RAPID: Hierarchical Carbon Adsorbent for Cytokines Removal from Blood of the Ebola Virus Disease Patients

PI：Mochalin，VadymProposal编号：1518999埃博拉病毒对人类的破坏性影响在很大程度上与过度产生促炎蛋白有关，这种蛋白被称为细胞因子，是埃博拉病毒致命临床症状的罪魁祸首：炎症、发烧、大量内出血和全身灾难性的血栓形成。在免疫系统准备清除病毒的同时，通过吸附从血液中快速去除促炎细胞因子对于缓解这些严重的临床症状至关重要。细胞因子的吸附由于其分子大小和形状的巨大变化而变得复杂，一些分子小而细长，另一些分子大而更球形，因此当这些分子的混合物存在时，较大的分子迅速粘在吸附剂的外表面上，阻止较小分子进入较小的孔道，显著减少了可用表面。解决方案是创建具有分级孔结构的吸附剂，其中包含适合所有可能大小和形状的细胞因子的大小和小孔。这些分级碳吸附剂将从聚合物前体合成，并针对特定、快速和完全去除埃博拉病毒患者血液中的细胞因子进行优化。这项拟议的研究将允许开发一系列具有精确控制的孔大小、孔体积、孔形状、表面积和表面化学的碳材料。开发的材料将在生物技术、生物工程、医药、净水和化妆品方面获得更广泛的应用。选择性蛋白质吸附的医学应用，包括从肾脏疾病或肝功能衰竭患者的血液中清除废物或毒素，可能特别受益于这项研究。该奖项由两个项目联合颁发：(1)化学和生物分离，(2)生物医学工程，在工程部的化学、生物工程、环境和运输系统司。拟议的研究重点是调查分级介孔碳的孔大小、形状和表面终止对细胞因子的吸附和孔内扩散的影响。基于这一知识，将合成并定制分级多孔炭吸附材料，以快速去除埃博拉病毒疾病特有的细胞因子混合物。开发的分层碳吸附剂的性能将在掺入细胞因子鸡尾酒的血浆样本上展示，其成分和浓度是埃博拉病毒患者的典型成分和浓度。这些吸附剂将由含硅聚合物陶瓷合成，然后通过高温氯化去除硅。这种工艺允许通过改变前驱体成分、氯化温度和时间来完全控制孔的大小和形状，并已被证明通过对孔大小的亚纳米控制来产生分级孔隙率。然后用酶联免疫吸附试验测定血浆对细胞因子的吸附。为了增加对细胞因子的亲和力，合成的吸附剂的表面化学将通过在空气或二氧化碳中氧化、在氢气中还原和在氨气中处理来进行修饰。在实验计划结束时，将开发具有分级孔结构和大颗粒尺寸的介孔碳吸附材料，用于通过体外灌流快速完全去除埃博拉病毒患者血液中的细胞因子。建议的治疗将降低死亡率，加快康复，并与新兴方法和支持性护理结合使用，将对患者的长期损害降至最低。

PI: Mochalin, VadymProposal Number: 1518999The devastating effects of the Ebola virus in humans are largely related to overproduction of pro-inflammatory proteins, called cytokines, which are responsible for fatal clinical symptoms of the Ebola disease: inflammation, fever, massive internal hemorrhage, and catastrophic thrombosis around the body. Quick removal of pro-inflammatory cytokines from blood by adsorption is essential to mitigate these severe clinical symptoms while the immune system prepares to eliminate the virus. The adsorption of cytokines is complicated by their large variations in molecular size and shape, some being small and elongated, others large and more globular, so when a mix of these molecules is present, larger molecules quickly stick to the outer surface of the adsorbent blocking access to the smaller pores for smaller molecules, significantly reducing available surface. The solution is to create adsorbents with hierarchical pore structure, containing large and small pores which fit all possible sizes and shapes of cytokines. These hierarchical carbon adsorbents will be synthesized from polymer precursors and optimized for specific, quick, and complete removal of cytokines from blood of the Ebola virus disease patients. The proposed research will allow the development of a range of carbon materials featuring precisely controlled pore size, pore volume, pore shape, surface area, and surface chemistry. The developed materials will find broader applications in biotechnology, bioengineering, medicine, water purification, and cosmetics. Medical applications of selective protein adsorption, including removal of wastes or toxins from blood of patients with kidney disease or liver failure, may particularly benefit from this research. This award is being made jointly by two Programs: (1) Chemical and Biological Separations, (2) Biomedical Engineering, both in the Chemical, Bioengineering, Environmental and Transport Systems Division in the Engineering Directorate.The proposed research is focused on investigation of the effects of pore size, shape, and surface termination in hierarchical mesoporous carbons on adsorption and intraporous diffusion of cytokines. Based on this knowledge, hierarchical porous carbon adsorbents will be synthesized and tailored for quick removal of a mix of cytokines specific for the Ebola virus disease. The performance of the developed hierarchical carbon adsorbents will be demonstrated on blood plasma samples spiked with cytokine cocktails in compositions and concentrations typical for those in patients with the Ebola virus disease. The adsorbents will be synthesized from silicon containing polymer-derived ceramics with subsequent removal of silicon by high temperature chlorination. This process allows for full control of pore size and shape through variations of precursor composition, chlorination temperature and time, and has been demonstrated to produce hierarchical porosity with subnanometer control of the pore size. Adsorption of cytokines from blood plasma will then be measured by the enzyme-linked immunosorbent assay. To increase their affinity to cytokines, surface chemistry of the synthesized adsorbents will be modified by oxidation in air or carbon dioxide, reduction in hydrogen, and treatment in ammonia gas. At the end of the experimental program, mesoporous carbon adsorbents with a hierarchical pore structure and large particle size will be developed for quick and complete removal of cytokines from blood of the Ebola virus disease patients by extracorporeal perfusion. The proposed treatments will reduce mortality, accelerate recovery and, when used in conjunction with emerging methods and supporting care, will minimize long-term damage to the patient.