Comparison of acute thrombogenicity and albumin adsorption in three different durable polymer coronary drug-eluting stents.

BACKGROUND: The relative thrombogenicity and albumin adsorption and retention of different durable polymers used in coronary stents has not been tested. AIMS: This study sought to compare the thromboresistance and albumin binding capacity of different durable polymer drug-eluting stents (DES) using dedicated preclinical and in vitro models. METHODS: In an ex vivo swine arteriovenous shunt model, a fluoropolymer everolimus-eluting stent (FP-EES) (n=14) was compared with two durable polymer DES, the BioLinx polymer-coated zotarolimus-eluting stent (BL-ZES) (n=9) and a CarboSil elastomer polymer-coated ridaforolimus-eluting stent (EP-RES) (n=6), and bare metal stents (BMS) (n=10). Stents underwent immunostaining using a cocktail of antiplatelet antibodies and a marker for inflammation and were then evaluated by confocal microscopy (CM). Albumin retention was assessed using a flow loop model with labelled human serum albumin (FP-EES [n=8], BL-ZES [n=4], EP-RES [n=4], and BMS [n=7]), and scanned by CM. RESULTS: The area of platelet adherence (normalised to total stent surface area) was lower in the order FP-EES (9.8%), BL-ZES (32.7%), EP-RES (87.6%) and BMS (202.0%), and inflammatory cell density was least for FP-EES

Acute thrombogenicity of fluoropolymer-coated versus biodegradable and polymer-free stents.

AIMS: Durable fluoropolymer-coated everolimus-eluting stents (FP-EES) have shown lower rates of stent thrombosis (ST) versus bare metal stents (BMS) and first-generation bioabsorbable polymer (BP) DES. The aim of the study was to evaluate the specific role of the FP in thromboresistance. METHODS AND RESULTS: A total of 57 stents were assessed in three separate ex vivo swine arteriovenous shunt model experiments (first shunt experiment, custom-made fluoropolymer-coated BMS [FP-only] vs. BMS [n=8 each]; second shunt experiment, FP-EES vs. abluminally coated biodegradable polymer sirolimus-eluting stents [BP-SES] vs. BMS [n=8 each]; and third shunt experiment, FP-EES vs. polymer-free Biolimus A9-coated stents [PF-BCS] vs. BMS [n=6 each]). After one hour of circulation, stents were bisected, and each half was dual-immunostained using a platelet cocktail and a marker for inflammation. Antibody staining was visualised by confocal microscopy. In addition, stents were evaluated by scanning electron microscopy. FP-only stents showed significantly lower platelet adherence compared with BMS (% fluorescence-positive area: FP-only=1.8%, BMS=5.6%, p=0.047) with similar inflammatory cell density. FP-EES also demonstrated the lowest platelet adherence compared with BP-SES (p=0.056), PF-BCS (p=0.013) and BMS (p=0.003) with the significantly lowest inflammatory cell density. CONCLUSIONS: Fluoropolymer coating imparts greater thromboresistance relative to BMS and to polymer-free DES designs, which reflects an unique phenomenon known as fluoropassivation, representing one proposed mechanism for clinically observed low ST rates in FP-EES.

Evaluation of chemical stability of polymers of XIENCE everolimus-eluting coronary stents in vivo by pyrolysis-gas chromatography/mass spectrometry.

The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis-gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1721-1729, 2018.

Stent Coating Integrity of Durable and Biodegradable Coated Drug Eluting Stents.

BACKGROUND: Coatings consisting of a polymer and drug are widely used in drug-eluting stents (DES) and are essential in providing programmable drug release kinetics. Among other factors, stent coating technologies can influence blood compatibility, affect acute and sub-acute healing, and potentially trigger a chronic inflammatory response. OBJECTIVE: The aim of this study was to investigate the short-term (7 and 28 days) and long-term (90 and 180 days) coating integrity of the Xience Prime Everolimus-Eluting Stent (EES), Resolute Zotarolimus-Eluting Stent (ZES), Taxus Paclitaxel-Eluting Stent (PES), and Nobori Biolimus A9-Eluting Stent (BES) in a rabbit ilio-femoral stent model. METHODS AND RESULTS: Stented arteries (n = 48) were harvested and the tissue surrounding the implanted stents digested away with an enzymatic solution. Results demonstrated that the majority of struts of EES were without any coating defects with a few struts showing minor defects. Similarly, for the ZES, most of the struts were without coating defects at all time points except at 180 days. The majority of PES demonstrated mostly webbing and uneven coating. In the BES group, the majority of strut coating showed polymer cracking. CONCLUSION: Overall, the EES and ZES had fewer coating defects than the PES and BES. Coating defects, however increase over time for the ZES, whereas the percent of coating irregularities remained constant for the EES. These results provide, for the first time, a comparison of the long-term durability of these drug-eluting stent coatings in vivo.

Mechanisms of tissue uptake and retention in zotarolimus-coated balloon therapy.

BACKGROUND: Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. METHODS AND RESULTS: Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. CONCLUSIONS: A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue-lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

Comparative assessment of transient exposure of paclitaxel or zotarolimus on in vitro vascular cell death, proliferation, migration, and proinflammatory biomarker expression.

Both paclitaxel and zotarolimus are currently employed in vascular interventional therapies, such as drug-eluting stents, and are under investigation for use in other novel drug-device combination products. Paclitaxel is a microtubule-stabilizing compound with potent antiproliferative properties and antimigration effects, whereas zotarolimus is a potent mammalian target of rapamycin inhibitor with antiproliferative and antiinflammatory properties. This study was intended to compare paclitaxel and zotarolimus for intravascular applications in which drug exposure time may be reduced, such as in drug-coated balloons. These applications are generally aimed at reducing neointimal hyperplasia by limiting smooth muscle cell (SMC) proliferation and inflammatory cell recruitment, while minimally interfering with vessel reendothelialization after balloon denudation. In the cellular models described in this study, transient exposure of zotarolimus resulted in the sustained inhibition of SMC proliferation and reduced endothelial cell (EC) proinflammatory cytokine expression, while not affecting EC migration and viability. Transient exposure of paclitaxel inhibited SMC proliferation, EC migration, and overall cell viability, with no effect on expression of the proinflammatory biomarkers studied.

Endothelial cell recovery, acute thrombogenicity, and monocyte adhesion and activation on fluorinated copolymer and phosphorylcholine polymer stent coatings.

This study compares the effects of two polymers currently being marketed on commercially available drug-eluting stents, PVDF-HFP fluorinated copolymer (FP) and phosphorylcholine polymer (PC), on re-endothelialization, acute thrombogenicity, and monocyte adhesion and activity. Rabbit iliac arteries were implanted with cobalt-chromium stents coated with FP or PC polymer (without drug) and assessed for endothelialization at 14 days by confocal and scanning electron microscopy (SEM). Endothelialization was equivalent and near complete for FP and PC polymer-coated stents (>80% by SEM). Acute thrombogenicity was assessed in a Chandler loop model using porcine blood. Thrombus adherence was similar for both polymers as assessed by clot weight, thrombin-antithrombin III complex, and lactate dehydrogenase expression. In vitro cell adhesion assays were performed on FP and PC polymer-coated glass coupon surfaces using HUVECs, HCAECs, and THP-1 monocytes. The number of ECs adhered to FP and control surfaces were equivalent and significantly greater than on PC surfaces (p<0.05). There were no differences in THP-1 monocyte adhesion and cytokine (MCP-1, RANTES, IL-6, MIP-1alpha, MIP-1beta, G-CSF) expression. The data suggests that biological responses to both FP and PC polymer are similar, with no mechanistic indication that these polymers would be causative factors for delayed vessel healing in an acute timeframe.