Mechanical Distraction Engages a Neuro-Immune Program to Drive Regenerative Soft-Tissue Healing in Ilizarov Bone...

The Ilizarov bone transport technique reproducibly accelerates soft-tissue healing around the distraction zone through an unexplained mechanism. Using a rat dynamic bone transport (DBT) model, we test whether a sensory neuro-immune axis links sustained mechanical distraction to tissue regeneration. DBT induced sensory reinnervation and established a calcitonin gene-related peptide (CGRP)-rich neurotrophic niche, which reorganized early inflammation and promoted vascular-epithelial expansion. Bulk RNA-seq revealed a neurodevelopmental transcriptional program, while single-cell RNA-seq showed reduced inflammatory myeloid subsets and expansion of reparative Arg1⁺ macrophages and protective neutrophil states. Capsaicin ablation of transient receptor potential vanilloid 1-positive (TRPV1⁺) sensory fibers abolished these transitions and DBT-enhanced repair, and local CGRP receptor blockade substantially attenuated it. We propose that the upstream step is mechanosensory; however, this component is a framework supported by correlative expression data, including Piezo1 detection in wound macrophages, and by functional perturbations of sensory nerves. Local strain was not measured, and direct mechanotransduction at the cellular level remains to be demonstrated. These findings indicate that Ilizarov-type distraction engages a sensory neuro-immune program that orchestrates inflammation resolution and soft-tissue regeneration, providing a mechanistic framework for a long-standing clinical observation.