Substrate stiffness regulates cell fate and its applications in the repair of motor system: From two dimensions to three dimensions

Abstract

Abstract Stiffness is a key mechanical cue of the extracellular matrix (ECM) and biomaterials in tissue engineering. It plays a pivotal role in regulating cellular behaviors and determining cell fate through specific mechanotransduction pathways, including integrin‐mediated signaling and cytoskeletal dynamics. Biomaterials with tunable stiffness in both two‐dimensional (2D) and three‐dimensional (3D) formats have been developed to investigate the influence of stiffness on tissue regeneration. This is particularly relevant in the motor system, where tissue stiffness spans a broad range and mechanical cues are crucial. In this review, we first highlight the multiple roles of matrix stiffness in biological processes, from guiding tissue development and maintaining homeostasis to regulating cell behaviors. We then summarize the design and fabrication strategies for tunable‐stiffness biomaterials in both 2D and 3D formats. Finally, we discuss the functional applications of these biomaterials in the motor system and their potential applications in regenerative medicine.