Adaptable sliding hydrogels enable pericellular pocket formation while enhancing MSC chondrogenesis and survival in 3D.

Hydrogels that recapitulate the dynamic mechanical cues of native extracellular matrix are powerful tools that can be leveraged for tissue engineering. Despite growing recognition that cues such as stress relaxation and plasticity modulate cell-matrix interactions, the influence of these properties on mesenchymal stromal cell (MSC) chondrogenesis has yet to be elucidated across a broad range of relaxation timescales and in the absence of confounding biochemical cues. Here, we report the adaptable sliding hydrogel (ASG) with tunable stress relaxation and plasticity as a novel MSC cell niche. By incorporating reversible hydrazone crosslinks into polyethylene glycol (PEG)-based sliding hydrogels (SG), ASG achieves a wide range of tunable stress relaxation and plasticity that are distinct from other dynamic hydrogels used for MSC chondrogenesis. Notably, increasing stress relaxation and plasticity in ASG promotes rapid and robust cartilage formation by human MSCs and supports long-term cell viability. Mechanistically, ASG facilitates local matrix remodeling and enables MSCs to form "pericellular pockets" in 3D that correlate with enhanced nascent extracellular matrix deposition and reorganization, integrin signaling, and nuclear dynamics. Overall, the ASG platform provides a tunable, synthetic microenvironment that helps probe the relationship between dynamic mechanical cues and stem cell fate and informs next-generation material design within the field of tissue engineering.