Nickan Research Institute Immunopathologia Persa 2423-8015 12 2 2026 07 01 Inflammation and bone healing; pathophysiological foundations of fracture and biological strategies for the treatment of nonunion e43983 e43983 10.34172/ipp.2026.43983 EN Asghar Elmi https://orcid.org/0000-0002-8936-3857 Sina Najafi https://orcid.org/0000-0002-1357-7795 Ahmad Behroz Rasikh https://orcid.org/0009-0003-4073-4519 Journal Article 10.34172/ipp.2026.43983 2025 08 22 2026 03 03 Fracture healing involves coordinated phases of inflammation, callus formation, and remodeling, regulated by complex interactions among immune mediators, bone cells, and vascular networks. Disruption of these processes can result in delayed union or nonunion, a significant orthopedic challenge. This review synthesizes current evidence on normal repair physiology, nonunion mechanisms, biomarkers, and emerging therapies. Key topics include immune cell and cytokine dynamics, extracellular matrix (ECM) deposition, angiogenesis, and osteoclast–osteoblast coordination; pathophysiological drivers of nonunion such as persistent inflammation, impaired osteogenesis, macrophage polarization imbalance, microvascular dysfunction, systemic risk factors, and characteristic radiological–histological profiles. The role of inflammatory, bone formation, and angiogenesis biomarkers, through gene expression and immunohistochemistry is examined, along with therapeutic strategies using growth factors, cell-based treatments, engineered scaffolds, and targeted immunomodulation. Comparative analyses of animal and in vitro models highlight their translational value and limitations, and evidence is discussed regarding conventional versus biologically driven approaches to optimize fracture repair outcomes.