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

埃博拉病毒对人类的破坏性影响在很大程度上与促炎蛋白（称为细胞因子）的过量产生有关，这种蛋白导致埃博拉病的致命临床症状：炎症、发烧、大量内出血和全身灾难性血栓形成。在免疫系统准备消灭病毒时，通过吸附快速清除血液中的促炎细胞因子对于减轻这些严重的临床症状至关重要。细胞因子的吸附因其分子大小和形状的巨大变化而变得复杂，有些分子小而细长，有些分子大而球状，所以当这些分子的混合物存在时，较大的分子迅速粘附在吸附剂的外表面，阻止较小分子进入较小的孔，大大减少了可用的表面。解决方案是创造具有分层孔结构的吸附剂，包含大小孔，适合所有可能的细胞因子大小和形状。这些分层碳吸附剂将由聚合物前体合成，并经过优化，可从埃博拉病毒病患者的血液中特异性、快速和完全去除细胞因子。拟议的研究将允许开发一系列具有精确控制孔径、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、水净化和化妆品等领域得到更广泛的应用。选择性蛋白质吸附的医疗应用，包括从肾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。该奖项是由两个项目联合颁发的：(1)化学和生物分离，(2)生物医学工程，这两个项目都隶属于工程局的化学、生物工程、环境和运输系统部门。本研究的重点是研究分级介孔碳的孔径、形状和表面终止对细胞因子吸附和孔内扩散的影响。基于这些知识，将合成和定制分层多孔碳吸附剂，以快速去除埃博拉病毒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血浆样品上得到验证，这些血浆样品中加入了埃博拉病毒病患者典型成分和浓度的细胞因子鸡尾酒。吸附剂将由含硅聚合物衍生陶瓷合成，随后通过高温氯化去除硅。该工艺允许通过前驱体组成、氯化温度和时间的变化来完全控制孔径和形状，并已被证明可以产生亚纳米级孔径控制的分层孔隙。然后用酶联免疫吸附法测定血浆中细胞因子的吸附量。为了增加其对细胞因子的亲和力，合成吸附剂的表面化学将通过在空气或二氧化碳中氧化，氢气还原和氨气处理来修饰。在实验计划的最后，将开发具有分级孔结构和大粒径的介孔碳吸附剂，通过体外灌注快速完全去除埃博拉病毒病患者血液中的细胞因子。拟议的治疗方法将降低死亡率，加速康复，并与新兴方法和支持性护理结合使用，将最大限度地减少对患者的长期损害。

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.