A decoupling strategy toward spatiotemporal regulation and biomechanical transmission of sandwiched scaffold for osteochondral regeneration

Abstract Osteochondral repair remains a great challenge due to the hierarchical complexity and functional heterogeneity. Despite significant efforts in gradient scaffolds, few strategies concern wavy interface and biomechanical functions of calcified cartilage layer (CCL) between the chondro-osseous junction. Here, a sandwich-layered hydrogel containing a biomimetic wavy CCL is developed with hypoxia-inducible capacity, spatiotemporal regulation and biomechanical transmission using a decoupling strategy. The scaffold presents intrinsic Fe 3+ -chelating with high activation and durable expression of HIF-1α signaling to facilitate cartilage development. Innovatively, synergistic effects of KGN and Mg 2+ suppress chondrogenic hypertrophy and boost chondrogenesis. Instead, chondrocytes transition into hypertrophy associated with Cu 2+ -induced vascularization trigger endochondral ossification. Finite element analysis and transcriptome studies reveal the role of wavy CCL in alleviating stress concentration and protecting articular cartilage, thus presenting high efficacy in rabbits’ osteochondral repair. Collectively, this study emphasizes the indispensability of wavy CCL in multileveled scaffolds toward osteochondral regeneration.