The genous™ endothelial progenitor cell capture stent accelerates stent re‐endothelialization but does not affect intimal hyperplasia in porcine coronary arteries

Beusekom, Heleen M.M. van; Ertaş, Gökhan; Sorop, Oana; Serruys, Patrick W.; Giessen, Willem J. van der

doi:10.1002/ccd.22928

Cited by 60 publications

(48 citation statements)

References 40 publications

(46 reference statements)

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“…7,32 However, compared with DES, the overall restenosis rates observed is within the range of bare metal stents. 33,34 The lack of any apparent advantage of the early stent endothelialization seen with this technology may be related to the nature of the coating or the cells attracted early to the cell surface. In a recent study, Granada et al 35 demonstrated that by adding an abluminal bioabsorbable sirolimus coating onto the anti-CD34 stent platform, inhibition of restenosis and enhanced endothelialization could be achieved.…”

Section: Discussionmentioning

confidence: 99%

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Sprague

Tio

Ahmed

et al. 2012

Circ: Cardiovascular Interventions

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D rug-eluting stents (DES) have dramatically reduced the long-term rate of reintervention and improved clinical outcomes among patients undergoing percutaneous coronary interventions.1 However, DES use still carries a small but critically important cumulative risk of late stent thrombosis. Human pathology studies suggest that delayed healing leads to incomplete strut coverage, which has been associated with late thrombotic events.2 Moreover, early DES platforms elicited enhanced platelet adhesion 3 and endothelial dysfunction. 4 Most DES technologies now embody thinner metallic platforms containing minimal amounts of polymeric drug formulations while maintaining drug concentrations and release profiles. 5,6 Although a slight decline in the overall stent thrombosis rate has been observed with the use of latest generation of DES platforms, these potentially lethal events still occur. Despite their efficacy in preventing restenosis, the antiproliferative effect of drugs used in commercially available DES appear to delay stent endothelialization. Technological approaches have been used to enhance stent endothelialization by modifying the stent surface with antibodies to selectively bind circulating endothelial progenitor cells. 7 An alternate strategy to encourage reendothelialization is to modify the stent surface to increase the natural rate of endothelial cell migration from adjacent arterial areas of intact healthy endothelium. Previous studies in our laboratory have shown that parallel microgrooves applied to the surface of different metals 8,9 increase the rate of human aortic endothelial cell migration by >2-fold compared with smooth coupons. More importantly, when this pattern was applied to the luminal surface of stents in an early pilot study, the endothelialization rate on these grooved stents was double compared with Background-Stent luminal surface characteristics influence surface endothelialization. We hypothesize that luminal stent microgrooves created in the direction of coronary flow accelerate endothelial cell migration, resulting in lower levels of neointimal formation. Methods and Results-Surface coverage efficiency was evaluated in vitro by allowing human aortic endothelial cells (HAEC) to migrate onto microgrooved (G) or smooth (NG) surfaces. HAEC functionality was assessed by proliferation rate, apoptosis rate, nitric oxide production, and inflammatory markers TNF-α and VCAM-1 expression. Early endothelialization and restenosis studies were performed using the porcine coronary injury model. Stainless steel stents of identical design with (GS) and without (NGS) luminal microgrooves were used. The commercially available Multi-Link Vision (MLVS) stent of identical design was used as a control. The degree of GS and NGS surface endothelialization was compared at 3 days. Biocompatibility and tissue response outcomes were evaluated at 28 days. The in vitro study demonstrated that at 7 days the presence of surface microgrooves increased HAEC migration distance >2-fold. Cell proliferation rate and nit...

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Section: Discussionmentioning

confidence: 99%

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Sprague

Tio

Ahmed

et al. 2012

Circ: Cardiovascular Interventions

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“…Rather than having two scenarios, we could of course have taken the initial fast recovery time and degree as additional uncertain parameters, which would be appropriate as the measurement they are based on has a high relative error. 33 However, reducing the number of uncertain parameters reduces computational cost, and with the present set-up, we can demonstrate a comparison between scenarios in the presence of uncertainty.…”

Section: Model Set-upmentioning

confidence: 96%

Uncertainty Quantification of a Multiscale Model for In-Stent Restenosis

Nikishova

Veen

Zun

et al. 2018

Cardiovasc Eng Tech

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Purpose-Coronary artery stenosis, or abnormal narrowing, is a widespread and potentially fatal cardiac disease. After treatment by balloon angioplasty and stenting, restenosis may occur inside the stent due to excessive neointima formation. Simulations of in-stent restenosis can provide new insight into this process. However, uncertainties due to variability in patient-specific parameters must be taken into account. Methods-We performed an uncertainty quantification (UQ) study on a complex two-dimensional in-stent restenosis model. We used a quasi-Monte Carlo method for UQ of the neointimal area, and the Sobol sensitivity analysis (SA) to estimate the proportions of aleatory and epistemic uncertainties and to determine the most important input parameters. Results-We observe approximately 30% uncertainty in the mean neointimal area as simulated by the model. Depending on whether a fast initial endothelium recovery occurs, the proportion of the model variance due to natural variability ranges from 15 to 35%. The endothelium regeneration time is identified as the most influential model parameter. Conclusion-The model output contains a moderate quantity of uncertainty, and the model precision can be increased by obtaining a more certain value on the endothelium regeneration time. We conclude that the quasi-Monte Carlo UQ and the Sobol SA are reliable methods for estimating uncertainties in the response of complicated multiscale cardiovascular models.

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“…In this issue of JCI, Santulli, et al (21) created a unique adenovirus that expresses the cyclin-dependent kinase inhibitor p27 Kip1 (p27) under a strong CMV promoter and bears four tandem copies of target sequences for the EC-enriched microRNA (miRNA) miR-126-3p (Ad-p27-126TS) in kinetics, stent alloy, architecture, polymer coating composition, or abluminal release of antimitotic drugs, among others (6,15,16). For example, the Genous (OrbusNeich) stent, designed to capture so-called CD34 + endothelial progenitor cells, which include both endothelial and nonendothelial progenitor subsets, demonstrated promising reendothelialization properties and reduced neointimal hyperplasia in preclinical studies (17). Unfortunately, compared with the Taxus (Boston Scientific) DES, the Genous stent showed no major differences in clinical events or target vessel revascularization out to two years (18).…”

Section: Preclinical and Clinical Reendothelialization Strategiesmentioning

confidence: 99%

Healing the injured vessel wall using microRNA-facilitated gene delivery

Feinberg¹

2014

J. Clin. Invest.

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C o m m e n t a r y 3 6 9 4jci.org Volume 124 Number 9 September 2014Healing the injured vessel wall using microRNA-facilitated gene delivery Vascular endothelium and injury from percutaneous coronary interventionOver the past 37 years, percutaneous coronary intervention (PCI) has revolutionized patient revascularization care for symptomatic ischemic coronary artery disease by improving myocardial perfusion and clinical outcomes. However, PCI has been considered a double-edged sword due to the endothelial injury and denudation that occurs from a combination of high-pressure balloon inflations and relatively noncompliant stent struts. The vascular response to mechanical endothelial cell (EC) and smooth muscle cell (SMC) injury represents a complex series of molecular and cellular events that involve the orchestration between resident and recruited vascular cells, leukocytes, and progenitor cells that regulate the ensuing neointimal hyperplasia, vascular remodeling, and reendothelialization (1). A range of innovative therapies and mechanical coronary device strategies have evolved to improve the outcomes and response to injury induced as a consequence of these procedures for patients with symptomatic coronary lesions. By 1993, baremetal stents (BMS) were FDA approved in the US. Compared with balloon angioplasty alone, BMS dramatically improved vessel remodeling with reduced restenosis rates and fewer subsequent reinterventions required. The improvements seen with BMS are thought to be primarily due to a reduction in late lumen loss, a process known as negative remodeling (2); however, clinical restenosis rates still occurred in approximately 20% to 30% of patients receiving BMS, in part, due to persistent neointimal hyperplasia (3, 4). A decade later, drug-eluting stents (DES), which release antimitotic drugs, such as sirolimus, paclitaxel, zotarolimus, or everolimus, were developed and potently inhibit SMC proliferation and extracellular matrix generation, resulting in markedly reduced neointimal hyperplasia and an approximately 70% reduction of coronary restenosis compared with BMS (5, 6). Because DES-dependent drug delivery does not discriminate between proliferating vascular SMCs (VSMCs) and ECs, delayed reendothelialization has been considered a major limiting factor for optimal vascular repair and may predispose patients to late thrombotic events (7,8). Indeed, preclinical studies and pathologic evaluation at the time of human autopsy have confirmed a delayed reendothelialization associated with DES (9, 10). Considerable attention has been focused on the possibility of late (30 days to 1 year) and very late (after 1 year) thrombosis associated with DES and whether extended dual antiplatelet therapy (DAPT) reduces this potential thrombotic risk (11-13). DAPT itself may also carry higher bleeding risks over this extended period. Every year, nearly 500,000 patients in the US undergo PCI for symptomatic coronary artery disease, and DES are deployed in at least 75% of these cases (14). As such, identification of...

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The genous™ endothelial progenitor cell capture stent accelerates stent re‐endothelialization but does not affect intimal hyperplasia in porcine coronary arteries

Abstract: The EPC capture stent improves early endothelialization in swine but this does not affect neointimal thickness as compared to control stents at 28 and 90 days.

Cited by 60 publications

References 40 publications

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Uncertainty Quantification of a Multiscale Model for In-Stent Restenosis

Healing the injured vessel wall using microRNA-facilitated gene delivery

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