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including the introduction of bioactive minerals, the norepinephrine (NE), neuropeptide Y (NPY), acetylcholine
release of neurotrophic factors, and exosome-mediated (ACh), and choline acetyltransferase, which are widely
innervation; and (3) major approaches to fabricating distributed in the Haversian system and the Volkmann’s
tissue-engineered bone organoids with enhanced nerve– canals. Similarly, sensory nerves also play a significant
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bone crosstalk, highlighting the applications of cell- role in bone metabolism and regeneration with abundant
laden and multicellular 3D-bioprinted constructs in neuropeptide secretion (calcitonin gene-related peptide
endogenous organoid activation and in vitro organoid [CGRP] and substance P [SP]) in the periosteum, bone
construction, respectively. We hope this review will be marrow, epiphyseal, and metaphyseal regions. Notably,
instructive in designing the novelty biomaterials for these sensory nerves extend along the growth plates of the
building innervated osteo-organoids and accelerating epiphysis, reaching into the bone tissue and establishing
bone regeneration, which may be of important value for direct contact with osteoclasts and secreting nerve growth
further clinical translation. factors (NGFs) essential for the survival and recruitment of
The literature search was conducted using the peptide fibers. 25-27
keyword Boolean operation, which includes “osteo- 2.2. Phenotypic changes of skeletal nerves during
organoids,” “bone organoids,” “neurogenesis,” “nerve,” bone injury
“bone regeneration,” and “tissue engineering,” on PubMed
and Web of Science databases. The accessible literatures When the skeletal system is subjected to mechanical injury
were selected according to the criteria that focus on the or pathological changes, the nerves within bone tissues
applications of neurogenesis and nerve–bone crosstalk in are often interfered with and rapidly respond to traumas.
skeleton development, biomaterial synthesis, bone tissue Following a bone injury, the signals from the lesion travel
engineering, and regeneration medicine. backward along the proximal axons to the cell bodies,
followed by transmission into the brain through dorsal
2. Nerve–bone crosstalk within root ganglion (DRG), whereas various neuropeptides
osteogenesis microenvironment and neurotransmitters, such as CGRP and SP expressed
around the injury site, initiate a series of feedback processes
2.1. Distributions and functions of skeletal nerves of neuromodulation for nerve restoration and bone
As presented in Figure 2, the skeletal system is innervated healing. 28,29
by a dense nerve network originating from both the central Recent research has shown an increase in NGF at the
nervous system (CNS) and the peripheral nervous system early stage of fracture, directly activating sensory neurons
(PNS). These nerves play a crucial role in the regulation with high expression of the NGF receptor tyrosine kinase
of bone metabolism and the response to pathological (TrkA+) to transmit the injury signals. Simultaneously,
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changes after bone injury. 18-20 As a signal transduction hub the distal axons undergo Wallerian degeneration, leading to
of mammal bodies, the CNS mainly contains the brain the deterioration of axons, myelin, and blood-nerve barrier.
and spinal cord and influences bone metabolism through Cells residing in the nervous system, such as mesenchymal
the production of neurotransmitters, such as serotonin cells and Schwann cells (SCs), undergo transformation and
(5-HT), which can modulate bone formation, absorption, proliferation following nerve degeneration. Subsequently,
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21
and energy consumption. In addition, the CNS can the SCs relocate to the lesion sites to clear debris for
express high levels of semaphorin 3A (Sema3A) in the restoration of axonal connection and simultaneously
hypothalamus, which may help direct the migration and recruit macrophages to aid in the clearance process. The
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innervation of neurons within the skeletal system. 22 temporary channels formed by the SC basal tubes guide
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The PNS, distributed in the periosteum, bone marrow, them to the target organ for bone reactivation. On the
cortex, and trabecular bone, is an information transmitter other hand, the inflammation at the fracture site sensitizes
associating the CNS with the skeleton system and is divided the sensory nerves, and the inflammatory factors released
into sensory and motor nerves, with the latter consisting from the activated immune cells also elevate the extremely
of both sympathetic and parasympathetic components. 18,23 high nerve sensitivity with neurotransmitter accumulation,
Similar to the CNS, these peripheral nerves also secrete as evidenced by the high expression of brain-derived
neuroactive components surrounding osteocytes, such neurotrophic factor (BDNF) and its receptor TrkB in
as neurotransmitters, neuropeptides, axonal growth, and endothelial cells and osteoblasts, as well as the high local
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neurotrophic factors, which regulate bone metabolism expression of Sema3A. Furthermore, the DRG, a main
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through the communications between the nerve resident connection pathway between the CNS and the skeleton
cells and skeletal cells. As an important motor nerve of system, also plays a pivotal role in bone remodeling and
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the PNS in the skeleton system, the sympathetic nervous homeostasis after bone fracture healing. It has been
system innervates the periosteum with high expression of presumed by the DRG transcriptome analysis that several

Volume 1 Issue 1 (2025) 3 doi: 10.36922/OR8294