Targeted Release of Endogenous Cations from Xenograft Bone Driven by Fluoride Incorporation Contributes to Enhanced Bone Regeneration

Abstract

Xenograft, namely bone-devired biological apatite (BAp), is widely recognized as a favorable biomaterial in bone tissue engineering owing to biodegradability, biocompatibility, and osteoconductive properties. Substitutions of endogenous trace ions are thought to improve osteogenic capacity of xenograft when compared with synthetic hydroxyapatite (HAp). In order to modify the physicochemical and biological properties of apatite, different approaches to induce trace ion incorporation have been widely considered. In this study, we demonstrate that the incorporation of fluoride ion into porcine bone-derived biological apatite (pBAp) contributes to altered crystal morphology of the apatite, sustained release of fluoride, and targeted release of endogenous trace ions (e.g., magnesium and calcium) into the peripheral tissue microenvironment. This ionic balanced perimaterial microenvironment not only leads to superior proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs), but also accelerates new bone formation of the calvarial defect on a rat model via the activation of Wnt/β-catenin signaling. These promising observations may attribute to the controlled release of endogenous trace ions from xenograft to the peripheral tissue microenvironment driven by fluoride ion incorporation. Lastly, this study may provide a new insight to strengthen the osteogenicity of xenografts for clinical applications in the future. Funding Statement: This work was supported by National Natural Science Foundation of China (81470783, 81400550, 31370957), the Natural Science Foundation of Guangdong Province (2015A030311051, 2016A030310173), Shenzhen Innovative Technology Commission Grant (Nos. JCYJ20140414090541811 and JCYJ20160429185449249), Hong Kong Research Grant Council General Research Funds (RGC GRF) (Nos. 718913E, 17214516 and 772113M) and Hong Kong Health and Medical Research Fund (No. 03142446). Declaration of Interests: The authors declare no conflict of interest. Ethical Approval Statement: All procedures involving laboratory animal usage were in accordance with the institutional guidelines and were approved by the Animal Care and Use Committee of the Sun Yat-sen University (IACUC-DB-16-0103).