Gradients in articular cartilage and cartilage tissue engineering

Articular cartilage (AC) possesses complex depth-dependent gradients in cell phenotype, matrix composition, metabolism, mechanics, and growth factors. These natural gradients are essential for cartilage function. Because of lack of blood vessels, the repair and treatment of AC defects have been a grand challenge for surgeons, the natural gradients inspired researchers to find solutioninthe gradient construction for AC repair in tissue engineering. This review emphasizes a critical shift from merely describing native gradients to actively implementing gradient-based strategies in scaffold design. Current biomimetic approaches focus on engineering controllable gradients-including cell density, metabolic factors (e.g., oxygen), matrix composition, mechanical properties, and growth factor concentrationswithinthe scaffold. These gradient-enabled constructs can be designed to guide zone-specific cellular responses and extracellular matrix formation, ultimately restoring the native structure and function of AC. We also highlight technologies such as 3D bioprinting, oxygen-releasing biomaterials, perfusion bioreactors, and graded microsphere systems that enable precise spatial control of scaffold properties. A successful gradient-based strategy integrates multiple interdependent gradients rather than relying on a single feature. This review provides a practical framework for developing next-generation biomimetic scaffolds capable of achieving functional AC regeneration for clinical translation.