Nerve–bone crosstalk manipulates bone organoid development and bone regeneration: A review and perspectives

As an innovative regenerative medicine technology, bone organoids represent a promising therapy for refractory bone injury repair, whereas the key to fabricating bone organoids is grounded in the utilization of biomaterials with osteogenesis cues. Considering the intricate crosstalk between neurons and osteocytes would support bone organoid development and bone wound healing, it is extremely essential to predicate biomaterial design and osteo-organoid construction on understanding the roles of neural growth in ossification center formation and bone-like tissue development. Therefore, this review presents the recent advances of bone organoids with innervated ossification centers after the detailed introduction in the nerve–bone crosstalk. Beginning with the exploration of underlying interaction mechanisms within the osteogenic microenvironment, the importance of the nerve–bone crosstalk on skeleton development and bone regeneration is emphasized at first. The following discussions mainly include diverse biomaterial strategies designed to enhance osteogenesis through early innervation, such as the incorporation of bioactive minerals, controlled release of neurotrophic factors, and exosome-mediated nerve regeneration. Last but not least, the review highlights the advanced technologies in fabricating tissue-engineered bone organoids, with a focus on the applications of cell-laden and multicellular 3D-bioprinted bone microtissues for constructing bone organoids with neurovascularization. These insights are critical to the development of novel biomaterials to construct innervated osteo-organoids, with significant implications for future clinical applications, while also exploring the potential to advance bone regenerative therapies through enhanced nerve–bone crosstalk and laying the foundation for innovative translational research in this field.