Matrix Metalloproteinase-Responsive Hydrogel with On-Demand Release of Phosphatidylserine Promotes Bone Regeneration Through Immunomodulation

Inflammation-responsive hydrogels loaded with therapeutic factors are effective biomaterials for bone tissue engineering and regenerative medicine. In this study, a matrix metalloproteinase (MMP)-responsive injectable hydrogel is constructed by integrating an MMP-cleavable peptide (pp) into a covalent tetra-armed poly-(ethylene glycol) (PEG) network for precise drug release upon inflammation stimulation. To establish a pro-regenerative environment, phosphatidylserine (PS) is encapsulated into a scaffold to form the PEG-pp-PS network, which could be triggered by MMP to release a large amount of PS during the early stage of inflammation and retain drug release persistently until the later stage of bone repair. The hydrogel is found to be mechanically and biologically adaptable to the complex bone defect area. In vivo and in vitro studies further demonstrated the ability of PEG-pp-PS to transform macrophages into the anti-inflammatory M2 phenotype and promote osteogenic differentiation, thus, resulting in new bone regeneration. Therefore, this study provides a facile, safe, and promising cell-free strategy on simultaneous immunoregulation and osteoinduction in bone engineering. A facile and efficient cell-free strategy of inflammation-responsive injectable hydrogel is reported, which for the first time encapsulates, the apoptotic signal molecule, phosphatidylserine into a matrix metalloproteinase-responsive poly (ethylene glycol) (PEG) network and allows the on-demand release of therapeutic factor under inflammatory stimulation, aiming to guide long-term bone regeneration via immune modulation and osteogenic induction. image