Understanding the Impact of Stent and Scaffold Material and Strut Design on Coronary Artery Thrombosis from the Basic and Clinical Points of View

Abstract

The technology of percutaneous coronary intervention (PCI) is constantly being refined in order to overcome the shortcomings of present day technologies. Even though current generation metallic drug-eluting stents (DES) perform very well in the short-term, concerns still exist about their long-term efficacy. Late clinical complications including late stent thrombosis (ST), restenosis, and neoatherosclerosis still exist and many of these events may be attributed to either the metallic platform and/or the drug and polymer left behind in the arterial wall. To overcome this limitation, the concept of totally bioresorbable vascular scaffolds (BRS) was invented with the idea that by eliminating long-term exposure of the vessel wall to the metal backbone, drug, and polymer, late outcomes would improve. The Absorb-bioabsorbable vascular scaffold (Absorb-BVS) represented the most advanced attempt to make such a device, with thicker struts, greater vessel surface area coverage and less radial force versus contemporary DES. Unfortunately, almost one year after its initial approval by the U.S. Food and Drug Administration, this scaffold was withdrawn from the market due to declining devise utilization driven by the concerns about scaffold thrombosis (ScT) seen in both early and late time points. Additionally, the specific causes of ScT have not yet been fully elucidated. In this review, we discuss the platform, vascular response, and clinical data of past and current metallic coronary stents with the Absorb-BVS and newer generation BRS, concentrating on their material/design and the mechanisms of thrombotic complications from the pre-clinical, pathologic, and clinical viewpoints.

Keywords: bioresorbable vascular scaffold; drug eluting stent; polymer; scaffold thrombosis; stent thrombosis.

Figure 1

Alteration of blood flow dynamics and thrombogenicity in the vicinity of thin or thick stent struts. Stent-induced flow disturbances affect thrombogenicity and re-endothelialization following stent implantation. (A) Healthy endothelium in the normal artery wall expresses anticoagulant and antithrombotic molecules, including NO, PGI2, TFPI, tPA, TM, and heparin-like molecules. (B) Stent placement results in local endothelial denudation, which leads to activation of the coagulation cascade. Stents, especially thicker strutted ones, may promote non-streamlined flow separation in regions proximal and distal to struts. Accelerated blood flow (high shear) over the strut edges can activate platelets through the release of thromboxane A2 and ADP, whereas flow recirculation zones with low shear rates are associated with inhibition of re-endothelialization, potentially enabling procoagulant and proinflammatory elements to accumulate, which contribute to thrombus formation. (C) A thin strut geometry reduces flow separation and low shear, leading to the inhibition of platelet activation. Moreover, the generation of recirculation zones proximal and distal to thin struts will be minimized, resulting in the reduced thrombogenicity. Undisturbed flow proximal and distal to streamlined struts promotes re-endothelialization, which further helps to maintain hemostatic balance and prevent thrombosis. Modified and reprinted with permission from Jimenez, J.M.; et al. Ann. Biomed. Eng. 2009 [14]. ADP: adenosine diphosphate, AR: aspect ratio, CFD: computed flow dynamics, NO: nitric oxide, PGI2: prostacyclin, TF: tissue factor, TFPI: tissue factor pathway inhibitor, TM: thrombomodulin, tPA: tissue plasminogen activator, vWF: von Willebrand factor.

Figure 2

Design characteristics of representative drug eluting stent and bioabsorbable scaffold/stent. (A) The characteristics of past and current commercial drug-eluting stents including durable polymer (DP)-, biodegradable polymer (BP)-, and polymer free-DES. Types of materials (alloy, drug, and polymer), strut thickness, and estimated duration for polymer absorption (in BP-DES) of each stent are described. (B) The characteristics of 1st and 2nd generation fully bioabsorbable scaffold/stents. Types of materials (polymer, alloy, and drug), strut thickness, and estimated duration for polymer absorption period (in BP-DES) of each stent were described. Co: cobalt, Cr: chromium, Ir: iridium, Mo: months, PBMA: poly(butyl methacrylate), PCL: poly-ε-caprolactone, PC: phosphorylcholine-coated, PDLA: poly-d-lactic acid, PDLLA: poly-d,l-lactic acid, PDLGA: poly(d,l-lactide-co-glycolide), PEVA: poly (ethylene-vinyl acetate), PGA: polyglycolic acid, PLLA: poly-l-lactic acid, PLGA: poly(lactide-co-glycolide), PolyCarb: poly-tyrosine-derived polycarbonate polymer, Pt: platinum, PTD-PC: polytyrosine-derived polycarbonate, SS: stainless steel, Ta: tantalum.

Figure 2

Design characteristics of representative drug eluting stent and bioabsorbable scaffold/stent. (A) The characteristics of past and current commercial drug-eluting stents including durable polymer (DP)-, biodegradable polymer (BP)-, and polymer free-DES. Types of materials (alloy, drug, and polymer), strut thickness, and estimated duration for polymer absorption (in BP-DES) of each stent are described. (B) The characteristics of 1st and 2nd generation fully bioabsorbable scaffold/stents. Types of materials (polymer, alloy, and drug), strut thickness, and estimated duration for polymer absorption period (in BP-DES) of each stent were described. Co: cobalt, Cr: chromium, Ir: iridium, Mo: months, PBMA: poly(butyl methacrylate), PCL: poly-ε-caprolactone, PC: phosphorylcholine-coated, PDLA: poly-d-lactic acid, PDLLA: poly-d,l-lactic acid, PDLGA: poly(d,l-lactide-co-glycolide), PEVA: poly (ethylene-vinyl acetate), PGA: polyglycolic acid, PLLA: poly-l-lactic acid, PLGA: poly(lactide-co-glycolide), PolyCarb: poly-tyrosine-derived polycarbonate polymer, Pt: platinum, PTD-PC: polytyrosine-derived polycarbonate, SS: stainless steel, Ta: tantalum.

Figure 3

Various mechanisms of very late stent (ST) and scaffold thrombosis (ScT). (A) Diagram illustrating the various mechanisms of very late stent (ST) (left) and scaffold thrombosis (ScT) (right). (B) Impact of each factor and its relationship to ST and ScT in different devices—BMS = bare metal stents, DES = drug-eluting stents, BRS = bioresorbable vascular scaffold. Permission obtained from Mori, H; et al. Coron. Artery Dis. 2017 [54].

Figure 4

Acute thrombogenicity and delayed endothelial coverage of Absorb-BVS in experimental models. (A) Ex-vivo arteriovenous porcine shunt model. Representative images derived from confocal microscopy after 1 h in a swine ex-vivo shunt model. Platelets were stained with anti-CD61 and CD42b primary antibody and red-fluorescent secondary antibody. (a) Biodegradable polymer everolimus-eluting stent (BP-EES); (b) fully bioabsorbable everolimus-eluting scaffold (Absorb-BVS); (c) biodegradable polymer biolimus-eluting stent (BES); and (d) bare metal stent (BMS). (e) Percent fluorescent positive area based on percentage of fluorescent positive staining against CD61 and CD42b within the entire stented segment. Values are expressed as mean ± SD in each group. BP-EES, Absorb-BVS, and BMS included n = 6 stents in each group, whereas BES included n = 5 stents. One BES was incompletely expanded and therefore excluded in the analysis. (B) Rabbit model. Representative images of endothelial coverage assessed by scanning electron microscopy (SEM) at 28 days. Low magnification (15×) SEM images provide an overview of the luminal surface of the bisected segment from proximal (top) to distal (bottom). (a) BP-EES, (b) Absorb-BVS, (c) BES, and (d) BMS. (e) Relative percentage of endothelial coverage above struts assessed by scanning electron microscopy is shown in box and whisker diagrams on the right. Values represent median with lower (25th percentile) and upper quartiles (75th percentile) and whiskers for minimum and maximum value. Each group has n = 6, respectively. Modified reprinted from Koppara, T; et al. Circ. Cardiovasc. Interv. 2015 [57].