From Nociception to Regeneration: Temporal Reprogramming of Sensory Neurons in Skeletal Healing

Abstract

Skeletal healing is constrained by a long-standing paradox. Specifically, analgesia is clinically essential, yet neural signaling is biologically required for effective repair. Recent evidence showed that bone-innervating sensory neurons are temporally plastic rather than functionally fixed. After injury, these neurons transition from an early nociceptive state to a later pro-regenerative secretory program, including trophic factors that are required for periosteal progenitor expansion and successful callus formation. Importantly, this switch is better interpreted as stage-linked than clock-like, broadly tracking the evolution from inflammatory injury signaling toward reparative callus formation with timing varying by skeletal site, age, and injury context. This dynamic framework helps explain why broad neural inhibition can relieve pain, while inadvertently compromising osteogenesis. The translational implication is not to reduce analgesia but to redesign analgesia. Future strategies should decouple nociceptive suppression from the loss of regenerative neural output. Defining therapeutic time windows and modality-specific effects on neurotrophic signaling as well as pain and developing biomarker-guided rescue strategies will be essential for next-generation skeletal management that preserves pain control and biological healing.

Keywords

Biomedical / engineering / neurosciences / orthopedics / physiology

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