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REVIEW ARTICLE

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

Shaoshuai Song1,2,3* ,  Jingyi Zhang1,4 ,  Ya Fang1,3,5 ,  Wenxing Li6 ,  Hong Zeng7 ,  Zhen Fang1 ,  Tianchang Wang1 ,  Youzhuan Xie1* ,  Chaozong Liu8 ,  Jinwu Wang1*
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1 Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, China
3 Laboratory of Digital Medicine and 3D Bioprinting, National Facility for Translational Medicine (Shanghai), Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
4 Department of Biological Sciences, Xi’an Jiaotong-Liverpool University Faculty of Science, Soochow, Jiangsu Province, China
5 Department of Pharmacy, School of Pharmacy, Jiangsu Ocean University, Lianyungang, Jiangsu Province, China
6 Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment of the PRC, Nanjing, Jiangsu Province, China
7 Department of Rehabilitation, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
8 Institute of Orthopaedic & Musculoskeletal Science, University of College London, Royal National Orthopaedic Hospital, Stanmore, London, United Kingdom
OR 2025, 1(1), 8294 https://doi.org/10.36922/or.8294
Received: 13 September 2024 | Revised: 15 October 2024 | Accepted: 21 January 2025 | Published online: 21 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

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.

Graphical abstract
Keywords
Biomaterials
Bone organoids
Bone regeneration
Innervated osteogenesis microenvironment
Nerve–bone crosstalk
3D-bioprinted osteo-organoids
Funding
This study was supported by Noncommunicable Chronic Diseases-National Science & Technology Major Project (2024ZD0530900), the Foundation of National Center for Translational Medicine (Shanghai) SHU Branch (grant number: SUITM-2023007), the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (grant number: GZC20231663), National Natural Science Foundation of China (grant number: 82372377, 82372420), and the Postdoctoral Research Start Up Foundation of Shanghai Ninth People’s Hospital (grant number: Songshaoshuai-202301005).
Conflict of interest
The authors declared no conflicts of interest.
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