Hydrogel-extracellular vesicle platforms: orchestrating the osteogenic microenvironment for cell-free bone regeneration.

Abstract

Bone defects remain difficult to treat because impaired vascularization, inflammation, infection and metabolic dysfunction limit endogenous repair. Unencapsulated extracellular vesicles (EVs) may also be rapidly cleared from defect sites. Hydrogel-EV systems combine vesicle bioactivity with local retention, controlled release and structural support, offering a cell-free strategy for bone regeneration. This review summarizes EV sources, separation, characterization and cargo, and outlines the endosomal biogenesis of exosomes. We examine EV-mediated regulation of osteogenesis, angiogenesis, immunity and osteoclast-mediated resorption. Hydrogel materials, EV-loading approaches, passive and stimuli-responsive release, and methods for evaluating EVs within hydrogels are discussed. Applications in uncomplicated, infected and diabetes-associated bone defects are compared according to their pathological microenvironments. Translational barriers include heterogeneous EV preparations, inconsistent separation and dosing standards, inadequate mechanical performance, and mismatched hydrogel degradation and bone-healing kinetics. Insufficient biodistribution and long-term safety data further limit clinical translation. This review provides a framework for developing hydrogel-EV platforms for bone regeneration.