Enzyme-Responsive Self-Evolving Hydrogel for Osteochondral Regeneration through Mechanosignaling Pathway

), generates a less dense network. This ALP-gradient-driven evolution delivers spatially and temporally dynamic mechanical cues, ranging from soft to stiff, which are transduced through extended integrin-mediated mechanosignaling and subsequently activate the PI3K/AKT/GSK-3β/β-catenin pathway. This cascade regulates key cell functions, such as spreading, migration, and differentiation. The dynamic and gradient-responsive SE gel supports osteochondral regeneration with tissue-specific heterogeneity. To the best of our knowledge, this is the first study to integrate an adaptive hydrogel with an ALP activity gradient, demonstrating its potential in osteochondral regeneration and highlighting the pivotal role of mechanobiology.