Maladaptive immune-fibrotic axis drives impaired long bone regeneration under mechanical instability

Delayed and nonhealing fractures, affecting 5 to 10% of cases, are associated with prolonged disability and diminished quality of life. Although acute inflammation is required to initiate repair, persistent mechanical instability can sustain maladaptive immune and fibrotic responses that impede regeneration. Existing animal models do not adequately recapitulate mechanical instability, the principal driver of hypertrophic nonunion in clinical settings, thereby limiting translational relevance. We developed a murine model of delayed fracture healing using tunable intramedullary fixation to impose controlled interfragmentary strain. High-strain conditions (low-stiffness nail, 15 to 30% strain) produced enlarged calluses characterized by delayed ossification, increased fibrotic tissue (3.3-fold, P = 0.0147), and reduced biomechanical integrity (1.6-fold decrease in stiffness, P = 0.024) relative to low-strain controls (high-stiffness nail,