A Smart MMP13‐Responsive Injectable Hydrogel with Inflammatory Diagnostic Logic and Multiphase Therapeutic Ability to Orchestrate Cartilage Regeneration

Abstract Despite numerous attempts to engineer cartilage tissue in recent years, significant challenges remain regarding hyaline cartilage regeneration. One main reason is that the overactivated inflammatory response after injury suppresses inherent cartilage regenerative capabilities. Since the arthritic microenvironment is constantly changing during posttraumatic stress, an inflammatory diagnostic logic‐based hydrogel for cartilage regeneration is developed for the first time through cross‐linking of 4‐arm poly(ethylene glycol)‐vinyl sulfone (PEG‐VS) and specific matrix metalloproteinase (MMP) 13‐sensitive peptides. The hydrogel exhibits diagnostic logic to identify the pathological cue MMP13 and accordingly determine drug release kinetics in an inflammatory microenvironment. Additionally, multiphase therapeutic ability is designed to program different cargo release behaviors to match the inflammation‐chondrogenesis cascade for better cartilage regeneration. Here, it is first proposed that MMP13 is a suitable diagnostic biomarker to modulate the inflammatory microenvironment in the early stage of cartilage injury. In vitro and in vivo studies show that the hydrogel has good injectability, on‐demand anti‐inflammation, and immunomodulation capabilities. Ultimately, loaded with multiple therapeutic factors, the hydrogel shows both microenvironmental modulation and chondrogenesis therapeutic ability, resulting in satisfactory hyaline cartilage regeneration. This study provides critical insight into the design and biological mechanism of both diagnostic and therapeutic ability‐based cartilage tissue engineering strategies.