Mechanical Signal-Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation

The aberrant mechanical microenvironment in degenerated tissues induces misdirection of cell fate, making it challenging to achieve efficient endogenous regeneration. Herein, a hydrogel microsphere-based synthetic niche with integrated cell recruitment and targeted cell differentiation properties via mechanotransduction is constructed . Through the incorporation of microfluidics and photo-polymerization strategies, fibronectin (Fn) modified methacrylated gelatin (GelMA) microspheres are prepared with the independently tunable elastic modulus (1-10Kpa) and ligand density (2 and 10 µg mL^-1 ), allowing a wide range of cytoskeleton modulation to trigger the corresponding mechanobiological signaling. The combination of the soft matrix (2Kpa) and low ligand density (2 µg mL^-1 ) can support the nucleus pulposus (NP)-like differentiation of intervertebral disc (IVD) progenitor/stem cells by translocating Yes-associated protein (YAP), without the addition of inducible biochemical factors. Meanwhile, platelet-derived growth factor-BB (PDGF-BB) is loaded onto Fn-GelMA microspheres (PDGF@Fn-GelMA) via the heparin-binding domain of Fn to initiate endogenous cell recruitment. In in vivo experiments, hydrogel microsphere-niche maintained the IVD structure and stimulated matrix synthesis. Overall, this synthetic niche with cell recruiting and mechanical training capabilities offered a promising strategy for endogenous tissue regeneration.