Cobalt‐containing bioactive glass mimics vascular endothelial growth factor A and hypoxia inducible factor 1 function

Abstract

Bioactive glasses (BGs) have shown great potential for tissue regeneration and their composition flexibility allows the incorporation of different ions with physiological activities and therapeutic properties in the glass network. Among the many ions that could be incorporated, cobalt (Co) is a significant one, as it mimics hypoxia, triggering the formation of new blood vessels by the vascular endothelial growth factor A (VEGFA), due to the stabilizing effect on the hypoxia inducible factor 1 subunit alpha (HIF1A), an activator of angiogenesis‐related genes, and is therefore of great interest for tissue engineering applications. However, despite its promising properties, the effects of glasses incorporated with Co on angiogenesis, through human umbilical cord vein endothelial cells (HUVECs) studies, need to be further investigated. Therefore, this work aimed to evaluate the biocompatibility and angiogenic potential of a new sol–gel BG, derived from the SiO2–CaO–P2O5–CoO system. The structural evaluation showed the predominance of an amorphous glass structure, and the homogeneous presence of cobalt in the samples was confirmed. in vitro experiments showed that Co‐containing glasses did not affect the viability of HUVECs, stimulated the formation of tubes and the gene expression of HIF1A and VEGFA. in vivo experiments showed that Co‐containing glasses stimulated VEGFA and HIF1A expression in blood vessels and cell nuclei, respectively, in the deep dermis layer of the dorsal region of rats, featuring considerable local stimulation of the angiogenesis process due to Co‐release. Co‐containing glasses showed therapeutic effect, and Co incorporation is a promising strategy for obtaining materials with superior angiogenesis properties for tissue engineering applications.

Metal ions: the unfading stars of bone regeneration—from bone metabolism regulation to biomaterial applications

“…Cu 2+ and Co 2+ can promote angiogenesis by contributing to a hypoxic microenvironment and increasing the expression of HIF-α . 109–113 More impressively, Bosch-Rué et al 226 demonstrated that Co 2+ significantly improved the capacity of HUVECs to form tubular structures. Although Fe 3+ still has strong pro-angiogenic effects, 227 its relatively high cytotoxicity and the oxidative damage it causes limit its further application.…”

A critical review of bioactive glasses and glass–ceramics in cancer therapy

“…If cobalt ion is released rapidly and extensively in situ, this ion can cause the death of cancer cells by ferroptosis. 120,[123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138] Ferroptosis is generally a type of cell death caused by ROS accumulation due to Fenton's or Fenton-like reactions. 120,[139][140][141] On the other hand, we cannot ignore that cobalt has a potent pro-angiogenic effect, which could contribute to cancer development, thus achieving an opposite effect.…”

“…Low and suitable concentrations of cobalt ions can cause angiogenesis during tissue regeneration due to their hypoxia‐mimetic effect. If cobalt ion is released rapidly and extensively in situ, this ion can cause the death of cancer cells by ferroptosis 120,123–138 . Ferroptosis is generally a type of cell death caused by ROS accumulation due to Fenton's or Fenton‐like reactions 120,139–141 .…”

Cobalt containing glass fibres and their synergistic effect on the HIF-1 pathway for wound healing applications

“…Cobalt-containing borate glasses also increased HIF-1α, VEGF protein secretion, ALP activity in hBMSC culture (Deng et al, 2019). Cobalt was also incorporated into silicate based sol-gel glass (Barrioni et al, 2018a;Barrioni et al, 2018b;Kermani et al, 2020), provoking VEGF expression from fibroblasts (Dziadek et al, 2018) and HUVECs (de Laia et al, 2021), and into inorganic/organic hybrid scaffolds (de Laia et al, 2020). Interestingly, the original 45S5 Bioglass composition has also been shown increase the expression of VEGF in fibroblasts (Day et al, 2004;Day, 2005;Gorustovich et al, 2010;Gerhardt et al, 2011) and endothelial cells (Leu and Leach, 2008) at specific concentrations.…”