Dynamic microenvironments for bone organoids: spatiotemporal regulation of angiogenic-osteogenic coupling through advanced hydrogel design

Abstract

Bone organoids are promising platforms for studying skeletal development, disease and regeneration, but their broader application is limited by inadequate vascularization and the difficulty of recapitulating the evolving native bone microenvironment. In vivo, angiogenesis and osteogenesis are tightly coupled processes that overlap spatially and temporally, with their relative dominance shifting during tissue development and repair. Conventional hydrogels are generally too static to reproduce this dynamic interplay. This Review examines how dynamic hydrogels can provide adaptive biochemical, mechanical and structural cues to direct angiogenic–osteogenic coupling in bone organoids. Tunable degradation, viscoelasticity, stimulus responsiveness, and release kinetics may promote an early angiogenic bias while supporting overlapping and progressively enhanced osteogenic differentiation, extracellular matrix deposition, and mineral maturation. The Review distinguishes direct evidence from bone organoid or organoid-like models from indirect evidence derived from related bone tissue-engineering systems. We discuss experimentally demonstrated and proposed strategies, including temporally biased delivery systems, stress-relaxing networks, piezoelectric hydrogels, and spatial patterning, and assess their potential effects on vascular stability, lineage specification, and host integration. We also outline key challenges facing the translation of dynamic hydrogel-based bone organoids into regenerative grafts. By recapitulating the developmental logic of bone formation, dynamic hydrogels may advance the engineering of vascularized bone tissues.