Graded Modulation of Inflammation by Metal Ion-Coordinated Peptide-Based Hydrogel Chemical Regulators Promotes Tendon–Bone Junction Regeneration

After rotator cuff injuries, uncontrolled inflammation hinders tendon–bone junction regeneration and induces scar formation in situ. Therefore, precisely controlling inflammation could be a solution to accelerate tendon–bone junction regeneration. In this study, we synthesized a peptide–metal ion complex hydrogel with thermosensitive capability that can be used as a hydrogel chemical regulator. By the coordination complex between Mg2+and BMP-12, the free and coordinated Mg2+can be programmability released from the hydrogel. The fast release of free Mg2+can prevent inflammation at the early stage of injuries, according to the results of RT-qPCR and immunofluorescence staining. Then, the coordinated Mg2+was slowly released from the hydrogel and provided an anti-inflammatory environment for tendon–bone junction regeneration in the long term. Finally, the hydrogel demonstrated enhanced therapeutic effects in a rat rotator cuff tear model. Overall, the Mg2+/BMP-12 peptide–metal ion complex-based hydrogel effectively addresses the regenerative requirements of the tendon–bone junction across various stages by graded modulating inflammation.