Rare earth metals used in biodegradable magnesium‐based stents do not interfere with proliferation of smooth muscle cells but do induce the upregulation of inflammatory genes

Abstract

Rare earth metals are added to corrodible magnesium-based alloys in low amounts (up to 10%) to improve their mechanical properties and to decrease the degradation rate. Cerium (Ce), neodymium (Nd), yttrium (Y), and ytterbium (Yb) are already used for degradable cardiovascular stents. Little is known about the biocompatibility of rare earth metals released during the degradation process of the implant. Therefore the biocompatibility of rare earth metals was assessed with regard to metabolic activity of human vascular smooth muscle cells (SMCs). After coincubation with the trivalent chlorides (0.5-100 microg/mL) of rare earth metals for 24, 72, 144, and 240 h metabolic activity was determined at each time point using the colometric WST-1 test. The tested rare earth metals did not lead to significant changes in metabolic activity over a wide concentration range. However, at high concentrations a decrease was observed. Apoptotic or necrotic effects were not observed. Furthermore, we analyzed the effects of Ce, Nd, Y, and Yb on the expression of genes involved in inflammatory processes. The expression of IL-6, IL-8, and ICAM-1 in SMCs after exposure to Ce, Nd, Y, and Yb (5 and 50 microg/mL) was measured using quantitative real-time PCR. Significant up-regulation of IL-6, IL-8, and ICAM-1 genes were only found after 24 h, mainly for a concentration of 50 microg/mL. Our cell culture data indicate that rare earth metals influence cellular processes of vascular cells. Whether adverse effects occur also in in vivo is the topic of further investigations.

Comparative in vitro study and biomechanical testing of two different magnesium alloys

“…41 These alloying elements are known to have adverse effects and potential longterm risks, [42][43][44][45] although some studies have reported good biocompatibility. 46,47 Allergic hypersensitivity, reduction of hemoglobin oxygen affinity, and fatty liver are some potential adverse effects of these elements at toxic doses. 43,45 Chelated REE are easily excreted in the urine, and mortality studies have revealed that REE are not highly toxic.…”

Cardiovascular Applications of Magnesium Alloys

“…Feyerabend et al found that aluminium and lithium exert toxic effects on perivascular cells only at concentrations above 1000 micromole [90]. Except for gadolinium, rare earth elements are only toxic at high concentrations, although calcium antagonistic effects could be shown, which in principle could affect many biochemical reactions, particularly muscle and heart muscle contractions as well as cardiac conduction [110]. Many RE elements have even been said to show some anti-carcinogenic properties [39].…”

Magnesium biomaterials: past, present and future

“…Similar biocompatibility concerns exist for alloys containing RE, which although studied in vitro [30][31][32][33] and in vivo 34,35 , also suffer from a similar lack of knowledge of their long term effects when implanted. 30,36 This creates the potential that the significant amount of work that has been and will be performed using alloys containing Al/RE may, in the end, go unused if the materials cannot be proven to be non-toxic. One immediate knowledge gap in the literature that should be addressed with some urgency) is the recommended daily dosage limits for RE elements (i.e.…”