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Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments.

ABSTRACT: The ability of cells to migrate through tissues and interstitial spaces is an essential factor during development and tissue homeostasis, immune cell mobility, and in various human diseases. Deformation of the nucleus and its associated lamina during 3-D migration is gathering increasing interest in the context of cancer metastasis, with the underlying hypothesis that a softer nucleus, resulting from reduced levels of lamin A/C, may aid tumour spreading. However, current methods to study the migration of cells in confining three dimensional (3-D) environments are limited by their imprecise control over the confinement, physiological relevance, and/or compatibility with high resolution imaging techniques. We describe the design of a polydimethylsiloxane (PDMS) microfluidic device composed of channels with precisely-defined constrictions mimicking physiological environments that enable high resolution imaging of live and fixed cells. The device promotes easy cell loading and rapid, yet long-lasting (>24 hours) chemotactic gradient formation without the need for continuous perfusion. Using this device, we obtained detailed, quantitative measurements of dynamic nuclear deformation as cells migrate through tight spaces, revealing distinct phases of nuclear translocation through the constriction, buckling of the nuclear lamina, and severe intranuclear strain. Furthermore, we found that lamin A/C-deficient cells exhibited increased and more plastic nuclear deformations compared to wild-type cells but only minimal changes in nuclear volume, implying that low lamin A/C levels facilitate migration through constrictions by increasing nuclear deformability rather than compressibility. The integration of our migration devices with high resolution time-lapse imaging provides a powerful new approach to study intracellular mechanics and dynamics in a variety of physiologically-relevant applications, ranging from cancer cell invasion to immune cell recruitment.

SUBMITTER: Davidson PM

PROVIDER: S-EPMC4666765 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments.

Davidson Patricia M PM Sliz Josiah J Isermann Philipp P Denais Celine C Lammerding Jan J

Integrative biology : quantitative biosciences from nano to macro 20151109 12

The ability of cells to migrate through tissues and interstitial spaces is an essential factor during development and tissue homeostasis, immune cell mobility, and in various human diseases. Deformation of the nucleus and its associated lamina during 3-D migration is gathering increasing interest in the context of cancer metastasis, with the underlying hypothesis that a softer nucleus, resulting from reduced levels of lamin A/C, may aid tumour spreading. However, current methods to study the mig ...[more]

PMID: 26549481

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Project description:Generating and maintaining the concentration dilutions of diffusible molecules in microchannels is critical for high-throughput chemical and biological analysis. Conventional serial network microfluidic technologies can generate high orders of arbitrary concentrations by a predefined microchannel network. However, a previous design requires a large occupancy area and is unable to dynamically generate different profiles in the same chip, limiting its applications. This study developed a microfluidic device enabling dynamic variations of both the concentration in the same channel and the concentration distribution in multiple channels by adjusting the flow resistance using programmable pneumatic microvalves. The key component (the pneumatic microvalve) allowed dynamic adjustment of the concentration profile but occupied a tiny space. Additionally, a Matlab program was developed to calculate the flow rates and flow resistance of various sections of the device, which provided theoretical guidance for dimension design. In silico investigations were conducted to evaluate the microvalve deformation with widths from 100 to 300 µm and membrane thicknesses of 20 and 30 µm under the activation pressures between 0 and 2000 mbar. The flow resistance of the deformed valve was studied both numerically and experimentally and an empirical model for valve flow resistance with the form of Rh=aebP was proposed. Afterward, the fluid flow in the valve region was characterized using Micro PIV to further demonstrate the adjustment mechanism of the flow resistance. Then, the herringbone structures were employed for fast mixing to allow both quick variation of concentration and minor space usage of the channel network. Finally, an empirical formula-supported computational program was developed to provide the activation pressures required for the specific concentration profile. Both linear (Ck = -0.2k + 1) and nonlinear (Ck = (110)k) concentration distribution in four channels were varied using the same device by adjusting microvalves. The device demonstrated the capability to control the concentration profile dynamically in a small space, offering superior application potentials in analytical chemistry, drug screening, and cell biology research.

Dataset Information

Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments.

Publications

Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments.

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