Click-chemistry hydrogel for blood vessel organoids self-sustaining delivery to enhance flap survival

Insufficient vascularization and ischemic stress severely limit flap survival in reconstructive surgery. To address this challenge, we developed a glucose-releasing hydrogel-encapsulated vascular organoid system (GL@BVOs) that integrates metabolic support with organoid-based therapy. The hydrogel integrates a photocrosslinked gelatin methacryloyl network with a Thiol-ene click-chemistry crosslinked laminarin network, constructed from C=C- and SH-modified laminarin while retaining its enzymatically cleavable backbone. By immobilizing glucose amylase within the matrix, the system enables gradual hydrolysis of laminarin fragments into monosaccharides, providing a sustained glucose source to support cells during ischemic stress. In a murine flap model, GL@BVOs significantly reduced necrotic area. Enhanced neovascularization was accompanied by attenuation of local inflammation and a marked shift in macrophage polarization toward a reparative phenotype. Mechanistically, multiplex cytokine profiling validation revealed that BVOs exhibited an enhanced paracrine secretion profile enriched in angiogenic and chemotactic factors, which promoted endothelial migration and tube formation under non-contact conditions. These findings support a paracrine-dominant, host-driven mode of vascular regeneration. Collectively, GL@BVOs represent a metabolically supported, paracrine-active platform that enhances flap survival and offers a promising strategy for ischemic tissue repair.