Evaluation of promoting effect of a novel Cu-bearing metal stent on endothelialization process from in vitro and in vivo studies

Abstract

Drug eluting stents (DES) have been extensively applied nowadays and reduce the incidence of in-stent restenosis (ISR) greatly as compared with bare metal stents (BMS). However, the development of DES is hindered by the risk of late stent thrombosis (LST) due to delayed re-endothelialization, while endothelialization is an important process related to ISR and LST after implantation. 316L is a traditional stent material without bioactivity and have a high risk of ISR. Cu is recognized for angiogenesis stimulation in these years. Hence a copper bearing 316L stainless steel (316L-Cu) was prepared and evaluated about its effect on endothelialization in this paper. Compared with traditional 316L, it was proved that 316L-Cu increased the proliferation of co-cultured human umbilical vein endothelial cells (HUVECs) at first day. Moreover, HUVECs stretched better on the surface of 316L-Cu. It also improved the expression of angiogenesis related genes and tube formation ability in vitro. 316L-Cu-BMS, DES and 316L-BMS were implanted in swine to evaluate the re-endothelialization ability in vivo. And 316L-Cu-BMS showed the best effect on endothelialization with good biosafety. Consequently, 316L-Cu is a kind of promising BMS material for coronary field.

Synergistic Effects of N/Cu Dual Ions Implantation on Stimulating Antibacterial Ability and Angiogenic Activity of Titanium

“…Therefore, the surface of N/Cu–Ti releases more copper ions than that of Cu–Ti. Copper ions in the concentration range of 10 mg/L are not cytotoxic and can promote HUVECs proliferation while killing bacteria effectively. − Copper ions release from the surface of Cu–Ti and N/Cu–Ti is less than 10 mg/L, so more Cu 2+ with save limit could enter into the microenvironment between the surface of sample and cells or bacteria, improving the angiogenic performance and antibacterial ability of the sample surface. , The “synergistic effect” of N/Cu dual implantation could have a good antibacterial effect and endow Ti with good angiogenic performance at the same time.…”

“…52−55 Copper ions release from the surface of Cu−Ti and N/Cu−Ti is less than 10 mg/L, so more Cu 2+ with save limit could enter into the microenvironment between the surface of sample and cells or bacteria, improving the angiogenic performance and antibacterial ability of the sample surface. 46,47 The "synergistic effect" of N/Cu dual implantation could have a good antibacterial effect and endow Ti with good angiogenic performance at the same time.…”

Biological applications of copper-containing materials

“…After absorption, Cu is transported into the liver and throughout the body through the blood. Apart for some Cu-containing proteins are stored in the liver, and the rest are synthesized in liver or other human tissues, such as cytochrome oxygenase and monoamine enzyme [ 8 , 15 ]. More than 90 different enzymes and proteins have been found to contain Cu to various extents [ 16 , 17 ].…”

“…They further found that vascular smooth muscle cells and vascular endothelial cells tended to undergo apoptosis to some degree when the Cu concentration was over 7.5 μg/ml. Moreover, Jin et al implanted 316L-Cu bare metal stents (BMS), drug-eluting stents (DES), and 316L BMS into swine to evaluate the re-endothelialization ability in vivo ; their results demonstrated that 316L-Cu BMS showed the best effect on endothelialization along with good biosafety [ 15 ]. Previous studies have shown that copper containing metal materials with copper content of 3-5 wt% could promote the endothelialization and inhibit the growth of smooth muscle cells [ 5 , 48 , 49 , 51 , 52 ].…”

Recent Advances in Copper-Doped Titanium Implants

“…In addition, N/Cu-Ti [ 53 ] and C/Cu-Ti [ 51 ] have excellent biocompatibility with MC3T3-1 ( Figure 3 c,g). Moreover, Cu ion can improve the angiogenic properties [ 54 ] of the Ti surface and promote the proliferation and migration of HUVESCs. Other strategies, including Cu/Zn [ 46 , 55 ] ion co-implantation, can also improve the mechanical properties and antimicrobial capacity of the sample surfaces.…”