Development of Novel Drug-Eluting Stents for Acute Myocardial Infarction

Abstract

Delayed arterial healing at culprit sites after drug-eluting stent (DES) placement for acute myocardial infarction (AMI) is associated with increased risk of late stent thrombosis. The Korea Acute Myocardial Infarction Registry was established in commemoration of the 50^th anniversary of Korea Circulation Society. Between November 2005 and December 2016, more than 62,000 patients were registered from 50 primary percutaneous coronary intervention (PCI) centers in Korea. DES in AMI may be safe and effective, however, there is concern about increased stent thrombosis after DES implantation in AMI patients, requiring longer-term dual anti-platelet therapy to reduce the risk of late stent thrombosis. Device innovation is needed to overcome issues such as stent thrombosis and restenosis by using new coating materials with biocompatible polymers, different coating methods using non-polymer techniques, bioabsorbable stents and pro-healing stents. In this review article, we describe the current usage of DES in AMI in Korea and introduce novel DES uses in development for patients with AMI. We have developed many types of DES in our research laboratory. Abciximab-coated stents inhibited platelet thrombi and restenosis. Furthermore, anti-oxidants (carvedilol, probucol and alpha-lipoic acid) were used for stent coating. Currently we are developing novel DESs using polymer-free and natural binding techniques, peptide coating stents, gene-and-drug delivery, bioabsorbable stents using 3D printing, endothelial progenitor cell capturing stents to promote reendothelialization and reduce stent thrombosis. New DESs in development may be safe and effective in preventing late stent thrombosis and restenosis in patients with AMI.

Keywords: Drug-Eluting Stents; Myocardial Infarction; Percutaneous Coronary Intervention; Thrombosis.

FIG. 1. Scanning electron microscopic findings after abciximab coating on the surface of the stent. [Fig. 1 of 18].

FIG. 2. Methyl methacrylate stain in the α-lipoic acid coated stent study. In-stent neointimal area was smaller in the α-lipoic acid coated stent group (B) compared with the control group (A). Magnification: 10×. [Modified from Fig. 4 of 22].

FIG. 3. Scanning electron microscopy images of the stent surface. Images of the stent according to longitudinal direction were represented (A). The coating thickness was measured in cross sectional view (B). [Fig. 2 of 28].

FIG. 4. Histomorphometric analysis of polymer-free DES in porcine coronary arteries. Area stenosis (A) and fibrin score (B). ^*p<0.05, ^**p<0.01, ^***p<0.001. Group 1: BMS, group 2: BMS with NTiO2, group 3: durable-polymer EES, and group 4: polymer-free EES using NTiO2. [Modified from Fig. 4 of 28]. BMS: bare-metal stent, DES: drug-eluting stent, EES: everolimus-eluting stent, NTiO2: nitrogen-doped titanium dioxide.

FIG. 5. Cross sections of rabbit iliac arteries 6 weeks after stent implantation. Immunohistochemistry for investigating re-endothelialization was performed using a CD31 antibody. CD31 staining was incomplete in BMS and durable-polymer EES (Xience Prime™) groups, whereas CD31 stained with a consecutive linear pattern in the HA-Pep and Pep/SRL groups, suggesting peptide coating promotes endothelialization. [Modified from Fig. 6 of 32]. BMS: bare-metal stent, EES: everolimus-eluting stent, HA-Pep: hyaluronic acid-peptide, Pep/SRL: sirolimus coated onto HA-Pep, SRL: sirolimus.

FIG. 6. Binding plasmid (gWIZ-beta-gal) was effectively transfected into 293 cells after detachment (Fig. 1A). Five days after implantation of TiO2-abciximab-beta-gal plasmid stainless steel plates in rat abdomen and implantation of TiO2-abciximab-beta-gal plasmid bound to a pig coronary stent, the expression of beta-gal plasmid was observed (Fig. 1B). To analyze the inhibitory effect on ISR, we used both TiO2-abciximab-KLF4-plasmid-cobalt chromium stent [TAK-CC, Fig. 1C (right)] and TiO2-only cobalt chromium stent [T-CC, Fig. 1C (left)]. Four weeks after implantation in porcine coronary artery, by histomorphometric analysis, the TAK-CC group showed decreased ISR (Fig. 1C). [Modified from Fig. 1. of 38]. ISR: in-stent restenosis, KLF4: Kruppel-like factor 4, TAK-CC: TiO2-abciximab-KLF4-plasmid-cobalt chromium stent, T-CC: TiO2-only cobalt chromium stent, TiO2: Titanium dioxide.

FIG. 7. Schematic design of a 3D-printing system (A), an ultrasonic-spray coating system (B), an optical microscope image of a BVS fabricated by a 3D-printing system (C), and a weight changes (D). [Modified from Fig. 1 of 40]. BVS: bioabsorbable vascular scaffold.

FIG. 8. Images of hematoxylin-eosin and Carstair fibrin staining after 4 weeks of drug-coated BVS (A and C) and BVS (B and D). Area restenosis (%) (E), and fibrin score (F). ^*p<0.05. Sirolimus-coated BVS was effective in reducing neointimal hyperplasia compared with non-coated BVS at 4 weeks after stent implantation (E). Fibrin score was higher in the drug-coated BVS group (F). [Modified from Fig. 3 of 40]. BVS: bioabsorbable vascular scaffold.