Microfluidic 3D cell culture: from tools to tissue models

Abstract

The transition from 2D to 3D cell culture techniques is an important step in a trend towards better biomimetic tissue models. Microfluidics allows spatial control over fluids in micrometer-sized channels has become a valuable tool to further increase the physiological relevance of 3D cell culture by enabling spatially controlled co-cultures, perfusion flow and spatial control over of signaling gradients. This paper reviews most important developments in microfluidic 3D culture since 2012. Most efforts were exerted in the field of vasculature, both as a tissue on its own and as part of cancer models. We observe that the focus is shifting from tool building to implementation of specific tissue models. The next big challenge for the field is the full validation of these models and subsequently the implementation of these models in drug development pipelines of the pharmaceutical industry and ultimately in personalized medicine applications.

Biomimetic channel modeling local vascular dynamics of pro-inflammatory endothelial changes

“…There are a few in vitro reports using microfluidic chips to study vascular functions. [3][4][5][6][7][8][9][10][11][12] Work by Tsou et al employed soft lithography based flow chamber to study how endothelial cells sense a gradient of flow shear stress (FSS) and tumor necrosis factor-alpha (TNF-a) triggering to transduce signals that regulate membrane expression of cell adhesion molecules and monocyte recruitment. 13 Sato et al used a microfluidic model separated by a membrane containing both blood and lymphatic vessels for examining vascular permeability.…”

In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications

“…Organ-on-a-chip platforms are attracting more and more attention for drug screening and toxicity assays and as alternatives to animal experimentation. In a recent review, van Duinen et al 58 mentioned that 87 publications have been reporting organ-on-a-chip platforms since 2012. Of particular interest for microbubble-related studies are vessel-on-a-chip, 59 tumor-on-a-chip, 60 and barrier models, such as the BBB on a chip.…”

Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes

“…Such conventional Transwell systems are poorly suited for high-resolution kinetic measurements and image-based readouts, and therefore provide only limited information on the underlying mechanisms, leading to barrier disruption. More importantly, it does not comply with the current paradigm in cell culture that is steadily shifting towards three-dimensional cultures, extracellular matrix (ECM) embedment and addition of perfusion flow [1][2][3][4][5] .…”

“…The field of microfluidics has rapidly gained momentum in the realm of in vitro modeling 3 An extracellular matrix gel (light gray) is patterned by two phaseguides (dark gray), e, f culture medium is introduced in the two lanes adjacent to the ECM gel, one of which comprises cells. g, h Cells are allowed to settle against the ECM gel surface by placing the plate on its side.…”