Bioinspired Injectable Hydrogels Dynamically Stiffen and Contract to Promote Mechanosensing-Mediated Chondrogenic Commitment of Stem Cells

Developing stiff and resilient injectable hydrogels that can mechanically support load-bearing joints while enabling chondrogenic differentiation of stem cells is a major challenge in the field of cartilage tissue engineering. In the present work, a triple-network injectable hydrogel system was engineered using Bombyx mori silk fibroin, carboxymethyl cellulose (CMC), and gelatin. The developed hydrogel demonstrated a simultaneous increase in both stiffness and contraction over time, thereby imparting a four-dimensional (4D) evolving niche to the cells. While resilience was provided by CMC, the dynamic alterations in the hydrogel matrix were attributed to the formation of β-sheets in silk. The engineered contraction facilitated condensation of cells that mimicked an important step during cartilage development. Subsequently, this led to downregulation of YAP signaling and enhanced chondrogenic commitment of stem cells. More importantly, the in vivo study showed that the ectopically regenerated cartilage was mature and closely resembled native articular cartilage. Overall, this strategy of engineering mechanotransduction that promotes chondrogenesis by contraction-mediated condensation is a promising and translatable approach for cartilage repair.