A 3D-printed citrate-based platform with gastrodin delivery for vascular and lymphatic bone regeneration

Bone repair involves dynamic vascular and lymphatic networks that deliver inductive signals to regulate tissue-specific functions. As an interconnected structure can serve as an essential guide for these vessels, designing a multifunctional biomaterial with fine architecture remains a promising yet challenging frontier in load-bearing bone regeneration. Herein, a novel 3D-printable ink composed of a biodegradable citrate-based polymer and nano-hydroxyapatite (n-HA) is developed to fabricate high-fidelity bionic structures with sub-100 μm resolution. The printed scaffolds demonstrate effective interphase load transfer, achieving high toughness and strength rivaling native bone or conventional composite materials. As an innovative platform for bone regeneration, these scaffolds enable localized loading and sustained release of gastrodin at the target site. Collaborating with osteoinductive citrate and n-HA, the Haversian bone-mimicking scaffolds enhance cellular activity and osteogenic/angiogenic gene expression. In a rabbit critical-sized segmental bone defect model, the scaffolds facilitate rapid osseointegration and robust regeneration while undergoing gradual degradation at an appropriate rate over the long term. Notably, H-type vessels associated with osterix + osteoprogenitors emerge within the advancing frontier of trabecular bone formation inside and around the scaffolds. Concurrently, lymphangiogenesis is observed within the bone tissues, which effectively synergizes angiogenesis and osteogenesis into an "all-in-one" regenerative strategy, thereby highlighting a transformative avenue in tissue engineering. This advanced graft propels the field of bone tissue engineering and holds great translational potential in practical applications.