Hypoxia‐Mimicking Mediated Macrophage‐Elimination of Erythrocytes Promotes Bone Regeneration via Regulating Integrin αvβ3/Fe2+‐Glycolysis‐Inflammation

Abstract Erythrocytes are the dominant component of a blood clot in terms of volume and number. However, longstanding compacted erythrocytes in blood clots form a physical barrier and make fibrin mesh more anti‐fibrinolytic, thus impeding infiltration of mesenchymal stem cells. The necrosis or lysis of erythrocytes that are not removed timely can also lead to the release of pro‐inflammatory toxic metabolites, interfering with bone regeneration. Proper bio‐elimination of erythrocytes is essential for an undisturbed bone regeneration process. Here, hypoxia‐mimicking is applied to enhance macrophage‐elimination of erythrocytes. The effect of macrophage‐elimination of erythrocytes on the macrophage intracellular reaction, bone regenerative microenvironment, and bone regeneration outcome is investigated. Results show that the hypoxia‐mimicking agent dimethyloxalylglycine successfully enhances erythrophagocytosis by macrophages in a dose‐dependent manner primarily by up‐regulating the expression of integrin α v β 3 . Increased phagocytosed erythrocytes then regulate macrophage intracellular Fe 2+ ‐glycolysis‐inflammation, creating an improved bone regenerative microenvironment characterized by loose fibrin meshes with down‐regulated local inflammatory responses in vivo, thus effectively promoting early osteogenesis and ultimate bone generation. Modulating macrophage‐elimination of erythrocytes can be a promising strategy for eradicating erythrocyte‐caused bone regeneration hindrance and offers a new direction for advanced biomaterial development focusing on the bio‐elimination of erythrocytes.