Modular living assembly of bone organoids with in situ guided vascularization.

Abstract

Organoids have emerged as a powerful strategy to recapitulate tissue architecture and function, opening new avenues for regenerative medicine. However, clinical translation is hindered by limited control over the assembly of heterogeneous organoid units and the resulting loss of spatial organization at the tissue scale. In addition, macroscale organoid constructs face diffusion-limited oxygen and nutrient transport, leading to central necrosis. The poor vascular integration can hinder the further development and maturation of the organoids, ultimately preventing functional integration. To address these limitations, we developed <b>Neo-Organoid Visualization and Assembly (NOVA)</b>, a living assembly strategy that integrates bioprinting with hydrogel-based bio-adhesive assembly to enable high-throughput modular assembly of bone organoids. Using this strategy, we generate a tissue-scale tubular bone organoid graft formed with in situ unidirectional guided vascularization. This structure enables the spatiotemporal coupling of angiogenesis and osteogenesis, enhances the maturation and function of bone organoids, and holds potential for one-step surgical transplantation with rapid perfusion to repair defects.