A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

Abstract

The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes–permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

Paving the Way Toward Complex Blood-Brain Barrier Models Using Pluripotent Stem Cells

“…This was confirmed in a recent study on rat primary BMECs, where TEER values rose fourfold to 1,300 Ocm 2 . In this study, cells were grown in a three-dimensional (3D) microfluidic device directly on a collagen bed, with medium flow applied through a medium channel on the cells [117]. The increased barrier tightening is believed to involve the adherens junction protein VE-cadherin, by signaling the shear stress response to occludin and changing TJ protein expression and organization [111].…”

From organotypic culture to body‐on‐a‐chip: A neuroendocrine perspective

“…115,121 Continuously perfused media provides a more consistent delivery of oxygen and nutrients, and removal of cellular waste products. "Brain" 121 and blood-brain barrier 124 have both been cultured using microfluidic systems. 120,122 Intestinal research has been at the forefront of recent developments for organ-on-a-chip systems.…”

“…Queval et al 125 Loughlin et al 76 Wydallis et al 85 Kim et al 114 Huang et al 121 Tedjo et al 86 Shah et al 115 Park et al 124 52 Despite these characterisations of the roller culture model, and its widespread use in studies of the hypothalamus among other brain regions, the model was not without its problems.…”

Biomimetic strategies to recapitulate organ specific microenvironments for studying breast cancer metastasis

“…constructed an in vitro BBB model using a microfluidic chip by systematically co-culturing endothelial cells and astrocytes in microfluidic channels to examine the extravasation of MDA-MB-231 BCCs. 89 The in vitro BBB models serve as a modular platform to study BCBrM providing flexibility to include various components of brain stroma. In vitro BBB models are mainly cellular constructs assembled in 2D and hence their physiological relevance is limited.…”