Mechanical‑immune feedback regulation in distraction osteogenesis: From mechanotransduction to immune microenvironment remodeling (Review).

Abstract

Distraction osteogenesis (DO) is a well‑established regenerative technique in which controlled tensile forces stimulate de novo bone formation between gradually separated bone segments. Although traditionally interpreted as a mechanically driven process, accumulating evidence indicates that successful DO depends on the coordinated regulation of mechanotransduction, immune microenvironment remodeling, angiogenesis, osteogenesis and subsequent bone remodeling. The present review summarizes current advances in the biological mechanisms of DO and proposes an integrative mechanical‑immune feedback framework to explain how mechanical cues and immune responses interact throughout the regenerative process. During the latency phase, osteotomy‑induced sterile injury initiates hematoma formation, inflammatory cell recruitment and early cytokine release, thereby establishing a preparatory microenvironment for tissue repair. During the distraction phase, various mechanical parameters, such as rate, rhythm, frequency and local tissue stiffness, are sensed by mechanosensitive structures, including integrin‑focal adhesion complexes, primary cilia, mechanosensitive ion channels and cytoskeleton‑associated nuclear signaling systems. These signals in turn activate downstream signaling pathways, including MAPK, Wnt/β‑catenin, bone morphogenetic protein‑Smad, Akt/mTOR/NF‑κB and Ras homolog family member A/Yes‑associated protein/transcriptional co‑activator with PDZ‑binding motif, which collectively promote osteogenic differentiation, matrix deposition and vascular remodeling. In parallel, mechanical stimulation can reshape the local immune milieu by regulating macrophage polarization, cytokine balance, osteoclast‑osteoblast coupling and angiogenesis‑osteogenesis interactions. During consolidation, immune‑mediated remodeling, extracellular matrix maturation and coordinated bone formation and resorption contribute to mineralization and structural integration of the regenerate. Based on these phase‑specific events, DO can be conceptualized as a dynamic process involving mechanical input, mechanotransduction, immune modulation, vascularized osteogenesis and remodeling feedback. This mechanical‑immune perspective provides a structured basis for understanding heterogeneity in DO outcomes across anatomical sites, age groups and pathological conditions, which may inform future optimization of distraction protocols, biomarker‑guided monitoring and targeted immunomodulatory strategies.