[Neural regulation mechanism in bone regeneration]

The global aging population has intensified the incidence of degenerative bone diseases and the therapeutic demand for traumatic bone injuries, thereby making bone regenerative medicine a research focus. There is a close connection and interaction between the skeletal system and the nervous system, and innervation plays an indispensable regulatory role in the process of bone regeneration: the sympathetic nervous system exerts a negative regulatory effect during bone regeneration, while the parasympathetic nervous system plays a positive regulatory role in this process. Nerve fibers within bones are distributed alongside blood vessels, with their density decreasing from the periosteum to the cancellous bone. Nerve signals regulate bone regeneration either by directly acting on target cell receptors or indirectly modulating the metabolism of the local microenvironment (such as the levels of inflammatory factors and the supply of nutrients). A variety of neuropeptides (e.g., calcitonin gene-related peptide, substance P, neuropeptide Y, vasoactive intestinal peptide, etc.) play a crucial role in bone tissue, constructing a "neuro-osseous" regulatory axis, which in turn regulates the osteoblast-osteoclast balance, angiogenesis, and the homeostasis of the local microenvironment. This review focuses on the neural regulatory mechanisms in bone regeneration, with an emphasis on sorting out the functions of key neuropeptides and related neurotransmitters. Neuropeptides are the core mediators of neuro-osseous interaction; however, the interaction network among neuropeptides remains to be further clarified, which requires the application of advanced in vitro models such as three-dimensional bioprinted bone models and organoid technology, as well as cutting-edge techniques like single-cell sequencing for analysis. In the future, the integration of neural regulation strategies with traditional bone regeneration technologies, along with the expansion into interdisciplinary fields such as neuro-vascular and neuro-muscular fields, is expected to provide new directions for the treatment of bone defects and large maxillofacial tissue defects, and promote the transformation of regenerative medicine from prosthetic treatment to functional and neurotized tissue regeneration.