Beyond Biomaterials: Engineering Bioactive Hydrogels as Immuno-Mechanobiological Niches for Osteochondral Regeneration.

Osteochondral regeneration remains a major clinical challenge due to the complex architecture and biomechanical demands of the osteochondral unit. Bioactive hydrogels have emerged as promising materials capable of supporting repair through their capacity to mimic the extracellular matrix (ECM), enable cell encapsulation, and deliver bioactive cues. However, recent insights reveal that simply engineering hydrogels for structural and cellular support is insufficient. A new paradigm is emerging-one that embraces the complexity of the osteochondral niche by integrating immunomodulatory and mechanobiological cues into biomaterial design. In particular, the hydrogel's capacity to modulate macrophage polarization and support the immunoregulatory function of mesenchymal stem cells (MSCs) is critical to orchestrate regenerative outcomes. Simultaneously, the mechanical properties of hydrogels-such as stiffness, porosity, and viscoelasticity-can profoundly influence stem cell fate and local tissue morphogenesis. This review discusses recent advances in hydrogel-based strategies for osteochondral repair, highlighting the interplay between immunological signals and the mechanical microenvironment, and calls for a shift from reductionist tissue-engineering approaches to systems-level design of tunable, immuno-mechanobiological microenvironments.