Mechanically Active Biomaterials for Stem Cell Differentiation.

Abstract

Mechanical cues have emerged as critical regulators of stem cell fate, acting alongside biochemical signals to govern differentiation and functional maturation. In native tissues, stem cells reside within dynamic and mechanically heterogeneous microenvironments, where physical factors such as matrix stiffness, viscoelasticity, topography, and externally applied forces play essential roles in directing cellular behavior. Recent advances in mechanically active biomaterials have enabled precise control over the mechanical properties of stem cell microenvironments, providing powerful platforms to investigate mechanotransduction mechanisms and guide lineage specification. These materials-including stiffness-tunable and viscoelastic hydrogels, stimuli-responsive scaffolds, and dynamic culture systems-facilitate spatiotemporal modulation of mechanical cues and allow systematic interrogation of force-mediated signaling pathways, such as integrin-based adhesion, cytoskeletal remodeling, and YAP/TAZ-dependent transcriptional regulation. In this review, we summarize the fundamental mechanisms underlying mechanical regulation of stem cell differentiation and compare two- and three-dimensional culture systems from a mechanobiological perspective. We further highlight how material design principles can enhance functional maturation and translational relevance. Finally, we discuss current challenges and future opportunities in the development of scalable, clinically compatible mechanically active biomaterials. By integrating insights from mechanobiology and materials science, this review aims to provide design-oriented frameworks for the rational engineering of next-generation stem cell-based healthcare technologies.