西罗莫司-聚三亚甲基碳酸酯改性镁合金的降解和药物释放行为

背景：冠状动脉镁合金支架腐蚀速率及药物释放的双重调控是目前镁合金支架需要解决的重要课题。可降解载药聚合物涂层作为一种有前途的改性策略引发了广泛关注。目的：研究可降解载药聚合物涂层修饰对镁合金降解的影响,以及镁合金降解对可降解载药聚合物涂层药物释放的影响。方法：制备不同的药物聚合物溶液,溶液S1：西罗莫司0.01 g、聚三亚甲基碳酸酯0.005 g、二氯甲烷1 mL;溶液S2：西罗莫司0.01 g、聚三亚甲基碳酸酯0.01 g、二氯甲烷1 mL;S3：西罗莫司0.01 g、聚三亚甲基碳酸酯0.02 g、二氯甲烷1 mL;S2-1：西罗莫司0.01 g、聚三亚甲基碳酸酯0.01 g、0.001 g聚乙二醇400、二氯甲烷1 mL;S2-2：西罗莫司0.01 g、聚三亚甲基碳酸酯0.01 g、0.002 g聚乙二醇400、二氯甲烷1 mL。将5种药物聚合物溶液涂覆在AZ31镁合金表面制备涂层,对比涂层在镁合金基底上的药物释放行为差异,以及各涂层对镁合金腐蚀能力的影响;探索基底对西罗莫司-聚三亚甲基碳酸酯涂层的影响;考察各修饰镁合金的体外细胞相容性与血液相容性。结果与结论：(1)西罗莫司-聚三...     

新型可交联医用涂层材料的研究

采用 α-甲基丙烯酰 - ω-羟基聚氧乙烯 (MPEO)、甲基丙烯酸十八酯 (SMA)、甲基丙烯酸羟丙酯 (HPMA)和甲基丙烯酸 (三硅氧烷 )丙酯 (TSMA) ,通过溶液自由基聚合合成了一系列不同组成的可交联聚合物。并通过浸涂 (Dip- coating)和热交联技术在玻璃和医用聚酯表面形成了稳定的含聚氧乙烯 (PEO)涂层。表面接触角结果显示涂层表面在水环境下 ,亲疏水性基团反转形成高亲水性表面。复钙化凝血时间和血小板黏附实验结果表明该四元共聚物涂层材料可延长复钙化凝血时间 ,限制并减少血小板黏附 ,是一种极具潜力的抗凝血涂层材料     

菌蚀型生物降解材料的合成与表征

本文力图设计与合成在人体结肠厌氧菌存在环境下,可被微生物降解的生物材料.用三种亲疏水性不同、软硬段不同的三种单体,即甲基丙烯酸羟乙酯(HEMA)、甲基丙烯酸(MAA)、甲基丙烯酸甲酯(MMA)为载体,并用对甲基丙烯酰胺偶氮苯(BMAAB)为偶联剂,合成了聚甲基丙烯酸羟乙酯-甲基丙烯酸甲酯-甲基丙烯酸[P(HEMA-MMA-MAA)]三元偶氮聚合物.用红外、紫外、核磁共振进行化学结构表征,并测定了该材料的溶胀性能,比较了聚合物降解前后分子量、热性能与形态变化.结果证明材料的降解程度与材料中亲水组分含量直接相关.     

具有杀精子能力的高聚物的合成

输精管粘堵法是一种新的男性绝育法。但此法易引起附睾淤积,且生育不可复。我们曾合成了一种三元共聚物,(聚羟乙基甲基丙烯酸-共—乙基甲基丙烯酸酯-共—甲基丙烯酸),在不使输精管堵塞的情况下起到杀精子作用,同时具有生育可复性。为了提高杀精子作用,我们又合成了另一种新的高分子材料:甲基丙烯酸水扬酸酯和甲基丙烯酸羟乙酯的共聚物(PSH)。这种高分子不仅本身具有杀精子作用,而且能释放出有杀精子作用的水杨酸小分子。本文还测定了高分子释放水杨酸的速度,以及杀精子能力。     

生物可吸收涂层和永久涂层药物支架治疗冠状动脉粥样硬化性心脏病的Meta分析

背景:生物可吸收涂层药物支架和永久涂层药物支架均广泛应用于冠状动脉粥样硬化性心脏病介入治疗中,由于支架架构、支架药物、药物载体上的差异,多个研究对两种支架疗效和安全性的比较结果不完全一致。目的:比较生物可吸收涂层药物支架和永久涂层药物支架在冠状动脉粥样硬化性心脏病介入治疗的临床结果,评价两类支架在疗效和安全性上的差异。方法:检索Medline(1966-01/2010-07)、Embase(1980-01/2010-07)、Cochrane library(2010-07)、中国生物医学文献数据库(CBM,1990-01/2010-07)及相关参考文献,收集比较生物可吸收涂层药物支架与永久涂层药物支架的对照研究,采用Cochrane的随机方法学评价文献质量,应用RevMan5.0软件进行Meta分析。结果与结论:纳入10个对照研究,共纳入4391例患者,其中生物可吸收涂层药物支架组2429例,永久涂层药物支架组1962例。Meta分析结果显示,生物可吸收涂层药物支架用于冠状动脉粥样硬化性心脏病患者,支架置入后6～12个月内心脏主要不良事件、靶血管血运重建、心脏性死亡、再发心肌梗死、支架内血栓形成和支架内再狭窄与永久涂层药物支架组差异无显著性意义。但生物可吸收涂层药物支架内晚期管腔丢失明显小于永久涂层药物支架组(P0.05)。提示生物可吸收涂层药物支架用于治疗冠状动脉粥样硬化性心脏病安全、有效,并不劣于永久涂层药物支架,且可能在减轻冠状动脉支架置入治疗后内膜过度增生方面更具优势。     

MPC-BMA共聚物的合成及其血小板粘附行为研究

本研究首先合成了含有磷酸胆碱基团的单体2-甲基丙烯酰氧乙基-2′-三甲胺乙基磷酸酯.内盐(MPC)和甲基丙烯酸正丁酯(BMA)的共聚物,采用红外光谱对其主要基团进行了表征分析,利用血小板粘附实验研究了磷脂聚合物膜的血小板粘附性,通过扫描电镜对血小板在聚合物膜上的形态和粘附量进行观察。结果表明:MPC含量越高,血小板的粘附量和变形程度越小;与其它亲水性单体如HEMA、HPOEM360、HPOEM526相比,等量MPC更能有效的降低其聚合物膜的血小板粘附性。     

β_2—M高效吸附剂的开发:聚苯乙烯—马来酸固定化吸附材料用于血液灌流

作者偿试开发β_2—M吸附剂,用聚苯乙烯—马来酸(Pst—MA)连接于聚甲基丙烯酸甲酯—二乙烯苯(PMMA—DVB)多孔载体上,这些多孔载体外层为2—甲基丙烯酸羟上酯—甲基丙烯酸二乙基氨基乙酯(PHEMA—DE)     

Mg-PLGA-rhbFGF复合支架在下肢缺血血运重建中的应用研究

目的 制备荷载生长因子的镁合金-聚乳酸-聚乙醇酸共聚物(Mg-PLGA)复合支架,构建大鼠下肢缺血模型,观察其对缺血骨骼肌血管新生的作用与效果.方法 在金属Mg支架表面涂覆包载重组人碱性成纤维细胞生长因子(rhbFGF)的生物降解性PLGA聚合物,制得药物涂层支架(Mg-PLGA-rhbFGF).体外试验研究支架中药物的释放性能.体内试验构建大鼠下肢缺血模型,机械打孔后植入支架,通过检测Mg2+在大鼠缺血骨骼肌、血浆、尿液和大便中的浓度,分析支架中的金属Mg在大鼠体内的降解与代谢情况;通过免疫组化分析支架对大鼠缺血下肢骨骼肌血管新生的作用.结果 在体外试验中,药物在Mg-PLGA药物涂层支架中具有良好的缓释性能,可持续释放4周.在体内试验中,大鼠血液、尿液和大便中的Mg2+度在正常范围内;免疫组化染色及血管密度定量分析表明,药物涂层支架组与空白支架组相比新生血管显著增多、血管壁增厚.结论 载rhbFGF的Mg-PLGA药物涂层支架可促进下肢缺血大鼠缺血骨骼肌血管新生,为危重症下肢缺血性疾病的治疗提供理论基础.     

培养在不同可湿性和带电的甲基丙烯酸酯表面人内皮细胞的粘连

曾报导不同类型的哺乳动物对具有聚合物特性的各种表面粘附和增生与表面可湿性及带电相同,常常用系列甲基丙烯酸酯和共聚物作血小板,纤维母细胞及上皮细胞粘连的研究。而作者在本文中介绍了人内皮细胞(HEC)对甲基丙烯酸酯复合聚合物粘附的研究,这种复合聚合物包括聚羟乙基甲基丙烯酸酯(PHEMA),聚甲基丙烯酸甲酯(PMMA)。HEMA与MMA共聚物及HEMA或MMA与甲基丙烯酸(MAA)或三甲基氨乙基甲基丙烯酸酯(TMAEA-HCl),将其材料涂层于玻璃或硅化玻     

冠状动脉支架表面涂层材料对置入效果的影响

目的:阐述冠状动脉内支架的临床应用进展,并探讨冠状动脉支架的表面涂层材料对置入后支架内血栓形成和再狭窄的影响。方法:作者以"冠脉内支架,表面涂层,血栓,再狭窄"为检索词,在中国期刊全文数据库(CNKI:2002/2008)及Medline数据库(PubMed:1974/2006)中,采用电子检索的方式进行文献检索。排除Meta分析及重复性研究,共检索到25篇文献,从冠状动脉内支架置入治疗进展,不同表面涂层材料及其对支架内血栓形成和再狭窄的影响等方面进行探讨。结果:冠状动脉内药物洗脱支架置入是治疗冠心病的常用方法,效果明显,并发症很少。冠状动脉内支架表面涂层材料有雷帕霉素、紫杉醇、肝素、二烯丙基三硫化物、地塞米松以及不可降解的聚合物等,均能促进内皮细胞修复,抑制平滑肌细胞增殖,防治支架内血栓形成和再狭窄,保持支架的通畅。由于残留的涂层材料刺激平滑肌细胞增殖,近年使用的可降解的聚合物涂层能进一步提高支架的通畅率。如肝素化聚氨酯涂层、聚乳酸聚羟基乙酸共聚物雷帕霉素涂层和聚砜-聚氧化乙酸共聚物雷帕霉素涂层具有良好的组织相容性,抑制内膜增生,改善再狭窄,有望成为新的冠状动脉内支架涂层材料。结论:冠状动脉内药物洗脱支架置入和阿司匹林、氯吡格雷联合应用是冠状动脉血运重建的良好方法,随着涂层材料的不断更新,支架的通畅率将得到进一步提高。     

An investigation of adhesion in drug-eluting stent layers

An atomic force microscopy (AFM) method was developed to quantify the adhesion forces between and cohesive forces within the layers of a drug-eluting stent (DES). Surface pairs representing both the individual components and the complete chemistry of each layer within the DES were prepared. As a model, the CYPHER Sirolimus-eluting Coronary Stent was studied. This DES consists of a stainless steel stent substrate, a parylene C primer layer, and a drug-eluting layer that contains poly(ethylene-co-vinyl acetate), poly(n-butyl methacrylate), and sirolimus (rapamycin). Coated AFM tips and two-dimensional substrates or coupons, which act as surrogates to the CYPHER Stent, were prepared and characterized. The force-displacement measurements were conducted to evaluate the adhesion between the middle parylene C layer and the 316L stainless steel substrate, the adhesion between the parylene C layer and the outer drug-eluting layer, and the cohesion between the three constituents of the drug-eluting layer. The average adhesion forces between the parylene C to drug layer varied from 88 to 167 nN, and the drug layer-to-drug layer interactions were between 194 and 486 nN within the model CYPHER Stent coating. All the adhesion forces measured were larger than those observed for gold-gold interactions, which yielded a pull of force of 19 nN (Zong et al., J Appl Phys 2006;100:104313-104323).     

Preparation and characterization of brush-like PEGMA-graft-PDA coating and its application for protein separation by CE

In this paper, a novel brush-like copolymer consisting of poly(ethylene glycol) methyl ether methacrylate and 2-aminoethyl methacrylate (AEMA) named as poly(PEGMA₃₀₀-co-AEMA) was synthesized by atom transfer radical polymerization (ATRP), and then, poly(PEGMA₃₀₀-co-AEMA) copolymer was immobilized onto material surfaces through polydopamine (PDA)-anchored coating. The defined copolymer structure was characterized by nuclear magnetic resonance hydrogen spectroscopy (¹H NMR) and gel permeation chromatography (GPC). The chemical component and surface morphology of the brush-like copolymer-graft-PDA coating were studied by using X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM), respectively. The hydrophilicity of the brush-like copolymer-graft-PDA coating was investigated by using static water contact angle. The protein-resistant property of the brush-like copolymer-graft-PDA coating was investigated by using quartz crystal microbalance with dissipation (QCM-D), and finally the coating was applied to capillary inner surface for protein separation by capillary electrophoresis (CE).     

Surface modification by grafting of poly(SBMA-co-AEMA)-g-PDA coating and its application in CE

In this paper, a novel copolymer consisting of sulfobetaine methacrylate (SBMA) and 2-aminoethyl methacrylate (AEMA) named as poly(SBMA-co-AEMA) was synthesized by conventional free-radical polymerization, the poly(SBMA-co-AEMA) zwitterionic copolymer was immobilized onto glass slides surface through polydopamine (PDA)-anchored coating and formed poly(SBMA-co-AEMA)-g-PDA coating. The defined copolymer was characterized by nuclear magnetic resonance hydrogen spectroscopy (¹H NMR) and gel permeation chromatography. The surface morphology, thickness, and chemical component of poly(SBMA-co-AEMA)-g-PDA coating were studied by atom force microscope, ellipsometry, and X-ray photoelectron spectroscopy, respectively. The hydrophilicity and stability of these coatings were investigated by static water contact angles. And finally, the poly(SBMA-co-AEMA)-g-PDA coating was successfully applied into capillary inner surface for suppression electro-osmotic flow and protein separation by capillary electrophoresis.     

Development, implantation, in vivo elution, and retrieval of a biocompatible, sustained release subretinal drug delivery system

A biocompatible, sustained-release subretinal drug-delivery platform was developed to overcome the therapeutic accessibility limitations of current retinal disease treatments. The prototype implants were fabricated by coating nitinol, poly(methyl methacrylate) or chromic gut core filaments, with a drug-eluting polymer matrix. The polymer coatings are manufactured and coated by SurModics. The coating is a mixture of poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). The drug is either triamcinolone acetonide or sirolimus. The rods were successfully implanted into the subretinal space of 20/24 rabbits. Four rabbits were lost to early surgery from a dysfunctional infusion line and hemorrhage. No serious complications were observed during the 4-week follow-up period. Slight conjunctival redness was reported in all rabbits by 1-day follow-up, but the redness had subsided by the following week. Intraocular lens touch occurred in six rabbits during the implantations; of these, four had a lensectomy at the time of surgery, and the remaining two developed cataract. Corneal edema developed in three rabbits by 1-week follow-up, but subsided within 2 weeks. Initial observations of the implantation and elution characteristics revealed that the implants are well tolerated by the retinal tissue and that the implant can elute triamcinolone acetonide for a period of at least 4 weeks without eliciting an inflammatory response or complications. There were adverse clinical indications with the sirolimus-loaded implants at the delivered dose. Device retrieval required an uncomplicated surgical procedure, and revealed no associated or adherent tissue. Implant drug content analysis and opacity changes to the polymer matrix coating following retrieval demonstrated the sustained elution of the drug.     

Fabrication of Balloon-Expandable Self-Lock Drug-Eluting Polycaprolactone Stents Using Micro-Injection Molding and Spray Coating Techniques

The purpose of this report was to develop novel balloon-expandable self-lock drug-eluting poly(ε-caprolactone) stents. To fabricate the biodegradable stents, polycaprolactone (PCL) components were first fabricated by a lab-scale micro-injection molded machine. They were then assembled and hot-spot welded into mesh-like stents of 3 and 5 mm in diameters. A special geometry of the components was designed to self-lock the assembled stents and to resist the external pressure of the blood vessels after being expanded by balloons. Characterization of the biodegradable PCL stents was carried out. PCL stents exhibited comparable mechanical property to that of metallic stents. No significant collapse pressure reduction and weight loss of the stents were observed after being submerged in PBS for 12 weeks. In addition, the developed stent was coated with paclitaxel by a spray coating technique and the release characteristic of the drug was determined by an in vitro elution method. The high-performance liquid chromatography analysis showed that the biodegradable stents could release a high concentration of paclitaxel for more than 60 days. By adopting the novel techniques, we will be able to fabricate biodegradable drug-eluting PCL stents of different sizes for various cardiovascular applications.     

In vivo biocompatibility of a plasma-activated, coronary stent coating

Bare metal and drug-eluting coronary stents suffer an inherent lack of vascular cell and blood compatibility resulting in adverse patient responses. We have developed a plasma-activated coating (PAC) for metallic coronary stents that is durable, withstands crimping and expansion, has low thrombogenicity and can covalently bind proteins, linker-free. This has been shown to enhance endothelial cell interactions in?vitro and has the potential to promote biointegration of stents. Using the rabbit denuded iliac artery model, we show for the first time that PAC is a feasible coating for coronary stents in?vivo. The coating integrity of PAC was maintained following implantation and expansion. The rate of endothelialization, strut coverage, neointimal response and the initial immune response were equivalent to bare metal stents. Furthermore, the initial thrombogenicity caused by the PAC stents showed a reduced trend compared to bare metal stents. This work demonstrates a robust, durable, non-cytotoxic plasma-based coating technology that has the ability to covalently immobilize bioactive molecules for surface modification of coronary stents. Improvements in the clinical performance of implantable cardiovascular devices could be achieved by the immobilization of proteins or peptides that trigger desirable cellular responses.     

Controlled drug release through a plasma polymerized tetramethylcyclo-tetrasiloxane coating barrier

A plasma polymerized tetramethylcyclo-tetrasiloxane (TMCTS) coating was deposited onto a metallic biomaterial, 316 stainless steel, to control the release rate of drugs, including daunomycin, rapamycin and NPC-15199 (N-(9-fluorenylmethoxy-carbonyl)-leucine), from the substrate surface. The plasma-state polymerized TMCTS thin film was deposited in a vacuum plasma reactor operated at a radio-frequency of 13.56 MHz, and was highly adhesive to the stainless steel, providing a smooth and hard coating layer for drugs coated on the substrate. To investigate the influence of plasma coating thickness on the drug diffusion profile, coatings were deposited at various time lengths from 20 s to 6 min, depending on the type of drug. Atomic force spectroscopy (AFM) was utilized to characterize coating thickness. Drug elution was measured using a spectrophotometer or high-performance liquid chromatography (HPLC) system. The experimental results indicate that plasma polymerized TMCTS can be used as an over-coating to control drug elution at the desired release rate. The drug-release rate was also found to be dependent on the molecular weight of the drug with plasma coating barrier on top of it. The in vitro cytotoxicity test result suggested that the TMCTS plasma coatings did not produce a cytotoxic response to mammalian cells. The non-cytotoxicity of TMCTS coating plus its high thrombo-resistance and biocompatibility are very beneficial to drug-eluting devices that contact blood.     

Controlled Drug Release through a Plasma Polymerized Tetramethylcyclo-tetrasiloxane Coating Barrier

A plasma polymerized tetramethylcyclo-tetrasiloxane (TMCTS) coating was deposited onto a metallic biomaterial, 316 stainless steel, to control the release rate of drugs, including daunomycin, rapamycin and NPC-15199 (N-(9-fluorenylmethoxy-carbonyl)-leucine), from the substrate surface. The plasma-state polymerized TMCTS thin film was deposited in a vacuum plasma reactor operated at a radio-frequency of 13.56 MHz, and was highly adhesive to the stainless steel, providing a smooth and hard coating layer for drugs coated on the substrate. To investigate the influence of plasma coating thickness on the drug diffusion profile, coatings were deposited at various time lengths from 20 s to 6 min, depending on the type of drug. Atomic force spectroscopy (AFM) was utilized to characterize coating thickness. Drug elution was measured using a spectrophotometer or high-performance liquid chromatography (HPLC) system. The experimental results indicate that plasma polymerized TMCTS can be used as an over-coating to control drug elution at the desired release rate. The drug-release rate was also found to be dependent on the molecular weight of the drug with plasma coating barrier on top of it. The in vitro cytotoxicity test result suggested that the TMCTS plasma coatings did not produce a cytotoxic response to mammalian cells. The non-cytotoxicity of TMCTS coating plus its high thrombo-resistance and biocompatibility are very beneficial to drug-eluting devices that contact blood.     

A theoretical model to characterize the drug release behavior of drug-eluting stents with durable polymer matrix coating

The time-dependent local drug delivery from drug-eluting stents (DES) plays a critical role in reducing restenosis in intravascular stenting. To better understand the basic mechanism of drug release for certain polymer-drug-coated DES platforms, a cylindrical diffusion model was applied successfully to quantitatively describe the experimental drug release data of Dynalink-E in vitro and in vivo. The results showed that the profiles of Dynalink-E everolimus release could be controlled by such characteristic parameters as coating thickness and diffusion coefficient. The model could be used to quantitatively characterize the drug release profiles and IVIV correlations.     

Physical characterization of controlled release of paclitaxel from the TAXUS Express2 drug-eluting stent

The polymer carrier technology in the TAXUS drug-eluting stent consists of a thermoplastic elastomer poly(styrene-b-isobutylene-b-styrene) (SIBS) with microphase-separated morphology resulting in optimal properties for a drug-delivery stent coating. Comprehensive physical characterization of the stent coatings and cast film formulations showed that paclitaxel (PTx) exists primarily as discrete nanoparticles embedded in the SIBS matrix. Thermal and chemical analysis did not show any evidence of solubility of PTx in SIBS or of any molecular miscibility between PTx and SIBS. Atomic force microscope data images revealed for the first time three-dimensional stent coating surfaces at high spatial resolutions in air and in situ under phosphate-buffered saline as drug was released. PTx release involves the initial dissolution of drug particles from the PTx/SIBS coating surface. Morphological examination of the stent coatings in vitro supported an early burst release in most formulations because of surface PTx followed by a sustained slower release of PTx from the bulk coating. The in vitro PTx release kinetics were dependent on the formulation and correlated to the drug-to-polymer ratio. Atomic force microscopy analysis confirmed this correlation and further supported the concept of a matrix-based drug-release coating.