Microfluidic Devices for Quantifying the Role of Soluble Gradients in Early Angiogenesis

Early angiogenesis, as defined by endothelial polarization and directional sprouting, is regulated by gradients of soluble factors in addition to a multitude of other anisotropic cues including interstitial flow, insoluble gradients, and topography of the extracellular matrix (ECM). Adding to this complexity, other microenvironmental inputs, such as matrix density and rigidity, are known to modulate the extent to which vascular endothelial cells react to these anisotropic cues. Given this complexity, novel platforms are needed to decouple and systematically assess signals regulating early angiogenesis. To this end, we discuss a microfluidic device that achieves stable, matrix-independent soluble gradients via passive diffusion, which shields the culture chamber from shear-induced anisotropy. These devices enable direct time-lapse imaging of single cell and collective cell phenomena within both two-dimensional (2D) and three-dimensional (3D) cultures. These experimental platforms have been used to quantify the growth factor concentration requirements that induce endothelial cell chemotaxis, to identify previously unknown regulators of brain angiogenesis, to screen biomaterials for their angiogenic potential, and to investigate the navigational ability of nascent sprouts.