生物可降解性血管内支架及药物释放支架的研制

目的探讨采用溶液中加入药物的方法制作雷帕霉素释放BES的可行性及载药量准确性;明确裸BES、雷帕霉素释放BES及ASODN涂层BES与金属支架在力学性能方面的差异。方法应用高分子材料PLLA制作生物可降解血管内支架;采用溶液中加入药物的方法制作生物可降解雷帕霉素释放支架;采用表面涂层方法制作生物可降解反义寡核苷酸涂层支架。应用HPLC法对雷帕霉素释放BES的载药量进行检测。对三种支架进行径向支撑力测试并与金属支架比较。结果制作出BES基杆直径为0.5mm,扩张后直径为4.5或5.0mm,长度均为15mm。三种BES外观无明显区别;雷帕霉素释放BES平均载药量为181.4μg,与支架制作过程中的设计载药量基本一致;支撑力测试结果表明:三种PLLA支架径向支撑力略低于金属支架;裸BES与涂层BES径向支撑力相似,略高于雷帕霉素BES。结论生物可降解材料PL-LA制作的裸支架、载药支架及涂层支架的径向支撑力均略低于金属支架,载药支架径向支撑力略低于裸支架及表面涂层支架。溶液中加入雷帕霉素的方法含量可靠,可以代替支架表面多孔构型的加工工艺。     

布洛芬缓释凝胶的制备

目的:制各布洛芬缓释凝胶,并进行质量标准的研究及释放度测定.方法:以聚乳酸-乙醇酸共聚物(75/25)作为基质,N-甲基-2-吡咯烷酮作为溶剂,制各布洛芬缓释凝胶,以高效液相色谱法测定其含量并进行质量控制,并观察其体外释放情况.结果:布洛芬在一定浓度范围内线性关系良好,平均回收率分别为99.3%,98.6%,100.5%.体外释放度实验中,第一点(1 h)累计释放率均小于30%,中间点(36 h)分别为53%,52%,55%,最后点(72 h)均大于80%,可见布洛芬缓释凝胶有明显的缓释作用.结论:以聚乳酸-乙醇酸共聚物(75/25)作为基质,N-甲基-2-吡咯烷酮作为溶剂,可制备出理想的布洛芬缓释凝胶,质量可靠,释放度合格.     

三维支架材料与脂肪干细胞的生物相容性

背景:构建组织工程化气管需要适合的三维支架。目的:观察脂肪干细胞与聚乳酸-乙醇酸共聚物及聚三亚甲基碳酸酯共聚物支架的生物相容性。方法:采用组织块法原代分离培养SD大鼠脂肪干细胞,行流式细胞术及多向分化能力鉴定。将脂肪干细胞分别种植于聚乳酸-乙醇酸共聚物和聚乳酸-乙醇酸-三亚甲基碳酸酯共聚物支架中,扫描电镜观察细胞与支架的生物相容性。结果与结论:脂肪干细胞种植于两种支架材料后生长速度快,扫描电镜观察可见脂肪干细胞呈球型,并伸展形成伪足,贴附于支架材料,细胞间相互连接成团。说明聚乳酸-乙醇酸共聚物与聚三亚甲基碳酸酯共聚物支架均具有良好的生物相容性,无细胞毒性,其多孔的三维立体状结构适合脂肪干细胞黏附生长。     

三维支架材料与脂肪干细胞的生物相容性

背景：构建组织工程化气管需要适合的三维支架。目的：观察脂肪干细胞与聚乳酸-乙醇酸共聚物及聚三亚甲基碳酸酯共聚物支架的生物相容性。方法：采用组织块法原代分离培养SD大鼠脂肪干细胞,行流式细胞术及多向分化能力鉴定。将脂肪干细胞分别种植于聚乳酸-乙醇酸共聚物和聚乳酸-乙醇酸-三亚甲基碳酸酯共聚物支架中,扫描电镜观察细胞与支架的生物相容性。结果与结论：脂肪干细胞种植于两种支架材料后生长速度快,扫描电镜观察可见脂肪干细胞呈球型,并伸展形成伪足,贴附于支架材料,细胞间相互连接成团。说明聚乳酸-乙醇酸共聚物与聚三亚甲基碳酸酯共聚物支架均具有良好的生物相容性,无细胞毒性,其多孔的三维立体状结构适合脂肪干细胞黏附生长。     

硫酸软骨素酶ABC-聚乳酸-聚乙醇酸共聚物缓释微球的制备及其体外性质

背景:硫酸软骨素酶ABC能够分解脊髓损伤局部持续产生的硫酸软骨素蛋白多糖,从而促进轴突的生长,但该酶性质不稳定,需要多次局部用药.目的:制备硫酸软骨素酶ABC-聚乳酸-聚乙醇酸共聚物缓释微球,观察其体外释药特性.设计、时间及地点:重复测量设计,于2006-03/2007-01在中国科学院成都有机所和四川大学华西医学中心药理实验室完成.材料:聚乳酸-聚乙醇酸共聚物、硫酸软骨素酶ABC、CH2Cl2、硫酸软骨素B.方法:复乳法制备硫酸软骨素酶ABC缓释微球,并以生理盐水为体外释药介质.主要观察指标:扫描电镜下观察硫酸软骨素酶ABC缓释微球的形态.应用Malvern激光粒度分布测试仪测定其粒径分布并自动计算微球的平均粒径和径距.采用酶解分光光度测定硫酸软骨素酶ABC含量,并计算载药量与包封率.于0.5,1,1.5,2,3,4,6,8,10,12,14,16,18,21 d取样,绘制体外释药曲线.结果:硫酸软骨素酶ABC缓释微球形态均匀.其平均粒径5.538 ì m,径距1.479,呈正态分布.平均载药量(15.554±0.90)×10 3%,甲均包封率(53.88±1,45)%,硫酸软骨素酶ABC微球在3周内的体外累积释药分数为O.851 4,释药平稳,其最佳体外释药拟合方程为Weibull方程:Inln(1/1-Y)=0.739 61nX-1.617,R2=0.993 3.结论:所制备的硫酸软骨素酶ABC微球形态均匀.粒径分布窄,再分散性好,3周内能维持有效的药物浓度.     

缓释降解支架复合碱性成纤维细胞生长因子诱导心肌血管再生的作用

背景:研究证实碱性成纤维细胞生长因子具有刺激血管再生及侧支重建的作用,但是,以往多通过外周静脉、左心房或冠脉介入途径给药,心肌局部难以达到有效治疗浓度.目的:基于高分子材料聚乳酸/乙醇酸的降解特性,复合碱性成纤维细胞生长因子,保证蛋白生长因子在局部组织中靶向释放,观察其诱导心肌血管再生效果.方法:以聚乳酸、乙醇酸为原料,二氯甲烷溶解后加入重组人碱性成纤维细胞生长因子,通过模具塑形,制成外径,内径分别为3.0,2.8 mm、壁厚0.1 mm、长度10 mm的圆柱形中空管状支架备用.于小型猪冠脉前降支中、远端1/3交界处阻断,局部心肌颜色变为暗紫色,超声观察前壁心尖局部室壁运动异常证实模型制作成功,随机分至空白支架对照组和碱性成纤维细胞生长因子支架组,支架通过自主设计的机械打孔装置植入.6周后,免疫组织化学染色量化分析血管重建的增殖细胞数量,并结合Image Pro Plus软件量化各组新生血管密度,SPECT结合软件Emory Cardiac Toolbox分析灌注缺损区域质量百分率的变化.结果与结论:6周后碱性成纤维细胞生长因子支架组增殖细胞数量、新生血管密度较空白支架组显著增加(P<0.001),心肌核素显像显示灌注质量缺损百分率较空白支架组显著减少(P<0.001). 结果证实,复合碱性成纤维细胞生长因子的聚乳酸,乙醇酸支架能够显著增加新生血管密度,进而改善缺血部位心肌血流灌注.     

药物缓释涂层支架的材料学特点及其生物相容性

目的:阐述药物涂层支架的材料学特点,分析其生物相容性.方法:检索PubMed数据库和中国期刊全文数据库有关药物缓释涂层支架材料学特点及生物相容性的文献,以"心血管,药物缓释,雷帕霉素,紫杉醇,冠状动脉,生物相容性,支架材料"为检索词,对资料进行初审,并查看文献后的引文文献.排除重复研究或Meta分析类文章.结果:①心血管支架中药物涂层支架材料的改进更新均以改善生物相容性和生物力学性能为目标.②心血管支架的生物相容性是一个复杂的连锁过程,血液相容性和组织相容性是评定生物相容性的两项基本内容.③利用有限元分析心血管支架材料的力学特性可为未来支架的优化设计提供有益的帮助.结论:药物涂层支架的研究涉及药物学、生物学、材料学多学科交叉,研究药物缓释载体的控释机制,寻找血液相容性更好的药物缓释载体,加强缓释载体与机体的结合强度是当前支架药物缓释载体研究所要解决的问题.     

包载雷帕霉素聚乳酸-聚乙醇酸纳米粒子的制备、表征及体外释放试验

背景：新型可生物降解多聚物纳米控释载药制剂能显著改善药物穿透组织能力、再分布时程和滞留时间,可能克服载药基质对血管修复的负性影响,有望避免药物洗脱支架晚期支架内血栓。目的：制备雷帕霉素-聚乳酸-聚乙醇酸纳米粒子（rapamycin poly（lactic-co-glycolic）acid nanoparticles,RPM-PLGA-NPs）并观察其表征及体外控释性能。设计、时间及地点：单一样本实验于2003-03/09在中国医学科学院,中国协和医科大学,生物医学工程研究所生物医学材料重点实验室完成。材料：聚乳酸-聚乙烯醇酸共聚物50∶50由美国Birmingham Polymers公司提供。方法：以可生物降解高分子材料聚乳酸-聚乙醇酸共聚物作载药基质,超声乳化-溶剂挥发法制备RPM-PLGA-NPs,采用双室扩散池行体外药物释放试验。主要观察指标：测定平均载药量、平均包封率;激光光散射实验测定纳米粒子的粒径及分布;扫描电镜观察纳米粒子的表面形态;高效液相色谱法计算体外药物释放量、绘制累积释放曲线。结果：成功制备了平均粒径为246.8nm的RPM-PLGA-NPs,平均粒径246.8nm,粒径分布集中在208～294nm,呈窄分布;包封率大于77%,平均载药量为19.42%。体外释放近似于零级过程,至2周释放75%的药物。结论：超声乳化-溶剂挥发法制备RPM-PLGA-NPs稳定可靠,包封效率高,载药量控制稳定,粒径小、范围窄,体外释放药物恒定、具有良好的控释效能。     

三种不同材料血管内支架的生物相容性

不可降解的覆膜支架和药物涂层支架从一定程度上抑制了内膜增生,降低了再狭窄的出现率,为冠心病的治疗带来了新的希望,但支架本身是一种金属异物,可以导致血栓的形成和引起机体的免疫反应.新型生物可降解支架具有良好的生物相容性和生物降解性,其降解产物降解为二氧化碳和水,参与新陈代谢,对人体无毒性,可以避免金属永久支架引起的并发症.但生物可降解支架也存在机械性能差、支撑力不足等问题.通过优化生物材料的整体性质,调整材料的分子结构,提高材料的生物稳定性和可控性,减少炎症反应及置入后血管再狭窄的发生,是医学和材料学界研究者关注的重要课题.     

Fabrication of biodegradable spheroidal microparticles for drug delivery applications

Particle shape, in addition to size, is becoming increasingly recognized as important in the design of drug carriers for in vivo use. However, few methods exist for fabricating non-spherical particles from biodegradable polymers. This work describes for the first time the fabrication of biodegradable spheroidal microparticles using the simple oil-in-water emulsion solvent evaporation technique (O/W ESE). Unloaded and paclitaxel-loaded spheroids were fabricated from poly(lactic-co-glycolic acid) (PLGA), and the shape and size of fabricated spheroids were manipulated by controlling fabrication process parameters including stir speed, aqueous and oil phase viscosity, aqueous phase pH, and the polymer molecular weight and end group. The presented data show that high aqueous phase viscosity, basic aqueous phase pH and hydrophilic polymer side chains and end groups are all conditions that favor the formation of spheroidal particles. The described technique is advantageous over methods currently described in the literature in its simplicity in setup, high particle yield and adaptability to a wide range of biodegradable polymers and therapeutics.     

New biodegradable polymers for injectable drug delivery systems.

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.     

Branched biodegradable polyesters for parenteral drug delivery systems.

Continuous, 'infusion-like' drug release profiles from biodegradable parenteral delivery systems are difficult to achieve for proteins and other hydrophilic macromolecular drugs with commonly used linear polyesters from lactic acid (PLA) and its random copolymers with glycolic acid (PLG). Drug release rates can be modified either by increasing the hydrophilicity of polyesters or by manipulating the polymer architecture to adjust polymer degradation rates and thus drug release. Therefore, we investigated different branching concepts for biodegradable polyesters of PLA and PLG. For one four- and eight-arm poly(ethylene oxide)s (PEO) were grafted with shorter polyester chains leading to star-branched structures. Secondly we obtained comb-like polyesters using both charged and uncharged dextrans or poly(vinyl alcohol)s (PVA) as hydrophilic backbones. The star-shaped and brush-like grafted polymers were intensively characterized by methods, such as NMR, IR, SEC-SLS, DSC and viscosity measurements. Tailor-made properties make these novel biodegradable polyesters promising candidates for parenteral protein delivery systems. While the star-branched polyesters have shown some interesting properties with respect to their degradation behavior, retaining the PEO blocks longer than ABA triblock copolymers, their release properties need further optimization. Brush-like branched polyesters on the other hand seem to possess both degradation and release properties meriting further investigations for parenteral protein delivery systems.     

Evaluation of polyanion-coated biodegradable polymeric micelles as drug delivery vehicles

Polymeric micelles, as drug delivery vehicles, must achieve specific targeting and high stability in the body for efficient drug delivery. We recently reported the preparation of polyanion-coated biodegradable polymeric micelles by coating positively charged polymeric micelles consisting of poly(l-lysine)-block-poly(l-lactide) (PLys-b-PLLA) AB diblock copolymers with anionic hyaluronic acid (HA) by polyion complex (PIC) formation. The obtained HA-coated micelles showed significantly higher stability in aqueous solution. In this study, to evaluate the HA-coated polymeric micelles as a drug carrier, model drug release from the micelles and cytotoxicity of the micelles were investigated. The HA-coated micelles showed sustained release of model drugs and low cytotoxicity. It is known that there are receptors for HA on liver sinusoidal endothelial cells (LSEC). Specific interactions of HA-coated micelles with LSECs and Kupffer cells were investigated and compared with polymeric micelles coated with other polyanionic polysaccharides, i.e., heparin (Hep) and carboxymethyl-dextran (CMDex). Although Hep-coated micelles and CMDex-coated micelles were incorporated into both Kupffer cells and LSECs, HA-coated micelles were taken up only into LSECs. These results suggest HA-coated micelles have potential utility as drug delivery vehicles exhibiting specific accumulation into LSECs.     

Preparation, characterization and anticoagulation of curcumin-eluting controlled biodegradable coating stents.

Curcumin is pharmaceutically active in many ways, having properties including anticoagulation, anti-proliferation, anti-inflammatory, and may be used to fabricate drug-eluting stents to treat in-stent restenosis after stent implantation. Here we describe our investigations of curcumin-eluting PLGA coatings formed using the biodegradable polymer PLGA (polylactic acid-co-glycolic acid) as drug carrier and uniformly fabricated on the surface of 316L stainless steel stents by an ultrasonic spray method. Three doses were explored--low dose ( approximately 140 microg per stent or 115 microg/cm(2)), moderate dose ( approximately 280 microg per stent or 230 microg/cm(2)), and high dose ( approximately 490 microg per stent or 408 microg/cm(2)). Pre- and post-expansion morphologies of the stent coating were examined by optical microscopy (OM) and scanning electron microscopy (SEM), indicating that the coating not only was very smooth and uniform but also had the ability to withstand the compressive and tensile strains imparted without cracking from the stent during the expansion process. Atomic force microscopy (AFM) images indicated the topography of the PLGA-only and moderate dose curcumin-eluting stent that showed an average roughness below 1 nm; no drug particles could be seen on the stent surface, indicating that curcumin can be mixed with PLGA at the molecular level using an ultrasonic atomization spray method. The structure of the coating films was characterized by Fourier Transform Infrared (FTIR) spectroscopy and X-ray electron spectroscopy (XPS), with results suggesting that there was no chemical reaction between curcumin and the drug. The results of in vitro measurements of drug release from curcumin-eluting stents showed that all the curcumin-eluting stents studied exhibited a nearly linear sustained-release profile with no significant burst releases within the measurement period. The in vitro anticoagulation behavior of curcumin-eluting stents was investigated by static platelet adhesion and APTT (activated partial thromboplastin time) tests, revealing that the anticoagulation properties of curcumin-eluting stents are superior to those for stainless steel stents and PLGA-only-coated stents. The anticoagulation behavior of curcumin stents improved significantly as the drug dose was increased.     

可生物降解材料载药双层微球的制备方法及其应用

可生物降解载药双层微球是一种新型的控制药物释放的给药系统.它将药物与一种生物降解聚合物均匀混合形成内核心,另一种生物降解聚合物作为外壳材料包裹于微球外部,通过壳部聚合物的降解来控制药物的释放.双层微球可以在若干方面用来提高药物传递技术,如减小释药初期的"爆破效应", 用生物降解材料制备微球可迭零级释放动力学和脉冲给药方式.这种微球制备的新技术可能应用于药物或蛋白质传递领域中.文章从制备工艺、应用进展及目前存在的问题等几方面探讨了可生物降解双层微球的研究状况,显示双层微球给药系统在药物缓释领域有着广阔的应用前景.     

生物可降解性消化道支架的应用及其生物相容性

背景：生物可降解支架可在消化道管腔内短期成形,具有良好的生物相容性,随后完全降解,并可以根据临床需要调节支架降解时间,避免了永久性支架的并发症。目的：评价不同材料制成的生物可降解性消化道支架的应用、相容性评价以及研究进展。方法：以＂生物可降解,消化道,支架,相容性＂为关键词,采用电子检索方式在万方数据库中检索1999-01/2009-12有关生物可降解性消化道支架的研究。排除重复研究、普通综述或Meta分析类文章,筛选纳入22篇文献进行评价。结果与结论：可降解支架在消化道疾病中的应用已经显示其有效的扩张性及临床安全性等。可降解材料大多是高分子材料,包括天然可降解高分子、微生物合成高分子材料和合成可降解高分子3类。天然可降解高分子大多是多糖类。天然可降解高分子一般生物相容性良好,但是力学性能较差。微生物合成高分子材料目前研究及应用尚较少。合成高分子种类比较多,常见的有聚丙交酯、聚己内酯、聚乙二醇等。合成高分子优点在于可以比较灵活的设计分子结构,通过发展共聚物、共混物来得到不同性质的材料。可降解支架可以解决良恶性狭窄的再通及瘘口的封堵等,但可降解支架在消化道系统中应用的效力还需要未来进行大量的研究工作来评估。     

Non-vascular drug eluting stents as localized controlled drug delivery platform: Preclinical and clinical experience

Stents occupy an important place in the medical field for their widespread application. They have been used in vascular as well as in non-vascular organs for various reasons. Among vascular stents, development of coronary drug eluting stents (DESs) has completely revolutionised the percutaneous coronary intervention. Similarly, attempts have been made to make use of this modality in non-vascular organs. This paper focuses on the preclinical and clinical experience with drug-eluting non-vascular stents with emphasis on drug delivery systems and regulatory requirements for their development.     

生物可降解性消化道支架的应用及其生物相容性

背景:生物可降解支架可在消化道管腔内短期成形,具有良好的生物相容性,随后完全降解,并可以根据临床需要调节支架降解时间,避免了永久性支架的并发症。目的:评价不同材料制成的生物可降解性消化道支架的应用、相容性评价以及研究进展。方法:以"生物可降解,消化道,支架,相容性"为关键词,采用电子检索方式在万方数据库中检索1999-01/2009-12有关生物可降解性消化道支架的研究。排除重复研究、普通综述或Meta分析类文章,筛选纳入22篇文献进行评价。结果与结论:可降解支架在消化道疾病中的应用已经显示其有效的扩张性及临床安全性等。可降解材料大多是高分子材料,包括天然可降解高分子、微生物合成高分子材料和合成可降解高分子3类。天然可降解高分子大多是多糖类。天然可降解高分子一般生物相容性良好,但是力学性能较差。微生物合成高分子材料目前研究及应用尚较少。合成高分子种类比较多,常见的有聚丙交酯、聚己内酯、聚乙二醇等。合成高分子优点在于可以比较灵活的设计分子结构,通过发展共聚物、共混物来得到不同性质的材料。可降解支架可以解决良恶性狭窄的再通及瘘口的封堵等,但可降解支架在消化道系统中应用的效力还需要未来进行大量的研究工作来评估。     

Porous hydroxyapatite scaffold with three-dimensional localized drug delivery system using biodegradable microspheres

In this study, ionic immobilization of dexamethasone (DEX)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres was performed on the hydroxyapatite (HAp) scaffold surfaces. It was hypothesized that in vivo bone regeneration could be enhanced with HAp scaffolds containing DEX-loaded PLGA microspheres compared to the use of HAp scaffolds alone. In vitro drug release from the encapsulated microspheres was measured prior to the implantation in the femur defects of beagle dogs. It was observed that porous, interconnected HAp scaffolds as well as DEX-loaded PLGA microspheres were successfully fabricated in this study. Additionally, PEI was successfully coated on PLGA microsphere surfaces, resulting in a net positive-charged surface. With such modification of the PLGA microsphere surfaces, DEX-loaded PLGA microspheres were immobilized on the negatively charged HAp scaffold surfaces. Release profile of DEX over a 4 week immersion study indicated an initial burst release followed by a sustained release. In vivo evaluation of the defects filled with DEX-loaded HAp scaffolds indicated enhanced volume and quality of new bone formation when compared to defects that were either unfilled or filled with HAp scaffolds alone. This innovative platform for bioactive molecule delivery more potently induced osteogenesis in vivo, which may be exploited in implantable bone graft substitutes for stem cell therapy or improved in vivo performance. It was thus concluded that various bioactive molecules for bone regeneration might be efficiently incorporated with calcium phosphate-based bioceramics using biodegradable polymeric microspheres.