Engineered 3D Printing Bilayer Scaffold with Spatiotemporal Release of Drug for Synergistic Osteochondral Regeneration

Osteoarthritis (OA) is characterized by the disruption of chondro-bone homeostasis, where progressive cartilage degeneration and aberrant bone remodeling exacerbate joint dysfunction. Restoring this imbalance remains a critical challenge in OA treatment. Here, a 3D-printed bilayer scaffold with spatiotemporal release is presented, which integrates an alendronate sodium-triphenylphosphine (ALN-TPP)-loaded polyacrylic acid/methacrylated flaxseed gum (PAA/FGMA) cartilage layer and an ALN-TPP-loaded PAA/vinyl-modified montmorillonite (vinyl-MMT) bone layer. Specifically, FGMA establishes a biomimetic microenvironment that supports the migration and proliferation of chondrocytes. vinyl-MMT improves the mechanical strength of the scaffold, providing structural support for bone regeneration. Crucially, the differential degradation kinetics of the scaffolds orchestrate a temporal release of the ALN-TPP. The faster-degrading upper layer ensures rapid initial release of ALN-TPP, which specifically targets dysfunctional mitochondrial metabolism characteristic of OA, reduces oxidative stress, and inhibits the expression of matrix-degrading enzymes during the early critical phase. Simultaneously, the slower-degrading lower layer provides a sustained release profile. ALN-TPP promotes osteogenesis by stimulating osteoblast differentiation, which effectively reverses abnormal bone remodeling in osteoarthritis. In a rabbit model with osteochondral defects, the bilayer scaffold facilitates effective formation of hyaline-like cartilage and achieves subchondral bone reconstruction. This work establishes a multifunctional therapeutic platform that can advance the repair of osteochondral defects.