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5. Conclusion and perspectives heat or electricity effects for stimulating neurogenesis
and osteogenesis. For instance, near-infrared-light
Recent advances in the field of bone regeneration responsive carbon nitride nanosheets not only released
are grounded more in the neurovascularization of the NGF from the silk fibroin scaffolds but also produced
tissue-engineered bone implants and bone organoids. endogenous electricity under irradiation of the near-
Nevertheless, the crosstalk mechanisms between infrared-light, significantly accelerating the activation
neurogenesis and osteogenesis remain obscure as of neurogenesis along with osteogenesis. Such a
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compared to what is known about vascularized bone smart, responsive biomaterial provides a novel, non-
regeneration, posing a major challenge in biomaterial invasive neuromodulation strategy with improved tissue
development for bone tissue engineering and regenerative regeneration efficiency that is of vital importance for
medicine. The first part of this review offers a detailed regenerative medicine.
summary of the neuromodulatory molecules and the
corresponding signaling pathways within skeleton 5.3. Lack of standardized protocols for bone
development and bone wound healing processes, organoid preparation, preservation, and
describing the innervation and the crosstalk mechanisms transplantation
within the osteogenesis microenvironment. With the
introduction of recent developments of biomaterials Bone organoids represent an emerging biofabrication
with neuromodulatory effects, several major biomaterial technology and a promising regeneration therapy. Despite
strategies, including bioactive inorganic mineral doping, involvement in partial reproduction of vascular and neural
neurotrophic factor release, and neural cell-derived structures and mimicry of bone tissues’ essential functions,
exosome conjugation, and the innovative 3D bioprinting the current bone organoids should be engineered into
technologies, which promote vascular, neural growth more sophisticated architectures, and their preparation
and bone regeneration in bone injury repair and bone and preservation methods should be standardized to guide
organoid development processes, are presented. Although autogenous bone graft replacement in future.
bone organoids provide a promising therapy for refractory Despite coverage on the nerve–bone crosstalk
bone defect repair, some existing intractable issues mechanisms and their applications in tissue engineering-
and challenges need to be addressed for future clinical based bone regeneration, the current review may contain
application. less-rigorous descriptions and lack a discussion of certain
key studies and evidence due to incomplete literature
5.1. Lack of strategies for regulating central nerve–
bone crosstalk selection, which is possibly attributed to the strict
adherence to publication years and term combinations
In numerous studies focusing on the roles of skeletal during literature.
peripheral nerves containing sensory nerves and
sympathetic nerves in bone health and regeneration, Acknowledgments
the stimuli to sensory neurons are often regarded as an We especially thank the support from the National Center
important approach for the rational design and enhanced for Translational Medicine (Shanghai) SHU Branch (project
osteogenic function of the current biomaterials. Moreover, number: SUITM-2023007).
brain-derived neuroactive substances are also involved in
communication between the skeleton and nervous systems, Funding
maintaining tissue homeostasis for bone injury healing.
Without feasible strategies, the modulation of brain- This study was supported by Noncommunicable Chronic
derived nerve activity and central nerve–bone crosstalk Diseases-National Science & Technology Major Project
is still a key challenge for biomaterial development and (2024ZD0530900), the Foundation of National Center for
should be further investigated in depth for possible clinical Translational Medicine (Shanghai) SHU Branch (grant
application. number: SUITM-2023007), the Postdoctoral Fellowship
Program (Grade C) of China Postdoctoral Science
5.2. Lack of non-invasive neuromodulation Foundation (grant number: GZC20231663), National
strategies for promoting innervated bone Natural Science Foundation of China (grant number:
regeneration 82372377, 82372420), and the Postdoctoral Research Start
Neurons can sense extracellular biophysical environments, Up Foundation of Shanghai Ninth People’s Hospital (grant
such as light, stress, and electromagnetic fields, and secrete number: Songshaoshuai-202301005).
more neurotransmitters and NGFs under the stimuli. Conflict of interest
Correspondingly, the functional biomaterials should
respond to the external physical signals, generating The authors declared no conflicts of interest.

Volume 1 Issue 1 (2025) 12 doi: 10.36922/OR8294