药物洗脱支架植入后再狭窄的研究进展

随着药物洗脱支架(Drug Eluting Stent,DES)的出现,再狭窄的问题得到进一步的有效控制.然而,药物洗脱支架也存在较低的再狭窄率,由于应用药物洗脱支架治疗人数非常多,这一比率就不容忽视.本文将阐述DES支架内再狭窄发生的病理生理学机制、临床表现、形态学特征以及处理策略.     

蛋白药物涂层支架的制备表征与体外释放研究

目的:探讨将蛋白大分子药物以较高的担载量涂层于心脏支架,并在不发生蛋白聚集的前提下实现数周之久缓释的方法.方法:将牛血清白蛋白通过稳定的水相-水相乳液技术制备成多糖玻璃体颗粒,并将多糖玻璃体颗粒分散于聚乳酸溶液中喷涂于支架表面制成蛋白涂层支架,在37°CPBs中进行体外释放动力学研究,用SEC-HPLC比较了蛋白涂层支架制备前后蛋白的聚集情况,并用扫描电镜等对蛋白涂层支架表面进行了表征.结果:蛋白涂层支架在电镜观察下外观圆整,表面光滑,制剂过程中未产生蛋白聚集,且能从涂层中缓慢释放达50天以上.结论:稳定的水相-水相乳液技术及其基础上制备的蛋白多糖玻璃体颗粒应用于心脏支架涂层上,能在有效保护蛋白构象的同时实现蛋白的缓释,为具有抗再狭窄活性蛋白应用于心脏支架提供了技术平台.     

药物涂层球囊概述及其在外周动脉疾病治疗中的应用进展

经皮经腔血管成形术(PTA)已广泛用于外周动脉疾病(PAD)的治疗。然而,该技术存在血管壁弹性回缩和内膜增生等不足。PTA术后植入金属裸支架(BMS)虽然可以减少血管壁弹性回缩,但由此引起的支架内再狭窄(ISR)又成为治疗中的一个突出问题。药物洗脱支架(DES)被用来解决狭窄问题,但晚期支架内血栓形成(LST)、内皮化延迟和必须长期抗血小板治疗等问题也随之而来。在这样的背景下,药物涂层球囊(DCB)获得了快速发展。DCB作为非支架方案,可将所携载的活性药物转移至病变段血管壁,对ISR或原发病变均有较好的治疗效果。本文简要介绍了DCB的发展历史,并通过实验室研究、动物实验和临床试验,从机制上阐述涂层技术、涂层药物、赋形剂等对DCB功效和安全性的影响以及DCB在PAD治疗中的应用进展。     

新型可降解涂层冠脉药物洗脱支架荣获国家技术发明二等奖

由中科院院士、复旦大学附属中山医院心内科主任葛均波教授自主研制的"新型可降解涂层冠脉药物洗脱支架",荣获国家技术发明二等奖。应用新型涂层材料——聚乳酸类材料,作为药物载体确保药物支架逐步稳定释放。应用"非对称性涂层技术",仅在支架与血管壁接触的侧面涂上药物载体。这样既克服了传     

PLGA微球复合明胶组织工程支架缓释蛋白药物的研究

目的：研究PLGA微球复合明胶支架对蛋白药物的释放影响。方法：将模型蛋白BSA通过复乳法制备成缓释PLGA微球,然后将微球埋置于明胶支架中,形成担载蛋白的PLGA微球复合明胶组织工程支架。考察复合支架体外蛋白释放行为,并用MicroBCA法定量测定释放的BSA量,采用β-半乳糖苷酶催化ONPG的方法检测制备前后蛋白的活性,并与不含PLGA微球直接担载蛋白的支架做对照。结果：PLGA微球复合支架蛋白的包封率能达到73．2％,其中第一天释放20％,对蛋白活性的保持达到70％以上。结论：微球复合明胶支架可以改善一般组织工程支架蛋白药物的突释,提高蛋白药物在制剂,贮存,释放过程中的稳定性。     

钛合金植入体表面抗感染涂层的制备及其体外抑菌性能研究

临床中,内植物引起的相关感染是矫形外科以及创伤外科面临的重要问题。以聚乳酸（PDLLA）为载体,采用溶剂浇铸（solvent-casting）的方法,在钛合金植入物基体表面制备了载万古霉素（VCM）的PDLLA涂层,期望通过缓释万古霉素来抑制细菌感染。体外释药实验表明,涂层具有良好的缓释作用,在磷酸盐缓冲液（PBS）中持续释放VCM20天以上;涂层对引起感染的主要致病菌（金黄色葡萄球菌）具有超过15天的抑制作用。提示该涂层钛合金植入物有望在预防植入材料相关感染方面获得应用。     

药物涂层冠脉金属支架系统研发成功

大连大学董何彦教授领导的科技团队经过十余年的努力,开发成功新型药物支架——药物涂层冠脉金属支架系统。日前该产品已获得国家食品药品监督管理局（SFDA）颁发的产品注册证。这是我国第一个获准上市的国产紫杉醇药物支架,同时也是在我国境内上市的第一个无高分子聚合物涂层的药物支架。支架是治疗心血管疾病的常用医疗器械之一。临床表明,单独使用支架,有的患者会出现血管再狭窄,在医学上被称为“恶性增生”。     

担载b-FGF的PLGA微球复合明胶支架的体外释放研究

目的:研究担载碱性成纤维细胞生长因子(b-FGF)微球复合明胶支架的外形特征、孔径、孔隙率及体外释放动力学,以期构建具有缓释功能、高孔隙率的担载细胞因子的新型复合明胶支架。方法:本文利用冷冻相分离法和S/O/W法先将b-FGF水溶液包裹于PLGA微球中,然后埋置于明胶溶液中制备为多孔复合明胶支架。分别对微球的形态和复合明胶支架的基本形态、孔径、孔隙率进行表征,通过Elisa法测定b-FGF在复合明胶支架中的体外释放行为。结果:制备成形态良好的三维复合明胶支架,其孔隙率为82.90%±1.45%,孔径范围为150~300μm,复合明胶支架中b-FGF在体外缓慢释放20余天。结论:担载蛋白微球复合明胶支架不仅满足组织工程支架的要求,还能有效缓释细胞因子,为细胞和组织生长提供良好的微环境,为进一步应用于组织工程领域提供了可能。     

一种新型的基因传递系统:PLGA微球

乳酸聚乙醇酸是一类可生物降解的高分子聚合材料,通过其自身降解来调节药物释放．具有良好的生物相容性。包裹或吸附药物而制成的微球多用于药物的缓释给药系统,近几年来将这一系统应用于包裹基因。该文介绍乳酸聚乙醇酸基因微球的制备方法、主动脱逸特性等。     

载溶菌酶的羟基磷灰石/壳聚糖复合骨填充材料体外释放规律研究

目的:考察载溶菌酶的羟基磷灰石/壳聚糖(HA/CS)复合骨填充材料的体外释放规律。方法:制备载不同剂量溶菌酶的骨填充材料小柱,于37℃模拟体液下释放,高效液相测定药物释放情况。结果:在释放初期有突释效应,释放周期为3周,释放曲线符合Weibull方程,释放百分比与载药量有关。结论:HA/CS复合骨填充材料对溶菌酶有缓释效果,具有一定的临床使用前景。     

Optimization of Drug Delivery by Drug-Eluting Stents

Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.     

Optimization of Cardiovascular Stent against Restenosis: Factorial Design-Based Statistical Analysis of Polymer Coating Conditions

The objective of this study was to optimize the physicodynamic conditions of polymeric system as a coating substrate for drug eluting stents against restenosis. As Nitric Oxide (NO) has multifunctional activities, such as regulating blood flow and pressure, and influencing thrombus formation, a continuous and spatiotemporal delivery of NO loaded in the polymer based nanoparticles could be a viable option to reduce and prevent restenosis. To identify the most suitable carrier for S-Nitrosoglutathione (GSNO), a NO prodrug, stents were coated with various polymers, such as poly (lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL), using solvent evaporation technique. Full factorial design was used to evaluate the effects of the formulation variables in polymer-based stent coatings on the GSNO release rate and weight loss rate. The least square regression model was used for data analysis in the optimization process. The polymer-coated stents were further assessed with Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy analysis (FTIR), Scanning electron microscopy (SEM) images and platelet adhesion studies. Stents coated with PCL matrix displayed more sustained and controlled drug release profiles than those coated with PLGA and PEG. Stents coated with PCL matrix showed the least platelet adhesion rate. Subsequently, stents coated with PCL matrix were subjected to the further optimization processes for improvement of surface morphology and enhancement of the drug release duration. The results of this study demonstrated that PCL matrix containing GSNO is a promising system for stent surface coating against restenosis.     

Stents Eluting 6-Mercaptopurine Reduce Neointima Formation and Inflammation while Enhancing Strut Coverage in Rabbits

Background

The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface.

Methods

Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions.

Results

Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27^Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation.

Conclusion

We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.     

Improving smooth muscle cell exposure to drugs from drug-eluting stents at early time points: a variable compression approach

The emergence of drug-eluting stents (DES) as a viable replacement for bare metal stenting has led to a significant decrease in the incidence of clinical restenosis. This is due to the transport of anti-restenotic drugs from within the polymer coating of a DES into the artery wall which arrests the cell cycle before restenosis can occur. The efficacy of DES is still under close scrutiny in the medical field as many issues regarding the effectiveness of DES drug transport in vivo still exist. One such issue, that has received less attention, is the limiting effect that stent strut compression has on the transport of drug species in the artery wall. Once the artery wall is compressed, the stents ability to transfer drug species into the arterial wall can be reduced. This leads to a reduction in the spatial therapeutic transfer of drug species to binding sites within the arterial wall. This paper investigates the concept of idealised variable compression as a means of demonstrating how such a stent design approach could improve the spatial delivery of drug species in the arterial wall. The study focused on assessing how the trends in concentration levels changed as a result of artery wall compression. Five idealised stent designs were created with a combination of thick struts that provide the necessary compression to restore luminal patency and thin uncompressive struts that improve the transport of drugs therein. By conducting numerical simulations of diffusive mass transport, this study found that the use of uncompressive struts results in a more uniform spatial distribution of drug species in the arterial wall.     

Liposome coated stents: a method to deliver drugs to the site of action and improve stent blood-compatibility

A method to correct stent related complications non-invasively, is the local delivery of therapeutic agents. Different drugs have been delivered on stents, after being either dispersed or encapsulated in polymeric materials, and placed on stents to form drug-eluting-stents (DE-stents). Investigation of possibility to cover polymer - coated metallic stents, with liposomal drugs, for preparation of novel DE-liposome-coated-stents, has been initiated few years ago. In this context our research has been focused on answering the following questions: (i) Can liposomes be applied as coatings on polymer covered stents? (ii) Can drug release from liposome coated-stents be controlled? And: (iii) how is haemo-compatibility of stents affected? The results of the experiments carried out demonstrate that liposomal formulations of drugs can be used as coating systems of polymer covered stents for achieving sustained release of drugs at the site of interest. By modifying liposome characteristics, different amounts of drugs may be placed on the stents and their release rates can be adjusted for maximum therapeutic benefit. Finally, haemocompatibility of stents is highly improved (mainly in terms of cell adhesion and activation of coagulation system), when stents are coated with heparin-encapsulating -DRV liposomes.     

Drug delivery patterns for different stenting techniques in coronary bifurcations: a comparative computational study

The treatment of coronary bifurcation lesions represents a challenge for the interventional cardiologists due to the lower rate of procedural success and the higher risk of restenosis. The advent of drug-eluting stents (DES) has dramatically reduced restenosis and consequently the request for re-intervention. The aim of the present work is to provide further insight about the effectiveness of DES by means of a computational study that combines virtual stent implantation, fluid dynamics and drug release for different stenting protocols currently used in the treatment of a coronary artery bifurcation. An explicit dynamic finite element model is developed in order to obtain realistic configurations of the implanted devices used to perform fluid dynamics analysis by means of a previously developed finite element method coupling the blood flow and the intramural plasma filtration in rigid arteries. To efficiently model the drug release, a multiscale strategy is adopted, ranging from lumped parameter model accounting for drug release to fully 3-D models for drug transport to the artery. Differences in drug delivery to the artery are evaluated with respect to local drug dosage. This model allowed to compare alternative stenting configurations (namely the Provisional Side Branch, the Culotte and the Inverted Culotte techniques), thus suggesting guidelines in the treatment of coronary bifurcation lesions and addressing clinical issues such as the effectiveness of drug delivery to lesions in the side branch, as well as the influence of incomplete strut apposition and overlapping stents.     

Current perspectives of biodegradable drug-eluting stents for improved safety

The introduction of the drug-eluting stent (DES) proved to be an important step forward in reducing the rates of restenosis and target lesion revascularization after percutaneous coronary intervention (PCI). However, the rapid implementation of DES in standard practice and the expansion of the indications for PCI to high-risk patients and complex lesions also introduced a new problem. DES in-stent restenosis (ISR) occurs in 3 ?? 20% of patients, depending on the patient, lesion characteristics and the DES type. The initial commercially available DES used a stainless steel platform coated with a permanent polymer to provide a controlled release of an anti-restenotic drug. The platform, polymer and drug are all targets for improvement. More advanced metallic and fully biodegradable stent platforms are currently under investigation. The permanent polymer coating, a likely contributor to adverse events, is being superseded by biocompatible and bioabsorbable alternatives. New drugs and drug combinations are also a research goal, as interventional cardiologists and the industry strive towards a safer anti-restenotic DES. This paper reviews the benefits, risks, and current status of biodegradable drug-eluting stents.     

Controlled delivery of antisense oligodeoxynucleotide from cationically modified phosphorylcholine polymer films

Antisense strategy is a promising approach for the prevention of in-stent restenosis if therapeutic agents such as antisense oligodeoxynucleotides (AS-ODNs) can be successfully delivered to the implant site. Optimizing the routes and conditions for controlled loading and release of therapeutic agents from a biocompatible polymer coating is still required. In this study, phosphorylcholine (PC) polymer films bearing different cationic charge densities were deposited onto smooth silicon substrates. The thickness of these films was determined by spectroscopic ellipsometry (SE). Human c-myc AS-ODNs were incorporated into the PC polymer films by immersion in concentrated AS-ODN solution and eluted into PBS under physiological conditions. The elution profile was monitored by UV spectrometry and gel electrophoresis. Cellular uptake of the eluted AS-ODN into vascular smooth muscle cells (VSMCs) was evaluated by fluorescence microscopy. The results showed that ODN loading capacities increased with film thickness and were also strongly dependent on the cationic charge density. AS-ODN release was characterized by a slight initial burst in the first half hour followed by a period of sustained release up to 8 days. Gel electrophoresis demonstrated DNA integrity, and different transfection efficiencies were observed when the eluted ODNs were transfected into VSMCs. These results demonstrated that cationically modified PC polymers are capable of delivery of antisense ODNs in a controlled manner and that they are well suited for specific biomedical devices such as DNA-eluting stents.