药物洗脱支架聚合物涂层的设计、制备与评价
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摘要
动脉粥样硬化导致的各种缺血性疾病已经严重威胁人类的健康,而经皮腔内成形术及支架植入术是治疗血管管腔狭窄的重要手段。由于金属裸支架植入人体后容易诱发急性血栓和血管内再狭窄,因此人们在传统金属支架的基础上发展了药物洗脱支架。药物洗脱支架及其相关的涂层制备与药物控制释放技术囊括了材料学、医学、药剂学、生物学、力学以及高分子化学等各个领域的知识,使之成为一种具有高技术含量的产品。本论文针对药物洗脱支架的涂层设计、制备及评价,对非降解与可降解涂层的物理化学性能、药物释放动力学以及多孔表面等问题进行了研究,并且利用计算软件MATLAB编程以蒙特卡洛法对可降解体系的失重特性与药物释放动力学进行分析与优化。论文的主要内容与结果包括:
1.深入研究了雷帕霉素与药物载体丙烯酸树脂或聚乳酸-乙醇酸(PLGA)之间的相互作用。雷帕霉素是一种抗增生型药物,丙烯酸树脂是一种通用的非降解型医用高分子材料,而PLGA是一种常用的可降解医用高分子材料。实验结果表明药物-载体共混体系中药物与载体的混合并没有发生化学作用,峰值强度为两种成分的叠加,而雷帕霉素在PLGA中具有更高的饱和溶解度,热稳定性也是雷帕霉素-PLGA共混体系更好。纯雷帕霉素是多晶粉末,但是载体会抑制雷帕霉素的结晶,因此两种共混体系均无明显的晶体峰。
2.使用硅烷偶联剂γ-氨丙基三乙氧基硅烷(γ-APS)处理316L不锈钢样品,这种处理方法使基体表面活化并使聚合物溶液有效铺展,从而提高PLGA涂层与基体的结合力。此外γ-APS层对不锈钢表面具有早期保护作用,可以避免因基体腐蚀造成的结合力下降。
3.使用蒙特卡洛法对PLGA膜的降解特性进行模拟与分析,结果表明这种方法对本体溶蚀材料进行比较准确的预测。PLGA材料的降解与溶蚀过程大致分成四个阶段:Ⅰ——初期快速失重阶段,Ⅱ——准稳定阶段,Ⅲ——快速失重阶段,Ⅳ——材料崩解阶段,而闭合降解区的积累与数量下降决定了阶段Ⅲ的开始与结束的时间,通过控制闭合降解区的变化状态可以控制PLGA膜的失重速率。
4.分析与对比了共混膜与梯度膜的降解特性。共混膜的性能介于两种初始成分之间,可以通过调整两种PLGA的比例来调节材料的降解特性,实现“定时失重”。梯度膜由两种不同共聚物组成的PLGA按不同配比进行层层叠加得到的,这样得到的不均匀成分分布可以改善PLGA膜的降解性能。当降解速度相对较快的PLGA(如PLGA50/50)的含量在多层结构由外至内梯度下降时,可以得到比较平稳的失重曲线。
5.对丙烯酸树脂与PLGA含药膜的药物释放动力学进行了测试和数值模拟。非降解的丙烯酸树脂含药膜基本符合Higuchi模型,但是常数项的存在使药物释放曲线偏离标准的Higuchi模型。对于可降解PLGA含药体系,基体降解使药物扩散系数发生极大变化,导致药物释放过程更加复杂。通过建立蒙特卡洛-扩散复合模型,并根据计算结果求解扩散系数,并使其成为位置与时间的函数。计算结果表明该法的计算结果优于Higuchi模型,与实验结果符合得很好。丙烯酸树脂与PLGA这两种载体进行对比,在其他条件相同时,雷帕霉素在PLGA中的释放速率更快。
6.利用相转化法在316L不锈钢表面制备PU和PLGA多孔涂层,并且通过改变溶液的浓度与环境的湿度来控制孔径。聚合物多孔涂层的孔径大体与溶液的浓度成正比,与环境湿度成反比。低浓度高湿度条件下PU溶液倾向于形成孔中有孔的结构,而提高溶液浓度可以有效降低这种现象的发生几率。对于PLGA涂层,由于其成孔性能比PU差,湿度较低时容易出现岛状结构。接触角实验结果表明多孔涂层具有强疏水性,而血小板粘附实验的观测结果表明,由于多孔涂层的强疏水性会导致血小板在材料表面的结合能下降,多孔涂层表面粘附血小板的数量最少,而且血小板的形态无显著变化,使多孔涂层具有良好的血液相容性。
Ischemic diseases induced by atherosclerosis are severe threats to mankind's health,and percutaneous stem implantation is an important method to deal with vascular stenosis. Because bare metal stems tend to induce acute thrombosis and in-steM restenosis, drug-eluting stents have been developed based on those traditional metal stents.Drug-eluting stents and correlated coating preparation and controlled drug release technology consist of the knowledge in materials,medicine,pharmacy,biology,mechanics and high polymer chemistry, and these stents are real high-technology products.To study the coating design,preparation and evaluation of drug-eluting stents,physical and chemical properties,drug release kinetics and porous surfaces for both non-degradable and degradable coatings are researched in this paper,furthermore,computing software MATLAB and Monte Carlo method are applied for the analysis and optimization of degradation properties and drug release kinetics for degradable system.The paper includes the following content:
1.The interaction between sirolimus and drug carrier(acrylate resin or poly (lactic-co-glycolic acid)(PLGA)) was thoroughly researched.Sirolimus is a kind of anti-proliferation drug,and acrylate resin is a kind of universal non-degradable biomaterial, moreover,PLGA is a kind of biodegradable medical polymer.For the blend system of drug and carrier,the results of experiment indicated no chemical reaction happened between them, and the peak intensity is only the sum of two componems.Furthermore,sirolimus had higher solubility in PLGA system than that in acrylic resin system,and the PLGA system also had better thermal stability than acrylic resin system.Pure sirolimus is in a state of polycrystalline powder,while carrier will inhibit the crystallization of sirolimus,and the blends showed no obovious crystal peak.
2.316L stainless steel samples were treated uing a kind of silane coupling agent namedγ-aminopropyltriethoxysilane(γ-APS) to active the substrate surface,and this treatment made casting solution spread effectively and enhanced the adherence between coating and substrate. In addition,γ-APS layer can provide early protection of the stainless steel substrate,and avoid adherence decrease due to substrate corrosion.
3.The degradation properties of PLGA coatings were simulated and analyzed using Monte Carlo method and the results indicated this method could be used to predict the degradation properties of bulk erosion materials.The degradation and erosion of PLGA could be divided into four stages:Ⅰ—early mass loss stage,Ⅱ—quasi-stable stage,Ⅲ—fast mass loss stage,Ⅳ—breakdown stage,and the accumulation and vanishing of closed and degradated regions controlled the occurring and ending time of stageⅢ.The degradation properties of PLGA coatings could be controlled by operating the transformation of closed and degradated regions and "controlled mass loss" will achieve.
4.The degradation properties of blend film and gradient film were analyzed and contrasted with each other.A blend film had balanced degradation property between two original components,and by adjusting the ratio of two components the degradation property of the blend could be easily controlled and "time mass loss" was achieved.A gradient film could be obtained by different ratio of two components in each sublayer,and this non-uniform structure could improve the degradation property of PLGA coating,when PLGA with higher degradation rate such as PLGA50/50 was distributed gradually from outer to inner part of matrix,stable mass loss curve could be obtained.
5.The drug release kinetics of acrylic resin and PLGA drug contained coatings were tested and numerically simulated.The release curves of non-degradable acrylic resin coatings almost fit Higuchi's model,while the existence of constant part made the curves deviate the standard Higuchi's model.For the degradable drug contained PLGA system,the drug diffusion coefficient was critically changed due to matrix degradation,and that would complicate the drug release process.The drug diffusion coefficient was considered as the function of distance and time,and calculated using Monte Carlo-diffusion combined model in this paper.The calculating result indicates that the result of above method is better than that of Higuchi's model,and it fit the experiment data well.To contrast the acrylic resin and PLGA,sirolimus tends to diffuse faster in PLGA systerm under the same condition.
6.Polyurethane(PU) and PLGA porous coatings by phase inversion method were obtained on the surface of 316L stainless steel,and the pore diameter was controlled by alternating casting solution concentration and atmospheric humidity.It was observed that pore diameter increased with the increase of casting solution concentration and the decrease of atmospheric humidity.PU casting solution tended to form pore-in-pore structure under under the condition of low solution concentration and high atmospheric humidity,and the probability of this phenomenon could be effectively decreased by increasing solution concentration.For PLGA coatings,island structure appeared under the condition of low atmospheric humidity due to the worse ability of pore formation than PU.The contact angle experiment showed strong hydrophobicity of porous coatings,and platelet adhesion experiment indicated that strong hydrophobicity resulted in the decrease of binding energy between platelets and coating surfaces.The surfaces of porous coatings had the least amount of platelets,and there was no significant change on the morphology of platelets.All of above factors make PU porous coatings achieve excellent blood compatibility.
1.深入研究了雷帕霉素与药物载体丙烯酸树脂或聚乳酸-乙醇酸(PLGA)之间的相互作用。雷帕霉素是一种抗增生型药物,丙烯酸树脂是一种通用的非降解型医用高分子材料,而PLGA是一种常用的可降解医用高分子材料。实验结果表明药物-载体共混体系中药物与载体的混合并没有发生化学作用,峰值强度为两种成分的叠加,而雷帕霉素在PLGA中具有更高的饱和溶解度,热稳定性也是雷帕霉素-PLGA共混体系更好。纯雷帕霉素是多晶粉末,但是载体会抑制雷帕霉素的结晶,因此两种共混体系均无明显的晶体峰。
2.使用硅烷偶联剂γ-氨丙基三乙氧基硅烷(γ-APS)处理316L不锈钢样品,这种处理方法使基体表面活化并使聚合物溶液有效铺展,从而提高PLGA涂层与基体的结合力。此外γ-APS层对不锈钢表面具有早期保护作用,可以避免因基体腐蚀造成的结合力下降。
3.使用蒙特卡洛法对PLGA膜的降解特性进行模拟与分析,结果表明这种方法对本体溶蚀材料进行比较准确的预测。PLGA材料的降解与溶蚀过程大致分成四个阶段:Ⅰ——初期快速失重阶段,Ⅱ——准稳定阶段,Ⅲ——快速失重阶段,Ⅳ——材料崩解阶段,而闭合降解区的积累与数量下降决定了阶段Ⅲ的开始与结束的时间,通过控制闭合降解区的变化状态可以控制PLGA膜的失重速率。
4.分析与对比了共混膜与梯度膜的降解特性。共混膜的性能介于两种初始成分之间,可以通过调整两种PLGA的比例来调节材料的降解特性,实现“定时失重”。梯度膜由两种不同共聚物组成的PLGA按不同配比进行层层叠加得到的,这样得到的不均匀成分分布可以改善PLGA膜的降解性能。当降解速度相对较快的PLGA(如PLGA50/50)的含量在多层结构由外至内梯度下降时,可以得到比较平稳的失重曲线。
5.对丙烯酸树脂与PLGA含药膜的药物释放动力学进行了测试和数值模拟。非降解的丙烯酸树脂含药膜基本符合Higuchi模型,但是常数项的存在使药物释放曲线偏离标准的Higuchi模型。对于可降解PLGA含药体系,基体降解使药物扩散系数发生极大变化,导致药物释放过程更加复杂。通过建立蒙特卡洛-扩散复合模型,并根据计算结果求解扩散系数,并使其成为位置与时间的函数。计算结果表明该法的计算结果优于Higuchi模型,与实验结果符合得很好。丙烯酸树脂与PLGA这两种载体进行对比,在其他条件相同时,雷帕霉素在PLGA中的释放速率更快。
6.利用相转化法在316L不锈钢表面制备PU和PLGA多孔涂层,并且通过改变溶液的浓度与环境的湿度来控制孔径。聚合物多孔涂层的孔径大体与溶液的浓度成正比,与环境湿度成反比。低浓度高湿度条件下PU溶液倾向于形成孔中有孔的结构,而提高溶液浓度可以有效降低这种现象的发生几率。对于PLGA涂层,由于其成孔性能比PU差,湿度较低时容易出现岛状结构。接触角实验结果表明多孔涂层具有强疏水性,而血小板粘附实验的观测结果表明,由于多孔涂层的强疏水性会导致血小板在材料表面的结合能下降,多孔涂层表面粘附血小板的数量最少,而且血小板的形态无显著变化,使多孔涂层具有良好的血液相容性。
Ischemic diseases induced by atherosclerosis are severe threats to mankind's health,and percutaneous stem implantation is an important method to deal with vascular stenosis. Because bare metal stems tend to induce acute thrombosis and in-steM restenosis, drug-eluting stents have been developed based on those traditional metal stents.Drug-eluting stents and correlated coating preparation and controlled drug release technology consist of the knowledge in materials,medicine,pharmacy,biology,mechanics and high polymer chemistry, and these stents are real high-technology products.To study the coating design,preparation and evaluation of drug-eluting stents,physical and chemical properties,drug release kinetics and porous surfaces for both non-degradable and degradable coatings are researched in this paper,furthermore,computing software MATLAB and Monte Carlo method are applied for the analysis and optimization of degradation properties and drug release kinetics for degradable system.The paper includes the following content:
1.The interaction between sirolimus and drug carrier(acrylate resin or poly (lactic-co-glycolic acid)(PLGA)) was thoroughly researched.Sirolimus is a kind of anti-proliferation drug,and acrylate resin is a kind of universal non-degradable biomaterial, moreover,PLGA is a kind of biodegradable medical polymer.For the blend system of drug and carrier,the results of experiment indicated no chemical reaction happened between them, and the peak intensity is only the sum of two componems.Furthermore,sirolimus had higher solubility in PLGA system than that in acrylic resin system,and the PLGA system also had better thermal stability than acrylic resin system.Pure sirolimus is in a state of polycrystalline powder,while carrier will inhibit the crystallization of sirolimus,and the blends showed no obovious crystal peak.
2.316L stainless steel samples were treated uing a kind of silane coupling agent namedγ-aminopropyltriethoxysilane(γ-APS) to active the substrate surface,and this treatment made casting solution spread effectively and enhanced the adherence between coating and substrate. In addition,γ-APS layer can provide early protection of the stainless steel substrate,and avoid adherence decrease due to substrate corrosion.
3.The degradation properties of PLGA coatings were simulated and analyzed using Monte Carlo method and the results indicated this method could be used to predict the degradation properties of bulk erosion materials.The degradation and erosion of PLGA could be divided into four stages:Ⅰ—early mass loss stage,Ⅱ—quasi-stable stage,Ⅲ—fast mass loss stage,Ⅳ—breakdown stage,and the accumulation and vanishing of closed and degradated regions controlled the occurring and ending time of stageⅢ.The degradation properties of PLGA coatings could be controlled by operating the transformation of closed and degradated regions and "controlled mass loss" will achieve.
4.The degradation properties of blend film and gradient film were analyzed and contrasted with each other.A blend film had balanced degradation property between two original components,and by adjusting the ratio of two components the degradation property of the blend could be easily controlled and "time mass loss" was achieved.A gradient film could be obtained by different ratio of two components in each sublayer,and this non-uniform structure could improve the degradation property of PLGA coating,when PLGA with higher degradation rate such as PLGA50/50 was distributed gradually from outer to inner part of matrix,stable mass loss curve could be obtained.
5.The drug release kinetics of acrylic resin and PLGA drug contained coatings were tested and numerically simulated.The release curves of non-degradable acrylic resin coatings almost fit Higuchi's model,while the existence of constant part made the curves deviate the standard Higuchi's model.For the degradable drug contained PLGA system,the drug diffusion coefficient was critically changed due to matrix degradation,and that would complicate the drug release process.The drug diffusion coefficient was considered as the function of distance and time,and calculated using Monte Carlo-diffusion combined model in this paper.The calculating result indicates that the result of above method is better than that of Higuchi's model,and it fit the experiment data well.To contrast the acrylic resin and PLGA,sirolimus tends to diffuse faster in PLGA systerm under the same condition.
6.Polyurethane(PU) and PLGA porous coatings by phase inversion method were obtained on the surface of 316L stainless steel,and the pore diameter was controlled by alternating casting solution concentration and atmospheric humidity.It was observed that pore diameter increased with the increase of casting solution concentration and the decrease of atmospheric humidity.PU casting solution tended to form pore-in-pore structure under under the condition of low solution concentration and high atmospheric humidity,and the probability of this phenomenon could be effectively decreased by increasing solution concentration.For PLGA coatings,island structure appeared under the condition of low atmospheric humidity due to the worse ability of pore formation than PU.The contact angle experiment showed strong hydrophobicity of porous coatings,and platelet adhesion experiment indicated that strong hydrophobicity resulted in the decrease of binding energy between platelets and coating surfaces.The surfaces of porous coatings had the least amount of platelets,and there was no significant change on the morphology of platelets.All of above factors make PU porous coatings achieve excellent blood compatibility.
引文
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