Cerium (Ce) is a promising candidate ion for application in bone tissue engineering (BTE) since it reduces the presence of reactive oxygen species. Ce-doped mesoporous bioactive glass nanoparticles (MBGNs) serving as vectors for the local application of Ce already demonstrated stimulating effects on the expression of pro-osteogenic genes in Saos-2 cells. So far, there is no evidence available about the effects of Ce-doped MBGNs on the viability, osteogenic differentiation and the formation of the osseous extracellular matrix (ECM) of primary human bone marrow-derived mesenchymal stromal cells (BMSCs). Therefore, in this study, the biocompatibility of the ionic dissolution products (IDPs) of MBGNs containing increasing concentrations of CeO2 (0.05 MCe-MBGNs, composition in mol%: 86.6SiO2-12.1CaO-1.3CeO2; and 0.2 MCe-MBGNs, composition in mol%: 86.0SiO2-11.8CaO-2.2CeO2) and unmodified MBGNs (composition in mol%: 86SiO2-14CaO) was evaluated using human BMSCs. Eventually, the impact of the MBGNs’ IDPs on the cellular osteogenic differentiation and their ability to build and mature a primitive osseous ECM was assessed. The Ce-doped MBGNs had a positive influence on the viability and stimulated the cellular osteogenic differentiation of human BMSCs evaluated by analyzing the activity of alkaline phosphate as a marker enzyme for osteoblasts in the present setting. Furthermore, the formation and calcification of a primitive osseous ECM was significantly stimulated in the presence of Ce-doped MBGNs in a positive concentration-dependent manner as demonstrated by an elevated presence of collagen and increased ECM calcification. The results of this in-vitro study show that Ce-doped MBGNs are attractive candidates for further application in BTE.

Mesoporous bioactive glass nanoparticles (MBGNs) have gained relevance in bone tissue engineering, especially since they can be used as vectors for therapeutically active ions like zinc (Zn) or copper (Cu). In this study, the osteogenic properties of the ionic dissolution products (IDPs) of undoped MBGNs (composition in mol%: 70 SiO2, 30 CaO) and MBGNs doped with 5 mol% of either Zn (5Zn-MBGNs) or Cu (5Cu-MBGNs; compositions in mol%: 70 SiO2, 25 CaO, 5 ZnO/CuO) on human bone marrow-derived mesenchymal stromal cells were evaluated. Extracellular matrix (ECM) formation and calcification were assessed, as well as the IDPs’ influence on viability, cellular osteogenic differentiation and the expression of genes encoding for relevant members of the ECM. The IDPs of undoped MBGNs and 5Zn-MBGNs had a comparable influence on cell viability, while it was enhanced by IDPs of 5Cu-MBGNs compared to the other MBGNs. IDPs of 5Cu-MBGNs had slightly positive effects on ECM formation and calcification. 5Zn-MBGNs provided the most favorable pro-osteogenic properties since they increased not only cellular osteogenic differentiation and ECM-related gene expression but also ECM formation and calcification significantly. Future studies should analyze other relevant properties of MBGNs, such as their impact on angiogenesis.

Due to the pivotal role of angiogenesis in bone regeneration, the angiogenic properties of biomaterials are of high importance since they directly correlate with the biomaterials’ osteogenic potential via ‘angiogenic-osteogenic coupling’ mechanisms. The impact of bioactive glasses (BGs) on vascularization can be tailored by incorporation of biologically active ions such as boron (B). Based on the ICIE16-BG composition (in mol%: 49.5 SiO2, 36.3 CaO, 6.6 Na2O, 1.1 P2O5, 6.6 K2O), three B-doped BGs have been developed (compositions in mol%: 46.5/45.5/41.5 SiO2, 36.3 CaO, 6.6 Na2O, 1.1 P2O5, 6.6 K2O, 3/4/8 B2O3). The influence of B-doping on the viability, cellular osteogenic differentiation and expression of osteogenic and angiogenic marker genes of bone marrow-derived mesenchymal stromal cells (BMSCs) was analyzed by cultivating BMSCs in presence of the BGs’ ionic dissolution products (IDPs). Furthermore, the influence of the IDPs on angiogenesis was evaluated in ovo using a chorioallantoic membrane (CAM) assay. The influence of B-doped BGs on BMSC viability was dose-dependent, with higher B concentrations showing limited negative effects. B-doping led to a slight stimulation of osteogenesis and angiogenesis in vitro. In contrast to that, B-doping significantly enhanced vascularization in ovo, especially in higher concentrations. Differences between the results of the in vitro and in ovo part of this study might be explained via the different importance of vascularization in both settings. The implementation of new experimental models that cover the ‘angiogenic-osteogenic coupling’ mechanisms is highly relevant, for instance via extending the application of the CAM assay from solely angiogenic to angiogenic and osteogenic purposes.