Biodegradable stents as a platform to drug loading

Despite technical and mechanical improvement in coronary stents the incidence of restenosis caused by in-stent neointimal hyperplasia remains high. Oral administration of numerous pharmacological agents has failed to reduce restenosis after coronary stenting in humans, possibly owing to insufficient local drug concentration. Therefore, drug-eluting stents were developed as a vehicle for local drug administration. The authors developed a new drug-eluting polymer stent that is made of poly-l-lactic acid polymer mixed with tranilast, an anti-allergic drug that inhibits the migration and proliferation of vascular smooth muscle cells induced by platelet-derived growth factor and transforming growth factor->1. Polymer stents might be superior to polymer-coated metallic stents as local drug delivery stents in terms of biodegradation and the amount of loaded drug. Drug-mixed polymer stents can be loaded with a larger amount of drug than can drug-coated metallic stents because the polymer stent struts can contain the drug. Clinical application is required to assess the safety and efficacy of drug-eluting polymer stents against stent restenosis.     

Methods to improve dose uniformity for radioactive stents in endovascular brachytherapy

Intravascular brachytherapy (IVBT) has rapidly gained acceptance as a new treatment modality for reducing restenosis and improving the success rate of percutaneous transluminal coronary angioplasty (PTCA). Recent clinical results on patients treated with beta-emitting 32P stents suggest that radiation reduces in-stent restenosis but may exacerbate neointimal growth at the edges of the stents. This has been referred to as the "candy wrapper effect." It is well known that radioactive stents yield extremely inhomogeneous dose distributions, with low doses delivered to tissues in between stent struts, at the ends of the stent, and also at depth. Some animal model studies suggest that low doses of radiation may stimulate rather than inhibit neointimal growth in an injured vessel, and it is hypothesized that dose inhomogeneity at the ends of a stent may contribute to the candy wrapper effect. We present here a theoretical study comparing dose distributions for beta stents vs. gamma stents; "dumbbell" radioactive loaded stents vs. uniformly loaded stents; and stents with alternate strut design. Calculations demonstrate that dose inhomogenieties between stent struts, at the ends of stents, and at depth can be reduced by better stent design and isotope selection. Prior to the introduction of radioactive stents, criteria for stent design included factors such as trackability, flexibility, strength, etc. We show here that if stent design also includes criteria for strut shape and spacing that improved dose distributions are possible, which in turn could reduce the candy wrapper effect.     

The effects of stenting on coronary endothelium from a molecular biological view: Time for improvement?

Coronary artery stenting following balloon angioplasty represents the gold standard in revascularization of coronary artery stenoses. However, stent deployment as well as percutaneous transluminal coronary angioplasty (PTCA) alone causes severe injury of vascular endothelium. The damaged endothelium is intrinsically repaired by locally derived endothelial cells and by circulating endothelial progenitor cells from the blood, leading to re‐population of the denuded regions within several weeks to months. However, the process of re‐endothelialization is often incomplete or dysfunctional, promoting in‐stent thrombosis and restenosis. The molecular and biomechanical mechanisms that influence the process of re‐endothelialization in stented segments are incompletely understood. Once the endothelium is restored, endothelial function might still be impaired. Several strategies have been followed to improve endothelial function after coronary stenting. In this review, the effects of stenting on coronary endothelium are outlined and current and future strategies to improve endothelial function after stent deployment are discussed.     

Nanoparticulate carriers for the treatment of coronary restenosis

The current treatment for coronary restenosis following balloon angioplasty involves the use of a mechanical or a drug-eluting stent. Despite the high usage of commercially-available drug-eluting stents in the cardiac field, there are a number of limitations. This review will present the background ofrestenosis, go briefly into the molecular and cellular mechanisms of restenosis, the use of mechanical stents in coronary restenosis, and will provide an overview of the drugs and genes tested to treat restenosis. The primary focus of this article is to present a comprehensive overview on the use of nanoparticulate delivery systems in the treatment of restenosis both in-vitro and in-vivo. Nanocarriers have been tested in a variety of animal models and in human clinical trials with favorable results. Polymer-based nanoparticles, liposomes, and micelles will be discussed, in addition to the findings presented in the field of cardiovascular drug targeting. Nanocarrier-based delivery presents a viable alternative to the current stent based therapies.     

Effects of bifurcation-specific and conventional stents on coronary bifurcation flow. An experimental and numerical study

Our paper builds on existing research into conventional bare metal stents in order to assess new devices specifically designed for coronary bifurcation angioplasty. The first aim is to validate the numerical model against data from in vitro experiments on stented coronary phantoms. A surface mesh was built in accordance with micro-computed tomography images obtained from coronary stents implanted in silicone models and used for numerical analysis. Computational simulations for steady and unsteady cases generally agreed with their experimental counterparts. A second objective is to compare the hemodynamic performance of one of these new devices (Stentys) to that of conventional devices and stenting techniques in a simplified coronary bifurcation model. Four different coronary bifurcation stenting techniques were analyzed. We have focused on factors contributing to restenosis, such as wall shear stress (WSS), oscillatory shear index (OSI), pressure loss, and local normalized helicity (LNH). It was found that bifurcation-specific stents implanted in the side branch led to increased malapposition. This effect has proved to be more important than stent specific design characteristics such as strut size (different for conventional and Stentys stent). This conclusion is confirmed by means of drop in pressure and mechanical energy loss rate calculation; for the latter, the increase ranged from 9% to 17%, depending on the stenting technique, when dedicated stents were implanted in the side branch. The behavior patterns presented in this study should be double-checked against those obtained in more realistic geometries.     

Efficiency of endovascular re-interventions for evolving restenosis of different types of stents

The paper compares the results of different treatment options (balloon angioplasty and restenting) for in-stent restenosis in case of evolving restenosis of drug- and nondrug eluting stents. The investigation enrolled 496 coronary heart disease patients with clinical presentation of angina pectoris and/or signs of myocardial ischemia, as well as hemodynamic restenosis of a previously implanted stent. Of them, 216 and 280 patients had restenosis of previously implanted drug- and nondrug-eluting stents, respectively. In the patients with non-drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis were significantly more frequently observed after balloon dilatation than after drug-eluting stent implantation (28.4 and 10.2%; p < 0.05; 19.9 and 8.7%; p < 0.05). In those with drug-eluting stent restenosis, recurrent angina pectoris and the frequency of repeated restenosis did not differ significantly between balloon dilatation of restenosis and implantation of a second drug-eluting stent.     

Cardiovascular stent design and vessel stresses: a finite element analysis

Intravascular stents of various designs are currently in use to restore patency in atherosclerotic coronary arteries and it has been found that different stents have different in-stent restenosis rates. It has been hypothesized that the level of vascular injury caused to a vessel by a stent determines the level of restenosis. Computational studies may be used to investigate the mechanical behaviour of stents and to determine the biomechanical interaction between the stent and the artery in a stenting procedure. In this paper, we test the hypothesis that two different stent designs will provoke different levels of stress within an atherosclerotic artery and hence cause different levels of vascular injury. The stents analysed using the finite-element method were the S7 (Medtronic AVE) and the NIR (Boston Scientific) stent designs. An analysis of the arterial wall stresses in the stented arteries indicates that the modular S7 stent design causes lower stress to an atherosclerotic vessel with a localized stenotic lesion compared to the slotted tube NIR design. These results correlate with observed clinical restenosis rates, which have found higher restenosis rates in the NIR compared with the S7 stent design. Therefore, the testing methodology outlined here is proposed as a pre-clinical testing tool, which could be used to compare and contrast existing stent designs and to develop novel stent designs.     

A multi-scale mechanobiological model of in-stent restenosis: deciphering the role of matrix metalloproteinase and extracellular matrix changes

Since their first introduction, stents have revolutionised the treatment of atherosclerosis; however, the development of in-stent restenosis still remains the Achilles' heel of stent deployment procedures. Computational modelling can be used as a means to model the biological response of arteries to different stent designs using mechanobiological models, whereby the mechanical environment may be used to dictate the growth and remodelling of vascular cells. Changes occurring within the arterial wall due to stent-induced mechanical injury, specifically changes within the extracellular matrix, have been postulated to be a major cause of activation of vascular smooth muscle cells and the subsequent development of in-stent restenosis. In this study, a mechanistic multi-scale mechanobiological model of in-stent restenosis using finite element models and agent-based modelling is presented, which allows quantitative evaluation of the collagen matrix turnover following stent-induced arterial injury and the subsequent development of in-stent restenosis. The model is specifically used to study the influence of stent deployment diameter and stent strut thickness on the level of in-stent restenosis. The model demonstrates that there exists a direct correlation between the stent deployment diameter and the level of in-stent restenosis. In addition, investigating the influence of stent strut thickness using the mechanobiological model reveals that thicker strut stents induce a higher level of in-stent restenosis due to a higher extent of arterial injury. The presented mechanobiological modelling framework provides a robust platform for testing hypotheses on the mechanisms underlying the development of in-stent restenosis and lends itself for use as a tool for optimisation of the mechanical parameters involved in stent design.     

血管内支架和支架内皮化

简要介绍了血管内支架产生的背景、发展进程及其应用于临床后出现的再狭窄问题,着重综述了十几年来内皮细胞种植血管内支架预防术后再狭窄的相关研究成果。血管内支架内皮化的最终实现可以使现行的血管支架具有正常血管内皮的生物相容性及生理功能,是控制支架植入术后再狭窄问题的很有前途的支架改进方法。     

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

This review concisely recapitulates the different existing modes of stent‐mediated gene/drug delivery, their considerable advancement in clinical trials and a rationale for other merging new technologies such as nanotechnology and microRNA‐based therapeutics, in addition to addressing the limitations in each of these perpetual stent platforms. Over the past decade, stent‐mediated gene/drug delivery has materialized as a hopeful alternative for cardiovascular disease and cancer in contrast to routine conventional treatment modalities. Regardless of the phenomenal recent developments achieved by coronary interventions and cancer therapies that employ gene and drug‐eluting stents, practical hurdles still remain a challenge. The present review highlights the limitations that each of the existing stent‐based gene/drug delivery system encompasses and therefore provides a vision for the future with respect to discovering an ideal stent therapeutic platform that would circumvent all the practical hurdles witnessed with the existing technology. Further study of the improvisation of next‐generation drug‐eluting stents has helped to overcome the issue of restenosis to some extent. However, current stent formulations fall short of the anticipated clinically meaningful outcomes and there is an explicit need for more randomized trials aiming to further evaluate stent platforms in favour of enhanced safety and clinical value. Gene‐eluting stents may hold promise in contributing new ideas for stent‐based prevention of in‐stent restenosis through genetic interventions by capitalizing on a wide variety of molecular targets. Therefore, the central consideration directs us toward finding an ideal stent therapeutic platform that would tackle all of the gaps in the existing technology.     

Why and how to avoid stenting during brachytherapy

Intracoronary radiation is a promising therapy to reduce restenosis after percutaneous coronary intervention. It may be anticipated that radiation and intracoronary stents - the current standard coronary revascularization procedure - have a synergic antirestenosis effect. However, this potential benefit has not been proven in the clinical scenario. Indeed, this combined approach (stenting plus brachytherapy) may even be harmful. Delayed endothelialization and late stent malapposition are important drawbacks of implanting a metallic prosthesis in the setting of radiation therapy. Owing to the relatively high frequency of late thrombosis after stenting irradiated coronary arteries, the Food and Drug Administration required that the labeling of both gamma- and beta-radiation devices recently approved for clinical use explicitly advise avoidance of the placement of new stents. The pathophysiologic aspects as well as the clinical implications of the implantation of a new stent in association with radiation delivered by radioactive stents or catheter-based systems are discussed in this paper.     

Stainless and shape memory alloy coronary stents: a computational study on the interaction with the vascular wall

Balloon-expandable and self-expandable stents are the two types of coronary stents available. Basically, they differ in the modality of expansion.The present study analyses the stress state induced on the vascular wall, by the expansion of balloon- and self-expandable stents, using the finite element method. Indeed, modified mechanical stress state is in part responsible in the restenosis process. The balloon-expandable stents herein investigated are assumed to be made of stainless steel, while the self-expandable stents are made of a shape memory alloy. The effects of the severity of the coronary stenosis, the atherosclerotic plaque stiffness and the stent design are investigated. Comparing the self-expandable stent with the balloon-expandable one, the former induces fewer stresses and lower damage to the vessel, but, on the other hand, its lower stiffness induces a lower capability to restore vasal lumen and to contrast arterial elastic recoil.     

Coronary Injury Score Correlates with Proliferating Cells and Alpha-Smooth Muscle Actin Expression in Stented Porcine Coronary Arteries

Neointimal formation and cell proliferation resulting into in-stent restenosis is a major pathophysiological event following the deployment of stents in the coronary arteries. In this study, we assessed the degree of injury, based on damage to internal elastic lamina, media, external elastic lamina, and adventitia following the intravascular stenting, and its relationship with the degree of smooth muscle cell proliferation. We examined the smooth muscle cell proliferation and their phenotype at different levels of stent injury in the coronary arteries of domestic swine fed a normal swine diet. Five weeks after stent implantation, swine with and without stents were euthanized and coronaries were excised. Arteries were embedded in methyl methacrylate and sections were stained with H&E, trichrome, and Movat’s pentachrome. The expression of Ki67, α-smooth muscle actin (SMA), vimentin, and HMGB1 was evaluated by immunofluorescence. There was a positive correlation between percent area stenosis and injury score. The distribution of SMA and vimentin was correlated with the degree of arterial injury such that arteries that had an injury score >2 did not have immunoreactivity to SMA in the neointimal cells near the stent struts, but these neointimal cells were positive for vimentin, suggesting a change in the smooth muscle cell phenotype. The Ki67 and HMGB1 immunoreactivity was highly correlated with the fragmentation of the IEL and injury in the tunica media. Thus, the extent of coronary arterial injury during interventional procedure will dictate the degree of neointimal hyperplasia, in-stent restenosis, and smooth muscle cell phenotype.     

Mechanistic evaluation of long-term in-stent restenosis based on models of tissue damage and growth

Development and application of advanced mechanical models of soft tissues and their growth represent one of the main directions in modern mechanics of solids. Such models are increasingly used to deal with complex biomedical problems. Prediction of in-stent restenosis for patients treated with coronary stents remains a highly challenging task. Using a finite element method, this paper presents a mechanistic approach to evaluate the development of in-stent restenosis in an artery following stent implantation. Hyperelastic models with damage, verified with experimental results, are used to describe the level of tissue damage in arterial layers and plaque caused by such intervention. A tissue-growth model, associated with vessel damage, is adopted to describe the growth behaviour of a media layer after stent implantation. Narrowing of lumen diameter with time is used to quantify the development of in-stent restenosis in the vessel after stenting. It is demonstrated that stent designs and materials strongly affect the stenting-induced damage in the media layer and the subsequent development of in-stent restenosis. The larger the artery expansion achieved during balloon inflation, the higher the damage introduced to the media layer, leading to an increased level of in-stent restenosis. In addition, the development of in-stent restenosis is directly correlated with the artery expansion during the stent deployment. The correlation is further used to predict the effect of a complex clinical procedure, such as stent overlapping, on the level of in-stent restenosis developed after percutaneous coronary intervention.

     

Stresses in peripheral arteries following stent placement: a finite element analysis

The success of stents to restore blood flow in atherosclerotic peripheral arteries is low relative to coronary arteries. It has been shown that joint flexion induces a mechanical environment that makes stent placement in these arteries highly incompatible, and damage and destruction of stents has been recorded. However, the effect of this environment on the stresses in the arteries is unknown. It is hypothesised that the stresses induced in arteries as a result of this mechanical environment could be sufficient to explain the relatively low success rates. To investigate this hypothesis, a finite element model of the stent-artery interaction was developed. Following stent expansion, bending was simulated by applying a displacement boundary condition to the artery. It is found that high stresses occur at the proximal/distal ends of the stent. As high stress and vascular injury are hypothesised to cause restenosis, the results presented here suggest that the mechanical environment of peripheral arteries could be the predominant cause of high restenosis rates.     

Fabrication of drug-eluting covered stents with micropores and differential coating of heparin and FK506

To reduce in-stent restenosis rates, we developed a novel drug-eluting covered stent with a microporous elastometric covered film, in which its luminal surface was flat and immobilized with heparin for anticoagulation and its outer surface immobilized with FK506 to prevent neointimal hyperplasia. One month after implantation into the bilateral common carotid arteries, all stented arteries were patent and the luminal surfaces were fully covered with a confluent of endothelial cells irrespective of the drug immobilization. In the control group, which consisted of covered stents without drug immobilization, intensive inflammatory cells adjacent to the stents and neointimal hyperplasia, indicating vascular injury, were observed. In contrast, in the developed drug-eluting stents, only a few inflammatory cells around the stent strut and covered film were observed, and there was no significant neointimal thickening.     

Effects of stents under asymmetric inflow conditions

Patient-to-patient variations in artery geometry may determine their susceptibility to stenosis formation. These geometrical variations can be linked to variations in flow characteristics such as wall shear stress through stents, which increases the risk of restenosis. This paper considers computer models of stents in non-symmetric flows and their effects on flow characteristics at the wall. This is a fresh approach from the point of view of identifying a stent design whose performance is insensitive to asymmetric flow. Measures of dissipated energy and power are introduced in order to discriminate between competing designs of stents.     

Effect of stent coating alone on in vitro vascular smooth muscle cell proliferation and apoptosis

Synthetic polymers, like methacrylate (MA) compounds, have been clinically introduced as inert coatings to locally deliver drugs that inhibit restenosis after stent. The aim of the present study was to evaluate the effects of MA coating alone on vascular smooth muscle cell (VSMC) growth in vitro. Stainless steel stents were coated with MA at the following doses: 0.3, 1.5, and 3 ml. Uncoated/bare metal stents were used as controls. VSMCs were cultured in dishes, and a MA-coated stent or an uncoated bare metal stent was gently added to each well. VSMC proliferation was assessed by bromodeoxyuridine (BrdU) incorporation. Apoptosis was analyzed by three distinct approaches: 1) annexin V/propidium iodide fluorescence detection; 2) DNA laddering; and 3) caspase-3 activation and PARP cleavage. MA-coated stents induced a significant decrease of BrdU incorporation compared with uncoated stents at both the low and high concentrations. In VSMCs incubated with MA-coated stents, annexin V/propidium iodide fluorescence detection showed a significant increase in apoptotic cells, which was corroborated by the typical DNA laddering. Apoptosis of VSMCs after incubation with MA-coated stents was characterized by caspase-3 activation and PARP cleavage. The MA-coated stent induced VSMC growth arrest by inducing apoptosis in a dose-dependent manner. Thus MA is not an inert platform for eluting drugs because it is biologically active per se. This effect should be taken in account when evaluating an association of this coating with antiproliferative agents for in-stent restenosis prevention.     

The potential role of homocysteine in percutaneous coronary interventions (PCI): review of current evidence and plausibility of action.

Several millions of patients with coronary heart disease worldwide are treated by means ofpercutaneous interventions each year. Above all conventional balloon dilation and implantation of uncoated stents are, however, only of limited success as reflected by 6-month restenosis rates of 50% (balloon dilation) and 25-35% (bare-metal stent). It is therefore of utmost importance to identify high-risk groups and explore further secondary-prophylactic measures for the prevention of restenosis. A large body of evidence suggests that elevated homocysteine and/or folate and B-vitamin deficiencies are relevant risk factors for restenoses due to their proatherothrombotic potential. Hyperhomocysteinemia is an ideal target as this parameter can be lowered easily, safely and at a low cost by means of folate and B-vitamin supplementation. The results of published studies exploring a potential correlation between homocysteine levels and the risk of restenosis and those of interventional studies for the reduction of the risk of restenosis have not yet lead to consistent conclusions. However, a critical assessment can by no means exclude the plausibility of postinterventional lowering of homocysteine levels. This review aims at providing insight into the current evidence and biological plausibility of homocysteine-lowering therapy in regard to PCI-related vascular damage. Currently available clinical observational and interventional studies are reviewed in detail.