Microvascular Mimetics for the Study of Leukocyte–Endothelial Interactions

Khire, Tejas; Salminen, Alec T.; Swamy, Harsha; Lucas, Kilean; McCloskey, Molly C.; Ajalik, Raquel E; Chung, Henry H.; Gaborski, Thomas R.; Waugh, Richard E.; Glading, Angela; McGrath, James L.

doi:10.1007/s12195-020-00611-6

Cited by 18 publications

(37 citation statements)

References 56 publications

(102 reference statements)

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“…To further investigate whether the cells can detect fiber alignment through the pores, our platform can be used with UPPs of different pore sizes and pore spacings to quantify the threshold cell‐collagen interaction that is required to induce cell alignment. The use of membrane modules also have importance in modeling barrier tissue functions such as studying the effects of ECM alignment on leukocyte transmigration, [ 49 ] or improving the adhesion of cells on a membrane under an applied fluid shear stress. [ 50 ]…”

Section: Resultsmentioning

confidence: 99%

Microengineered 3D Collagen Gels with Independently Tunable Fiber Anisotropy and Directionality

Ahmed

Joshi

Larson

et al. 2021

Adv Materials Technologies

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Cellular processes are linked to the alignment (anisotropy) and orientation (directionality) of collagen fibers (i.e., landscape) in the native extracellular matrix (ECM). Given the vital role that cell‐matrix interactions play in regulating biological functions, several microfluidic methods have successfully established anisotropic 3D collagen gels to develop quantitative relationships between structural cues and cellular responses. However, independently tailoring the fiber anisotropy and fiber directionality within a landscape remains a challenge. Here, a user‐friendly microfluidic platform with a non‐uniform channel geometry is used to control the degree of fiber anisotropy and directionality as a function of extensional strain rate and a defined flow path, respectively. New experimental capabilities, including independent control over the degree of fiber anisotropy and directionality, spatial gradients in anisotropy, and multi‐material interfaces, are demonstrated. A channel peel‐off technique provides direct access to the microengineered collagen landscapes, and the alignment of single MD‐MB‐231 cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC) is shown. Finally, the platform's modular capability is highlighted by integrating an ultrathin porous Parylene (UPP) membrane onto the microengineered collagen landscape as a method to control the degree of cell‐matrix interaction.

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Section: Resultsmentioning

confidence: 99%

Microengineered 3D Collagen Gels with Independently Tunable Fiber Anisotropy and Directionality

Ahmed

Joshi

Larson

et al. 2021

Adv Materials Technologies

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“…This process of intravascular crawling involves specific regulation of integrin binding and cell polarization, allowing immune cells to efficiently navigate to a site of vascular exit ( 2 ). While advances in in vivo imaging techniques have greatly contributed to the understanding of immune cell intravascular crawling, the benefits of the high spatial and temporal resolution afforded by in vitro vascular mimetics is just beginning to be realized ( 14 , 17 ).…”

Section: Immune Cell Extravasationmentioning

confidence: 99%

“…Recently, our lab studied the effects of chemokine driven neutrophil TEM on vascular barrier integrity using a novel vascular mimetic ( 14 ). While most TEM studies employ the use of inflammatory cytokines, or a combination of cytokines and chemokines, our work aimed to directly probe the consequence of neutrophil transmigration in the absence of EC inflammatory effects.…”

Section: Immune Cell Extravasationmentioning

confidence: 99%

“…Additionally, the relatively thick membrane structure is limited in physiological relevance. For instance, ECs and astrocytes (or glial cells) in the Blood-Brain Barrier (BBB) are separated by <300 nm, while the thickness of track-etched membranes used to recapitulate this tissue barrier often exceed 10 μm ( 14 , 173 ). When considering experimental potential, another notable deficiency is the lack of optical transparency for imaging purposes which limits high-resolution imaging ( 173 , 175 ).…”

Section: Emerging Topics In Transendothelial Migrationmentioning

confidence: 99%

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In vitro Studies of Transendothelial Migration for Biological and Drug Discovery

Salminen

Allahyari

Gholizadeh

et al. 2020

Front. Med. Technol.

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Inflammatory diseases and cancer metastases lack concrete pharmaceuticals for their effective treatment despite great strides in advancing our understanding of disease progression. One feature of these disease pathogeneses that remains to be fully explored, both biologically and pharmaceutically, is the passage of cancer and immune cells from the blood to the underlying tissue in the process of extravasation. Regardless of migratory cell type, all steps in extravasation involve molecular interactions that serve as a rich landscape of targets for pharmaceutical inhibition or promotion. Transendothelial migration (TEM), or the migration of the cell through the vascular endothelium, is a particularly promising area of interest as it constitutes the final and most involved step in the extravasation cascade. While in vivo models of cancer metastasis and inflammatory diseases have contributed to our current understanding of TEM, the knowledge surrounding this phenomenon would be significantly lacking without the use of in vitro platforms. In addition to the ease of use, low cost, and high controllability, in vitro platforms permit the use of human cell lines to represent certain features of disease pathology better, as seen in the clinic. These benefits over traditional pre-clinical models for efficacy and toxicity testing are especially important in the modern pursuit of novel drug candidates. Here, we review the cellular and molecular events involved in leukocyte and cancer cell extravasation, with a keen focus on TEM, as discovered by seminal and progressive in vitro platforms. In vitro studies of TEM, specifically, showcase the great experimental progress at the lab bench and highlight the historical success of in vitro platforms for biological discovery. This success shows the potential for applying these platforms for pharmaceutical compound screening. In addition to immune and cancer cell TEM, we discuss the promise of hepatocyte transplantation, a process in which systemically delivered hepatocytes must transmigrate across the liver sinusoidal endothelium to successfully engraft and restore liver function. Lastly, we concisely summarize the evolving field of porous membranes for the study of TEM.

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“…[8,11,22] To address the lack of flow capabilities in conventional open-well assays, microfluidic platforms (e.g., microphysiological systems) that incorporate a porous culture membrane between the individually addressable top (luminal) and bottom (abluminal) fluidic channels have emerged. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] While microfluidic platforms offer distinct fluidic routing capabilities and feature dynamic control over biophysical and biochemical stimuli, they have not been widely adopted by bioscience laboratories where static, open-well assays remain the gold standard. [10,11,42] This issue can be attributed in part to incompatibilities between microfluidic and conventional experimental workflows.…”

Section: Introductionmentioning

confidence: 99%

The Modular μSiM Reconfigured: Integration of Microfluidic Capabilities to Study in vitro Barrier Tissue Models under Flow

Mansouri

Ahmed

Ahamd

et al. 2022

Preprint

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Microfluidic approaches to study tissue barriers have emerged to address the lack of fluid flow in conventional "open-well" Transwell™-like devices. However, microfluidic techniques have not achieved widespread usage in bioscience laboratories because they are not fully compatible with conventional tried-and-true experimental protocols. To advance barrier tissue research, there is a need for a platform that combines the advantages of both conventional open-well and microfluidic systems. Here, we develop a plug-and-play flow module to add on-demand microfluidic capabilities to a modular microfluidic system featuring a silicon membrane "m-μSiM" as an open-well device with live-cell imaging capabilities. The magnetic latching assembly of our design enables bi-directional reconfiguration between open-well and fluidic modes. This design feature provides users with the flexibility to conduct an experiment in an open-well format with established protocols and then add or remove microfluidic capabilities as desired. Our work also provides an experimentally-validated flow model to help select desired flow conditions based on the experimental needs. As a proof-of-concept, we demonstrate flow-induced alignment of endothelial cells and visualize different phases of neutrophil transmigration across an endothelial monolayer under flow. We anticipate that our reconfigurable design will be adopted by both engineering and bioscience laboratories due to the compatibility with standard open-well protocols and the simple flow addition capabilities.

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Microvascular Mimetics for the Study of Leukocyte–Endothelial Interactions

Cited by 18 publications

References 56 publications

Microengineered 3D Collagen Gels with Independently Tunable Fiber Anisotropy and Directionality

Microengineered 3D Collagen Gels with Independently Tunable Fiber Anisotropy and Directionality

In vitro Studies of Transendothelial Migration for Biological and Drug Discovery

The Modular μSiM Reconfigured: Integration of Microfluidic Capabilities to Study in vitro Barrier Tissue Models under Flow

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