Engineering high-fidelity bone organoids: Operational classification, multilineage crosstalk, biofabrication evidence, and translational validation

Abstract

Bone organoids are emerging as three-dimensional models of skeletal development, disease and regeneration. The term bone organoid is applied inconsistently to osteogenic spheroids, scaffold-dominated constructs and self-organizing skeletal tissues. This review establishes an operational five-class framework that distinguishes osteogenic spheroids, bone-like microtissues, engineered skeletal constructs, bone organoids and high-fidelity bone organoids. Core organoid criteria are separated from advanced, application-dependent features, and a structured evidence map applies the terminology to representative original studies. We summarize the coordinated osteogenic, chondrogenic, vascular, neural and immune programs that govern bone formation and examine how cell source, induction sequence, matrix composition, mass transport and mechanical stimulation affect maturation. Inkjet, extrusion, laser-assisted and photocuring-based bioprinting are compared using common technical and biological criteria, including resolution, viscosity, cell density, injury mechanisms, mineral compatibility, perfusable channels, scalability and direct bone-organoid evidence. Current data show that printing reliably controls initial geometry, but rarely demonstrates improved self-organization, multilineage interaction or long-term function relative to composition-matched controls. Translational requirements are therefore evaluated separately for developmental and genetic disease, metabolic and inflammatory disease, tumor-bone interactions, drug screening and regenerative grafts. We also define material-aware controls for active mineralization and scale-resolved mechanical testing. Available models reproduce important subsets of bone biology; however, among the representative studies examined, no single platform yet demonstrates hierarchical matrix maturation, coupled formation-resorption and controlled mechanosensitivity in combination. These evidence thresholds provide a practical basis for terminology, benchmarking and future translation.

Abstract of "Engineering high-fidelity bone organoids: Operational classification, multilineage crosstalk, biofabrication evidence, and translational validation" by Huang Y, Zhang T, Chen S et al., https://doi.org/10.1016/j.mtbio.2026.103676, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.