聚醚砜（PES）改性血液相容性材料的制备及相关生物学特性研究
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摘要
本文研究工作的目的是以聚醚砜(PES)为基材,采用整体肝素化方法开发研究用于与血液接触的器官制造及设备如人工心脏、透析膜等的生物材料,对材料的改性磺化、胺化、肝素化等制备过程与机制、材料的表征、材料的血液相容性及力学性能进行了较系统的研究。本研究首先以氯磺酸为磺化剂对聚醚砜(PES)进行磺化处理,选用直链二胺为空间臂,通过2-(N-吗啉代)乙烷磺酸(MES)和盐酸乙基-3-(二甲氨基丙基)碳二亚胺(EDC)的催化实现,磺酸基与二胺一端的氨基发生脱水缩合反应,将二胺固定在聚醚砜材料上,二胺另一端的氨基与肝素分子中的酯磺酸基或羧基又通过2-(N-吗啉代)乙烷磺酸(MES)和盐酸乙基-3-(二甲氨基丙基)碳二亚胺(EDC)的催化,再次发生脱水缩合反应,肝素被固定在聚醚砜上,从而得到肝素化的磺化聚醚砜材料。由于聚醚砜分子中每一个苯环上都连着强吸电子性能的砜基(-SO2-),砜基使相邻的苯环钝化,从而使亲电取代的磺化变得异常困难,仅有反应活性很高的亲电试剂才能做为它的磺化剂,只有成功地对本来化学性质呈惰性的聚醚砜活化后,才能对其进行下一步的改性。实验研究了聚醚砜的磺化过程中各影响因素。对用氯磺酸为磺化剂,浓硫酸为溶剂磺化过程中的磺化时间、反应温度、搅拌速度和氯磺酸与聚醚砜的摩尔比等因素进行了探讨,发现低温下磺化效果较好,用浓硫酸作溶剂,由于反应体系接近为均相,故可得到均匀的磺化产物。同时通过改变氯磺酸与聚醚砜的摩尔比,可以对反应进行控制。得到最佳的反应参数为:10℃、800rpm、磺化时间2小时。在低温脱水剂2-(N-吗啉代)乙烷磺酸和盐酸乙基-3-(二甲氨基丙基)碳二亚胺的催化作用下,在室温、300rpm、反应3小时,实现了磺化聚醚砜接枝胺化。由于磺化、胺化、肝素化三过程是一个连串的相互影响的复杂过程,综合考虑以上三个步骤的影响,进行了正交实验,实验结果表明,磺化和胺化的交互作用和胺化对材料抗凝血性能影响最大,通过分析可得最佳工艺条件为:磺化过程磺化度为10%、胺化过程二胺的分子量为200、肝素化过程氨基摩尔比100%。
磺化、胺化、肝素化三过程是否成功,磺酸基团是否成功地连接在实验方案设计的基团位置,二胺“空间臂”分布是否均匀,肝素在材料表面的分布均匀性和牢固性如何,本研究采用红外光谱、扫描电子显微镜和荧光分析方法结合游离肝素分析对制备的材料进行了表征和分析。结果表明,通过在磺化PES表面链接重氮盐的荧光分析方法确定了PES磺化的均匀性,磺酸基是非常均匀地分布在基材PES的表面,该方法对指导和控制磺化度具有重要意义。红外光谱的分析结果显示,最初分子设计路线与实验结果一致,通过磺化、胺化及肝素化过程制备整体肝素化聚醚砜
材料可保持肝素结构原有特性, 肝素未遭到破坏,仍维持其原来的成分和结构,从而保持肝素的抗凝血活性。通过甲苯胺蓝与肝素结合后,其在632nm处出现最大吸收峰的方法检测胺化PES表面接入肝素的量,实验材料的肝素含量为:65mg/g。除去游离肝素的质量,实际固定的量为58.365mg/g,根据表面积计算为5.8mg/cm2,材料达到了作为抗凝血肝素化表面的要求。
制备的肝素化磺化聚醚砜材料是在与血液接触环境中使用,因此,材料的血液相容性性能评价显得尤为重要。本研究选择了合成的肝素化磺化聚醚砜材料,聚醚氨酯、聚醚砜材料和亲水接枝的聚乙烯GAMBRO和FRESENIUS材料进行了血液相容性实验评价及比较研究。生物材料与血液或机体内环境接触首先发生的现象就是蛋白质的吸附。生物材料表面性能会对蛋白吸附层的成分和构象等性能产生影响。实验结果显示,表面亲水性的提高可以减少血浆总蛋白的吸附量,提高白蛋白的吸附比例,减少球蛋白的吸附,肝素化比提高表面亲水性的方法更有利于减少蛋白的吸附和提高白蛋白吸附的比例。通过扫描电镜结果分析表明,聚醚砜在肝素化前后有显著的区别,亲水性较好的聚氨酯明显比聚醚砜吸附有较多的白蛋白,两种亲水接枝的聚乙烯GAMBRO和FRESENIUS又比前两者有更多的吸附量。聚醚砜在未肝素化前引起了白蛋白的某些变化,出现絮凝状和网状凝聚蛋白,肝素化后吸附的蛋白分散非常的均匀,表面光滑,表明肝素的海藻状结构起到了作用。
材料表面与血液接触时吸附血浆蛋白的种类与血小板贴壁的数量密切相关,表面吸附了白蛋白可减少血小板的贴壁,表面吸附球蛋白,若主要是纤维蛋白原及Y一球蛋白(以IgG为主)时,将发生大量的血小板粘附在吸附球蛋白的材科表面粘附、聚集。我们的实验也验证了这一观点。研究显示,血浆蛋白吸附最多的整体肝素化聚醚砜血小板的黏附量比本体材料减少了55%,达到19×109/L;比GAMBRO和FRESENIUS两种亲水性改性聚乙烯减少了23%。显微观察表明,聚醚砜表面血小板聚集成絮状,而整体肝素化聚醚砜表面清晰,未有可见异物。血小板的计数,也为这一现象提供数量上证据。对五种材料血小板黏附的研究发现,材料表面亲水性的提高可以减少血小板的黏附,肝素化对减少血小板的黏附有更大的帮助。复钙实验研究显示GAMBRO和FRESENIUS两种经过表面亲水性改性的聚乙烯,由于亲水性的提高,对凝血因子的激活有延缓的作用,因而表现出复钙时间比空白延长。从复钙时间来看,全身肝素化聚醚砜超过7分钟,是本体材料的3倍多,而且含有肝素的材料引?
In this study, we use polyethersulfone(PES) as basic material to develop a biomaterials ,which can make artificial organs and equipments such as artificial heart,dialyzer and so no. The main research target is to study the process and technics of sulfonated, aminated and heparinized , biocompatibility and material’s mechanical property.
The principles and methods of organic synthesis were applied for heparinizating PES wholly. After sulfonated, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid served as condensation reagent ,1,30-Hexanediamine was connected noto PES. And then 1,30-Hexanediamine served as space arm, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid as condensation reagent too,thus heparin was linked to the PES materials modified by sulfonation via covalent bond . Because each benzene in PES molecule connects a sulfonyl(-so2-), which has the strong ability to attract electrons and deactivates the benzene.It is very difficult to sulfonate PES by electrophilic aromatic substitution reaction.Thus, sulfonated agent must have high reactivity and reation conditions affect on sulfonating process much.In our experiment, some factors such as reacting temperature, reacting time, stirring velocity and mole ratio of chlorosulfonic acid and PES, had been studied. The real reaction indicated that it is more suitable for sulfonating reaction in low temperature, dissolved by vitriol would make reacting system more symmetrical, controlling the relation of the sulfonated degree and the mole ratio of chlorosulfonic acid and PES it’s likely to control the mole ratio to get proper products. Polyethersulfone (PES) was activated by chlorosulfonic acid as sulfonated agent in 10℃ reacting temperature, 2 hours reacting time and 800rpm stirring rate. After that, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid served as condensation reagent , in 300rpm, 25℃ reacting temperature, 3 hours, 1,30-Hexanediamine was connected noto PES. Because sulfonated process, aminated process and heparinized process are consecutive and complex courses.For studying these 3 process, we designed a perpendicular experiment. It indecates that interaction of sulfonated process and aminated process and different hexanediamine affected the whole process the most greatly. The best processing condition is that: sulfonated degree is 10%,
hexanediamine molecular weight is 200 and amido mole ratio is 1:1 in heparinized process.
For proving above 3 process had been made, we used ultraviolet spectroscopy analysis, scan electron microscope and fluorescence analysis to characterize. In fluorescence analysis,diazonium salt was connect onto sulfonated PES surface. And then through fluorescence microscope, we foung that sulfonic group is well-proportioned. It is very important to using this method to guide the sulfonated process. By ultraviolet spectroscopy analysis, it showed that experimental result is concurrent with origenal synthesis route. After sulfonated process, aminated process and heparinized process, heparin keeped initial structure and activity didn’t changed.In coloring determination with toluidine quantitatively, the heparin content was 58.365mg/g.According suface caculation,the heparin content was 5.8mg/cm2.It reach the standard of heparinized anticoagulate biomaterials.
It’s important to evaluate biocompatibility of materials, because heparinized PES will contact with blood. In our research, we choose PEU, PES, GAMBRO and FRESENIUS hemodialysis vessel as contrast materials. When materials contact with blood, plasma protein adsorption is occured at first. Ingredient and structure of adsorbed layer deside the performance. In our experient, we found that improving surface hydrophilicity can decrease the quantity of plasma protein adsorption, increase the ratio of white protein in total plasma protein and reduce ball protein adsorption. But heparinized materials wer
磺化、胺化、肝素化三过程是否成功,磺酸基团是否成功地连接在实验方案设计的基团位置,二胺“空间臂”分布是否均匀,肝素在材料表面的分布均匀性和牢固性如何,本研究采用红外光谱、扫描电子显微镜和荧光分析方法结合游离肝素分析对制备的材料进行了表征和分析。结果表明,通过在磺化PES表面链接重氮盐的荧光分析方法确定了PES磺化的均匀性,磺酸基是非常均匀地分布在基材PES的表面,该方法对指导和控制磺化度具有重要意义。红外光谱的分析结果显示,最初分子设计路线与实验结果一致,通过磺化、胺化及肝素化过程制备整体肝素化聚醚砜
材料可保持肝素结构原有特性, 肝素未遭到破坏,仍维持其原来的成分和结构,从而保持肝素的抗凝血活性。通过甲苯胺蓝与肝素结合后,其在632nm处出现最大吸收峰的方法检测胺化PES表面接入肝素的量,实验材料的肝素含量为:65mg/g。除去游离肝素的质量,实际固定的量为58.365mg/g,根据表面积计算为5.8mg/cm2,材料达到了作为抗凝血肝素化表面的要求。
制备的肝素化磺化聚醚砜材料是在与血液接触环境中使用,因此,材料的血液相容性性能评价显得尤为重要。本研究选择了合成的肝素化磺化聚醚砜材料,聚醚氨酯、聚醚砜材料和亲水接枝的聚乙烯GAMBRO和FRESENIUS材料进行了血液相容性实验评价及比较研究。生物材料与血液或机体内环境接触首先发生的现象就是蛋白质的吸附。生物材料表面性能会对蛋白吸附层的成分和构象等性能产生影响。实验结果显示,表面亲水性的提高可以减少血浆总蛋白的吸附量,提高白蛋白的吸附比例,减少球蛋白的吸附,肝素化比提高表面亲水性的方法更有利于减少蛋白的吸附和提高白蛋白吸附的比例。通过扫描电镜结果分析表明,聚醚砜在肝素化前后有显著的区别,亲水性较好的聚氨酯明显比聚醚砜吸附有较多的白蛋白,两种亲水接枝的聚乙烯GAMBRO和FRESENIUS又比前两者有更多的吸附量。聚醚砜在未肝素化前引起了白蛋白的某些变化,出现絮凝状和网状凝聚蛋白,肝素化后吸附的蛋白分散非常的均匀,表面光滑,表明肝素的海藻状结构起到了作用。
材料表面与血液接触时吸附血浆蛋白的种类与血小板贴壁的数量密切相关,表面吸附了白蛋白可减少血小板的贴壁,表面吸附球蛋白,若主要是纤维蛋白原及Y一球蛋白(以IgG为主)时,将发生大量的血小板粘附在吸附球蛋白的材科表面粘附、聚集。我们的实验也验证了这一观点。研究显示,血浆蛋白吸附最多的整体肝素化聚醚砜血小板的黏附量比本体材料减少了55%,达到19×109/L;比GAMBRO和FRESENIUS两种亲水性改性聚乙烯减少了23%。显微观察表明,聚醚砜表面血小板聚集成絮状,而整体肝素化聚醚砜表面清晰,未有可见异物。血小板的计数,也为这一现象提供数量上证据。对五种材料血小板黏附的研究发现,材料表面亲水性的提高可以减少血小板的黏附,肝素化对减少血小板的黏附有更大的帮助。复钙实验研究显示GAMBRO和FRESENIUS两种经过表面亲水性改性的聚乙烯,由于亲水性的提高,对凝血因子的激活有延缓的作用,因而表现出复钙时间比空白延长。从复钙时间来看,全身肝素化聚醚砜超过7分钟,是本体材料的3倍多,而且含有肝素的材料引?
In this study, we use polyethersulfone(PES) as basic material to develop a biomaterials ,which can make artificial organs and equipments such as artificial heart,dialyzer and so no. The main research target is to study the process and technics of sulfonated, aminated and heparinized , biocompatibility and material’s mechanical property.
The principles and methods of organic synthesis were applied for heparinizating PES wholly. After sulfonated, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid served as condensation reagent ,1,30-Hexanediamine was connected noto PES. And then 1,30-Hexanediamine served as space arm, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid as condensation reagent too,thus heparin was linked to the PES materials modified by sulfonation via covalent bond . Because each benzene in PES molecule connects a sulfonyl(-so2-), which has the strong ability to attract electrons and deactivates the benzene.It is very difficult to sulfonate PES by electrophilic aromatic substitution reaction.Thus, sulfonated agent must have high reactivity and reation conditions affect on sulfonating process much.In our experiment, some factors such as reacting temperature, reacting time, stirring velocity and mole ratio of chlorosulfonic acid and PES, had been studied. The real reaction indicated that it is more suitable for sulfonating reaction in low temperature, dissolved by vitriol would make reacting system more symmetrical, controlling the relation of the sulfonated degree and the mole ratio of chlorosulfonic acid and PES it’s likely to control the mole ratio to get proper products. Polyethersulfone (PES) was activated by chlorosulfonic acid as sulfonated agent in 10℃ reacting temperature, 2 hours reacting time and 800rpm stirring rate. After that, 2-Morpholinoethanesulfoni acid monohydrate and N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimidhydrochlorid served as condensation reagent , in 300rpm, 25℃ reacting temperature, 3 hours, 1,30-Hexanediamine was connected noto PES. Because sulfonated process, aminated process and heparinized process are consecutive and complex courses.For studying these 3 process, we designed a perpendicular experiment. It indecates that interaction of sulfonated process and aminated process and different hexanediamine affected the whole process the most greatly. The best processing condition is that: sulfonated degree is 10%,
hexanediamine molecular weight is 200 and amido mole ratio is 1:1 in heparinized process.
For proving above 3 process had been made, we used ultraviolet spectroscopy analysis, scan electron microscope and fluorescence analysis to characterize. In fluorescence analysis,diazonium salt was connect onto sulfonated PES surface. And then through fluorescence microscope, we foung that sulfonic group is well-proportioned. It is very important to using this method to guide the sulfonated process. By ultraviolet spectroscopy analysis, it showed that experimental result is concurrent with origenal synthesis route. After sulfonated process, aminated process and heparinized process, heparin keeped initial structure and activity didn’t changed.In coloring determination with toluidine quantitatively, the heparin content was 58.365mg/g.According suface caculation,the heparin content was 5.8mg/cm2.It reach the standard of heparinized anticoagulate biomaterials.
It’s important to evaluate biocompatibility of materials, because heparinized PES will contact with blood. In our research, we choose PEU, PES, GAMBRO and FRESENIUS hemodialysis vessel as contrast materials. When materials contact with blood, plasma protein adsorption is occured at first. Ingredient and structure of adsorbed layer deside the performance. In our experient, we found that improving surface hydrophilicity can decrease the quantity of plasma protein adsorption, increase the ratio of white protein in total plasma protein and reduce ball protein adsorption. But heparinized materials wer
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