A Dose‐Dependent Spatiotemporal Response of Angiogenesis Elicited by Zn Biodegradation during the Initial Stage of Bone Regeneration

Abstract Zinc (Zn) plays a crucial role in bone metabolism and imbues biodegradable Zn‐based materials with the ability to promote bone regeneration in bone trauma. However, the impact of Zn biodegradation on bone repair, particularly its influence on angiogenesis, remains unexplored. This study reveals that Zn biodegradation induces a consistent dose‐dependent spatiotemporal response in angiogenesis,both in vivo and in vitro. In a critical bone defect model, an increase in Zn release intensity from day 3 to 10 post‐surgery is observed. By day 10, the CD31‐positive area around the Zn implant significantly surpasses that of the Ti implant, indicating enhanced angiogenesis. Furthermore,angiogenesis exhibits a distance‐dependent pattern closely mirroring the distribution of Zn signals from the implant. In vitro experiments demonstrate that Zn extraction fosters the proliferation and migration of human umbilical vein endothelial cells and upregulates the key genes associated with tube formation, such as HIF‐1α and VEGF‐A, peaking at a concentration of 22.5 µM. Additionally, Zn concentrations within the range of 11.25−45 µM promote the polarization of M0‐type macrophages toward the M2‐type, while inhibiting polarization toward the M1‐type. These findings provide essential insights into the biological effects of Zn on bone repair, shedding light on its potential applications.