Coronary stenting has demonstrated a consistent ability to reduce restenosis rates compared with percutaneous “plain old” balloon catheter angioplasty. However, in-stent restenosis has long remained the major limitation of coronary stenting. Recent randomized trials have shown that the use of both paclitaxel- and sirolimus-eluting stents (Taxus®, Boston Scientific, Natick, Massachusetts and Cypher™, Cordis Corp., Miami, Florida, respectively) by polymer-regulated delivery appears to markedly reduce the risk of in-stent restenosis following treatment of de novo lesions1–4 and even lesions at high risk for in-stent restenosis.5,6 Although drug-eluting stents (DES) are effective for restenosis reduction, there are concerns regarding long-term safety and efficacy. Meta-analysis data of DES randomized clinical trials have recently reported that DES did not reduce mortality or myocardial infarction for the follow-up period of 6–12 months7; furthermore, there have been reports of late sudden DES occlusion from hypersensitivity reactions.8 A DES consists of a metallic stent covered with drug-containing polymer to prolong drug release. Polymer compositions include: poly [phosphorylcholine-lauryl methacrylate] for BiodivYsio (Abbott Vascular/Biocompatibles Ltd., Farnham, United Kingdom); poly [styrene-isobutyl-styrene] for Taxus®, and poly-n-butyl methacrylate + polyethylene-vinyl acetate for Cypher™.9,10 Polymer layers are used both as drug reservoirs as well nondrug top-coated films to achieve optimal drug release kinetics. By conducting a meta-analysis of DES clinical trials data, Babapulle et al have shown that polymer-based DES are more effective for restenosis reduction compared with nonpolymer-based DES.7 Although the polymer coating is an integral component of DES, there are concerns regarding the integrity of polymer coatings on the metal surfaces and the potential relation of polymer defects to acute or late adverse events. The morphology of polymer coatings, particularly in relation to balloon catheter expansion, have not been previously reported; therefore, using scanning electron microscopy (SEM), we evaluated the polymer layers of commercially available BiodivYsio, Taxus and Cypher stents for discernible defects and irregularities that might contribute to such outcomes. Our results document that all three stent types have substantial flaws in the polymer layers that may relate to unfavorable clinical occurrences. Materials and Methods Scanning electron microscopy (SEM). One BiodivYsio (3.5 x 15 mm), 1 Taxus (3.0 x 24 mm) and 1 Cypher (3.0 x 28 mm) unexpanded, and 2 BiodivYsio (3.5 x 15 mm), 3 Taxus (3.0 x 24 mm) and 2 Cypher (3.0 x 28 mm) stents in the expanded state were used in this study. Expansion to nominal diameter was performed with a single balloon catheter inflation, with the stent immersed in physiological saline solution at 37°C to stimulate in vivo conditions. The balloon was deflated after ~30 seconds and carefully withdrawn. The samples of each expanded stent were rinsed in distilled water and exchanged with ethanol until completely dehydrated as follows: 30% ethanol x 1 for 2 minutes; 50% ethanol x 1 for 2 minutes; 70% ethanol x 1 for 2 minutes; 90% ethanol x 1 for 2 minutes; 100% ethanol x 2 for 3 minutes each. The wet samples were then critical-point dried from liquid CO2 using thermoregulation and flow monitoring. All samples of expanded and unexpanded stent were gently adhered to aluminum specimen support stubs using double-sided carbon tape. Specimens were then magnetron sputter-coated with ~25 nm gold and examined in the secondary electron imaging mode on the lower stage of a Topcon DS-130 microscope equipped with a LaB6 emitter. The instrument was operated at 10 kV, accelerating voltage with a 20 mm working distance and 4.8 Mb images were acquired digitally on a Micro Pentium 166 PC. Morphologic descriptions of the appearance of the polymer layers, including any irregularities or defects, were generated and recorded at least on 3 regions per stent. Two or 3 stents of each type were also imaged after expansion under dry conditions in air followed by metal coating to assess potential differences in polymer layer morphologies induced by the two conditions. Results Unexpanded BiodivYsio, Taxus and Cypher stents. Polymer layer morphology differed among BiodivYsio, Taxus and Cypher stents. Figure 1 shows low and high magnification of SEM images of the 3 different stents. Outer surfaces of BiodivYsio (Figures 1a and d) and Taxus (Figures 1b and e) were smooth, but there were occasional continuities or bridges of polymer across the stent struts. The outer surface region of the Cypher stent showed widespread irregularities including waving and wrinkling and shallow depressions of the polymer layer, indicating that the polymer coating lacked uniformity (Figures 1c and f). Expanded stents BiodivYsio stent. Figure 2 shows low and high magnification images of a balloon-expanded BiodivYsio stent. The inner surface region displayed excess polymer on the strut edges, polymer layer cracking on the loop and straight regions and apparent peeling of polymer from the inner stent surface. The outer surface had no major defects or irregularities in the majority of the coating but the strut edges consistently exhibited an irregular fringe of the polymer layer. Taxus stent. Figure 3 shows low- and high-magnification images of a balloon-expanded Taxus stent. There were frequent regions of polymer voids exposing the stent metal and indicative of mechanical damage in the inner surface, primarily at loop regions. Occasional polymer bridging across stent strut loops with linear cracking of bridges was observed. There were also shallow depressions in the polymer layer on the outer surface. Apparent deposition defects in the polymer layer were also present. Cypher stent. Figure 4 shows low- and high-magnification images of a balloon-expanded Cypher stent. The outer surface region of one stent showed multiple round, small defects of the top-coating. There was also apparent peeling of the outside polymer layer in the inner loop regions. The Cypher inner surface demonstrated apparent peeling of the polymer top-coating, primarily at the inner surface, but also present on the outer surfaces. There was also occasional evidence of polymer peeling exposing the stent metal, and cracking suggestive of mechanical damage at the loop regions. Irregularities and wrinkling of polymer were present on the outer surface regions. Discussion The use of DES appears to markedly reduce the risk of in-stent restenosis following treatment of coronary stenosis,1–6 but there is no evidence of reduced mortality for an intermediate-term period.7 Polymer-based DES are consistently effective for reducing in-stent restenosis, but nonpolymer-based DES were found largely ineffective.7 Thus, it appears that at least for some drugs, a polymer coating is needed as a reservoir to achieve a sustained drug release. Some early prototype biodegradable and nonbiodegradable polymers markedly induced inflammation and enhanced neointimal formation.11 Later, the phosphorylcholine polymer of the BiodivYsio stent showed biocompatibility in normal porcine coronary arteries.12 Although the polymers of the Cypher stent or the Taxus stent seem to be biologically inert and stable in pig coronary arteries for at least 2 to 6 months,13,14 it has been reported that a poly-n-butyl methacrylate similar in composition to the polymer of the Cypher stent promoted an inflammatory reaction when implanted subcutaneously.15 Recently, adverse effects such as late thrombosis due to hypersensitivity to polymer have been reported in angioplasty patients treated with the Cypher stent.8 These may be due to innate polymer reactions, drug-polymer interactions or as-yet unknown causes. However, should the polymer layers be implicated, polymer composition may be a major limiting factor for the further development of DES. The elution profile and release kinetics of a drug from such coatings depend in part on the physical properties of the drug and of the polymer coating.9 Polymer disruption would likely result in nonuniform local drug distribution that may then allow neointimal hyperplasia in nontreated regions. Moreover, cracking of the polymer layer may also induce adverse and interrelated effects such as local inflammation and thrombosis; the size and composition of thrombus affect local drug release from DES, further confounding drug uptake homogeneity.16 The failure of current DES, possibly because of thrombotic occlusion in the absence of effective antiplatelet therapy, may be secondary to polymer layer defects.17 We found evidence of several different forms of polymer layer cracking among commercially available BiodivYsio, Taxus and Cypher stents after expansion to a nominal diameter. Peeling of the polymer layer from an inner surface probably results from shearing during balloon inflation and withdrawal. Polymer bridging of expanded Taxus stents may be associated with continuity of polymer seen in unexpanded Taxus stents. Peeling of the top-coating as we observed in the Cypher stent may induce uncontrolled release of sirolimus because the drug-free top-coating polymer serves as a diffusion barrier to slow the release of sirolimus. The present study indicates that peeling of the polymer layer readily occurred at the inner stent strut, even after balloon expansion to only a nominal diameter. This finding suggests there is a real risk of coronary microembolism by peeling-off of polymer pieces during stent implantation that might contribute to microcirculatory insufficiency, depressed left ventricular function and other adverse outcomes. We discovered cracking of polymer on coated stents after only single balloon inflation expansion to a nominal diameter. It is expected that the use of DES will increase for complex lesions such as bifurcations because their use has reduced the risk of in-stent restenosis compared with bare-metal stents.18–20 Complex techniques such as “T-stenting”, “Y-stenting” and “crush stenting” are used for treatment of bifurcation lesions. These complex techniques are likely to cause even more distortion of polymer coatings on DES, and may induce more serious cracking and peeling of the polymer layer. In addition, overexpansion of undersized stents or stenting for calcified coronary arteries may also induce more polymer cracking. Complex techniques such as bifurcation stenting have been associated with more complications, particularly subacute thrombosis,21,22 as well as restenosis at the side branch.23 Future studies should involve the use of similar experiments on bifurcation lesions using bifurcation stents with techniques such as “T-stenting”, “Y-stenting” and “crush stenting”. By the Premarket Approval submission for the Cypher stent, the company had found polymer cracking on the stent after expansion, but concluded that polymer cracking had minimal adverse effects based on their interpretation of clinical trial results in patients with noncomplex de novo lesions.24 However, we suggest that: (1) the clinical evaluations were neither powered nor designed to specifically address this issue; and (2) subsequent clinical trials have shown that DES stenting of complex lesions such as bifurcations has been associated with increased subacute thrombosis, as well as restenosis in the side branch in real-world experience. We believe that such phenomena may indeed be related to polymer cracking and delamination that is likely to occur with stenting of complex lesions. We also examined BiodivYsio, Taxus and Cypher stents after expansion in air (Figure 5). There was no difference in the appearance of BiodivYsio stents between expansions in air compared to saline solution at 37°C. However, expanded Taxus and Cypher stents showed somewhat more bridging and cracking after expansion in air. This discrepancy may reflect physicochemical properties of the polymers in relation to stent expansion dynamic changes; it also highlights a noteworthy fact that SEM examination of polymer-coated stents should be carried out under physiological conditions. For evaluation of DES in preclinical studies, requirements such as study design, experimental performance and histopathologic evaluation, emphasizing safety and efficacy at multiple timepoints, have been previously recommended by a consensus group.25 Our data suggest that in addition to these tests, careful SEM examination should be conducted to assess integrity of the polymer, if present. This report shows that there are several common types of cracking and peeling or flaking of polymer layers on three commercially available polymer-coated stents after expansion. In addition to standard in vivo evaluation, preclinical study for new DES should include investigation of devices with SEM to assess polymer layer morphology before and after stent expansion. Furthermore, future DES developers should pay more attention to the durability of the polymer coatings and resistance to cracking and webbing. An ideal DES delivery system would have a structurally intact, as well as a biologically inert, polymer coating. Study limitations. This was a bench study which, for reasons of practical limitations, used small numbers of samples. Our results may therefore not be entirely representative of all devices produced by one or more of the manufacturers. Furthermore, these observations are necessarily qualitative and descriptive in nature, rather then being quantitative. Conclusions We found defects of polymer layers on commercially available polymer-coated stents. This finding suggests the potential risks of thrombosis at cracking sites, coronary microembolism of polymer pieces and excessive chronic inflammatory and neointimal reactions. Acknowledgement. The authors gratefully acknowledge Ms. Jeannette V. Taylor (Department of Chemistry, Emory University) for her technical support in scanning electron microscopy specimen preparation and imaging.
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