Cell Migration Research Based on Organ-on-Chip-Related Approaches

Abstract

Microfluidic devices have been widely used for cell migration research over the last two decades, owing to their attractive features in cellular microenvironment control and quantitative single-cell migration analysis. However, the majority of the microfluidic cell migration studies have focused on single cell types and have configured microenvironments that are greatly simplified compared with the in-vivo conditions they aspire to model. In addition, although cell migration is considered an important target for disease diagnosis and therapeutics, very few microfluidic cell migration studies involved clinical samples from patients. Therefore, more sophisticated microfluidic systems are required to model the complex in-vivo microenvironment at the tissue or organ level for cell migration studies and to explore cell migration-related clinical applications. Research in this direction that employs organ-on-chip-related approaches for cell migration analysis has been increasingly reported in recent years. In this paper, we briefly introduce the general background of cell migration and organ-on-chip research, followed by a detailed review of specific cell migration studies using organ-on-chip-related approaches, and conclude by discussing our perspectives of the challenges, opportunities and future directions.

Keywords: cell migration; microfluidic device; organ-on-chip.

Figure 1

A schematic illustration of different cell migration research approaches to study this important and complicated process in humans. (A) Schematic presentation of human body and transendothelial migration of immune cells; (B) Schematic presentation of in-vivo animal models; (C) Schematic presentation of in-vitro cell migration assays; (D) An example of the organ-on-chip approach. Figure 1D was adapted from reference [35] with permission from the Royal Society of Chemistry. BM: basement membrane; EC: endothelial cell; ECM: extracellular matrices.

Figure 2

Examples of tumor-on-chip cell migration study. (A) The 3D microfluidic model for investigating endothelial barrier function during tumor cell intravasation. The left panel shows the microfluidic device (green: endothelial cell channel; red: tumor channel; dark gray: 3D ECM channel; black arrow: Y junction); the upper-right panel shows a representative phase-contrast image of tumor cell (red) invasion through 3D ECM region (dark gray) to the endothelium (green); the bottom-right panel shows a 3D confocal image of the selective area in the white-dashed square (red: tumor cells; green: endothelium); (B) The ultrasonics-based 3D microdevice for studying immune surveillance of NK cells for specific tumors. The left panel illustrates the main components of the microfluidic system; the right panel shows some representative experimental images of NK–tumor interaction at different time points (orange: NK cells; green: solid tumors); (C) The breast-cancer-on-chip model to investigate ECM activation during tumor progression. The figure shows the microfluidic system and magnified view of the chip (green: stromal microtissues; red: tumor microtissues; blue arrow: fluid flow direction; white arrow: 3D microtissue injection direction); (D) The tumor-on-chip model to investigate the interactions between neurons and cancer cells during tumor PNI. The upper panel illustrates the microfluidic device; the bottom panel shows a representative image of tumor cell (red) migration behavior along the contacted neurites at different time points. Figure 2A was adapted from reference [36] with permission from the National Academy of Sciences; Figure 2B was adapted from reference [37] with permission from the Royal Society of Chemistry; Figure 2C was adapted from reference [38] with permission from John Wiley and Sons; Figure 2D was adapted from reference [39] with permission from the Royal Society of Chemistry.

Figure 3

Examples of lung-on-chip cell migration study. (A) Microfluidics-based approach for investigating neutrophil chemotaxis with clinical samples for rapid diagnosis of COPD. The upper-left panel illustrates the microfluidic device; the upper-right panel shows a representative cell image in the device; the bottom-left panel shows cell migration test data using the microfluidic device (C.I.: chemotactic index); the bottom-right panel shows cell tracks from a representative experiment; (B) Microfluidics-based approach for investigating neutrophil chemotaxis with clinical samples for asthma detection. The upper panel illustrates rapid on-chip neutrophil isolation from blood; the bottom panel illustrates the microfluidic method for neutrophil chemotaxis test. Figure 3A was adapted from reference [26] with permission from PLOS; Figure 3B was reproduced from reference [27] with permission from the National Academy of Sciences. fMLP: N-formyl-methionyl-leucyl-phenylalanine.

Figure 4

Examples of vessel-on-chip cell migration study. (A) The vessel-on-chip model for investigating neutrophil TEM during the inflammatory process. The left panel shows the schematic presentation of neutrophil TEM under inflammatory conditions; the upper-right panel shows the dimensions of the microfluidic device; the bottom-right panel shows the schematic presentation of neutrophil TEM (side view); (B) The vessel-on-chip model for investigating tumor TEI. The upper-left panel shows the schematic presentation of tumor TEI; the bottom-left panel shows representative experimental images of tumor cells (red) during TEI; the upper-right panel shows the microfluidic device; the bottom-right panel shows representative experimental images of the selective area; (C) The vessel-on-chip model for investigating tumor cell extravasation. The left panel shows the microfluidic device and the detailed information of the selective area; the middle panel shows the magnified view of the selective area (green: microvascular network; red: tumor cells); the right panel shows representative experimental images of one transmigrating tumor cell in the white dashed box. Figure 4A was adapted from reference [35] with permission from the Royal Society of Chemistry; Figure 4B was adapted from reference [42] with permission from the Royal Society of Chemistry; Figure 4C was adapted from reference [43] with permission from Nature Publishing Group. PDMS: polydimethylsiloxane.

Figure 5

Examples of LN-on-chip cell migration study. (A) The LN-on-chip flow device for investigating the interaction between T cells and DCs. The upper-left and upper-right panels show the real microfluidic device and its schematic illustration, respectively; the bottom-left panel shows one representative 3D confocal image of the interaction between T cells (red) and DC monolayer (green); the bottom-right panel shows the schematic illustration of the microchannel in side view; (B) The LN-on-chip model for evaluating DC chemotaxis and DC–T cell interaction. The upper panel shows the microfluidic device; the bottom panel shows representative data of CCL19 gradient-induced mature DC (mDC) migration. (C) The 3D agarose-based microfluidic device for investigating differential chemotaxis of DCs to CCL21 and CCL19. The upper panel shows the schematic illustration of microfluidic device (side view) (S1&S2: chemokine/buffer loading channels; C: cell–gel mixture injection channel); the bottom panel shows representative data of the average velocity (Vx) of DCs in the competing gradients (dark columns: 1.5 mg/mL collagen plus 10% Matrigel; white columns: collagen alone); (D) The LN-on-chip model for studying the guidance of CCR7 ligands for T cell migration in LNs. The upper-left panel illustrates the microfluidic device and the method for data analysis; the bottom-left shows a mimicked LN model with complex chemokine gradients; the right panel shows the proposed combinatorial guiding mechanism for T cell trafficking in LN. Figure 5A was adapted from reference [45] with permission from the Royal Society of Chemistry; Figure 5B was adapted from reference [46] with permission from the Royal Society of Chemistry; Figure 5C was adapted from reference [47] with permission from the National Academy of Sciences; Figure 5D was adapted from reference [5] with permission from PLOS.

Figure 6

Examples of brain-on-chip cell migration study. (A) The brain-on-chip model for investigating neuronal differentiation and chemotaxis. The image shows the detailed information of the microfluidic system. (B) The brain-on-chip model for investigating neuronal migration. The upper-left & middle panels show the mouse embryonic brain explants (Cx: cortex; MGE: medial ganglionic eminence); the upper-right panel shows schematic presentation of the microfluidic device; the bottom panel shows representative experimental images of the selective areas. (C) The brain-on-chip model for investigating brain tumor metastasis. The image shows the schematic illustration of blood–brain barrier (BBB) and the microfluidic system with magnified views of selective regions. Figure 6A was adapted from reference [49] with permission from the Royal Society of Chemistry; Figure 6B was adapted from reference [50] with permission from Elsevier; Figure 6C was adapted from reference [52] with permission from Nature Publishing Group. BMECs: brain microvascular endothelial cells.