Inflammation-Responsive Functional Core–Shell Micro-Hydrogels Promote Rotator Cuff Tendon-To-Bone Healing by Recruiting MSCs and Immuno-Modulating Macrophages in Rats

Rotator cuff injuries often necessitate surgical intervention, but the outcomes are often unsatisfactory. The underlying reasons can be attributed to multiple factors, with the intricate inflammatory activities and insufficient presence of stem cells being particularly significant. In this study, an innovative inflammation-responsive core–shell micro-hydrogel is designed for independent release of SDF-1 and IL-4 within a single delivery system to promote tendon-to-bone healing by recruiting MSCs and modulating M2 macrophages polarization. First, a MMP-2 responsive hydrogel loaded with IL-4 (GelMA-MMP/IL-4) is synthesized by cross-linking gelatin methacrylate (GelMA) with MMP-2 substrate peptide. Then, the resulting core particles are coated with a shell of chitosan /SDF-1/hyaluronic acid (CS/HA/SDF-1) using the layer-by-layer electrostatic deposition method to form a core–shell micro-hydrogel composite. The core–shell micro-hydrogel shows sustained release of SDF-1 and MMP-2-responsive release of IL-4 associated in situ MSCs homing and smart inflammation regulation by promoting M2 macrophages polarization. Additionally, by injecting these micro-hydrogels into a rat rotator cuff tear and repair model, notable improvements of fibrocartilage layer are observed between tendon and bone. Notably, this study presents a new and potentially powerful environment-responsive drug delivery strategy that offers valuable insights for regulating the intricate micro-environment associated with tissue regeneration.