GelMA–silk fibroin composite hydrogels for articular cartilage regeneration: emerging strategies and translational frontiers

Abstract

Abstract Articular cartilage (AC) is avascular and has a low cell density, which has limited its ability for self-repair. This leads to the generation of biomechanically inferior fibrocartilage after injury or degeneration. Hydrogels are promising scaffolds for cartilage regeneration because of their high-water content, viscoelasticity, and tunable degradation. They mimic the extracellular matrix (ECM) and enable controlled release of cells and bioactive factors. Gelatin methacryloyl (GelMA) is inherently bioactive and photocrosslinkable. However, it is mechanically weak and rapidly degrading. Silk fibroin (SF) offers excellent mechanical robustness and structural stability. Recent studies on GelMA/SF composite hydrogels explored interpenetrating networks (IPNs) and hybrid cross-linking strategies to improve mechanical stability while maintaining cell viability and supporting chondrogenic differentiation. Other novel approaches to improve cartilage-specific regeneration include growth factors, zonal architectures, cell-homing strategies, 3D bioprinting, and organoid-based systems. Preclinical trials reported encouraging results. Yet, challenges remain in matching scaffold degradation to tissue formation, long-term mechanical durability and integration, host responses and reproducible manufacturing. This is particularly the case for aged and osteoarthritic joints where the regenerative process is less supportive. Further validation in clinically relevant models and long-term studies are required to confirm the translational potential of GelMA/SF hydrogels for load bearing cartilage regeneration. Graphical abstractKnee joint showing damaged cartilage on the left, injection of GelMA/SF hydrogel in center, and regenerated cartilage on the right.The illustration depicts a three-step process of knee cartilage treatment. On the left, damaged cartilage is shown with irregular surfaces. The center features a syringe injecting a GelMA/SF IPN hydrogel, with an inset highlighting its structural networks. On the right, regenerated hyaline cartilage appears smooth. Below, icons represent properties: mechanical strength, high hydration, porous structure, and cell biocompatibility.