Injectable, viscoelastic hydrogel precisely regulates developmental tissue regeneration

Extracellular matrix viscoelasticity is a crucial parameter for designing biomaterials in tissue regeneration. However, the precise control of viscoelastic properties for reproducing the mechanical environment that cells experience in vivo remains a challenge. Here, we developed a series of injectable, viscoelastic PEGylated poly (glycerol sebacate) (PEGS-OH) hydrogels crosslinked via click chemistry and investigated the role of viscoelasticity in developmental tissue regeneration. We found that, compared to 100% and 60% crosslink degrees, 80% crosslinked PEGS-OH with incomplete network slipping promoted a striking increase in the adhesion and differentiation of bone mesenchymal stem cells (BMSCs). Moreover, with PEG segments increasing, the elastic hydrogel turned into viscous state and regulated BMSCs differentiation from osteogenesis to adipogenesis. Further studies revealed that the crosslink degree- and PEG segment-induced BMSCs response was greatly relied on the mechanosensitive Piezo1 mechanism. With in vivo cartilago articularis and skull defect regeneration as models, tendencies from experiments in vitro were further confirmed. Our findings highlight a potential material-biological strategy to precisely regulate cell fate and ensuing tissue regeneration, and provide insight into the relevance of material viscoelasticity in the fate of stem cell differentiation.