Programmable Microgel Degradation in Dynamic Granular Hydrogels Guides Extracellular Matrix Assembly During Tissue Repair

Granular hydrogels have attracted widespread interest for wound healing applications, yet their static design, in which microstructure and void space remain fixed, contrasts with the dynamic nature of tissue repair where processes like provisional extracellular matrix (pECM) assembly, cell organization, and nascent tissue formation evolve over time. Here, this disparity is addressed by designing dynamic granular hydrogels that are modularly assembled using microgels with pre-programmed and precise degradation rates ranging from a few days to several weeks. Microgel degradation is controlled via modulation of hydrolytic susceptibility of hyaluronic acid polymers. The biological significance of timed pore expansion in dynamic granular hydrogels is investigated in a mouse muscle crush injury model. While slow-degrading hydrogels support a distinct spatial assembly of cell-instructive interstitial matrix and basement membrane proteins in the expanded pore space, this pECM remodeling is adversely altered in non-degrading or fast-degrading hydrogels. Slow-degrading dynamic granular hydrogels also show long-term therapeutic benefits on muscle wound healing, evidenced by reduced fibrosis, enhanced myogenesis, and improved functional force recovery. Collectively, these striking results demonstrate the profound significance of incorporating dynamicity through controlled microgel degradation in advanced granular biomaterials to improve tissue repair outcomes.