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BACKGROUND In patients at high bleeding risk (HBR), the LEADERS FREE (LF) trial established the safety and efficacy of a polymer-free drug coated (Biolimus-A9) stainless steel stent (SS-DCS) with 30 days of dual antiplatelet treatment (DAPT). In LEADERS FREE III, we studied a new cobalt-chromium thin-strut stent (CoCr-DCS) in HBR patients. METHODS The CoCr-DCS shares all of the design features of the SS-DCS but has a CoCr stent platform with strut thickness of 84-88 μm. The primary safety endpoint was a composite of cardiac death, myocardial infarction (MI), and definite/probable stent thrombosis. The primary efficacy endpoint was clinically indicated target lesion revascularization. Outcomes were compared to those of LF (non-inferiority to SS-DCS for safety and superiority to SS-BMS for efficacy). Additional propensity-matched comparisons were performed to account for baseline differences. RESULTS We recruited 401 HBR patients using identical criteria to the LF trial. At 1 year, the primary safety endpoint was reached by 31/401 (8.0%) of patients treated with the CoCr-DCS versus 35/401 (8.9%) for the propensity-matched cohort (HR: 0.89, [0.55-1.44], p

Background Very long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus. Methods We investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years. Results This analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73–1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88–1.11; P = 0.88). Conclusion At 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time. Trial registration ClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533 Graphic abstract Kaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons).

Background Polymer-coating represents one of components of drug-eluting stents (DES) to have experienced a more intensive technological evolution. Polymer-free DES (PF-DES) have offered promising angiographic results, with earlier complete re-endothelization, potentially reducing the thrombotic risk and offering the option of a shorter antiplatelet therapy. However, contrasting prognostic data have been reported so far with PF-DES. Therefore, the aim of the present study was to perform a comprehensive updated meta-analysis of randomized trials (RCT) comparing the impact of PF-DES vs polymer- coated DES (PC-DES) on clinical outcome. Methods Literature and main scientific session abstracts were searched for RCTs comparing PF-DES vs PC-DES for the treatment of CAD. The primary efficacy endpoint was mortality, secondary endpoints were cardiovascular death, myocardial infarction, target lesion revascularization (TLR) and stent thrombosis. Results We included 16 randomized clinical trials, with a total of 15,689 patients, including 50.6% randomized to PF-DES. At a median follow-up of 24 months, PF-DES were associated to a significant reduction in mortality as compared to PC-DES (0.82 [0.68, 0.99], p = .03, I2 = 0%; phet = 0.93). However, no significant benefit was observed in terms of cardiovascular death or major ischemic endpoints (respectively CV death: OR [95% CI] = 0.92 [0.71, 1.18] p = .50, I2 = 0.50; phet = 0.84; MI: OR [95% CI] = 1.08 [0.90, 1.29], p = .42; I2 = 0%, phet = 0.98; TLR: OR [95% CI] = 1.02 [0.78, 1.32], p = .91; I2 = 0.63 phet = 0.0003; ST: OR [95% CI] = 0.98 [0.87, 1.10], p = .72; I2 = 0% phet = 0.64). By meta-regression analysis, the mortality benefits of PF-DES were not conditioned by the rate of diabetes mellitus or acute coronary syndromes. Conclusions Based on the current meta-analysis, PF-DES are associated to a significant reduction in mortality as compared to PC-DES, but not in the occurrence of major ischemic events. Future larger studies are certainly needed to further investigate and confirm our findings, especially in particular subsets of patients, such as those with high bleeding risk or acute myocardial infarction.

The gas separation membrane field has seen exceptional growth since its inception, with extensive research being performed to find novel, high performance polymer membrane materials for application in industrial separations. In this review, we examine recent advances of polymer design strategies to overcome the permeability/selectivity tradeoff relationship and the diminished performance caused by physical aging. We explore fundamental structure–property relationships within current state-of-the-art polymer materials to discern promising routes for continued membrane materials research and development, highlighting promising macromolecular architectures and design strategies providing tailorable polymer free volume for high performance gas separation membranes. Finally, we provide our perspective on encouraging design routes moving forward.

Background Polymer-free (PF) stents were designed as an alternative to durable-polymer (DP) drug-eluting stents to minimize the time on dual antiplatelet treatment for patients at high-risk of bleeding. Nonetheless, the efficacy and safety of PF vs. DP stents in patients undergoing percutaneous coronary intervention (PCI) remain controversial. Methods We performed a metanalysis with currently available studies that assessed the effect of PF-stents vs. DP-stents after performing a systematic search. The endpoints analyzed were all-cause death, myocardial infarction, target lesion revascularization (TLR) and probable or definite stent thrombosis. The raw numbers of incident end-points reported in each study were used. We performed analyses in short and long term (1 year follow-up) studies. Results We included 12464 patients from 8 studies (5 short-term and 3 long-term): 6723 treated with PF-stents and 5741 with DP stents. Females represented 23.3% (n=3284) and 33.7% (n=4202) were included in the setting of acute coronary syndromes. As shown in the figure, PF-stents were associated to lower incidence of all-cause mortality (HR: 0.91 95% CI 0.84–0.98; p=0.016) and TLR (HR: 0.88 95% CI 0.80–0.96; p=0.003). No differences were observed in the risk of cardiovascular death (HR: 0.96 95% CI 0.86–1.06 p=0.415), myocardial infarction (HR: 0.90 95% CI 0.80–1.01; p=0.061) or probable-definite stent thrombosis (HR: 0.92 95% CI 0.74–1.14; p=0.447). Finally, no differences in the primary end-point (HR: 0.92 95% CI 0.83–1.03; p=0.143) were detected with PF-stents vs. DP-stents. No significant heterogenicity was observed in any of the endpoints, except for the incidence of stent thrombosis. Conclusions Under current PCI techniques the use of PF-stent might be associated to better outcomes, especially in terms of all-cause mortality and TLR. Funding Acknowledgement Type of funding sources: None.

The present review discusses the use of cyclodextrins and their derivatives to prepare electrospun nanofibers with specific features. Cyclodextrins, owing to their unique capability to form inclusion complexes with hydrophobic and volatile molecules, can indeed facilitate the encapsulation of bioactive compounds in electrospun nanofibers allowing fast-dissolving products for food, biomedical, and pharmaceutical purposes, filtering materials for wastewater and air purification, as well as a variety of other technological applications. Additionally, cyclodextrins can improve the processability of naturally occurring biopolymers helping the fabrication of "green" materials with a strong industrial relevance. Hence, this review provides a comprehensive state-of-the-art of different cyclodextrins-based nanofibers including those made of pure cyclodextrins, of polycyclodextrins, and those made of natural biopolymer functionalized with cyclodextrins. To this end, the advantages and disadvantages of such approaches and their possible applications are investigated along with the current limitations in the exploitation of electrospinning at the industrial level.

The fluoropolymer paclitaxel-eluting stent (FP-PES; Eluvia, Boston Scientific, Marlborough, Massachusetts) is the new-generation drug-eluting stent, allowing controlled and sustained paclitaxel release over 12 months after stent implantation. To date, however, there are few data regarding vascular

Background: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES as compared with latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have not yet been investigated in a large randomized trial. Methods: In this physician-initiated, prospective, multicenter, randomized, noninferiority trial, an all-comers population requiring percutaneous coronary intervention was enrolled across 3 European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after stratification for troponin status and diabetes mellitus. In both treatment arms, troponin-positive patients were planned for 12-month dual antiplatelet therapy, whereas troponin-negative patients were planned for 1-month dual antiplatelet therapy. Outcome assessors were blinded to the allocated treatment. The device-oriented primary end point of target-lesion failure was defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed by modified intention-to-treat (80% power, and a 3.5% noninferiority margin). Results: In total, 1502 patients were randomized and 1491 treated with the assigned stent and available for follow-up. The primary end point occurred in 42 (5.6%) of the 744 patients receiving PP-ZES versus 46 (6.2%) of the 747 patients receiving PF-AES. PF-AES were clinically noninferior to PP-ZES (risk difference, 0.5%; upper limit 1-sided 95% confidence interval, 2.6%; P noninferiority =0.0086). Cardiac death occurred in 10 (1.3%) versus 10 patients (1.3%; P value for difference, 1.00), target-vessel myocardial infarction occurred in 18 (2.4%) versus 17 patients (2.3%; P value for difference, 0.87), and target-lesion revascularization occurred in 22 (2.9%) versus 20 patients (2.6%; P value for difference, 0.75) for PF-AES as compared with PP-ZES. Overall, definite or probable stent thrombosis occurred in 1.0%. Conclusions: PF-AES were noninferior to PP-ZES regarding target-lesion failure at 12 months. Findings regarding the secondary end point and prespecified subgroups were generally consistent with that of the primary end point. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02328898.

Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant., Polymer-based systems are often considered a necessity for controlled drug delivery, but have well-known limitations. Here, the authors report on drug delivery implants formed solely from corticosteroid dimers, which demonstrate controlled release and overcome many of the challenges of polymer-based systems.

Nanoparticle-loaded hydrogels are attractive pharmaceutical drug delivery systems that combine the advantages of both hydrogel (local administration and/or sustained drug release) and nanoparticle (stealthiness, targeting and decreased toxicity). The design of nanoparticle-loaded hydrogels is largely conventional, consisting of the dispersion of nanoparticles in a natural or synthetic polymer matrix to form a gel network. Novel nanoparticle-loaded hydrogels architecture could provide advantages in terms of innovation and application. We focused on the development of lipid nanocapsule (LNC)-based hydrogels without the use of a polymer matrix as a platform for drug delivery. Cytidine was modified by grafting palmitoyl chains (CytC16) and the new entity was added during the LNC phase-inversion formulation process allowing spontaneous gelation. Positioned at the oil/water interface, CytC16 acts as a crosslinking agent between LNCs. Association of the LNCs in a three-dimensional network led to the formation of polymer-free hydrogels. The viscoelastic properties of the LNC-based hydrogels depended on the LNC concentration and CytC16 loading but were not affected by the LNC size distribution. The LNC and drug-release profiles were controlled by the mechanical properties of the LNC-based hydrogels (slower release profiles correlated with higher viscoelasticity). Finally, the subcutaneous administration of LNC-based hydrogels led to classic inflammatory reactions of the foreign body-reaction type due to the endogenous character of CytC16, shown by cellular viability assays. New-generation nanoparticle-loaded hydrogels (LNC-based polymer-free hydrogels) show promise as implants for pharmaceutical applications. Once LNC release is completed, no gel matrix remains at the injection site, minimizing the additional toxicity due to the persistence of polymeric implants. Sustained drug-release profiles can be controlled by the mechanical properties of the hydrogels and could be tailor-made, depending on the therapeutic strategy chosen.

The main goal of this work is to achieve a direct transfer of graphene and examine the exact effect of surface tension (ST) on graphene during this type of transfer. To reach this target, we designed a specific transfer container with two-sided ports to facilitate replacing liquids underneath graphene and monitor the effect of ST. We prepared liquids with various STs by mixing pure deionized-water with different ratios of isopropanol (IPA). Our results indicate that high ST does not break the graphene structure if graphene has good quality. Besides, a ST gap (STG) can be applied to graphene at a specific level without damaging the graphene monolayer. Comparing those results to the defective graphene features after applying high ST and varied STGs confirms that standing high ST and STG can be considered as a key feature of good quality graphene. Thus, good-quality graphene can be transferred at high ST (ST of water: 72 dyne/cm) with no sign of structural damage. In addition, this type of graphene can stand STG ≤ 40 dyne/cm. This new understanding of the ST effect on graphene could simplify the current direct transfer techniques and widen the graphene applications by expanding the choices of the target substrates and transfer liquids.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Polymers and polymeric materials exhibit flexibility between neighboring components of their molecular chains, permitting disordered conformations relative to the crystalline state. The disordered chain conformations lead to entanglements between neighboring chains, and the local intersections of polymer chains lead to voids in the material. Such voids or holes are named polymer free volume elements (FVEs). In their study of how FVEs in polymeric materials are related to their intrinsic microporosity and transport of gases, Budd, McKeown, and Fritsch (1) found inspiration from Lucretius. To paraphrase Lucretius’ teachings about atomistic theories from the Greeks, “Nature …has two forms …: the bodies, and the void where the bodies are placed and travel their varied paths” (ref. 1, p. 1977). More recently, we find that FVE sizes are key descriptors in molecular theories of polymers, polymeric materials, and glasses (1⇓⇓⇓–5). FVE distributions are critically important in applications of such materials to self-assembled amphiphiles (6), polymer composites (7), and perm-selective membranes (8). Thus, a great deal of attention has been paid to characterizing FVEs; the major methods used in these measurements are discussed below. Knowledge of FVE distributions in polymeric materials is needed for engineering of structural plastics. High-strength products require treatment to control and minimize the FVEs. One example is the processing of polyethylene chains (comprising repeats of the C H 2 group). When long polyethylene chains are extruded to maximize their alignment, the result is high-density polyethylene (HDPE), a widely used plastic material that we consume in vast quantities. Voids in HDPE result from shorter chains, poor chain alignment, and exposure to higher temperatures, so an increase in the number and size of FVEs correlates with a reduction in structural integrity. In other applications, such as using polymers to engineer perm-selective membranes for gas separations, increasing … [↵][1]1Email: ecastner{at}chem.rutgers.edu. [1]: #xref-corresp-1-1

Background: In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared with a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is noninferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention. Methods: The SORT OUT IX trial (Scandinavian Organization for Randomized Trials With Clinical Outcome IX), was a large-scale, registry-based, randomized, multicenter, single-blind, 2-arm, noninferiority trial. The primary end point, major adverse cardiovascular events, was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess noninferiority for major adverse cardiovascular events of the BioFreedom stent compared with the Orsiro stent with a predetermined noninferiority margin of 0.021. Results: Between December 14, 2015 and April 21, 2017, 3151 patients were assigned to treatment with the BioFreedom stent (1572 patients, 1966 lesions) or to the Orsiro stent (1579 patients, 1985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of patients, and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary end point (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; P noni nferiority =0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI, 1.66–4.62]; P Conclusions: The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for major adverse cardiovascular events at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02623140.

Background: High bleeding risk (HBR) patients undergoing percutaneous coronary intervention have been widely excluded from randomized device registration trials. The LF study (LEADERS FREE) reported superior outcomes of HBR patients receiving 30-day dual antiplatelet therapy after percutaneous coronary intervention with a polymer-free drug-coated stent (DCS). LFII was designed to assess the reproducibility and generalizability of the benefits of DCS observed in LF to inform the US Food and Drug Administration in a device registration decision. Methods: LFII was a single-arm study using HBR inclusion/exclusion criteria and 30-day dual antiplatelet therapy after percutaneous coronary intervention with DCS, identical to LF. The 365-day rates of the primary effectiveness (clinically indicated target lesion revascularization) and safety (composite cardiac death and myocardial infarction) end points were reported using a propensity-stratified analysis compared with the LF bare metal stent arm patients as controls. Results: A total of 1203 LFII patients were enrolled with an average 1.7 HBR criteria per patient, including 60.7% >75 years of age, 34.1% on anticoagulants, and 14.7% with renal failure. Propensity-adjusted 365-day clinically indicated target lesion revascularization was significantly lower with DCS (7.2% versus 9.2%; hazard ratio, 0.72 [95% CI, 0.52–0.98]; P =0.0338 for superiority), as was the primary safety (cardiac death and myocardial infarction) composite (9.3% versus 12.4%; hazard ratio, 0.72 [95% CI, 0.55–0.94]; P =0.0150 for superiority). Stent thrombosis rates were 2.0% DCS and 2.2% bare metal stent. Major bleeding at 1 year occurred in 7.2% DCS patients and 7.2% bare metal stent. Conclusions: LFII reproduces the results of the DCS arm of LF in an independent, predominantly North American cohort of HBR patients.

Aim To compare the inflammatory response of polymer-free versus permanent polymer drug-eluting stents in patients with stable coronary artery disease undergoing elective PCI, and the effect of this inflammatory response on the 6 month clinical outcomes. Methods This randomized prospective comparative study was conducted on 100 patients with stable coronary artery disease planned for elective PCI divided into 50 patients with deployed permanent polymer DES (PP-DES) groups and 50 patients with polymer free DES (PF-DES). Blood samples were taken to assess serum level of hsCRP before the procedure and the first day after the procedure. The target end points were the recurrence of effort angina, incidence of target lesion revascularization (TLR) over a period of 6 months and the inflammatory response by measuring the percentage of rise in hsCRP level. Results There was no statistically significant difference in the clinical outcome in the first six months between the patients who had PP-DES and the patients who had PF-DES regarding recurrence of effort angina (p-value = 0.822) and TLR (p-value = 0.727), with no patients developing myocardial infarction or stent thrombosis. There was a statistically significant inflammatory response after stent deployment in both groups represented by a significant rise in the serum level of hsCRP on the first day after the procedure in both groups (p-value < 0.001), but there was no statistically significant difference in the inflammatory response between PP-DES and PF-DES (p-value = 0.978). The number of patients having recurrence of anginal symptoms and TLR with hsCRP rise ≥ 11.36% was higher than those having the same with hsCRP < 11.36%. However, this difference was not statistically significant regarding recurrence of anginal symptoms (p = 0.057) and TLR (p = 0.092). Conclusion The PF-DES was proved to be non-inferior to PP-DES regarding the short-term clinical outcome and the early inflammatory response. It was concluded that the presence of polymeric coating in PP-DES did not add to the magnitude of the inflammatory response and it did not significantly increase the incidence of recurrence of anginal symptoms and TLR in this group of patients.

In this paper we provide the representation of the symplectic group $Sp(2n, \mathbb{R})$ in polymer quantum mechanics. We derive the propagator of the polymer free particle and the polymer harmonic oscillator without considering a polymer scale. The polymer scale is then introduced to reconcile our results with those expressions for the polymer free particle. The propagator for the polymer harmonic oscillator implies non-unitary evolution., 20 pages

Background: polymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited. Methods: in an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus-coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority. Results: a total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drug-coated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P = 0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P = 0.007 for noninferiority). Conclusions: among patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.).

We have studied polymer-free cladding power strippers for high-power fiber laser applications. A practical, rapid, and process-on-place chemical etching technique is presented to form surface roughness for efficient removal of the cladding light. The technique is methodically studied and performance contours are determined for frequently used 130, 250, and 400 µm double-clad fibers. The stripping efficiency and the thermal performance of the fabricated strippers are investigated with respect to such process parameters as etching time and etched fiber length. At least 15 dB attenuation with < 0.045 ( ∘ C / W ) thermal slope is demonstrated for all fiber types. To show the power scalability of the proposed technique, ∼ 600 W power is stripped with an ultra-low thermal slope of ∼ 0.021 ( ∘ C / W ) over a 400 µm fiber.

A prospective randomized clinical trial showed that the BioFreedom stent (Biosensors International), which is a polymer-free and carrier-free drug-coated stent, was significantly superior to a bare-metal stent (BMS) in patients at high bleeding risk who were receiving a 1-month course of dual antiplatelet therapy (DAPT). However, the stent thrombosis rate (2.01% for BioFreedom vs. 2.20% for BMS) was 4-6-fold higher than that of approved drug-eluting stents based on real-world data in Japan. Furthermore, the frequency of stent thrombosis at more than 1 month with the BioFreedom stent was slightly higher than that at less than 1 month. This result suggested that it would not be acceptable to stop DAPT universally at 1 month. Thus, the target patients for the BioFreedom stent are unspecified patients at high bleeding risk needing to continue DAPT for as long as necessary in Japan. Therefore, based on the pre- and post-marketing balance of medical devices regulations, regulatory approval was given for unspecified patients conditionally upon real-world data collection of 2,000 patients with a Use-Results Survey, instead of conducting additional pre-marketing clinical trial(s). The Use-Results Survey System is part of a strategy to expedite patients' access to innovative medical devices and to accelerate the development of medical devices.

Polymer-free drug-eluting stents (PF-DES) were designed with the expectation of avoiding late restenosis and thrombosis related to the polymer used in traditional DES platforms. Furthermore, due to similarities with bare metal stents after drug elution, PF-DES has been considered as particularly suitable for patients at high bleeding risk. A variety of PF-DES platforms have been clinically tested. Despite their theoretical advantages, PF platforms showed comparable clinical outcomes with modern permanent- or biodegradable polymer-based DES up to 5 years after implantation. Use of more biocompatible polymers on the modern DES platforms is one of the reasons therefore. Their improved safety profile allows already less intensive antithrombotic regimes after DES. Hence, nowadays PF-DES platforms can be considered as one of many DES options for percutaneous treatment of coronary artery disease.

Despite impressive improvements in drug-eluting stent (DES) technologies, patients with diabetes remain at high risk for adverse events after percutaneous revascularization. Among novel DES, the Cre8 polymer-free amphilimus-eluting stent (AES) has shown promising results [(1)][1]. Recently, we

OBJECTIVES To evaluate the 9-month safety and efficacy of polymer-free sirolimus eluting drug eluting stents in septuagenarians and octogenarians. METHODS An all-comer, worldwide single armed trial (ClinicalTrials.gov Identifier NCT02629575) was conducted to demonstrate the safety and efficacy of an ultra-thin strut, polymer-free sirolimus eluting stent (PF-SES). The primary endpoint was the 9-month target revascularization rate (TLR). Secondary endpoints included the rates of major adverse cardiac events (MACE), stent thrombosis (ST) and bleeding (BARC) in septuagenarians (≥70 years

The paper reports the synthesis and characterization of curcumin (CUR) and beta-cyclodextrin (β-CD) based inclusion complexes (ICs) prepared using co-solvent (IC-1) and common solvent (IC-2) precipitation techniques. The complexes were subjected to thermal and microstructural characterization to study the complexation behavior of the ICs. IC-2 exhibited a complete encapsulation of CUR with β-CD from both sides. The morphological and in-vitro release of CUR in Phosphate Buffer Saline (PBS) was evaluated. The fabrication of nanoparticles (NPs) of IC-2 led to the finest particle diameter (~ 350 nm) and minimal diameter variation using the Taguchi design of experiments. The study demonstrates the possibility to fabricate optimally controlled NPs of CUR/ β-CD IC, exhibiting the significant potential to be electrosprayed on biomedical surfaces of implants and devices with enhanced efficacy and stability of CUR release.

In this study, sirolimus (SRL) was loaded within biomimetic apatite formed on cobalt-chromium (Co-Cr) alloy, which has been reported for the first time, to inhibit the in-stent restenosis. Two different groups of loading SRL within biomimetic apatite were prepared: Group A (mono-layer of apatite/SRL) and Group B (bi-layer of apatite/SRL). Group A and Group B showed the biphasic pattern of SRL release up to 40 and 90days, respectively. The attachment of human artery smooth muscle cell (HASMC) for both Group A and Group B was significantly inhibited, and proliferation dramatically decreased with the release of SRL. Noteworthily, biomimetic apatite alone also suppressed the SMC proliferation. The porous biomimetic apatite uniformly covered Co-Cr stent without crack or webbings. After balloon expansion, the integrity of biomimetic apatite was sufficient to resist delamination or destruction. Thus, this study demonstrated that biomimetic apatite is a promising drug carrier for potential use in stents.

The LEADERS FREE trial concluded that the polymer free drug-coated BioFreedom™ stent appeared to be both safer and more effective than bare-metal stents (BMS) with an ISR rate comparable to traditional DES without the need for prolonged DAPT. We implanted 45 BioFreedom™ stents in 34 patients over a 4-month period. 4 patients represented early (106-238 days after the implant procedure) with angina symptoms and severe ISR was detected in all patients. The rate of severe and early ISR detected in our patient population of 11.8% is comparable to that of traditional BMS. Further studies are warranted.

Background To assess clinical outcomes of patients needing short dual antiplatelet therapy (S-DAPT) after PCI with Cre8 polymer-free amphilimus eluting-stent (AES). The Cre8-AES with pure i-Carbofilm coating was supposed to induce faster stent endothelialization and reduce device thrombogenicity. Methods We performed a sub-analysis of unrestricted consecutive patients treated with Cre8-AES between August 2011 and January 2015. Two groups were formed: 1) patients discharged with S-DAPT (≤ 3-month), because of high bleeding risk or attending urgent non-cardiac surgery; and 2) patients discharged with Recommended DAPT duration (R-DAPT; ≥ 6-month). The primary ischemic- and bleeding-safety endpoints were Target Vessel Failure (TVF, composite endpoint of cardiac-death, target vessel-myocardial infarction and target vessel-revascularization), and major-bleeding (BARC ≥ type-3a) at 6-month and 1-year. Results 106 patients (8.7%) were discharged with ≤ 3-month DAPT (83 ± 19 days; S-DAPT group) and 1102 patients (90.6%) with ≥ 6-month DAPT (342 ± 62 days; R-DAPT group). Between S-DAPT and R-DAPT groups no significant differences were observed in TVF at 1-year (5.7% vs 5.1%); 1-year BARC major bleeding rate was higher in S-DAPT group (3.4% vs 0.2%, p = 0.007) with all bleeding events occurred within 3 months. The landmark analysis (started at 90 days, ended at 1 year) showed no differences in BARC major bleedings between groups (0% vs. 0.3%). Conclusions The results of this multicenter registry show that the use of Cre8 AES in patients needing short DAPT (≤ 3-month) was safe regarding ischemic events and could favor a reduction of bleeding events related to the recommended DAPT. A large randomized trial is necessary to support these preliminary findings.

Optical coherence tomography (OCT) is a high resolution imaging modality and has been considered as the ideal tool for the evaluation of neointimal tissue and vascular responses following stent implantation. However, vascular response profiles following the implantation of a novel nano polymer-free sirolimus-eluting stent (SES) assessed by OCT has not been fully investigated. Therefore, the aim of the present study was to determine the effects of a nano polymer-free SES on neointimal formation using OCT. A total of 16 nano polymer-free SESs were implanted in the coronary arteries of 8 pigs. At 3 (n=4) or 6 months (n=4), the animals were euthanized following OCT evaluation and the stented arterial segments were analyzed by histological analysis. Neointimal area, thickness and burden were evaluated by OCT. In addition, strut-associated inflammation, stent endothelialization and arterial injury were investigated by histomorphological analysis. OCT examination showed that at 6 months, neointimal thickness (193.3±109.5 vs. 167.2±119.7 µm, P=0.023) and neointimal burden (29.3±14.3 vs. 24.8±17.4%, P=0.006) significantly increased compared with at 3 months. Histomorphological analysis indicated that the endothelialization score was significantly greater at 6 months compared with at 3 months (2.85±0.36 vs. 2.52±0.60, P

Objectives This study sought to assess the safety and effectiveness of the drug-filled stent (DFS) (Medtronic, Santa Rosa, California) in the treatment of patients with coronary artery disease. Background Polymer-free drug-eluting stents have the potential to improve clinical outcomes and facilitate shorter durations of dual antiplatelet therapy. The polymer-free DFS is made from a trilayered continuous wire with an outer cobalt chromium layer, a middle tantalum layer, and an inner lumen coated with sirolimus. Small laser-drilled holes on the abluminal stent surface control drug elution. Methods The RevElution trial enrolled 100 patients with de novo coronary lesions 2.25 to 3.50 mm in diameter and length ≤27 mm in 2 cohorts of 50 patients for angiographic, intravascular ultrasound, and clinical assessment at 9 or 24 months, with optical coherence tomography performed in a subset of 30 patients at each time period. The primary endpoint was angiographic in-stent late lumen loss at 9 months compared with Resolute zotarolimus-eluting stent (Medtronic) historical control data. Results Fifty patients with 56 lesions were treated with DFS in the 9-month cohort. In-stent late lumen loss was 0.26 ± 0.28 mm for DFS and 0.36 ± 0.52 mm for Resolute (pnoninferiority Conclusions At 9 months, the polymer-free DFS was safe and effective with high rates of early strut coverage and noninferior late lumen loss compared to Resolute. (Medtronic RevElution Trial [RevElution]; NCT02480348)

Vessel healing seems to be associated with stent strut coverage at an early post-implantation stage and is potentially related to stent thrombosis ([1][1]). We report the results of a randomized controlled trial to assess the timing and degree of intracoronary healing of 2 different sirolimus

Background Polymer-free biolimus A9-coated stent (DCS) has currently emerged as expected better arterial healing compared to durable polymer drug-eluting stent (DP-DES). However, superiority of DCS on arterial healing over DP-DES has not been well elucidated using intracoronary images. Methods This study examined 288 stents in 224 patients with de novo coronary artery lesions. We angioscopically compared 55 DCS from 35 patients with 233 DP-DES from 189 patients 10±2 months after the implantation. We assessed thrombus adhesion, which is a marker of incomplete re-endothelialization. Dominant neointimal coverage (NIC) grade, heterogeneity of NIC and maximum yellow color of plaque underneath the stent were also evaluated. Neointimal coverage was graded as follows: grade 0, stent struts exposed; grade 1, struts bulged into the lumen, although covered; grade 2, struts embedded by the neointima, but translucent; grade 3, struts fully embedded and invisible. NIC was judged as heterogeneous when differences in the NIC grade became apparent. Yellow plaque was graded as follows: grade 0, white; grade 1, light yellow; grade 2, yellow; grade 3, intensive yellow. Results Thrombus adhesion was similar between DCS and DP-DES (29% versus 23%, P=0.32). Dominant NIC was greater in DCS than in BP-DES (P Conclusion DCS provided similar thrombus adhesion to DP-DES, which suggested similar re-endothelialization 10 months after implantation. However, DCS showed thick and heterogeneous NIC compared to DP-DES. The specific feature of polymer-free and Biolimus A9 would cause the difference, and further investigation is necessary to evaluate the longer-term safety and efficacy. Acknowledgement/Funding None

Background The LEADERS FREE trial established the favourable clinical profile of a new polymer-free biolimus A9-eluting stent (PF-BES) in patients at high bleeding risk when used with a 1-month dual anti-platelet therapy (DAPT) strategy. Purpose This is the first study evaluating real-world reasons and outcomes for a 1-month versus longer DAPT strategies following PF-BES percutaneous coronary intervention (PCI). Methods FREEDOM is an all-comers registry including all patients who underwent PCI with at least one PF-BES at 10 sites, between January 2016 and July 2018. Patients were stratified according to DAPT strategy at discharge (1-month vs >1-month). Baseline features, reasons for PF-BES as reported by the treating physician, and outcomes were compared between groups. Primary outcomes were the 390-day estimates of a patient-oriented composite endpoint (POCE: death, myocardial infarction (MI) or target vessel revascularization) and of a device-oriented composite endpoint (DOCE: cardiac death, target vessel-MI or ischemia-driven target lesion revascularization). Incidence rates were adjusted for clinically relevant factors and outcome predictors. To avoid survival bias, landmark analyses starting from 1-month post-PCI were further carried. Results Following PF-BES PCI, 328 (40.3%) patients were discharged with 1-month DAPT and 485 (59.6%) patients with longer DAPT (median 12 months, IQR 6–12 months). Patients with hypertension or on oral anticoagulation (OAT) were more likely and patients with a previous or an index MI were less likely to be discharged on 1-month DAPT. Patients prescribed with 1-month DAPT were more likely to have had a PF-BES for a LEADERS FREE high bleeding risk criterium than those with longer DAPT (90.2% vs 69.9%, p=0.001). The same association was observed when the reason for PF-BES was a planned major surgery (13.1% vs 6.2%; p=0.001) or OAC to be continued after PCI (38.7% vs 16.5%, p1-month DAPT: POCE 11.9% vs 13.2%, p=0.747; adj-HR 1.29 [95% CI 0.78–2.10]; DOCE: 4.8% vs 8.1%, p=0.500; adj-HR 1.01 [95% CI 0.50–2.07]) and of bleedings (any: 11.3% vs 9.4%, p=0.472; adj-HR 0.87 [95% CI 0.51–1-50]; BARC 3–5: 4.2% vs 2.2%; p=0.108; adj-HR 1.50 [95% CI 0.58–3.87]) were observed. Landmark analyses showed similar results. Conclusions In a large contemporary all-comers registry, factors reflecting the operator-perceived patient high bleeding risk were the main drivers of a very-short DAPT strategy following PF-BES PCI. We found no interaction of DAPT duration with outcomes following PF-BES PCI, an observation warranting investigation in adequately powered randomised studies.

Background The absence of a polymer-coat along with fast drug absorption represent the benchmark counterpart of the favourable clinical profile of a new polymer-free biolimus A9-eluting stent (PF-BES), also when used with a very short dual antiplatelet therapy (DAPT) strategy. Its current use in the real-world setting has not been thoroughly assessed. Purpose We evaluated contemporary patterns of indications, DAPT strategies and outcomes for the PF-BES. Methods FREEDOM is a multicenter registry including all patients who underwent percutaneous coronary intervention (PCI) with at least one PF-BES at 10 italian sites. Reasons for PF-BES PCI and planned antithrombotic regimen at discharge were collected. Primary outcomes were the 390-day Kaplan Meier estimates of a patient-oriented composite endpoint (POCE: death, any myocardial infarction [MI] or any target vessel revascularization [TVR]) and of a device-oriented composite endpoint (DOCE: cardiac death, target vessel-MI or ischemia-driven target lesion revascularization [ID-TLR]). The independent outcomes predictors were assessed through multivariate Cox proportional hazards analysis. Results Between January 2016 and July 2018, 858 patients (age: 74±10 years, 64.6% males, 58.7% acute coronary syndrome presentation) underwent PF-BES PCI. Main reasons for PF-BES physician's choice were advanced age (26.0%), oral anticoagulation (OAT) to be continued after PCI (25.3%), operator preference for PF-BES (9.9%), planned major surgery (8.6%), cancer (8.6%), anemia (7.9%) and recent bleeding (7.0%). Overall, the operator choice to implant a PF-BES reflected a perceived high bleeding risk in 77.7% of patients. At discharge, 99.2% of patients were on DAPT, 19.5% on triple therapy, and 0.8% on single antiplatelet therapy plus OAT. Planned DAPT duration was 1-month in 40.3% of patients, with 33.8% of these being on triple therapy. At 390-day follow-up (median 340 days, interquartile range: 187–390 days) the incident estimate of POCE was 13.1% (any MI 3.7%, any TVR 3.4%) and of DOCE was 7.1% (TV-MI 3.6%, ID-TLR 1.4%); while 390-day estimate of any bleeding event was 11.1% (BARC 3–5 bleeding 3.0%). Independent predictors of 390-day POCE were eGFR≤60 ml/min (HR 1.81; 95% CI 1.09–3.04, p=0.028), a history of cancer (HR 2.62; 95% CI 1.43–4.81, p=0.002) and severely calcified lesion/s (HR 2.05; 95% CI 1.09–3.85, p=0.025). Independent predictors of DOCE were a previous MI (HR 2.06; 95% CI 1.03–4.15, p=0.041), a history of cancer (HR 2.69; 95% CI 1.18–6.13, p=0.019) and bifurcation lesion/s (HR 2.66; 95% CI 1.38–5.13, p=0.004). Conclusions In a large, contemporary all-comers registry, the main reasons for PF-BES use reflected in most cases the operator-perceived high bleeding risk of the patient. Following PF-BES PCI, a very-short DAPT strategy was frequently implemented. The outcomes observed in this registry suggest a favorable safety and efficacy profile for the PF-BES in a real-world clinical setting.

Background Polymer‐free amphilimus‐eluting stents (PF‐AES) represent a novel elution‐technology in coronary stenting. We aimed to assess 1‐year clinical outcomes of PF‐AES as compared to latest‐generation permanent polymer zotarolimus‐eluting stents (PP‐ZES) in a real‐world all‐comers setting. Methods A prospective registry of patients treated with either PF‐AES or PP‐ZES between 2014 and 2016 was conducted. The primary outcome was defined as major adverse cardiac and cerebrovascular events (MACCE), and the secondary outcome was defined as target‐lesion failure (TLF) at 1 year. To account for measured confounders, a propensity‐score adjusted Cox proportional‐hazard model was built to evaluate clinical outcomes. Results A total of 734 consecutive patients with 1,269 DES implantations were enrolled. The population was characterized by 28% diabetes, 24% ST‐segment elevation myocardial infarction, and a high number of complex lesions (69%). The rate of MACCE was 11.5% for PF‐AES and 13.6% for PP‐ZES, plog‐rank = 0.11. TLF was numerically lower in PF‐AES as compared to PP‐ZES (5.4 vs. 6.1%, plog‐rank = 0.68). After propensity‐score adjustment, PF‐AES showed a trend toward a lower rate of MACCE and a favorable rate of TLF as compared to PP‐ZES (HR 0.70; 95%CI 0.45 to 1.10, P = 0.12; and HR 0.88; 95%CI 0.47 to 1.65, P = 0.68, respectively). Rates of definite ST were low (0.8 vs. 0.3%, plog‐rank = 0.62). Conclusions Our study suggests that implantation of PF‐AES was safe and effective in real‐world patients, with low‐rates of MACCE and TLF at 1 year. Our data needs to be confirmed by a large trial to evaluate the clinical outcomes of this novel polymer‐free, eluting‐technology used in PF‐AES.