新生儿高效黄疸灌流吸附剂的研制及其多维协同效应机制研究

Perfusion therapy still fails in the clinical emergency of severe neonatal jaundice because of the very low efficiency of jaundice perfusion adsorbent,and developing high efficient and safe jaundice adsorbent can enable it to be used for the treatment instead of the in-use blood exchange transfusion therapy where there exist many limitations, which has important health implications and good perspective. In this proposal, we attempt to explore several adsorption mechanisms, such as the resemblance, electrostatic/hydrogen bonding interaction, spatial conformation, affinity and biocompatibility, to cleverly work together, with an aim to outcome expected positive cooperativity. I.e, the specific monomers will be used to prepare the carrier particles, and then the particles will be aminated and followed with grafting functional molecules, finally coupled with specific ligands, with an expectation to achieve safe and highly efficient adsorbent. For this proposal, we will study the design of its molecule structure and function, as well as its preparation process; investigate its physical and chemical properties, biocompatibility, adsorptive properties and reactivation conditions; explore the relationship between the synergistic effect mechanism and its adsorption characteristics, from which we hope to discover the mechanism how to enhance the adsorption characteristics from molecular level. The success of the proposal will solve the issues existing in adult jaundice perfusion adsorbent, such as low adsorption effectiveness, high impact on blood indicators and the great blood consumption, as well as provide new ideas, development of methods and experimental evidence to develop safe and high efficient perfusion adsorbent for the treatment of severe neonatal jaundice.

医用黄疸灌流吸附剂吸附效率的低下，严重制约了灌流疗法在新生儿重度黄疸临床急救中的应用,研制高效的吸附剂可使灌流法替代目前存在诸多客观局限的换血疗法,具有重要的卫生意义和应用前景。本课题尝试将几种吸附结合作用机制有机协同起来,并兼顾生物相容性，设计并合成该吸附剂,即用特定单体复合制备出吸附剂载体微粒，再行胺化改造，接枝功能分子臂，偶联特异性配基，以期达到安全高效。课题研究吸附剂的分子结构与功能的设计及其制备工艺；考察其物化性能、生物相容性、吸附性能及条件，再生复用条件；探究这几种吸附结合协同效应机制与其吸附特性的关系，以从分子水平上发现增强吸附性能的机制。课题的成功，可解决现行的成人黄疸灌流吸附剂在新生儿重度黄疸上应用时吸附效力严重低下、血象指标影响大、耗血量大等问题，并为临床上开发安全高效的新生儿重度黄疸灌流吸附剂提供新的研制思路、方法和实验依据。

项目背景：新生儿黄疸是临床高发病，目前临床上采用换血疗法抢救病理性重度新生儿黄疸，但此法存在血液供应、血液匹配、输血综合征、血液制品交叉感染等局限，其虽有效实用但存在潜在医疗风险。血液净化术的胆红素灌流吸附疗法因不牵涉外来血液，故安全有效且适应强。但目前临床用的成人黄疸灌流吸附剂实际临床效率低，且对血液其他有益成分如白蛋白损失量过大，更因新生儿总血量少，胆红素水平畸高，故如此低效的成人黄疸灌流吸附剂无法适用于新生儿的。灌流吸附疗法是可替代换血急救疗法的一种更安全理想的疗法，前提是存在对胆红素吸附效率更高，对其他血液有益成分影响较小的灌流吸附剂。而研究胆红素与吸附剂之间的结合作用机制，是研制高效安全胆红素吸附剂的理论前提。.主要研究内容：.1)从分子水平设计胆红素吸附剂的分子结构和成分，并合成出该吸附剂；2)评价其对胆红素的吸附效果;3)评价其有关物化性能，医用安全性等;4)归纳吸附结合作用机制的表现行为。.重要结果：1)吸附结合作用机制中的静电作用、氢键作用、亲和作用、相似相容作用(亲水性/疏水性)，以及范德华力(质量大小)作用集合在一起时，总体上均表现为正协同效应；2)起亲和作用的功能配基白蛋白起有效作用是有前提的；3)初步医用安全性评价均表现出良好的医用安全性。.关键数据：1)所得吸附剂为光滑无孔致密微球状，平均粒径0.5mm；2)静态吸附平衡时间约在50min；3)最佳吸附pH为弱碱性8.0，离子强度对吸附效果无影响；4) 在最优条件即： pH=8.0、0.9%NaCl、T=37℃、200mL 300mg/L的胆红素溶液、10g吸附剂下，胆红素的动态下降率最高达59%，吸附容量最高达3.4mg/g；而国内某知名品牌大孔树脂型Bxxxx医用胆红素灌流吸附柱在此相同条件下的动态下降率最高达66%，其吸附容量达3.9mg/g。.科学意义：1)基于本研究所得的已知的上述五种物质间相互结合作用均表现出正协同效应，则可通过更科学的成分和结构的配伍，有望研制出更高效的胆红素吸附剂；2)通过调节吸附剂比表面积，调节胆红素内源性天然结合白蛋白的嫁接方式，以使亲和结合作用最大化，有望研制出更高效的胆红素吸附剂。