Lose the stress: Viscoelastic materials for cell engineering.

Biomaterials are widely used to study and control a variety of cell behaviors, including stem cell differentiation, organogenesis, and tumor invasion. While considerable attention has historically been paid to biomaterial elastic (storage) properties, it has recently become clear that viscous (loss) properties can also powerfully influence cell behavior. Here we review advances in viscoelastic materials for cell engineering. We begin by discussing collagen, an abundant naturally occurring biomaterial that derives its viscoelastic properties from its fibrillar architecture, which enables dissipation of applied stresses. We then turn to two other naturally occurring biomaterials that are more frequently modified for engineering applications, alginate and hyaluronic acid, whose viscoelastic properties may be tuned by modulating network composition and crosslinking. We also discuss the potential of exploiting engineered fibrous materials, particularly electrospun fiber-based materials, to control viscoelastic properties. Finally, we review mechanisms through which cells process viscous and viscoelastic cues as they move along and within these materials. The ability of viscoelastic materials to relax cell-imposed stresses can dramatically alter migration on two-dimensional surfaces and confinement-imposed barriers to engraftment and infiltration in three-dimensional scaffolds. STATEMENT OF SIGNIFICANCE: Most tissues and many biomaterials exhibit some viscous character, a property that is increasingly understood to influence cell behavior in profound ways. This review discusses the origin and significance of viscoelastic properties of common biomaterials, as well as how these cues are processed by cells to influence migration. A deeper understanding of the mechanisms of viscoelastic behavior in biomaterials and how cells interpret these inputs should aid the design and selection of biomaterials for specific applications.