid share-stress. J Biomech Eng-T Asme, 1981, 103(3): 177-185.
23.	Zhao W, Zhao H, Li M, et al. Microfluidic devices for neutrophil chemotaxis studies. J Transl Med, 2020, 18(1): 168.
24.	Touré F, Zahm J M, Garnotel R, et al. Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix. Biochem J, 2008, 416(2): 255-261.
25.	Schetz P, Castro P, Shapiro N I. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care, 2011, 34(3): 771-778.
26.	Advani A, Marshall S M, Thomas T H. Impaired neutrophil store-mediated calcium entry in Type 2 diabetes. Eur J Clin Invest, 2004, 34(1): 43-49.
27.	Wang X, Liu J, Yang Y, et al. An update on the potential role of advanced glycation end products in glycolipid metabolism. Life Sci, 2020, 245: 117344.
28.	Spadaccio C, De Marco F, Di Domenico F, et al. Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by advanced glycation endproducts. Thromb Res, 2014, 133(3): 418-425.

1. Miskolci V, Klemm L C, Huttenlocher A. Cell migration guided by cell–cell contacts in innate immunity. Trends Cell Biol, 2021, 31(2): 86-94.
2. Kameritsch P, Renkawitz J. Principles of leukocyte migration strategies. Trends Cell Biol, 2020, 30(10): 818-832.
3. Vasudevan J, Lim C T, Fernandez J G. Cell migration and breast cancer metastasis in biomimetic extracellular matrices with independently tunable stiffness. Adv Funct Mater, 2020, 30(49): 2005383.
4. Hopke A, Scherer A, Kreuzburg S, et al. Neutrophil swarming delays the growth of clusters of pathogenic fungi. Nat Commun, 2020, 11(1): 2031.
5. Garcia-Seyda N, Aoun L, Tishkova V, et al. Microfluidic device to study flow-free chemotaxis of swimming cells. Lab Chip, 2020, 20(9): 1639-1647.
6. Ren X, Getschman A E, Hwang S, et al. Investigations on T cell transmigration in a human skin-on-chip (SoC) model. Lab Chip, 2021, 21(8): 1527-1539.
7. Zheng L, Wang B, Sun Y, et al. An oxygen-concentration-controllable multiorgan microfluidic platform for studying hypoxia-induced lung cancer-liver metastasis and screening drugs. ACS Sensors, 2021, 6(3): 823-832.
8. Ge Y, An Q, Gao Y, et al. A microfluidic device for generation of chemical gradients. Micosyst Technol, 2015, 21(8): 1797-1804.
9. Wu J, Hillier C, Komenda P, et al. A microfluidic platform for evaluating neutrophil chemotaxis induced by sputum from COPD patients. Plos One, 2015, 10(5): e0126523.
10. Satti S, Deng P, Matthews K, et al. Multiplexed end-point microfluidic chemotaxis assay using centrifugal alignment. Lab Chip, 2020, 20(17): 3096-3103.
11. Yang K, Peretz-soroka H, Wu J D, et al. Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices. Sci Rep, 2017, 7: 3100.
12. Yang K, Wu J, Peretz-soroka H, et al. M-kit: A cell migration assay based on microfluidic device and smartphone. Biosens Bioelectron, 2018, 99: 259-267.
13. Yang K, Wu J, Santos S, et al. Recent development of portable imaging platforms for cell-based assays. Biosens Bioelectron, 2019, 124: 150-160.
14. Yan Y, Zhang B, Fu Q, et al. A fully integrated biomimetic microfluidic device for evaluation of sperm response to thermotaxis and chemotaxis. Lab Chip, 2021, 21(2): 310-318.
15. Ellett F, Jalali F, Marand A L, et al. Microfluidic arenas for war games between neutrophils and microbes. Lab Chip, 2019, 19(7): 1205-1216.
16. Arriodupont M, Cribier S, Foucauly G, et al. Diffusion of fluorescently labeled macromolecules in cultured muscle cells. Biophys J, 1996, 70(5): 2327-2332.
17. Grigolato F, Egholm C, Impellizzieri D, et al. Establishment of a scalable microfluidic assay for characterization of population-based neutrophil chemotaxis. Allergy, 2020, 75(6): 1382-1393.
18. Collison K S, ParharR S, Saleh S S, et al. RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukocyte Biol, 2002, 71(3): 433-444.
19. Makita Z, Vlassara H, Cerami A, et al. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem, 1992, 267(8): 5133-5138.
20. Gao Y, Sun J, Lin W H, et al. A compact microfluidic gradient generator using passive pumping. Microfluid Nanofluid, 2012, 12(6): 887-895.
21. Davies P F. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med, 2009, 6(1): 16-26.
22. Dewey C F, Bussolari S R, Gimbrone M A, et al. The dynamic-response of vascular endothelial-cells to fluid share-stress. J Biomech Eng-T Asme, 1981, 103(3): 177-185.
23. Zhao W, Zhao H, Li M, et al. Microfluidic devices for neutrophil chemotaxis studies. J Transl Med, 2020, 18(1): 168.
24. Touré F, Zahm J M, Garnotel R, et al. Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix. Biochem J, 2008, 416(2): 255-261.
25. Schetz P, Castro P, Shapiro N I. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care, 2011, 34(3): 771-778.
26. Advani A, Marshall S M, Thomas T H. Impaired neutrophil store-mediated calcium entry in Type 2 diabetes. Eur J Clin Invest, 2004, 34(1): 43-49.
27. Wang X, Liu J, Yang Y, et al. An update on the potential role of advanced glycation end products in glycolipid metabolism. Life Sci, 2020, 245: 117344.
28. Spadaccio C, De Marco F, Di Domenico F, et al. Simvastatin attenuates the endothelial pro-thrombotic shift in saphenous vein grafts induced by advanced glycation endproducts. Thromb Res, 2014, 133(3): 418-425.

Journal of Biomedical Engineering

Design, simulation and application of multichannel microfluidic chip for cell migration

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