VEGF-sustained regulation and hydrogel-activated graded porous titanium scaffold for functional regeneration of the tendon-bone interface

Recapitulating the complex coupling mechanisms at the tendon-bone interface, which involve gradients in structure, composition, and mechanics, poses a primary challenge for healing. In this study, a 3D-printed graded porous Ti6Al4V scaffold was designed and fabricated to address this challenge. This scaffold features a gradient pore architecture tailored to the distinct requirements of both soft and hard tissues. The scaffold was further functionalized with a GelMA and silk fibroin hydrogel to activate the interface. Additionally, chitosan-stabilized BSA nanospheres loaded with VEGF were encapsulated within this hydrogel to achieve sustained release. In vitro studies demonstrated that this composite scaffold effectively promoted the migration and proliferation of tendon-derived stem cells, upregulated tenogenic marker genes, and enhanced angiogenic activity and synergistic osteogenesis. Animal model evaluations confirmed that the scaffold promoted the regeneration of type I collagen and Sharpey-like fibers, angiogenesis, and improved osseointegration, ultimately leading to a biologically continuous tendon-bone connection. The ultimate failure load of the repaired interface reached 107.61 ± 5.16 N, restoring 82% of the native enthesis strength. In conclusion, the synergistic strategy of "Structural Adaptation — Interface Activation — Signaling Regulation" presented in this study demonstrated the capacity to facilitate the regeneration of a biologically continuous tendon-bone interface in vivo and significantly improve functional integration. This approach provides a novel solution for enthesis regeneration and holds promise for clinical translation. Schematic illustration of preparation of Ti@GS-VNS scaffold and its mechanism for tendon-bone interface repair • Biomimetic strategy guided by the “Structure–Interface–Signal” regeneration paradigm. • 3D-printed graded titanium scaffold integrated with VEGF-functionalized hydrogel. • Spatially coordinated mechanical and biochemical cues mimic native enthesis. • Achieved 82% recovery of native failure load, restoring functional integration. • Provides a translational platform for orthopaedic and sports medicine repair