交联壳聚糖表面仿细胞膜结构改性
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摘要
胆红素是血红蛋白的降解产物,当肝脏组织受到损伤或发生病变时,会导致血液中游离胆红素含量增高,人体无法依靠自身代谢排除过高浓度的胆红素。过高浓度的胆红素可以对机体产生严重的神经毒性作用,使胃肠道、脾、肾、性腺、骨髓和呼吸道粘膜等处出现渐进性坏死。其中,未结合胆红素的毒性尤其明显,出现高未结合胆红素血症。对于高胆红素症,通过吸附作用直接从血液中吸附过量的胆红素的血液灌流法是最具吸引力的体外血液净化疗法。这就要求吸附剂具有较好的吸附性能和良好的血液相容性,并且制备容易,成本较低。而通常所用的吸附材料存在着血液相容性较差的问题,如材料表面发生蛋白质的吸附和血小板的黏附聚集,临床上难以达到满意的效果。本论文以壳聚糖为原料,用二氯磷酰胆碱对壳聚糖表面进行改性得到了一种新型的吸附树脂,对改性过程和改性后的性能进行了较系统的研究。本论文主要的研究内容有以下几个方面:
     (1)在无水条件下通过一步法合成了二氯磷酰胆碱。通过对投料方式和反应配比的研究发现,增加三氯氧磷的投料量,可以显著提高目标产物的含量。同时采用抽气法对产物进行处理,能够进一步的提高产物含量。用改进的磷酸电位滴定法对产物中二氯磷酰胆碱的含量进行了分析,结果表明当三氯氧磷与氯化胆碱按照3∶1的比例投料时,二氯磷酰胆碱的含量可达88%,再将该产物进行抽气处理后二氯磷酰胆碱的含量可增加至96%。
     (2)用戊二醛对壳聚糖进行交联,制得交联壳聚糖膜。X射线光电子能谱(XPS)、衰减全反射红外光谱(ATR-FTIR)的结果表明壳聚糖成功发生交联,交联度约为17%,同时还确定了实验中所用壳聚糖的脱乙酰度约为92%。在氯仿介质中将二氯磷酰胆碱接枝到交联壳聚糖膜的表面,通过X射线光电子能谱(XPS)、衰减全反射红外光谱(ATR-FTIR)和动态接触角(DCA)等方法对改性后交联壳聚糖膜表面磷酰胆碱基团的接枝率以及亲水性变化进行了分析。ATR-FTIR和DCA的测试结果表明了改性反应的成功,根据XPS的测试数据估算出了改性材料表面磷酰胆碱的接枝率为28%。血小板黏附实验说明了血小板在交联壳聚糖膜表面产生了激活、凝聚。相比之下,在磷酰胆碱改性交联壳聚糖膜表面黏附的血小板基本保持2~4μm的原始尺寸,这表明血小板未发生激活和凝聚。蛋白质吸附试验表明牛血清白蛋白(BSA)在交联壳聚糖表面的吸附量为0.74μg/cm~2,而在磷酰胆碱基团改性的交联壳聚糖表面的吸附量为0.21μg/cm~2。该结果表明交联壳聚糖表面接枝磷酰胆碱基团后,BSA的吸附量减少了72%。纤维蛋白原(Fg)在交联壳聚糖表面的吸附量为0.87μg/cm~2,而在磷酰胆碱基团改性的交联壳聚糖表面的吸附量为0.35μg/cm~2,交联壳聚糖表面接枝磷酰胆碱基团后Fg的吸附量减少了60%。血小板黏附和蛋白质吸附实验结果表明,表面接枝磷酰胆碱基团可以显著提高交联壳聚糖膜的血液相容性。
     (3)采用乳化交联法制备了交联壳聚糖微球,在氯仿介质中用二氯磷酰胆碱制备了改性交联壳聚糖微球。红外光谱结果表明,在2950 cm~(-1)出现了明显的亚甲基伸缩振动峰,同时在1646 cm~(-1)处出现了Schiff碱中-C=N的特征吸收峰,证明了交联反应的完成。与交联壳聚糖微球相比,磷酰胆碱基团改性交联壳聚糖微球在1475 cm~(-1)处的峰明显增强,这是由于磷酰胆碱(PC)基团中N~+(CH_3)_3上的-CH_3所造成的,这说明,改性过程的成功。同时扫描电镜结果显示交联壳聚糖微球的粒径约为100μm,改性前后交联壳聚糖微球的大小和表面形貌未发生明显变化,说明改性过程未改变交联壳聚糖微球的表面形貌。蛋白吸附实验显示,改性前后的树脂微球对BSA的吸附量随吸附时间的增加而增加;相同吸附时间下,磷酰胆碱改性交联壳聚糖微球对BSA的吸附容量明显低于交联壳聚糖微球的吸附容量。对胆红素的吸附实验显示,磷酰胆碱接枝改性的交联壳聚糖微球,在显著降低蛋白质吸附的同时,对胆红素的吸附量和清除率没有明显降低。在37℃、pH=7.4、初始浓度为10μg/mL的胆红素溶液中吸附2 h后,基本达到吸附平衡,对胆红素的吸附率可达最大吸附量的93%。该初步研究结果说明,通过表面磷酰胆碱接枝改性,血液灌流吸附剂非选择性降低血液中蛋白含量的这一关键问题可能得到解决。该研究对发展血液灌流材料,提升血液灌流技术水平提供了新途径。
Bilirubin is the metabolite of hemoglobin in senescent red blood cells. Liver damage and related malfunctions can result in hyperbilirubinemia, especially among newborn infants, and may cause jaundice, a yellow discoloration of skin and other tissues. Excess free bilirubin (unconjugated bilirubin) tends to deposit in tissues, especially in the brain. Human body cannot removal the excess free bilirubin by metabolism. Hemoperfusion is an attractive treatment of blood purification. Successful hemoperfusion requires the adsorbents to be specific; high capacity of adsorption; blood compatible; and not being poisonous. Nevertheless, the current adsorbents show poor hemocompatibility, such as promoting plasma protein adsorption, platelet adhesion and activation, and thrombus development, and consequently not satisfactory for use in hemoperfusion. In this thesis, we prepared a new kind of adsorbent by modifying chitosan with phosphorylcholine dichloride. The modification process and the performance of the modified surfaces were investigated systematically.
     The main work of the thesis includes the following three parts:
     (1) Phosphorylcholine dichloride was prepared with phosphoryl chloride and choline chloride under anhydrous condition in a single step reaction. After investigating the relationship between the content of phosphorylcholine dichloride and the molar feed ratio of phosphoryl chloride to choline chloride, we found increasing the molar ratio can increase the content of phosphorylcholine dichloride. Meanwhile the content of phosphorylcholine dichloride can be increased by exhausting the excess phosphoryl chloride from the product. The content of the phosphorylcholine dichloride was determined by a modified potentiometric titration method. The result showed that the content of the phosphorylcholine dichloride reaches 88 % as the molar ratio of phosphoryl chloride and choline chloride in feed is 3:1 and after exhausting the excess phosphoryl chloride from the product, the content increases to 96 %.
     (2) We prepared the crosslinked chitosan (CS-GA) film with glutaraldehyde. The results of X-ray Photoelectron Spectroscopy (XPS) and ATR-FTIR indicated that the chitosan (CS) was successfully crosslinked by glutaraldehyde and the degree of cross linking was approximately 17 %. The degree of deacetylation of chitosan was also calculated about 92 %. The phosphorylcholine modified CS-GA film (CS-GA-PC) was prepared by grafting CS-GA with PC groups in chloroform. The change of hydrophilicity and the grafted PC density were characterised by dynamic contact angle (DCA) and X-ray Photoelectron Spectroscopy (XPS) measurements respectively. The results of ATR-FTIR and DCA confirmed that the modification process was successful. According to the data of XPS, we estimate the grafted PC ratio was approximately 28 %. Platelet adhesion assay revealed that the adhered platelets on CS-GA-PC surface shows random distribution with the size of individual platelets (2-4μm). On the contrary, the adhered platelets on CS-GA surface displays remarkable aggregation of the platelets and finally form agglomerate, suggesting the activation of platelets. Protein absorption experiments revealed that the adsorbed amounts of bovine serum albumin (BSA) and fibrinogen (Fg) on the CS-GA-PC surface are much less than that on CS-GA. After the PC modification, the adsorbedamounts of BSA and Fg decrease from 0.74μg/cm~2 and 0.87μg/cm~2 to 0.21 ug/cm and 0.35μg/cm~2 respectively. The reductions reach 72 % and 60 % for BSA and Fg respectively. These results demonstrated that surface modification with phosphorylcholine dichloride is a promising route to improve the hemocompatibility of chitosan.
     (3) CS-GA microspheres were prepared by emulsification-crosslink method and phosphorylcholine modified CS-GA microspheres were synthetized by grafting CS-GA microsphere with PC groups in chloroform. The result of ATR-IR showed that the peak in 2950 cm-1 was stretching vibration of methylene and the peak in 1646 cm~(-1) was the characteristic absorption peak of -C=N. That indicated crosslinking process was successful. Compared with CS-GA microspheres, the enhanced absorption around 1041, 1076 cm~(-1) (symmetric O=P—O stretch) and 1450 cm~(-1) (CH_3 bending from N~+(CH_3)_3) of CS-GA-PC is the evidence of the successful grafting of PC groups. The result of scanning electron microscope (SEM) revealed that particle diameters of CS-GA microspheres and phosphorylcholine modified CS-GA microspheres are not affected during the modification; both are about 100μm with a narrow size distribution. After modification, the morphology structure of the surface was not changed. Protein absorption experiments showed that the adsorptive capacity of BSA on the CS-GA-PC microspheres is not reduced obviously compared with that on the CS-GA microspheres. Bilirubin adsorption experiment demonstrated that the absorption reaches equilibrum in 2 h, and 90 % of the bilirubin is removed (adsorbed) in the adsorption condition.
引文
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