Fig. 2.

Microfluidic devices have been developed to investigate the biological responses of cells and tissues to various mechanical stimuli. Schematics (left) and the images (center) of microfluidic devices developed to study the effect of mechanical stimuli are shown along with typical biological responses to each stimulus (right). (a) Fluid flow through confined channels imparts shear stress on cells cultured within microfluidic devices. Such platforms have allowed investigation of the effect of physiologic shear stress on endothelial cells, which align the cells in the direction of flow (right, modified from van der Meer et al.¹⁷ and Song et al.¹⁵). (b) Applying a fluid pressure gradient across a hydrogel allows the investigation of the effect of interstitial flow on cell migration and alignment. For example, interstitial flow (blue arrow) was applied to cancer cells seeded within a collagen hydrogel (left and center), and this platform allowed elucidation of parameters that govern upstream and downstream migration in response to flow (modified from Polacheck et al.¹⁰³). (c) By incorporating flexible substrates into microfluidic platforms, devices have been developed to study the effect of mechanical stretch on the cells cultured on the deformable substrate. For example, gut epithelial cells were cultured as a monolayer on top of a PDMS membrane, which is deformed by applying suction in the lateral channels, and cyclic strain causes cells to assume a more physiologically relevant phenotype (right, modified from⁷⁹). (d) Gradients in stiffness of a substrate within a microfluidic device were used to study the effect of stiffness gradient on axon outgrowth; axons preferentially grow into the direction of decreasing stiffness (right, modified from Sundararaghaven et al.⁴⁹). (e) A microfluidic system was used to study the effect of geometric confinement on axon outgrowth. In this example, axons were allowed to grow into microgrooves of decreasing width. This microgroove confines the growth of an axon in the direction of decreasing width (left and center), and the number of axons growing from the narrow side to the wide side (red) is much lower than the number of axons growing in the opposite direction (blue, modified from Peyrin et al.⁶²). (f) Devices have been developed to measure force generated by mechanically active cells and tissues. In this example, cardiac microtissue was grown around two micro-cantilevers. As the muscle tissue contracted, it displaced the cantilevers, which was used to measure the force generated by muscle tissue (left and center, modified from Legant et al.¹²²). Among other results, this study revealed that an increase in the stiffness of the cantilevers can lead to an increase in tension exerted by the cells.