Emerging themes and unifying concepts underlying cell behavior regulation by the pericellular space.

Cells reside in a complex three-dimensional (3D) microenvironment where physical, chemical, and architectural features of the pericellular space regulate important cellular functions like migration, differentiation, and morphogenesis. A major goal of tissue engineering is to identify which properties of the pericellular space orchestrate these emergent cell behaviors and how. In this review, we highlight recent studies at the interface of biomaterials and single cell biophysics that are lending deeper insight towards this goal. Advanced methods have enabled the decoupling of architectural and mechanical features of the microenvironment, revealing multiple mechanisms of adhesion and mechanosensing modulation by biomaterials. Such studies are revealing important roles for pericellular space degradability, hydration, and adhesion competition in cell shape, volume, and differentiation regulation. STATEMENT OF SIGNIFICANCE: Cell fate and function are closely regulated by the local extracellular microenvironment. Advanced methods at the interface of single cell biophysics and biomaterials have shed new light on regulators of cell-pericellular space interactions by decoupling more features of the complex pericellular milieu than ever before. These findings lend deeper mechanistic insight into how biomaterials can be designed to fine-tune outcomes like differentiation, migration, and collective morphogenesis.