Mechanically Robust Hydrogels Facilitating Bone Regeneration through Epigenetic Modulation

Development of artificial biomaterials by mimicking extracellular matrix of bone tissue is a promising strategy for bone regeneration. Hydrogel has emerged as a type of viable substitute, but its inhomogeneous networks and weak mechanics greatly impede clinical applications. Here, a dual crosslinked gelling system is developed with tunable architectures and mechanics to promote osteogenic capacity. Polyhedral oligomeric silsesquioxane (POSS) is designated as a rigid core surrounded by six disulfide-linked PEG shells and two 2-ureido-4[1H]-pyrimidinone (UPy) groups. Thiol-disulfide exchange is employed to fabricate chemical network because of the pH-responsive "on/off" function. While self-complementary UPy motif is capable of optimizing local microstructure to enhance mechanical properties. Taking the merits of biocompatibility and high-mechanics in periodontal ligament stem cells (PDLSCs) proliferation, attachment, and osteogenesis, hybrid hydrogel exhibits outstanding osteogenic potential both in vitro and in vivo. Importantly, it is the first time that a key epigenetic regulator of ten-eleven translocation 2 (Tet2) is discovered to significantly elevate the continuously active the WNT/β-catenin through Tet2/HDAC1/E-cadherin/β-catenin signaling cascade, thereby promoting PDLSCs osteogenesis. This work represents a general strategy to design the hydrogels with customized networks and biomimetic mechanics, and illustrates underlying osteogenic mechanisms that will extend the design rationales for high-functional biomaterials in tissue engineering.