Biomimetic gradient hydrogels for osteochondral regeneration: from multi-dimensional design to clinical translation

Osteochondral defects represent a significant clinical challenge due to the complex, graded architecture of the osteochondral unit and the limited regenerative capacity of articular cartilage. Gradient hydrogels have emerged as a promising class of biomimetic scaffolds that replicate the continuous transitions in structure, mechanics, composition, and biochemistry spanning from cartilage to subchondral bone. This review comprehensively examines recent advances in gradient hydrogel design for osteochondral regeneration. We discuss fundamental design principles encompassing structural porosity gradients, mechanical stiffness gradients (kPa-to-GPa transitions), compositional mineral gradients, and biochemical growth factor gradients, as well as their multi-dimensional integration. Fabrication strategies-including layer-by-layer assembly, 3D bioprinting, microfluidic generation, diffusion-based methods, and injectable in situ systems-are critically compared regarding scalability, precision, and translational potential. Material selection spanning natural polymers (collagen, gelatin methacryloyl (GelMA), hyaluronic acid, silk fibroin), synthetic polymers (polyethylene glycol, polycaprolactone), and polymer-ceramic composites is evaluated alongside crosslinking chemistries enabling spatial control. We examine biological mechanisms through which gradients direct cell fate, including mechanotransduction via Yes-associated protein/transcriptional co-activator with PDZ-binding motif signaling, spatiotemporal growth factor delivery, zone-specific cell migration, immunomodulation, and extracellular vesicle-mediated paracrine signaling. Preclinical evidence from small and large animal models is synthesized, demonstrating superior outcomes for gradient versus uniform scaffolds. Finally, we address current limitations in long-term durability, vascularization, and regulatory pathways, and highlight emerging technologies-4D printing, AI-aided design, organ-on-chip screening, and personalized medicine-that may accelerate clinical translation.