Immune-Guided Bone Healing: The Role of Osteoimmunity in Tissue Engineering Approaches.

The skeletal and immune systems are intricately linked, forming a dynamic interface that regulates both bone homeostasis and immune function. This bidirectional relationship, central to the field of osteoimmunology, highlights how bone and immune cells interact via shared progenitors and signaling pathways. Osteoclasts and osteoblasts not only coordinate bone remodeling but also influence hematopoietic and immune functions within the bone marrow microenvironment. The concept of the "bone immune system" underscores this crosstalk, particularly in pathological and regenerative contexts. Despite progress, contradictory findings complicate our understanding of cytokine activity. Pro-inflammatory mediators such as TNF-α and IL-17 are typically associated with bone loss, yet under certain conditions, they paradoxically promote repair by stimulating osteoblast differentiation. Conversely, anti-inflammatory cytokines like IL-10 and TGF-β are generally protective, but their effects vary depending on local context, sometimes even impairing regeneration. These inconsistencies highlight unresolved questions and gaps in mechanistic insight into immune-bone interactions. Bone tissue engineering (BTE) has advanced through biomimetic scaffolds, osteogenic cells, and bioactive molecules, offering hope for large defect repair. However, clinical translation remains limited, largely because immune modulation is not fully integrated into scaffold design. Current preclinical models often fail to capture the complexity of immune-skeletal interplay, reducing predictive value. Addressing these gaps requires improved models and systematic evaluation of immunoregulatory biomaterials, paving the way for more effective and personalized regenerative therapies.