Synergizing adaptive immunity and regenerative signals to enhance osteochondral defects repair

In clinical practice, repairing osteochondral defects (OCDs) is challenging because of the complex cartilage/subchondral bone structure and intricate immunological microenvironment. Here, we identify the crucial role of adaptive immunity dysfunction by revealing that an increase of T helper 17 (Th17) cells exacerbated osteochondral tissue degradation via its pro-inflammatory cytokine interleukin-17 (IL-17) in the early-stage OCDs. Next, we leveraged this adaptive immunity mechanism and combined it with regenerative signals to develop a multifunctional hydrogel system capable of simultaneously tackling immune dysfunction and regenerative deficiency. Rapid IL-4 release from the methacrylated hyaluronic acid (HAMA) hydrogel exerts a potent immunomodulatory effect by inhibiting the differentiation and function of Th17 cells. Moreover, transforming growth factor-beta1 anchored on methacrylated hyaluronic acid and heparin (HAMA@HepMA) microparticles provides sustained regenerative signals, which synergistically transform the pro-inflammatory microenvironment into a pro-regenerative niche for enhanced OCDs healing. Our study suggests that targeting specific immune pathways can significantly enhance the efficacy of regenerative strategies, paving the way for innovative treatments in orthopedic medicine.