Assessing the potential role of copper and cobalt in stimulating angiogenesis for tissue regeneration

Abstract

The use of copper (Cu2+) and cobalt (Co2+) has been described to stimulate blood vessel formation, a key process for the success of tissue regeneration. However, understanding how different concentrations of these ions affect cellular response is important to design scaffolds for their delivery to better fine tune the angiogenic response. On the one hand, gene expression analysis and the assessment of tubular formation structures with human umbilical vein endothelial cells (HUVEC) revealed that high concentrations (10μM) of Cu2+ in early times and lower concentrations (0.1 and 1μM) at later times (day 7) enhanced angiogenic response. On the other hand, higher concentrations (25μM) of Co2+ during all time course increased the angiogenic gene expression and 0.5, 5 and 25μM enhanced the ability to form tubular structures. To further explore synergistic effects combining both ions, the non-toxic concentrations were used simultaneously, although results showed an increased cell toxicity and no improvement of angiogenic response. These results provide useful information for the design of Cu2+ or Co2+ delivery scaffolds in order to release the appropriate concentration during time course for blood vessel stimulation.

Transition metals in angiogenesis – A narrative review

“…Indeed, the integration of CoCl 2 in the biomaterials increased angiogenesis. The results corroborated with the previously mentioned findings and further studies [ 105 , 106 ]. Through the use of similar experimental techniques using HUVECs and the in vitro angiogenesis assay, the researchers found enhanced VEGF-A and HIF1-α gene expression in addition to advanced tubal formation in the cobalt treated groups [ 104 ].…”

Preparation and Properties of Bimetallic Chitosan Spherical Microgels

“…Copper and zinc ions have proved their potential as antibacterial, angiogenic and osteogenic components of biomedical materials. In addition to antibacterial properties, copper is one of the most important metals for the human body, since it is involved in several physiological functions, from increasing the expression levels of pro-angiogenic and growth factors (VEGF or FGF-2) to regulating bone metabolism and turnover [ 40 , 41 ]. Zinc is an essential trace element which is needed for immune system functioning and bone development and plays a vital role in the wound healing process [ 13 , 14 , 41 ].…”

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.…”