Advances in biomaterial-based composite spheroid for articular cartilage regeneration

Articular cartilage plays a crucial role in reducing friction between bones and enabling movements; however, it is frequently degraded due to persistent joint stress, aging, and osteoarthritis. As its self-repair ability is limited, various cell-based therapeutic strategies have been developed for cartilage regeneration. Conventional two-dimensional (2D) cell cultures inadequately replicate the complex intercellular interactions of native cartilage. In contrast, three-dimensional (3D) cell spheroid cultures can more accurately mimic in vivo cellular physiology, offering superior regenerative potential via improved cell-cell and cell-matrix interactions. These interactions can be enhanced with biomaterials to form composite spheroids, which exhibit substantial potential for improving cartilage regeneration and attenuating osteoarthritis progression in vivo by promoting cell survival and tissue integration. This review highlights current strategies for developing biomimetic composite spheroid systems, including spheroid encapsulation, scaffold incorporation, and 3D bioprinting. Furthermore, we discuss their advantages, translational potential for in vivo cartilage repair, and the challenges and future directions in cartilage tissue engineering.