Stent Coatings Research Articles

New stent surface materials: The impact of polymer-dependent interactions of human endothelial cells, smooth muscle cells, and platelets

Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.

TCT-565 OCT evaluation of the time course of vessel healing following implantation of new generation biodegradable polymer-coated and sirolimus-eluting cobalt-chromium coronary stent system (ALEX OCT Study).

Biodegradable stent coatings are hoped to improve the vessel wall healing. ALEX is a new generation, biodegradable polymer-coated, sirolimus-eluting, cobalt-chromium coronary stent system. A prospective, single arm, multi-centre registry enrolled 60 patients with de novo native coronary lesions

Surface modification of a polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer as a stent coating for enhanced capture of endothelial progenitor cells

An unmet need exists for the development of next-generation multifunctional nanocomposite materials for biomedical applications, particularly in the field of cardiovascular regenerative biology. Herein, we describe the preparation and characterization of a novel polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer with covalently attached anti-CD34 antibodies to enhance capture of circulating endothelial progenitor cells (EPC). This material may be used as a new coating for bare metal stents used after balloon angioplasty to improve re-endothelialization. Biophysical characterization techniques were used to assess POSS-PCU and its subsequent functionalization with anti-CD34 antibodies. Results indicated successful covalent attachment of anti-CD34 antibodies on the surface of POSS-PCU leading to an increased propensity for EPC capture, whilst maintaining in vitro biocompatibility and hemocompatibility. POSS-PCU has already been used in 3 first-in-man studies, as a bypass graft, lacrimal duct and a bioartificial trachea. We therefore postulate that its superior biocompatibility and unique biophysical properties would render it an ideal candidate for coating medical devices, with stents as a prime example. Taken together, anti-CD34 functionalized POSS-PCU could form the basis of a nano-inspired polymer platform for the next generation stent coatings.

Development of Hydrophobized Alginate Hydrogels for the Vessel-Simulating Flow-Through Cell and Their Usage for Biorelevant Drug-Eluting Stent Testing

The vessel-simulating flow-through cell (vFTC) has been used to examine release and distribution from drug-eluting stents in an in vitro model adapted to the stent placement in vivo. The aim of this study was to examine the effect of the admixture of different hydrophobic additives to the vessel wall simulating hydrogel compartment on release and distribution from model substance-coated stents. Four alginate-based gel formulations containing reversed-phase column microparticles LiChroprep® RP-18 or medium-chain triglycerides in form of preprocessed oil-in-water emulsions Lipofundin® MCT in different concentrations were successfully developed. Alginate and modified gels were characterized regarding the distribution coefficient for the fluorescent model substances, fluorescein and triamterene, and release as well as distribution of model substances from coated stents were investigated in the vFTC. Distribution coefficients for the hydrophobic model substance triamterene and the hydrophobized gel formulations were up to four times higher than for the reference gel. However, comparison of the obtained release profiles yielded no major differences in dissolution and distribution behavior for both fluorescent model substances (fluorescein, triamterene). Comparison of the test results with mathematically modeled data acquired using finite element methods demonstrated a good agreement between modeled data and experimental results indicating that gel hydrophobicity will only influence release in cases of fast releasing stent coatings.

Improved Safety and Reduction in Stent Thrombosis Associated With Biodegradable Polymer-Based Biolimus-Eluting Stents Versus Durable Polymer-Based Sirolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) Randomized, Noninferiority Trial

This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N=1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n= 857) or durable polymer sirolimus-eluting stents (SES) (n= 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, pfor superiority= 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority= 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n= 5 [0.7%] vs. n= 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p= 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n= 3 of 749 vs. n= 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p= 0.005). The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220).

Myokardrevaskularisation

Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision-making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team").

In vitro study of dual drug-eluting stents with locally focused sirolimus and atorvastatin release

Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70% respectively 90% of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.

Polyelectrolyte/silver nanocomposite multilayer films as multifunctional thin film platforms for remote activated protein and drug delivery

We demonstrate a nanoparticle loading protocol to develop a transparent, multifunctional polyelectrolyte multilayer film for externally activated drug and protein delivery. The composite film was designed by alternate adsorption of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on a glass substrate followed by nanoparticle synthesis through a polyol reduction method. The films showed a uniform distribution of spherical silver nanoparticles with an average diameter of 50±20nm, which increased to 80±20nm when the AgNO3 concentration was increased from 25 to 50mM. The porous and supramolecular structure of the polyelectrolyte multilayer film was used to immobilize ciprofloxacin hydrochloride (CH) and bovine serum albumin (BSA) within the polymeric network of the film. When exposed to external triggers such as ultrasonication and laser light the loaded films were ruptured and released the loaded BSA and CH. The release of CH is faster than that of BSA due to a higher diffusion rate. Circular dichroism measurements confirmed that there was no significant change in the conformation of released BSA in comparison with native BSA. The fabricated films showed significant antibacterial activity against the bacterial pathogen Staphylococcus aureus. Applications envisioned for such drug-loaded films include drug and vaccine delivery through the transdermal route, antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents.

A combined computational and experimental methodology to determine the adhesion properties of stent polymer coatings

Reports from recent studies indicate that commercial stent coatings are susceptible to delamination, therefore warranting further research into their adhesion properties. In the present study a robust combined computational–experimental methodology to determine the characteristic interface properties for polyurethane stent coatings bonded to stainless steel is presented. Specifically, delamination of dry and hydrated stent coatings is investigated during 90° peel tests with the force and peel radius being experimentally measured. A comprehensive computational parametric study then establishes the relationship between peel force, peel radius, interface strength and interface characteristic length. Such uniquely determined interface properties are validated for different coating thickness and stiffness. Where accurate measurement of the peeling radius is not possible, it is demonstrated that the slope of the steady state load displacement curve can be used to uniquely characterise the interface. Results suggest that aging does not change the interfacial properties but stiffens the polymer coating. Hydration is found to reduce the interface strength by an order of magnitude, and also decreases the coating stiffness. Such alterations in interface and coating properties are of critical importance in prediction of coating delamination during stent deployment.

Liposomal surface coatings of metal stents for efficient non-viral gene delivery to the injured vasculature

Despite the widespread use of drug eluting stents (DES), in-stent restenosis (ISR), delayed arterial healing and thrombosis remain important clinical complications. Gene-eluting stents (GES) represent a potential strategy for the prevention of ISR by delivering a therapeutic gene via a vector from the stent surface to the vessel wall. To this end, a model in vitro system was established to examine whether cationic liposomes could be used for gene delivery to human artery cells. Three different formulations were compared (DOTMA/DOPE, DDAB/DOPE or DDAB/POPC/Chol) to examine the effects of different cationic and neutral lipids on the transfection efficiency of lipoplex-coatings of metal surfaces. Upon completion of the characterization and optimization of the materials for gene delivery in vitro, these coatings were examined on a range of stents and deployed in a rabbit iliac artery injury model in vivo. Maximal transfection efficiencies for all coatings were observed on day 28, followed by declining, but persisting gene expression 42days after stent placement, thereby, presenting liposomal coatings for gene eluting stents as treatment options for clinical complications associated with stenting procedures.

New biomaterial as a promising alternative to silicone breast implants

One in eight American women develops breast cancer. Of the many patients requiring mastectomy yearly as a consequence, most elect some form of breast reconstruction. Since 2006, only silicone breast implants have been approved by the FDA for the public use. Unfortunately, over one-third of women with these implants experience complications as a result of tissue-material biocompatibility issues, which may include capsular contracture, calcification, hematoma, necrosis and implant rupture. Our group has been working on developing alternatives to silicone. Linear triblock poly(styrene-b-isobutylene-b-styrene) (SIBS) polymers are self-assembling nanostructured thermoplastic rubbers, already in clinical practice as drug eluting stent coatings. New generations with a branched (arborescent or dendritic) polyisobutylene core show promising potential as a biomaterial alternative to silicone rubber. The purpose of this pre-clinical research was to evaluate the material-tissue interactions of a new arborescent block copolymer (TPE1) in a rabbit implantation model compared to a linear SIBS (SIBSTAR 103T) and silicone rubber. This study is the first to compare the molecular weight and molecular weight distribution, tensile properties and histological evaluation of arborescent SIBS-type materials with silicone rubber before implantation and after explantation.

Bioactive coronary stent coating based on layer-by-layer technology for siRNA release

One procedure to treat stenotic coronary arteries is the percutaneous transluminal coronary angioplasty (PTCA). In recent years, drug-eluting stents (DESs) have demonstrated elaborate ways to improve outcomes of intravascular interventions. To enhance DESs, the idea has evolved to design stents that elute specific small interfering RNA (siRNA) for better vascular wall regeneration. Layer-by-layer (LbL) technology offers the possibility of incorporating siRNA nanoplexes (NPs) to achieve bioactive medical implant coatings. The LbL technique was used to achieve hyaluronic acid/chitosan (HA/Chi) films with incorporated Chi-siRNA NPs. The multilayer growth was monitored by quartz crystal microbalance. The coating on the stents and its thickness were analyzed using fluorescence and scanning electron microscopy. All stents showed a homogeneous coating, and the polyelectrolyte multilayers (PEMs) were not disrupted after ethylene oxide sterilization or expansion. The in vitro uptake of fluorescent-labeled NPs from PEMs in primary human endothelial cells (ECs) was analyzed by flow cytometry for 2, 6 and 9days. Furthermore, stents coated with HA/Chi and Chi-siRNA NPs were expanded into porcine arteries and showed ex vivo delivery of NPs. The films showed no critical results in terms of hemocompatibility. This study demonstrates that Chi-siRNA NPs can be incorporated into PEMs consisting of HA and Chi. We conclude that the NPs were delivered to ECs under in vitro conditions. Furthermore, under ex vivo conditions, NPs were transferred into porcine artery walls. Due to their good hemocompatibility, they might make an innovative tool for achieving bioactive coatings for coronary stents.

Investigating the Applicability of Fluidized-Bed Technology for High-Throughput Coating of Stents

Investigating the Applicability of Fluidized-Bed Technology for High-Throughput Coating of Stents

Cell membrane mimetic films immobilized by synergistic grafting and crosslinking

Blood compatibility is a critical requirement for materials to be used in medical applications. We describe here a simple and robust method to enhance the biocompatibility of chitosan (CS) surfaces, using random copolymers (PMT) of 2-methacryloyloxyethyl phosphorylcholine (MPC) and trimethoxysilylpropyl methacrylate (TSMA, 6, 14, and 25 mol%) synthesized by free radical copolymerization. The copolymers dissolved in methanol were dip-coated on CS films. The PMT coatings were anchored on CS surfaces during the coating process by covalent bonding of the trimethoxysilane groups with surface amine and/or hydroxyl groups of CS. The composite films were stabilized by crosslinking of the copolymers via amine-catalyzed reactions of the trimethoxysilane groups and further heating (110 °C). Analysis of the PMT-modified CS surfaces by X-ray photoelectron spectroscopy and contact angle measurements indicated that the zwitterionic PC groups were located on or near the film outer surface, which mimics the structure of the cell outer membrane. Film stability studies indicated that PMT copolymers containing 14 mol% TSMA units were linked permanently to CS, whereas PMTs of lower TSMA content were released from the films upon prolonged soaking in water. The CS-PMT (14% TSMA) composite films possessed excellent hemocompatibility, as confirmed by a 60% decrease in protein (bovine serum albumin or fibrinogen) adsorption and a 96% suppression of platelet adhesion, compared to CS films. This simple and stable coating strategy should be useful in a variety of biomedical applications including drug delivery, tissue engineering, stent coatings, and implantable medical devices.

Advances in Coronary Stent Technology - Active Drug-Loaded Stent Surfaces for Prevention of Restenosis and Improvement of Biocompatibility

Beyond their originally sole mechanical function, current drug-eluting stents (DES) implement the concept of local drug delivery for the re-opening of stenotic arterial vessels, and for prevention of in-stent restenosis as one of the major limitations of conventional bare metal stents (BMS). Current DES consist of a permanent metallic stent platform and an active agent being released from a drug-incorporated polymer coating or a porous stent surface. Although DES have impressively demonstrated their capability of reducing in-stent restenosis, their safety remains under debate due to potential risks, such as delayed healing, late thrombosis and hypersensitivity demanding further development. Current advancements in the stent design address the stent platform, the pharmacologically active substance and/or the drug carrier. For instance, novel biocompatible absorbable stent platforms and drug carriers are developed and novel drugs with a differential effect on vascular endothelial and smooth muscle cells, providing efficient inhibition of muscle cells without altering the endothelial cell function, are identified. Moreover, biofunctionalization of the stent's surface with capture molecules for endothelial progenitor cells are under investigation in order to achieve an in situ endothelialization of the implant. In this context, this review paper discusses the current advances in coronary stent technology with a special focus on novel stent platforms, drugs and stent coatings for the prevention of restenosis and improvement of biocompatibility.

Influence of fibre diameter and orientation of electrospun copolyetheresterurethanes on smooth muscle and endothelial cell behaviour

Polymers exhibiting cell-selective effects represent an extensive research field with high relevance for biomedical applications e.g. in the cardiovascular field supporting re-endothelialization while suppressing smooth muscle cell overgrowth. Such an endothelial cell-selective effect could be recently demonstrated for a copolyetheresterurethane (PDC) containing biodegradable poly(p-dioxanone) and poly(ε-caprolactone) segments, which selectively enhanced the adhesion of human umbilical vein endothelial cells (HUVEC) while suppressing the attachment of smooth muscle cells (SMC). In this study we investigated the influence of the fibre orientation (random and aligned) and fibre diameter (2 μm and 500 nm) of electrospun PDC scaffolds on the adhesion, proliferation and apoptosis of HUVEC and SMC. Adhesion, viability and proliferation of HUVEC was diminished when the fibre diameter was reduced to a submicron scale, while the orientation of the microfibres did only slightly influence the cellular behaviour. In contrast, a submicron fibre diameter improved SMC viability. In conclusion, PDC scaffolds with micron-sized single fibres could be promising candidate materials for cell-selective stent coatings.

A multi-scale molecular dynamics study of the assembly of micron-size supraparticles from 30 nm alkyl-coated nanoparticles

Atomistic and meso scale computer simulations of nanoparticle aggregation are combined to describe the self-assembly of supraparticles in bulk and on surfaces under vacuum conditions. At the nano scale, atomic resolution molecular dynamics simulations provide the structures of 30 nm-diameter nanoparticles bound to each other and to coated hydrophobic surfaces, through the physical contacting of their alkyl coats. This "molecular velcro" has been recently exploited in experiments to direct the aggregation of coated nanoparticles into stable assemblies on electronics platforms. Interaction potentials are extracted from the nano scale simulations and transferred to coarse grained Brownian dynamics simulations that describe multi-nanoparticle aggregation and surface deposition. The simulation results show that the large interaction area between 30 nm nanoparticles provides a strong driving force for assembly of strongly-welded, porous supraparticles under vacuum conditions. Interaction forces are significantly larger than those found in earlier simulations of the aggregation of smaller nanoparticles, indicating that supraparticle assembly using large 30 nm nanoparticles may be kinetically controlled. The porosity programmed into kinetic assembly may potentially benefit emerging applications of nanoparticle assemblies in medicine, in particular the development of nanostructured drug-eluting stent coatings. Future work will involve potential of mean force calculations in a variety of solvents to estimate the porosity obtainable for specific applications.

An Analysis of Three Dimensional Diffusion in a Representative Arterial Wall Mass Transport Model

The development and use of drug eluting stents has brought about significant improvements in reducing in-stent restenosis, however, their long term presence in the artery is still under examination due to restenosis reoccurring. Current studies focus mainly on stent design, coatings and deployment techniques but few studies address the issue of the physics of three dimensional mass transport in the artery wall. There is a dearth of adequate validated numerical mass transport models that simulate the physics of diffusion dominated drug transport in the artery wall whilst under compression. A novel experimental setup used in a previous study was adapted and an expansion of that research was carried out to validate the physics of three dimensional diffusive mass transport into a compressed porous media. This study developed a more sensitive method for measuring the concentration of the species of interest. It revalidated mass transport in the radial direction and presented results which highlight the need for an evaluation of the governing equation for transient diffusive mass transport in a porous media, in its current form, to be carried out.

Recent insights from scanning electron microscopic assessment of durable polymer-coated drug-eluting stents

Research on drug-eluting stents (DES) has had to be highly dynamic because of the rapid modification of stent platforms and coatings, and even the development of completely new stent designs and concepts. Through various mechanisms, coating irregularities of DES might contribute to some of the remaining problems of DES, such as (late) stent thrombosis and (side-branch) restenosis. This article sheds light on recent bench-top testing of DES coatings, providing an update on the latest examinations of DES coating morphology with scanning electron microscopy. It also reviews the different methods used to quantify DES coating irregularities, and proposes stepwise examination of coatings of both customary and novel DES. There is still a need to carefully assess novel DES with scanning electron microscopy in order to obtain data that may complement preclinical and clinical studies. Stent manufacturers have a responsibility to continuously monitor the quality of their products and generally strive to perfect their devices. In addition, independent, external assessment of DES coatings was shown to provide valuable data that permit meaningful comparisons of different DES types. Likewise, interventional cardiologists may use such complementary information from bench-side research as one of the pieces of evidence available to tailor therapy in clinical practice

Bioactive coatings for coronary stents: Modulation of cell proliferation by controlled release of anti-proliferative drugs

Drug eluting coronary stents coated with a bioactive and biostable polymer system (THBA70), based on acrylate copolymers bearing a salicylic acid derivative as side substituent, were evaluated. The microstructural architecture of the copolymer THBA70 comprises a random copolymer of a methacrylate derivative from triflusal (4-trifluoromethyl salicylic acid) with 45 mol% of THEMA (2-methacryloyloxyethyl [2-(acetyloxy)-4-(trifluoromethyl)] benzoate), which makes the system anti-thrombogenic with good adhesion to the surface of metallic stents. The bioactive coating prevented thrombosis, an adverse effect associated with the implantation of drug-eluting stents. The in vitro drug delivery of drug-eluting stents under dynamic conditions indicated excellent controlled drug release. The THBA70 films loaded with relatively low concentrations of taxol or simvastatin in contact with fibroblasts produced inhibition of cell proliferation with a dose-dependent bioactivity.