Ameloblastoma is a benign, epithelial cancer of the jawbone, which causes bone resorption and disfigurement to patients affected. The interaction of ameloblastoma with its tumour stroma drives invasion and progression. We used stiff collagen matrices to engineer active bone forming stroma, to probe the interaction of ameloblastoma with its native tumour bone microenvironment. This bone-stroma was assessed by nano-CT, transmission electron microscopy (TEM), Raman spectroscopy and gene analysis. Furthermore, we investigated gene correlation between bone forming 3D bone stroma and ameloblastoma introduced 3D bone stroma. Ameloblastoma cells increased expression of MMP-2 and -9 and RANK temporally in 3D compared to 2D. Our 3D biomimetic model formed bone nodules of an average surface area of 0.1 mm2 and average height of 92.37 $$\pm $$ ± 7.96 μm over 21 days. We demonstrate a woven bone phenotype with distinct mineral and matrix components and increased expression of bone formation genes in our engineered bone. Introducing ameloblastoma to the bone stroma, completely inhibited bone formation, in a spatially specific manner. Multivariate gene analysis showed that ameloblastoma cells downregulate bone formation genes such as RUNX2. Through the development of a comprehensive bone stroma, we show that an ameloblastoma tumour mass prevents osteoblasts from forming new bone nodules and severely restricted the growth of existing bone nodules. We have identified potential pathways for this inhibition. More critically, we present novel findings on the interaction of stromal osteoblasts with ameloblastoma.

Diabetic patients have an increased risk of fracture and an increased occurrence of impaired fracture healing. Diabetic and hyperglycaemic conditions have been shown to impair the cellular response to hypoxia, via an inhibited hypoxia inducible factor (HIF)-1α pathway. We investigated, using an in vitro hyperglycaemia bone tissue engineering model (and a multidisciplinary bone characterisation approach), the differing effects of glucose levels, hypoxia and chemicals known to stabilise HIF-1α (CoCl2 and DMOG) on bone formation. Hypoxia (1% O2) inhibited bone nodule formation and resulted in discrete biomineralisation as opposed to the mineralised extracellular collagen fibres found in normoxia (20% O2). Unlike hypoxia, the use of hypoxia mimetics did not prevent nodule formation in normal glucose level. Hyperglycaemic conditions (25 mM and 50 mM glucose) inhibited biomineralisation. Interestingly, both hypoxia mimetics (CoCl2 and DMOG) partly restored hyperglycaemia inhibited bone nodule formation. These results highlight the difference in osteoblast responses between hypoxia mimetics and actual hypoxia and suggests a role of HIF-1α stabilisation in bone biomineralisation that extends that of promoting neovascularisation, or other system effects associated with hypoxia and bone regeneration in vivo. This study demonstrates that targeting the HIF pathway may represent a promising strategy for bone regeneration in diabetic patients.

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Introduction Bioactive glasses (BGs) provide an alternative to allogenic bone grafts. Various ions can be incorporated into the BGs structure to further influence regenerative or antimicrobial properties. Boron has recently been purposed as element that can be incorporated into BGs to promote desirable cellular regenerative response. This study aims to systematically review literature to determine the level of evidence that boron bioactive glasses (BBGs) and boron can promote desirable bone regenerative responses both in vitro and in vivo. Methods A systematic review of Web of Science was conducted in accordance with PRISMA guidelines. Data collected included bone cell behavioural analysis in response to boron or BBG compared to controls. Material properties of BBG (mechanical properties, degradation rate) compared to BG were compared. Results A total of 105 articles were included; 98 regarding BBG, and 12 articles studying the effect of boron. A higher biodegradation rate was observed in BBG compared with silicate-based BGs. BBGs have a lower compressive strength and increased fragility, as the percentage of B203 increases. 16 articles demonstrated a positive correlation with BBG and expression of OCN, VEGF, osteopontin, and RUNX2. Overall, metabolic activity of cells up to 14 days was lower in comparison to media and silicate BG. Conclusion BBGs have gained increased attention in the literature but the lack of heterogeneity and paucity of data does not provide convincing evidence of the effect of boron on bone regeneration and indicates the need for further quantitative research with a standardised approach to assessment. Take-home message Bioactive glasses can promote regeneration of bone, however the lack of heterogeneity and paucity of data regarding boron bioactive glass indicate the need for further quantitative research and standardised approach to assessment.