Search

Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Due to improved tissue regeneration and the enabling of post-operative minimally invasive interventions in the same vessel segment, biodegradable polymeric scaffolds represent a competitive approach to permanent metallic stents in vascular applications. Despite these advantages some challenges, such as the improvement of the scaffold mechanics and enhancement of scaffold visibility during the implantation procedure, are persisting. Therefore, the scope of our studies was to investigate the potential of gold, silver and magnetite nanoparticles incorporated in a polymeric blend of poly(L-lactide)/poly(4-hydroxybutyrate) for image enhancement in X-ray, magnetic resonance or near-infrared imaging. Their impact on mechanical properties of such modified scaffold materials was also evaluated. [ABSTRACT FROM AUTHOR]

Abstract: A novel in vitro dissolution test for drug-eluting stents (DES) based on the compendial flow-through cell was developed. The model contains an additional compartment simulating the vessel wall enabling the examination of drug release and distribution. The compartment consists of alginate hydrogel containing a central aperture forming the lumen for stent placement and media flow. The method was tested utilizing stents coated with hydrophilic (fluorescein sodium) and hydrophobic (triamterene) fluorescent model substances as well as the cytostatic drug doxorubicin hydrochloride and compared to standard dissolution methods. The results show the suitability of the developed method to observe drug release and distribution. The determination of model substance content in the compartments media, hydrogel and stent yielded differing distribution patterns for the model compounds and enabled the observation of redistribution processes. The dissolution profiles differed from the results of compendial dissolution testing. Besides lower endpoints and slower rises of media concentrations due to distribution into the hydrogel, the release rates from the stent coatings were altered. These findings emphasize the necessity to adapt dissolution testing for DES to the unique conditions influencing delivery to the vessel wall to learn more about local distribution and to anticipate the in vivo performance of DES. [Copyright &y& Elsevier]

In this study, absorbable polymer stent coatings for localized drug delivery based on poly( l-lactide) (PLLA) and cyclosporine A (CsA) were developed and tested in vitro. Metallic stents were coated with different compositions of PLLA/CsA (70/30, 60/40, 50/50% w/w) and β-sterilized. The specimens were used to assess the drug release kinetics with HPLC. Sterilization influenced polymer degradation was measured with GPC. Mechanical integrity of the stent coatings was studied with SEM. The interconnection of the coated stents with a balloon-catheter was characterized by the measurement of stent dislodgment force. A migration assay was used to determine the inhibitory effect of the model drug CsA on smooth muscle cell (SMC) migration. The release of CsA was established over time periods up to 24 days in sodium chloride solution and in porcine blood plasma. An inhibition of SMC migration (max. 26–33%) was found for CsA concentrations of 4 × 10−5 to 4 × 10−7 mol/l. Marked molecular weight reduction (70–80%) of the PLLA matrix occurred after β-sterilization. We also observed a substantial decrease of in vitro degradation time. The maintenance of the mechanical integrity of the polymer coating during crimping and dilation of the specimens could be verified, and a sufficient stent dislodgment force of 0.8–0.9 N was measured. [ABSTRACT FROM AUTHOR]

Purpose: To assess technical feasibility and biocompatibility of a new biodegradable sirolimus eluting poly-L-lactide (PLLA) vascular anastomotic stent. Methods: A polytetrafluoroethylene bifurcated graft was implanted in 9 pigs through a midline abdominal incision. After transverse graft limb incision, 6 unloaded PLLAs, 6 sirolimus loaded PLLAs, and 6 unloaded stainless steel (316L) stents were randomly implant ed at both lilac anastomotic sites. Stents were deployed with a 6 mm balloon under direct vision without the use of angiography. Prior to sacrifice after 6 weeks, contrast-enhanced computed tomography (CT) was performed to determine patency of the target vessels. Stented segments were surgically explanted and processed for histology to measure the mean luminal diameter and intimal thickness and to assign vascular injury and inflammation scores. Results: No animals were lost during the study period. All stented graft limbs were patent on CT and histology. At the anastomotic sites and iliac arteries, the mean luminal diameter of SIR-PLLA stents (4.11±0.15 and 4.08±0.13 mm, respectively) were comparable to metal stents (4.23±0.35 and 4.21±0.26 mm, respectively), but significantly higher compared to unloaded PLLA stents [3.32±0.56 mm (p<0.001) and 3.29±0.39 mm (p=0.013), respectively]. At the iliac arteries, the mean intimal thickness was significantly lower with SIR-PLLA stents (0.09±0.02 mm) compared to unloaded PLLA stents (0.31±0.15 mm, p<0.001) and metal stents (0.19±0.04 mm, p=0.004). Vascular injury scores demonstrated only mild vascular trauma for all stents (SIR-PLLA: 0.42±0.63, PLLA: 0.51±0.62, metal: 0.50±0.62). Only mild inflammatory reaction was noted around SIR-PLLA stent struts (1.14±0.46), which was comparable to metal stents (1.27±0.45) but significantly lower than PLLA stents (1.79±0.56, p<0.001). Conclusion: SIR-PLLA stents showed comparable luminal diameter compared to metal stents, so incorporating sirolimus could reduce the inflammatory and neointimal response to PLLA stents. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To assess the technical feasibility, thrombogenicity, and biocompatibility of a new biodegradable poly-L-lactic acid (PLLA) anastomotic stent. Methods: A polytetrafluoroethylene bifurcated graft was implanted in 17 pigs through a midline abdominal incision. After transverse graft incision, 17 316L stainless steel stents and 17 PLLA stents were randomly implanted at both lilac anastomotic sites and deployed with a 6-mm balloon under direct vision without angiography. Intended follow-up was 1 week in 6 pigs receiving oral acetylsalicylic acid (ASA) and in 7 pigs receiving ASA/clopidogrel; 4 pigs receiving ASA/clopidogrel were followed for 6 weeks. At the end of the study, the segments containing the stents were surgically explanted and processed for histology to measure the mean luminal diameter, intimal thickness, and the vascular injury and inflammation scores. Results: Initial technical success of stent placement was achieved in all animals without rupture of the suture. Two pigs died (unrelated to the stent) at 3 days after operation (1 in groups A and B). At 1 week, all PLLA stents showed thrombotic occlusion with the use of ASA alone. In contrast, all PLLA stents remained patent with concurrent administration of ASA/clopidogrel. All metal stents were patent regardless of the antiplatelet regimen. The mean luminal diameter of patent PLLA stents (4.13±0.17 mm) was comparable to metal stents (4.27±0.35 mm, p=0.78) at 1 week, but significantly diminished at 6 weeks (3.21±0.44 versus 4.19±0.18 mm, p=0.005). Histological analysis showed no signs of excessive recoil. PLLA stents induced a higher inflammation score (1.79±0.56) and more intimal hyperplasia (0.34±0.11 mm) compared to metal stents [1.27±0.44 mm (p<0.001) and 0.18±0.04 mm (p=0.006), respectively] at 6 weeks. Vascular injury was comparable between PLLA and metal stents. Conclusion: Biodegradable PLLA stents showed higher thrombogenicity and reduced patency compared to metal stents during early follow-up. Although ASA and clopidogrel prevented thrombotic occlusion, the increased inflammatory response and neointima formation remain major concerns of PLLA stents. A solution to this problem might be the incorporation of anti-inflammatory drugs into the PLLA stent. [ABSTRACT FROM AUTHOR]

Background: To assess technical feasibility and biocompatibility of a new Sirolimus (SIR)-eluting biodegradable poly-l-lactide (PLLA) stent for peripheral vascular application. Material and methods: In 15 pigs, both common carotid arteries (CCA) were surgically exposed and clamped in the proximal segment. After transverse incision, 12 316L stents, 12 unloaded and 6 SIR-loaded PLLA stents mounted on 6.0 × 40-mm balloon catheters were randomly implanted into the CCA and inflated to 8 bar. Angiographic equipment was not available. Stented CCA were explanted after 1 week (6 pigs; 316L versus PLLA) and 6 weeks (9 pigs; 316L versus PLLA versus SIR-PLLA), and processed for quantitative histomorphometry and estimation of vascular inflammation and injury scores. Results: No animals were lost during follow-up. All stents were patent on histological analysis without any signs of excessive recoiling or collapse. Unloaded PLLA stents showed decreased residual lumen area and increased neointimal area after 1 week (13.16 ± 0.34, 1.94 ± 0.26) and 6 weeks (11.57 ± 0.30, 2.85 ± 0.24) as compared with 316L stents (15.26 ± 0.13, 1.27 ± 0.41 and 13.99 ± 0.51, 1.54 ± 0.59). SIR-eluting stents demonstrated comparable neointimal area (1.75 ± 0.38) and 50% lower intimal thickness as compared with 316L stents after 6 weeks, but a slightly decreased residual lumen (13.06 ± 0.32) in the consequence of differences in strut thickness (PLLA, 270 μm; 316L, 155 μm). The vascular inflammation score against PLLA-stents could be reduced by Sirolimus. The vascular injury scores were low and similar in all groups. Conclusions: PLLA stents showed sufficient mechanical stability after porcine CCA stenting. By incorporation of Sirolimus, a significant reduction of the inflammatory and neointimal response to the PLLA stent was seen without systemic toxicity or thrombotic complications. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy. The greater strut height of PLLA stents is a major limitation and requires modification. [Copyright &y& Elsevier]

Background: The development of endoluminal stents from polymeric materials requires an understanding of the basic mechanical properties of the polymer and the effects of manufacturing and sterilization on those properties. Methods: Pure poly(L-lactide) (PLLA ) and PLLA containing varying amounts of triethylcitrate (TEC) as a plasticizer (5-10-15%) were studied. The specimens were solution-cast and CO2 laser-cut. Specimen dimensions were adapted to the strut size of polymeric vascular stents. The properties of the PLLA micro-specimens were assessed before and after sterilization (EtO cold gas, H2O2-plasma, beta- and gamma-irradiation). Tensile tests, and creep and recovery tests were carried out at 37°C. Additionally the thermal and thermo-mechanical characteristics were investigated using dynamic-mechanical analysis (DMA) and differential scanning calorimetry (DSC). Results: The results showed the dramatic influence of the plasticizer content and sterilization procedure on the mechanical properties of the material. Laser cutting had a lesser effect. Hence the effects of processing and sterilization must not be overlooked in the material selection and design phases of the development process leading to clinical use. Altogether, the results of these studies provide a clearer understanding of the complex interaction between the laser machining process and terminal sterilization on the primary mechanical properties of PLLA and PLLA plasticized with TEC. [ABSTRACT FROM AUTHOR]

Abstract: Commercial non-degradable glaucoma implants are often associated with undesired hypotony, fibrosis, long term failure, and damage of adjacent tissues, which may be overcome by a multifunctional polymeric microstent for suprachoroidal drainage. This study reports the design and fabrication of such devices with tailorable internal diameters (50–300μm) by solvent-free, continuous hot melt extrusion from blends of poly[(ε-caprolactone)-co-glycolide] and poly(ε-caprolactone) [PCL]. A spatially directed release was supported by bilayered microstents with an internal drug-free PCL layer, and a quantitative description of release kinetics with diclofenac sodium as model drug was provided. Furthermore, the slow degradation pattern (>1year) was analyzed and potential effects of 1–5wt.% drug loading on material properties were excluded. Translational aspects including sterilization by γ-irradiation on dry ice, in vitro biocompatibility, and in vivo implantation were addressed. The promising results support further functional analysis of long-term in vivo performance and suppression of disadvantageous capsule formation. [Copyright &y& Elsevier]

Abstract: The recently introduced vessel-simulating flow-through cell offers new possibilities to examine the release from drug-eluting stents in vitro. In comparison with standard dissolution methods, the additional compartment allows for the examination of distribution processes and creates dissolution conditions which simulate the physiological situation at the site of implantation. It was shown previously that these conditions have a distinct influence on the release rate from the stent coating. In this work, different preparation techniques were developed to examine the spatial distribution within the compartment simulating the vessel wall. These methods allowed for the examination of diffusion depth and the distribution resulting in the innermost layer of the compartment simulating the vessel wall. Furthermore, the in vitro release and distribution examined experimentally were modelled mathematically using finite element (FE) methods to gain further insight into the release and distribution behaviour. The FE modelling employing the experimentally determined diffusion coefficients yielded a good general description of the experimental data. The results of the modelling also provided important indications that inhomogeneous coating layer thicknesses around the strut may result from the coating process which influence release and distribution behaviour. Taken together, the vessel-simulating flow-through cell in combination with FE modelling represents a unique method to analyse drug release and distribution from drug-eluting stents in vitro with particular opportunities regarding the examination of spatial distributions within the vessel-simulating compartment. [Copyright &y& Elsevier]