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REVIEW ARTICLE
Nerve–bone crosstalk manipulates bone organoid

development and bone regeneration: A review and
perspectives

Shaoshuai Song 1,2,3† * , Jingyi Zhang 1,4† , Ya Fang 1,3,5 , Wenxing Li , Hong Zeng , Zhen Fang , Tianchang Wang ,
7
1
1
6
Youzhuan Xie * , Chaozong Liu , and Jinwu Wang *
1
1
8
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
† These authors contributed equally to this work.
*Corresponding authors: Shaoshuai Song (shsh_song@163.com); Youzhuan Xie (drxie_miss@163.com);
Jinwu Wang (wangjw-team@shsmu.edu.cn)

Citation: Song S, Zhang J, Fang Y, Abstract
et al. Nerve–bone crosstalk
manipulates bone organoid
development and bone regeneration: As an innovative regenerative medicine technology, bone organoids represent a promising
A review and perspectives. Organoid therapy for refractory bone injury repair, whereas the key to fabricating bone organoids
Res. 2025;1(1):8294. is grounded in the utilization of biomaterials with osteogenesis cues. Considering the
doi: 10.36922/OR8294 intricate crosstalk between neurons and osteocytes would support bone organoid
Received: September 13, 2024 development and bone wound healing, it is extremely essential to predicate biomaterial
Revised: October 15, 2024 design and osteo-organoid construction on understanding the roles of neural growth in
ossification center formation and bone-like tissue development. Therefore, this review
Accepted: January 21, 2025 presents the recent advances of bone organoids with innervated ossification centers after
Published online: March 21, 2025 the detailed introduction in the nerve–bone crosstalk. Beginning with the exploration
Copyright: © 2025 Author(s). of underlying interaction mechanisms within the osteogenic microenvironment,
This is an Open-Access article the importance of the nerve–bone crosstalk on skeleton development and bone
distributed under the terms of the regeneration is emphasized at first. The following discussions mainly include diverse
Creative Commons Attribution
License, permitting distribution, and biomaterial strategies designed to enhance osteogenesis through early innervation, such
reproduction in any medium, which as the incorporation of bioactive minerals, controlled release of neurotrophic factors,
provided that the original work is and exosome-mediated nerve regeneration. Last but not least, the review highlights the
properly cited.
advanced technologies in fabricating tissue-engineered bone organoids, with a focus
Publisher’s Note: AccScience on the applications of cell-laden and multicellular 3D-bioprinted bone microtissues for
Publishing remains neutral with regard
to jurisdictional claims in published constructing bone organoids with neurovascularization. These insights are critical to
maps and institutional affiliations. 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.

Keywords: Biomaterials; Bone organoids; Bone regeneration; Innervated osteogenesis
microenvironment; Nerve–bone crosstalk; 3D-bioprinted osteo-organoids

Volume 1 Issue 1 (2025) 1 doi: 10.36922/OR8294