Microfluidic Collective Cell Migration Assay for Study of Endothelial Cell Proliferation and Migration under Combinations of Oxygen Gradients, Tensions, and Drug Treatments

Shih, Hsiu-Chen; Lee, Tse-Ang; Wu, Hsiao-Mei; Ko, Ping-Liang; Liao, Wei-Hao; Tung, Yi-Chung

doi:10.1038/s41598-019-44594-5

Cited by 39 publications

(26 citation statements)

References 29 publications

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“…Simultaneous changes in H + and oxygen concentrations under the GCG are similar to those found in solid tumors and, therefore, experimentation using the GCG reflects a clinically relevant setting. Unlike the recent microfluidic devices designed for investigating cell migration under oxygen concentration gradients [15][16][17][18], the magnitude of the metabolic gradients under our GCG depends on the metabolic activity of cells per unit volume and cannot be easily manipulated; control of the gradient would require a redesign of the GCG or an accurate adjustment of the cell density ( Figure 1C). It is also impossible for our GCG to produce concentration gradients of a specific molecule in the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

“…The average local oxygen concentration along the oxygen gradient varied from 1% to 7%, which did not significantly affect the forward migration index of the individual cell. Shih et al [17] proposed a microfluidic device in which oxygen concentration gradients with a magnitude of 18% O 2 /mm were established along the 900 µm-wide cell channel using oxygen scavenging chemical reactions. HUVECs located at the boundaries of 300 µm-wide cell regions migrated differently in the oxygen gradient; cells initially located at the boundary with higher oxygen concentration in the gradient migrated slowly compared to those with lower oxygen concentration, resulting in a collective cell migration toward lower oxygen.…”

Section: Discussionmentioning

confidence: 99%

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A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

Takahashi

Yamaguchi

Yamaoka

2020

IJMS

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Hematogenous tumor metastasis begins with the invasion and spread of primary tumor cells in the local tissue leading to intravasation. We hypothesized that tumor cells might actively migrate toward intratumor vessels with the extracellular metabolic gradient acting as a guiding cue. Here, we determined in vitro whether the extracellular gradient of pH can act as a cue for directional migration in MDA-MB-231 cells. Cell migration was determined by the wound-healing assay under gradients of extracellular pH (~0.2 units/mm) and oxygen concentration (~6% O2/mm) that were produced by a microfluidic device, gap cover glass (GCG). Without GCG, the migration of cells was spatially homogeneous; the same number of cells migrated to the rectangular wound space from the left and right boundaries. In contrast, when GCG generated pH/O2 gradients across the wound space, the number of cells migrating to the wound space from the boundary with higher pH/O2 values was considerably decreased, indicating a preferential movement of cells toward the region of higher pH/O2 in the gradient. The addition of hepes in the extracellular medium abolished both the extracellular pH gradient and the directional cell migration under GCG. We conclude that relatively small gradients of pH in the extracellular medium compared to those found in Na+/H+ exchanger-driven cell migration were sufficient to guide MDA-MB-231 cells. The directional cell migration as guided by the metabolic gradient could effectively elevate the probability of intravasation and, ultimately, hematogenous metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

Takahashi

Yamaguchi

Yamaoka

2020

IJMS

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“…Jeong et al presented a migration assay for endothelial cell migration and sprouting using microfluidic chip technology [51], providing endothelial cells with a 3D microenvironment in two scaffold channels to investigate the effect of growth factors on cell migration behavior. Shih et al advanced a conventional enzymatic endothelial wounding assay with an on-chip chemical oxygen concentration generator to demonstrate that the influence of oxygen gradients is more severe than homogenous hypoxic oxygen tension on the directionality of endothelial cell migration towards low oxygen concentrations [52]. Only the gradient, but not stable hypoxia, induced this migratory directionality, which was not affected by migration inhibitory drugs.…”

Section: Enzymatic Depletionmentioning

confidence: 99%

Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

2021

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Cutaneous wound healing is a complex, multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the physically, chemically, and biologically injured area, resulting in wound closure. Understanding the conditions under which cell migration is impaired and elucidating the cellular and molecular mechanisms that improve healing dynamics are therefore crucial in devising novel therapeutic strategies to elevate patient suffering, reduce scaring, and eliminate chronic wounds. Following the global trend towards the automation, miniaturization, and integration of cell-based assays into microphysiological systems, conventional wound healing assays such as the scratch assay and cell exclusion assay have recently been translated and improved using microfluidics and lab-on-a-chip technologies. These miniaturized cell analysis systems allow for precise spatial and temporal control over a range of dynamic microenvironmental factors including shear stress, biochemical and oxygen gradients to create more reliable in vitro models that resemble the in vivo microenvironment of a wound more closely on a molecular, cellular, and tissue level. The current review provides (a) an overview on the main molecular and cellular processes that take place during wound healing, (b) a brief introduction into conventional in vitro wound healing assays, and (c) a perspective on future cutaneous and vascular wound healing research using microfluidic technology.

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“…Jeong et al presented a migration assay for endothelial cell migration and sprouting using microfluidic chip technology [50], providing endothelial cells with a 3D microenvironment in two scaffold channels to investigate the effect of growth factors on cell migration behavior. Shih et al advanced a conventional enzymatic endothelial wounding assay with an on-chip chemical oxygen concentration generator to demonstrate the influence of oxygen gradients compared to homogenous hypoxic oxygen tension severely influences the directionality of endothelial cell migration towards low oxygen concentrations [51]. Only the gradient but not stable hypoxia induced this migratory directionality which was not affected by migration inhibitory drugs.…”

Section: Advanced Microfluidic Wound-healing Assaysmentioning

confidence: 99%

Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

Monfared

Ertl

Rothbauer

2021

Preprint

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Cutaneous wound healing is a complex multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the physically, chemically and biologically injured area resulting in wound closure. Understanding the conditions under which cell migration is impaired and elucidating the cellular and molecular mechanisms that improve healing dynamics is therefore crucial in devising novel therapeutic strategies to elevate patient suffering, reduce scaring and eliminate chronic wounds. Following the global trend towards automation, miniaturization and integration of cell-based assays into microphysiological systems, conventional wound healing assays such as the scratch assay or cell exclusion assay have recently been translated and improved using microfluidics and lab-on-a-chip technologies. These miniaturized cell analysis systems allow precise spatial and temporal control over a range of dynamic microenvironmental factors including shear stress, biochemical and oxygen gradients to create more reliable in vitro models that resemble the in vivo microenvironment of a wound more closely on a molecular, cellular, and tissue level. The current review provides (a) an overview on the main molecular and cellular processes that take place during wound healing, (b) a brief introduction into conventional in vitro wound healing assays, and (c) a perspective on future cutaneous and vascular wound healing research using microfluidic technology.

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Microfluidic Collective Cell Migration Assay for Study of Endothelial Cell Proliferation and Migration under Combinations of Oxygen Gradients, Tensions, and Drug Treatments

Cited by 39 publications

References 29 publications

A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro

Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

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