Developmentally Inspired, Mechanical–Metabolic Dual Gradient Osteochondral Constructs Bridging Regeneration and Therapeutic Screening

ABSTRACT The osteochondral interface is a finely tuned junction between cartilage and bone, coordinated by gradients in mechanics and metabolism. Recreating this complexity in vitro has remained elusive. Here, we present a developmentally inspired, dual‐gradient 3D‐printed construct that unites native‐like stiffness and metabolic microenvironments to drive spatially resolved regeneration and model osteoarthritis in a phase‐specific manner. Human bone marrow‐derived mesenchymal stem cell spheroids are placed in soft, hypoxic niches to promote chondrogenesis, and in stiff, vascular‐rich regions to induce osteogenesis—preserving cartilage–bone crosstalk within one platform. This integration of gradients amplifies extracellular matrix formation beyond single‐cue designs through the synergistic effect of porosity and stiffness. Furthermore, its anisotropic architecture maintains cartilage–bone crosstalk and allows drug response assessment, highlighting its potential as a physiologically relevant platform for osteoarthritis modeling and therapy screening. By bridging functional regeneration with preclinical drug screening, this model offers a physiologically relevant translational platform for advancing both osteochondral repair and disease research.