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题名	以菊芋多糖和魔芋多糖为基质的血浆代用品的制备及评价
作者	李苏平
学位类别	博士
答辩日期	2010-07-30
授予单位	中国科学院研究生院
授予地点	北京
导师	苏志国
关键词	血浆代用品 交联菊糖 羧甲基化 魔芋葡甘聚糖
其他题名	Preparation and Evaluation of Inulin and Konjac Glucomannan Based Plasma Substitute
学位专业	生物化工
中文摘要	血浆代用品的研究具有重大的科学和社会意义。传统的胶体溶液如人血白蛋白、羟乙基淀粉等已被大量应用于临床，但都出现不同程度的副作用。本文旨在开拓新的血浆代用品，选择两种植物多糖—菊芋多糖和魔芋多糖为对象，通过交联、降解反应，考察其作为血浆代用品的特点和可行性，以期提供性能更好的产品。 首先以菊芋多糖为对象，通过交联法制备出不同分子量的交联菊糖，从而调节其胶体渗透压，满足作为血浆代用品的基本功能。实验采用环氧氯丙烷为交联剂，通过控制反应时间和剂量来实现对菊芋多糖的交联度的控制，制备了三种不同分子量的产品，进行理化性质的鉴定。通过凝胶渗透色谱与多角度激光散射偶联技术测得这三种交联菊糖（CLI1、CLI2和CLI3）的平均分子量分别为54 kDa、100 kDa和146 kDa。体外检测这三种交联菊糖（CLI1、CLI2和CLI3）的胶体渗透压值达到血浆代用品要求时的浓度分别2.7 g/L、3.0 g/L和4.8 g/L，都低于商品化血浆代用品羟乙基淀粉HES产生相同的胶体渗透压所需要的浓度（6%），显示了更好的扩容效果。以大鼠和大耳白兔为动物实验模型，进行换血试验，检测了体内的各种生物学性质，包括血压、血液粘度、红细胞聚集指数、变形指数和组织切片检查。结果表明，交联菊糖的平均分子量对这些参数有重要影响：分子量增大则扩容能力增强，扩容时间延长，动物血压维持时间延长（CLI1小于2 h，CLI2和CLI3大于2 h），但红细胞的聚集指数随分子量的增加而增大，血液粘度随着分子量的增加也逐步增大。对代谢的检测发现：分子量增大，代谢速度减慢，其中，CLI1和CLI2经过42 h后，血液中基本不含有交联菊糖，而30%的CLI3仍残留在血液中。组织切片表明随着分子量增大，造成在肾脏中的残留，容易引起肾组织的损伤。 在对菊芋多糖研究的基础上，本论文又对以魔芋葡甘聚糖为主要原料制备新型血浆代用品。实验根据魔芋葡甘聚糖的特点，首先对魔芋葡甘聚糖进行降解，然后以氯乙酸为修饰剂对魔芋葡甘聚糖进行修饰制备出四种不同取代度的羧甲基魔芋葡甘聚糖（CKGM），并对其理化性质主要是胶体渗透压COP值进行了检测。结果表明：CKGM的取代度越高，第二维利系数A2就越小，COP值越低，当取代度为0.57、0.46、0.30和0.22依次降低时，A2值依次为0.57、2.1、3.3和13.6；在相同浓度下，COP值依次为15.6、29.2、37.8和72。这主要是因为当取代度增加时，CKGM分子上的羟基就会相应的减少，与溶剂水分子的相互作用就会降低。取代度为0.22的CKGM溶液所产生的胶体渗透压值与商品化血浆代用品HES130相对比，1%CKGM的胶体渗透压值与6%的HES相当，大于5%的HSA溶液，表明1%CKGM具有与6%HES相当的扩充血容量的能力。最后，以大鼠和大耳白兔为动物实验模型，进行换血试验。以商品化血浆代用品（羟乙基淀粉HES130、人血白蛋白HSA和聚明胶肽PG）为对照，检测了体内动力学参数和流变学参数性质，包括血压、血液粘度、红细胞聚集指数、变形指数和组织切片检查。结果表明，CKGM较低的输入量极大地降低了由于其它商品化血浆代用品大量输入而带来的毒副作用；CKGM很明显地改善了失血动物的血压，具有很好的血液动力学参数和流变学参数，没有发现组织切片的损伤，是一种潜在的血浆代用品。CKGM的理化特性接近于最近研发的PEG-BSA，而原料来源于植物，价格低廉，使用量可以远低于现有的羟乙基淀粉，是一种有发展潜力的血浆代用品。
英文摘要	Plasma substitute research has great scientific and social significance. The conventional colloid solution, e.g. human serum albumin (HSA), hydroxyethyl starch (HES), is infused in a large amount as plasma substitutes and may lead to undesirable physiological response from human body. In order to develop perfect plasma substitutes, two kinds of polysaccharides from plants (inulin and konjac glucomannan) have been chosen in this study. In the first part, inulin was cross-linked and evaluated as a new potential plasma substitute in vitro and in vivo. Epichlorohydrin was used as the crosslinker to regulate the molecular weight (Mw) of the product through control of the reaction time and dose of the crosslinker. Three products of cross-linked inulin (CLI), with molecular weights 54, 100 and 146 kDa, were prepared. The products were characterized by gel filtration chromatography and multi-angle laser light scattering. Using a commercial product of hydroxyethyl starch (HES 130) as comparison, the colloid osmotic pressure of HES 130, at concentration of 6%, could be achieved by CLI1、CLI2 and CLI3) at smaller concentrations of 2.7 g/L、3.0 g/L and 4.8 g/L respectively. Their in vivo physiological properties, including blood pressure, erythrocyte deformation index, erythrocyte aggregation index, and organ function, were tested in a rat model and a rabbit model. The results demonstrated that the expansion efficacy and the expansion duration increased with the increase of Mw of CLI, whereas the rate metabolism for CLI in blood decreased. Compared to the other two CLI products, the CLI2 with molecular weight (Mw) of 100 kDa was advantageous as a potential plasma expander for its strong expansion efficacy and no organ dysfunction. Moreover, CLI2 showed a high colloid osmotic pressure (COP). The COP of 3% CLI2 is equal to that of 6% HES. Thus, much less CLI2 can be infused with the same effects as normal HES, and its potential side effects could be minimized. In the second part, konjac glucomannan (KGM) was hydrolyzed, modified and evaluated as another new potential plasma substitute. Monochloroacetic acid (MCA) was used as the modification reagent to regulate the charge on the KGM. Four products of carboxylmethylated (CKGM) with different degree substitute (0.57, 0.46, 0.43 and 0.30) were prepared. These products were also characterized by a membrane colloid oncometer. The parameters, A2 and COP, decreased with increase of the degree substitution (DS).More hydroxyls of CKGM could be exposed in solvent so that the A2 value and the COP value of CKGM were high. The in vivo hemodynamic and hemorheologic parameters, including blood pressure, blood viscosity, haematocrit, erythrocyte deformation index and erythrocyte aggregation index, were evaluated in a rat model and a rabbit model. Comparison was made between CKGM and four other plasma substitutes, including HSA, HES, polygeline (PG) and normal saline (NS). CKGM showed an exceptionally high COP. 1% CKGM would produce a COP that was comparable to those of 6% HES and 5% HSA. Accordingly, much less CKGM was infused in the bleeding animals as compared to other plasma substitutes. The CKGM-treated group showed an improved intravascular persistence, good hemodynamic and hemorheologic properties. There was no organ dysfunction found in this study. The inexpensive CKGM may be considered as a potential plasma substitute that could be infused less amount and produce better expander ability than the products currently available on the market.
公开日期	2013-09-17
页码	143
内容类型	学位论文
源URL	[http://ir.ipe.ac.cn/handle/122111/1485]
专题	过程工程研究所_研究所（批量导入）
推荐引用方式 GB/T 7714	李苏平. 以菊芋多糖和魔芋多糖为基质的血浆代用品的制备及评价[D]. 北京. 中国科学院研究生院. 2010.

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