Bilirubin coating attenuates the inflammatory response to everolimus‐coated stents

Abstract

The aim of this study was to evaluate the effects of bilirubin- and/or everolimus (EVL)-coated stents to prevent arterial neointimal hyperplasia and inflammation in vitro and in vivo. The stents were prepared by spray coating bare metal stents (BMS) with bilirubin and/or EVL. Study groups were divided into (1) BMS, (2) bilirubin-coated stents (BES), (3) commercialized stents (Synergy™; EES), and (4) bilirubin/EVL-coated stents (B-EES). The coating thickness and drug release rates were comparable to previous reports (i.e., <4 µm thickness and 50% drug release in 7 days). Smooth muscle cell migration was inhibited in both EVL-containing groups (20.5 ± 3.80% in EES and 18.4 ± 2.55% in B-EES) compared to the non-EVL-containing groups (78.0 ± 6.41% in BMS and 76.1 ± 4.88% in BES) (n = 10, p < 0.05). Stents were randomly implanted to 40 coronary arteries in 20 pigs and subjected to various analyses after 4 weeks of implantation. As results, the inflammation score was dramatically increased in the EES group (2.1 ± 0.42) compared to that of the other groups (1.5 ± 0.55, 1.3 ± 0.23, and 1.5 ± 0.27 for BMS, BES, and B-EES, respectively, n = 10, p < 0.05). Immunofluorescence analysis revealed that inflammation was prevented in the bilirubin-containing groups (BES and B-EES). However, the percent area of restenosis was decreased in the EVL-containing groups (20.5 ± 4.11% for EES and 18.4 ± 3.61% for B-EES) compared to the non-EVL-containing groups (32.3 ± 6.41% for BMS and 29.6 ± 5.95% for BES, n = 10, p < 0.05). The percent areas of restenosis determined by histopathology, optical coherence tomography, and micro-computed tomography were consistent. In addition, the stent was barely covered in the EES and B-EES groups at 4 weeks postimplantation. These dual drug-coated stents may be especially beneficial to patients who have an increased risk of inflammation. These stents have great potential for use in cardiovascular applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1486-1495, 2018.

Evaluation of cellular response and drug delivery efficacy of nanoporous stainless steel material

“…The metal disk was first processed for 1 h in an acidic environment (50% H 2 SO 4 ) to remove and crush the burr. Thereafter, the samples underwent electropolishing (E-polishing), as described in our previous reports [ 18 , 19 ]. In brief, the disks were positioned lengthwise in the E-polishing chamber containing H 2 SO 4 .…”

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

“…Furthermore, the use of nanoparticle of PEGylated bilirubin has been reported to protect liver tissue from ischemia-reperfusion damage (Kim et al, 2017) and to reduce lung inflammation (Kim et al, 2017). Notably, the use of bilirubin-coated stents reduces inflammation and endothelial activation preventing restenosis in porcine carotid arteries (Bae et al, 2018).…”

Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

“…Subsequently, we discovered that local application of a bilirubin-containing pluronic gel to the adventitia of injured carotid arteries led to a marked decrease in neointima formation [45]. More recently, the coating of everolimus (rapamycin)-containing stents with bilirubin was shown to reduce the inflammatory response following their implantation into coronary arteries of the pig, but the area of restenosis was not significantly improved [78]. Failure of exogenous administration of bilirubin to restrict neointima formation may reflect the ability of rapamycin to stimulate HO-1 gene expression and sufficiently raise intracellular levels of bilirubin in SMCs so that additional increases in bilirubin evoke no further decrease in cell growth [79].…”