A Dose-Dependent Spatiotemporal Response of Angiogenesis Elicited by Zn Biodegradation During The Initial Stage of Bone Regeneration.

The indispensable role of zinc (Zn) in bone metabolism endows biodegradable Zn-based materials with the bioactivity to facilitate bone regeneration in bone trauma. However, the impact of Zn biodegradation on the progress of bone repair remains to be unfolded, especially the angiogenesis, which plays a vital role in the subsequent bone regeneration. It is found that a consistent dose-dependent spatiotemporal response of angiogenesis is induced by Zn biodegradation both in vivo and in vitro. In a critical bone defect model, the intensity of Zn release due to biodegradation increases over the 3 to 10 days postoperative. Meanwhile, the area ratio of the CD31-positive area around the Zn implant is significantly higher than that of the Ti implant at day 10, indicating enhanced angiogenesis. Furthermore, the angiogenesis shows a distance-dependent feature that correlates well with the intensity distribution of the Zn signal from the Zn implant. In vitro, Zn extraction promotes the proliferation and migration of human umbilical vein endothelial cells (HUVECs) and upregulates the key gene for tube formation HIF-1α and VEGF-A, with a peak concentration of 22.5 μм. Additionally, Zn concentration in the range of 11.25-45 μм promotes M0-type macrophage polarization towards the M2-type while inhibiting the polarization towards the M1-type. The findings here provide essential information for a better understanding of the biological effects of Zn on bone repair. This article is protected by copyright. All rights reserved.