AIMSDrug-eluting stents (DES) have evolved to using bioresorbable polymers as a method of drug delivery. The impact of bioresorbable polymer on long-term neointimal formation, inflammation, and healing has not been fully characterised. This study aimed to evaluate the biological effect of polymer resorption on vascular healing and inflammation.METHODS AND RESULTSA comparative DES study was performed in the familial hypercholesterolaemic swine model of coronary stenosis. Permanent polymer DES (zotarolimus-eluting [ZES] or everolimus-eluting [EES]) were compared to bioresorbable polymer everolimus-eluting stents (BP-EES) and BMS. Post implantation in 29 swine, stents were explanted and analysed up to 180 days. Area stenosis was reduced in all DES compared to BMS at 30 days. At 180 days, BP-EES had significantly lower area stenosis than EES or ZES. Severe inflammatory activity persisted in permanent polymer DES at 180 days compared to BP-EES or BMS. Qualitative para-strut inflammation areas (graded as none to severe) were elevated but similar in all groups at 30 days, peaked at 90 days in DES compared to BMS (p<0.05) and, at 180 days, were similar between BMS and BP-EES but were significantly greater in DES.CONCLUSIONSBP-EES resulted in a lower net long-term reduction in neointimal formation and inflammation compared to permanent polymer DES in an animal model. Further study of the long-term neointima formation deserves study in human clinical trials.

Thrombosis associated with medical devices may lead to dramatic increases in morbidity, mortality and increased health care costs. Innovative strategies are being developed to reduce this complication and provide a safe biocompatible interface between device and blood. This article aims to describe the biological phenomena underlying device-associated thrombosis, and surveys the literature describing current and developing technologies designed to overcome this challenge. To reduce thrombosis, biomaterials with varying topographical properties and incorporating anti-thrombogenic substances on their surface have demonstrated potential. Overall, there is extensive literature describing technical solutions to reduce thrombosis associated with medical devices, but clinical results are required to demonstrate significant long-term benefits.

AIMS Our aim was to evaluate arterial responses to paclitaxel and a novel fluorocopolymer-coated nitinol low-dose paclitaxel-eluting stent (FP-PES). METHODS AND RESULTS Human smooth muscle cell (SMC) migration was assessed after exposure to paclitaxel in vitro. For pharmacokinetics and vascular response, FP-PES or bare metal stents (BMS) were implanted in porcine iliofemoral arteries. Paclitaxel significantly inhibited human coronary and femoral artery SMC migration at doses as low as 1 pM. Inhibition was significantly greater for femoral compared with coronary artery SMCs from 1 pM to 1 μM. Pharmacokinetics showed consistent paclitaxel release from FP-PES over the study duration. The peak arterial wall paclitaxel level was 3.7 ng/mg at 10 days, with levels decreasing to 50% of peak at 60 days and 10% at 180 days. Paclitaxel was not detected in blood or remote organs. Arteriogram and histomorphometry analyses showed FP-PES significantly inhibits neointimal proliferation versus BMS at 30 and 90 days. Re-endothelialisation scores were not different between groups. CONCLUSIONS Paclitaxel affected femoral artery SMC migration at lower concentrations and to a greater degree than it did coronary artery SMCs. The novel FP-PES used in this preclinical study demonstrated a vascular healing response similar to BMS, while significantly inhibiting neointimal formation up to 90 days.

Esophageal stents are used in the clinic to maintain esophageal luminal patency and for palliative care. Complications with current self-expanding metal and plastic stents include pain, tissue overgrowth, and migration (up to 60%). Naive swine models are not ideal for esophageal stent evaluation as stents frequently migrate into the stomach, and healthy animals do not mimic clinical conditions. We sought to establish a swine model of clinical benign esophageal stricture for better evaluation of next generation esophageal stents.

Bioresorbable polymer coatings are hoped to minimize persistent inflammation associated with durable polymer usage as a drug carrier in drug-eluting stents (DES). We examined the time course of para-strut inflammation (PI) of 3 contemporary DES featuring abluminal bioresorbable polymer coating (

Background The utility of animal models for the prediction of drug-eluting stent (DES) efficacy in human clinical trials is still unclear. The familial hypercholesterolemic swine (FHS) model has been shown to induce a human-like neointimal response to bare metal stent (BMS) implantation. However, its utility to discriminate efficacy signals following DES implantation is unknown. In this study, we aimed to test the efficacy and healing response of several everolimus-eluting stent (EES) platforms in the coronary territory of the FHS. Methods A total of 19 EES platforms (SYNERGY=6, SYNERGY½-dose=7, and PROMUS Element=6) and an identical BMS control (Element=6) were implanted into the coronary arteries of nine FHS. All implants were performed under intravascular ultrasound guidance using a 1.2 : 1 overstretch ratio. At 30 days, the vascular response to the implant was evaluated by quantitative coronary angiography, optical coherence tomography, and histology. Results At 28 days, all EES platforms showed a significant decrease in angiographic late lumen loss (between 27 and 37%) compared with the BMS control group. This finding was confirmed both by optical coherence tomography (mean neointimal thickness=28–42% reduction) and by histology (mean neointimal thickness=44–55% reduction). All EES platforms showed similar degrees of neointimal inhibition. The presence of moderate to severe para-strut inflammation was observed in 83% of the stent sections in the BMS group compared with 28.6% in the SYNERGY½-dose group and 0% in the SYNERGY and PROMUS groups (P=0.0002). There was a 68–95% reduction in MMP9 expression in the media in all EES platforms compared with the BMS controls. The presence of mild to moderate para-strut fibrin deposits ranged from 66.7 to 83.4% in all EES platforms compared with 16.7% in the EBMS group. Conclusion The FHS coronary injury model showed the efficacy of several EES platforms compared with an identical BMS control. Everolimus eluted from different polymeric platforms showed lower levels of inflammation and slightly higher fibrin deposits compared with BMS controls.

Background— Emerging drug-eluting stent technologies are evolving toward the elimination of polymeric component used as the method for modulating drug delivery. Although this technological approach seems to be biologically appealing, the impact of durable polymers and metallic stent surfaces on vascular healing remains unclear. In the present study, we aimed to compare the independent effect of a durable polymer and a metallic stent surface on thrombogenicity and endothelial cell coverage using different in vitro and in vivo experimental models. Methods and Results— Platinum chromium (PtCr) and polyvinylidene fluoride-co-hexafluoropropene (PVDF-HFP)–coated surfaces were evaluated in this study. Thrombogenicity was assessed by exposing all surfaces to human blood under shear flow conditions. The inflammatory potential of the material was evaluated by measuring cytokine release from THP-1 cells exposed to all surfaces for 24 hours. Endothelial cell coverage was evaluated by detection of CD31 after the stents were exposed to human coronary artery endothelial cells for ≤14 days. Platelet adhesion ( P <0.01) and activation ( P =0.03) on PVDF-HFP were greater than on PtCr. In vivo, PVDF-HFP revealed more neointimal area ( P <0.01) and residual parastrut fibrin ( P =0.01) at 30 days compared with PtCr. PtCr displayed higher endothelialization rates and higher vascular endothelial-cadherin expression at 7 and 14 days ( P =0.02) compared with PVDF-HFP. Conclusions— Thrombogenicity and vascular healing differ among metallic and polymeric stent surfaces. PVDF-HFP exhibits higher degrees of platelet activation–adhesion and thrombus accumulation in vivo compared with PtCr. PtCr displayed higher degrees of endothelial surface coverage compared with PVDF-HFP surfaces.

AimsSYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent.Methods and ResultsSYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3x polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types.ConclusionIn a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3x safety margin, demonstrated vascular compatibility similar to bare metal stent controls. (c) 2015 Wiley Periodicals, Inc.

AIMS:To evaluate the time-course of vasomotor function and re-endothelialisation after implantation of a novel platinum-chromium (PtCr) abluminal biodegradable polymer-coated paclitaxel-eluting stent (PES, Labcoat Element) in rabbit iliac arteries.METHODS AND RESULTS:Either PES (n=18) or an identical platform of bare metal stents (BMS, Element, n=18) were implanted in rabbit iliac arteries (six animals per time-point). At 14, 30, and 90 days, acetylcholine- and nitroglycerine-induced vasomotor reactivity at 5-10 mm distal to the stent was measured. Subsequently, the animals were terminated. The stented artery was bisected longitudinally for either SEM or en face CD31 immunochemistry examination. All arteries were patent with normal angiographic flow. Decreased endothelial-dependent vasomotion was found at both 14 and 30 days for PES compared to BMS (p<0.01, respectively); however, these differences resolved by 90 days. Endothelial-independent vasorelaxation was similar at all three time-points. Both SEM and en face staining demonstrated equivalent endothelial coverage on the surface of the stented segments above and between struts at all time-points.CONCLUSIONS:This novel bioabsorbable polymer abluminal-coated PES demonstrated vasomotor function comparable to BMS within three months post-deployment in the rabbit iliac model. Despite indistinguishable endothelial cell coverage on the stent surface between groups, earlier differences in vasomotion were detected: this finding suggests that the timing of restoration vasomotor function lags morphologic endothelial recovery.

Background: The performance of zotarolimus-eluting stents (Medtronic Inc., Santa Clara, CA, USA) versus other limus-eluting stents (LES) and the possible improvements of Resolute zotarolimus-eluting stents (R-ZES) versus Endeavor zotarolimus-eluting stents (E-ZES) still remain to be defined. We sought to evaluate efficacy and safety of two zotarolimus-eluting stent generations versus other LES and to compare R-ZES versus E-ZES. Methods: We undertook a meta-analysis of trials in which patients were randomly assigned to percutaneous coronary interventions (PCI) with R-ZES versus LES or with E-ZES versus LES as well as an indirect comparison of R-ZES versus E-ZES, with LES as common comparator. The primary efficacy endpoint was ischemia-driven target vessel revascularization (ID-TVR); the primary safety endpoints were cardiac death and cumulative definite/probable stent thrombosis (ST). Results: Overall, 13,709 patients were assigned to PCI with R-ZES versus LES (n 7,185) or with E-ZES versus LES (n 6,524). The risk of ID-TVR (odds ratio [95% confidence interval] 1.06 [0.90-1.25], p 0.47), cardiac death (0.99 [0.69-1.42], p 0.96) and ST (1.18 [0.68-2.03], p 0.56) did not differ between R-ZES and LES. Patients receiving E-ZES were more likely to undergo ID-TVR as compared to those receiving LES (1.95 [1.40-2.73], p 0.0001). Cardiac death (1.02 [0.54-1.91], p 0.96) and ST (1.10 [0.50-2.44], p 0.81) were similar between E-ZES and LES. At indirect comparison, PCI with R-ZES versus E-ZES reduced the risk of ID-TVR (0.54 [0.37-0.78], p 0.001), without increasing cardiac death (0.97 [0.46-2.00], p 0.93) and ST (1.07 [0.40-2.80], p 0.88). Conclusions: The antirestenotic efficacy of Resolute zotarolimus-eluting stents is superior to Endeavor zotarolimus-eluting stents and similar to other limus-eluting stents. Endeavor zotarolimus-eluting stents increase the risk of reinterventions as compared to other limus-eluting stents. First and second zotarolimus-eluting stent generations have similar thrombogenicity compared to other limus-eluting stents.

Everolimus, a pharmaceutical component of drug-eluting stents, inhibits coronary vessel restenosis, but the antirestenotic mechanisms of action remain unclear. Here, we describe the effects of everolimus on key contributors to vessel restenosis, smooth muscle cell proliferation, and migration. In a dose-dependent fashion, everolimus reduced human coronary artery smooth muscle cell (HCASMC) proliferation without toxicity in a bimodal fashion, with accentuated potency occurring at 10 μM. Everolimus arrested the majority of HCASMCs in G1-phase, whereas it reduced the fraction of cells in S-phase at doses that inhibited DNA synthesis (bromodeoxyuridine incorporation). Consistent with this, Western blotting demonstrated that everolimus reduced activation and expression of G1-phase cell cycle progression factors, including p70S6K and cyclin D, respectively, decreased levels of proliferating cell nuclear antigen, and attenuated growth factor/serum-induced phosphorylation of the cell cycle phase transition intermediate, retinoblastoma protein. Everolimus did not, however, affect HCASMC migration. These observations suggest that everolimus acts as an antiproliferative, but not antimigratory, compound to account for at least some of the clinical efficacy exhibited by this drug as an antirestenotic agent. Moreover, everolimus-induced inhibition of the mammalian target of rapamycin complex 1 and regulation of cyclin-mediated cell cycle progression actions likely account for the antiproliferative effects of this compound on HCASMCs.

Patients with diabetes are particularly prone to coronary atherosclerosis, and the presence of diabetes increases the annual mortality risk in patients with proven coronary artery disease. Patients with diabetes also have an increased risk of restenosis following both balloon angioplasty and bare-metal stent (BMS) placement, due to differences in cellular proliferative signalling and a consequent accentuated neointimal response compared with that seen in patients without diabetes. Drug-eluting stents (DES) generally moderate this neointimal response and reduce restenosis in patients both with and without diabetes, without increasing the safety risk compared with BMS. However, it is unknown whether the different antiproliferative agents used in DES influence their comparative safety and efficacy. This article summarises recent peer-reviewed data from a range of molecular, cellular, imaging and clinical studies to provide an integrated bench-to-bedside perspective on the relative effects of commercially available DES in patients with diabetes versus patients without diabetes.

The desire to reduce the strut thickness of cardiovascular stents has driven the development of a new high strength radiopaque alloy, based on additions of platinum to a chromium-rich iron based matrix. This paper reports on initial development of the alloy and the rationale for selection of the composition. Data is presented for tensile and microstructural characterization, surface oxide analysis, corrosion resistance and endothelial cell response of the alloy. The results demonstrate the solid solution strengthening effect of the platinum, with an average yield strength of 480 MPa achieved. The material surface consists of primarily chromium oxide which contributes to the high corrosion resistance observed. The cell assay result suggests that surfaces of this Pt-enhanced alloy endothelialize in a manner comparable to stainless steel.

Coronary artery disease is commonly characterized by atherosclerotic obstruction of vessels responsible for providing adequate blood supply to the myocardium. Disruption of atheromatous plaques can promote thrombosis, significant reductions in cardiac perfusion, and devastating acute (i.e, death) or chronic (i.e., congestive heart failure) consequences. Minimally invasive, catheter-based techniques have been implemented throughout the past three decades and include balloon angioplasty and stent implantation, to alleviate occlusive plaque burden in coronary vessels. Yet, these techniques have not come without complication, namely the tendency for vessels to re-occlude, or undergo restenosis. This manifestation is characterized by acute physical and longer-lasting cellular/biochemical components. To maximize clinical effectiveness, researchers and clinicians have exploited recognition that use of a rigid bare metal stent bound to a drug-bearing polymer, or so-called drug-eluting stent (DES), is best to combat the mechanical and biological contributors to restenosis. In this report, we review restenosis factors in detail, the corresponding rationale for drug choice for DES, and the results of trials conducted with such DES agents. Particular emphasis is given to paclitaxel, a natural compound included in a first-generation DES (Taxus(R) Express(2(R))) made available for clinical use by Boston Scientific Corporation. We use paclitaxel as a model to illustrate alternatives for drug delivery to coronary vessels, broad concerns about DES use in the context of disease backgrounds, such as diabetes, and suggestions related to the continuing evolution of DES.

Coronary artery disease is commonly characterized by atherosclerotic obstruction of vessels responsible for providing adequate blood supply to the myocardium. Disruption of atheromatous plaques can promote thrombosis, significant reductions in cardiac perfusion, and devastating acute (i.e, death) or chronic (i.e., congestive heart failure) consequences. Minimally invasive, catheter-based techniques have been implemented throughout the past three decades and include balloon angioplasty and stent implantation, to alleviate occlusive plaque burden in coronary vessels. Yet, these techniques have not come without complication, namely the tendency for vessels to re-occlude, or undergo restenosis. This manifestation is characterized by acute physical and longer-lasting cellular/biochemical components. To maximize clinical effectiveness, researchers and clinicians have exploited recognition that use of a rigid bare metal stent bound to a drug-bearing polymer, or so-called drug-eluting stent (DES), is best to combat the mechanical and biological contributors to restenosis. In this report, we review restenosis factors in detail, the corresponding rationale for drug choice for DES, and the results of trials conducted with such DES agents. Particular emphasis is given to paclitaxel, a natural compound included on a first-generation DES (Taxus® Express(2)®) made available for clinical use by Boston Scientific Corporation. We use paclitaxel as a model to illustrate alternatives for drug delivery to coronary vessels, broad concerns about DES use in the context of disease backgrounds, such as diabetes, and suggestions related to the continuing evolution of DES.

Rationale: Sirolimus-eluting coronary stents (SESs) and paclitaxel-eluting coronary stents (PESs) are used to reduce restenosis but have different sites of action. The molecular targets of sirolimus overlap with those of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone (RSG) but the consequence of this interaction on endothelialization is unknown.Objective: Using the New Zealand white rabbit iliac model of stenting, we examined the effects of RSG on SESs, PESs, and bare metal stents endothelialization.Methods and Results: Animals receiving SESs, PESs, or bare metal stents and either RSG (3 mg/kg per day) or placebo were euthanized at 28 days, and arteries were evaluated by scanning electron microscopy. Fourteen-day organ culture and Western blotting of iliac arteries and tissue culture experiments were conducted. Endothelialization was significantly reduced by RSG in SESs but not in PESs or bare metal stents. Organ culture revealed reduced vascular endothelial growth factor in SESs receiving RSG compared to RSG animals receiving bare metal stent or PESs. Quantitative polymerase chain reaction in human aortic endothelial cells (HAECs) revealed that sirolimus (but not paclitaxel) inhibited RSG-induced vascular endothelial growth factor transcription. Western blotting demonstrated that inhibition of molecular signaling in SES+RSG-treated arteries was similar to findings in HAECs treated with RSG and small interfering RNA to PPAR gamma, suggesting that sirolimus inhibits PPAR gamma. Transfection of HAECs with mTOR (mammalian target of rapamycin) short hairpin RNA and with Akt2 small interfering RNA significantly inhibited RSG-mediated transcriptional upregulation of heme oxygenase-1, a PPAR gamma target gene. Chromatin immunoprecipitation assay demonstrated sirolimus interferes with binding of PPAR gamma to its response elements in heme oxygenase-1 promoter.Conclusions: mTOR/Akt2 is required for optimal PPAR gamma activation. Patients who receive SESs during concomitant RSG treatment may be at risk for delayed stent healing. (Circ Res. 2009;105:1003-1012.)

To elucidate the actions of drugs that are useful in treating in‐stent restenosis, we compared the activities of both Paclitaxel and Sirolimus against dexamethasone, actinomycin D, or 17β‐estradiol in a panel of human cell‐based assays that model biological processes involved in restenosis. Paclitaxel and Sirolimus each inhibited endothelial cell (EC) and vascular smooth muscle cell (VSMC) growth, while dexamethasone promoted VSMC proliferation. Sirolimus and actinomycin D each decreased tissue remodeling markers in ECs and fibroblasts. Paclitaxel had no remarkable effects, while dexamethasone enhanced PAI‐1 expression. Paclitaxel did not affect T cell activation or peripheral blood mononuclear cell (PBMC)/T cell CD40/CD40 ligand and MCP‐1 expression. Sirolimus, 17β‐estradiol, dexamethasone, and actinomycin D each inhibited one or more of these inflammatory markers. In VSMC cultures, Paclitaxel up‐regulated thrombomodulin and decreased tissue factor expression. In contrast, Sirolimus increased tissue factor expression, but had no effect on thrombomodulin in cultures containing ECs and PBMCs. Dexamethasone, 17β‐estradiol, and actinomycin D each had little or no effect on these thrombosis factors. These results suggest that drugs considered for future use in DES platforms should inhibit VSMC proliferation to afford clinical efficacy with in‐stent restenosis. Further optimization would include drug actions that are not directed at ECs so as to permit proper vascular healing following DES deployment.