Biophysical cues and cell behavior: the big impact of little things

The extracellular matrix is composed of a variety of proteins, polysaccharides, and glycosaminoglycans that self-assemble into a hierarchical order of nanometer- to micrometer-scale fibrils and fibers. The shapes, sizes, and elasticity present within this highly ordered meshwork regulate behaviors in most cell types. It has been well documented that cellular migration, proliferation, differentiation, and tissue development are all influenced by matrix geometries and compliance, but how these external biophysical cues are translated into activated intracellular signaling cascades remains poorly understood. Fortunately, technological improvements in artificial substrate fabrication have provided biologists with tools to test cellular interactions within controlled three-dimensional environments. Here, we review cellular responses to biophysical cues and discuss their clinical relevancy and application. We focus especially on integrative approaches that aim to first characterize the properties of specific extracellular matrices and then precisely fabricate biomimetic materials to elucidate how relevant cells respond to the individual biophysical cues present in their native tissues. Through these types of comprehensive studies, biologists have begun to understand and appreciate how exceedingly small features can have a significant impact on the regulation, development, and homeostasis of cells and tissues.