Human pluripotent stem cells possess extensive self-renewal capacity and the ability to differentiate into three germ layers, making them central to regenerative medicine, disease modeling, and tissue engineering. However, achieving controlled lineage specification remains challenging in traditional two-dimensional culture systems that rely on poorly defined biological matrices. Engineered biomaterials are increasingly used to recreate key physical and biochemical properties of the native extracellular matrix. Central to this process is cell-matrix mechanotransduction, through which physical cues are translated into biochemical signaling that influences gene expression, metabolism, and cell fate. This review critically examines how tunable material properties, including static stiffness, viscoelastic stress relaxation, nanoscale topography, and geometric confinement, act as biophysical switches to direct stem cell lineage specification. Furthermore, it highlights the synergistic integration of advanced biochemical cues within stimuli-responsive four-dimensional architectures, bioorthogonal ligand presentation, and affinity-based morphogen delivery. Finally, we discuss current translational bottlenecks and evaluate how the convergence of fully synthetic matrices, automated bioreactors, single-cell multi-omics, and computational modeling are beginning to support the rational design of biomaterials for stem cell-based therapies.
Sarımen et al. (Mon,) studied this question.