Neuroimmune Regulation in Posttraumatic Bone Repair: From Inflammatory Transition to Neurovascular Coupling and...

Posttraumatic bone repair is not a simple osteogenic process but a spatiotemporal dynamic reconstruction involving the coordinated participation of neural, immune, vascular, and bone-lineage cells. Clinically, structural healing does not always align with pain relief, weight-bearing recovery, and improvement in motor function, suggesting that beyond mechanical stability and bone formation, neuro-immune regulation may govern overall repair quality. This article adopts a structured narrative review framework to discuss the stage-specific roles of the neuro-immune axis in post-traumatic bone repair, focusing on inflammatory initiation and resolution, reinnervation, neurovascular coupling, and functional outcomes. Existing studies on fractures and bone defects indicate that neuropeptides, neurotransmitters, and neurotrophic signals derived from sensory and autonomic nerves can modulate immune cell recruitment and functional status, and contribute to vascularization, osteogenesis, and bone remodeling. The effects of neural signals are highly context-dependent. Appropriate and temporally coordinated neural activation may support inflammatory resolution and tissue reconstruction, whereas nerve injury, sustained excitation, or signaling dysregulation may be associated with abnormal reinnervation, pain sensitization, and impaired repair. The relationship between neural and immune responses is not a fixed unidirectional upstream-downstream cascade but is better characterized as stage-dependent parallel activation and bidirectional regulation. Some mechanisms are still primarily derived from models of peripheral nerve injury, chronic pain, or other tissues, and their applicability to traumatic bone repair requires direct validation. This article further evaluates the evidence base, safety, potential application scenarios, and translational pathways of pharmacological modulation of neural signals, modulation of local immune function, extracellular vesicles, neuroaffinity biomaterials, and neuromodulation techniques. Overall, localized, stage-specific, and adjunctive interventions hold the most immediate translational potential, offering a bridge between structural healing, pain control, and functional recovery. However, their intervention windows, safety boundaries, and beneficiary populations still need to be clarified through clinically relevant models, dynamic biomarkers, and patient stratification.