Microphysiological endothelial models to characterize subcutaneous drug absorption.

The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability.

The CCL2-CCR2 astrocyte-cancer cell axis in tumor extravasation at the brain.

Although brain metastases are common in cancer patients, little is known about the mechanisms of cancer extravasation across the blood-brain barrier (BBB), a key step in the metastatic cascade that regulates the entry of cancer cells into the brain parenchyma. Here, we show, in a three-dimensional in vitro BBB microvascular model, that astrocytes promote cancer cell transmigration via their secretion of C-C motif chemokine ligand 2 (CCL2). We found that this chemokine, produced primarily by astrocytes, promoted the chemotaxis and chemokinesis of cancer cells via their C-C chemokine receptor type 2 (CCR2), with no notable changes in vascular permeability.

Microheart: A microfluidic pump for functional vascular culture in microphysiological systems.

Advances in microphysiological systems have prompted the need for long-term cell culture under physiological flow conditions. Conventional laboratory pumps typically lack the ability to deliver cell culture media at the low flow rates required to meet the physiological ranges of fluid flow, and are often pulsatile or require flow reversal. Here, a microfluidic-based pump is presented, which allows for the controlled delivery of media for vascular microphysiological applications.

The effects of luminal and trans-endothelial fluid flows on the extravasation and tissue invasion of tumor cells in a 3D in vitro microvascular platform.

Throughout the process of metastatic dissemination, tumor cells are continuously subjected to mechanical forces resulting from complex fluid flows due to changes in pressures in their local microenvironments. While these forces have been associated with invasive phenotypes in 3D matrices, their role in key steps of the metastatic cascade, namely extravasation and subsequent interstitial migration, remains poorly understood. In this study, an in vitro model of the human microvasculature was employed to subject tumor cells to physiological luminal, trans-endothelial, and interstitial flows to evaluate their effects on those key steps of metastasis.

Interstitial flow promotes macrophage polarization toward an M2 phenotype.

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored.