Hydrogel-Based Mechano-Immunomodulation in Bone Fracture Healing: Mechanical Regulation of Macrophage Phenotypes,...

Bone fracture healing is a meticulously regulated process encompassing the inflammatory, reparative, and remodelling phases. Macrophages serve as pivotal coordinators within this cascade, with their polarisation from pro-inflammatory M1 to proregenerative M2 phenotypes, which play a crucial role in determining the repair outcome. Emerging evidence underscores the significant influence of mechanical cues such as strain, stiffness, vibration, and scaffold topography on macrophage behaviour, thereby linking mechanobiology with immunology. This review summarises the current knowledge on mechano-immunomodulation in fracture repair, emphasising how mechanotransduction pathways, including Piezo1, YAP/TAZ, and PI3K/AKT, affect macrophage polarisation and their interactions with mesenchymal stem cells, osteoblasts, and endothelial cells. This review examined biomaterial strategies that leverage mechanical properties ranging from ceramic scaffolds and calcium phosphate coatings to hydrogels and advanced magnetic/electrical interfaces to shape the osteoimmune niche. Translational perspectives highlight mechanobiologics, immunometabolic reprogramming, and personalised loading regimens as next-generation approaches for fracture care. The remaining challenges include context-dependent macrophage responses, limited bone-specific mechanosensing data, and the need for standardised models and regulatory-compliant biomaterials. Collectively, these insights establish mechano-immunomodulation as a promising paradigm for enhancing bone regeneration and addressing the limitations of the current fixation-centric therapies.