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DEVELOPMENT OF INTEGRATED BEAD AND FIBER ANTIBODY FILTERS FOR SPECIFIC REMOVAL OF ANTI-A ANTIBODIES FROM BLOOD

机译:特异性去除血液中抗-A抗体的整合珠和纤维抗体过滤器的开发

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摘要

Removal of anti-A/B antibodies from blood in the peri-transplantation period eliminates the risk of hyperacute rejection in ABO-incompatible transplantation. We are developing anti-A/B immunoadsorption devices, compatible with whole blood perfusion. In this study we developed a new antibody filtering device based on integrated microfiltration fibers with antibody capturing beads distributed within the interstitial fiber space (BSAF device). As blood flows through the fibers in BSAF devices, Starling flow carries plasma from the inner fiber lumen to the beads in the shell compartment where antibodies diffuse and bind to covalently attached antigens within the shell-side porous beads. We first investigated the possibility of using synthetic blood group A/B-trisaccharide epitopes, conjugated with poly-N hydroxyethylacrylamide spacers, as the immunoadsorbent material in our antibody filtering devices. The glycopolymers were equipped with biotin tags and deposited on streptavidin-coated sensor chips. Antibody removal capacity per unit surface area and kinetics of antibody binding to immobilized glycoconjugates were quantified using surface plasmon resonance. We then developed a simple mathematical model to guide the choice of key design and operational parameters for a clinical BSAF device. The model demonstrated that for a given flow rate and reservoir volume, antibody removal rate in a BSAF was dependent on the magnitude of a lumped dimensionless parameter which characterized the ratio of antibody uptake rate by the beads to the Starling flow rate in the device. The highest antibody removal rate was predicted for a perfusion limited regime. Once this maximum limit was obtained, any further increase in the antibody removal rate was only possible by increasing the flow rate in the device. Key model predictions were validated in a series of in vitro monoclonal anti-A antibody capture studies in BSAF devices packed with anti-A specific beads. Once validated, we used the model to design a BSAF device that would generate a clinically relevant rate of anti-A removal. We fabricated and tested scaled down prototypes of the "clinical" BSAF device and showed significant reduction in IgM and IgG anti-A antibody titers within two hours of whole blood perfusion through our fabricated BSAF devices.
机译:在移植期间从血液中去除抗A / B抗体消除了与ABO不兼容的移植中超急性排斥的风险。我们正在开发与全血灌注兼容的抗A / B免疫吸附设备。在这项研究中,我们开发了一种基于集成微滤纤维的新型抗体过滤装置,其中抗体捕获珠分布在间隙纤维空间内(BSAF装置)。当血液流过BSAF设备中的纤维时,Starling流将血浆从内部纤维内腔带到壳室中的珠子,在那里抗体扩散并结合到壳侧多孔珠子中的共价结合抗原上。我们首先研究了在我们的抗体过滤设备中使用与聚N羟乙基丙烯酰胺间隔子结合的合成血型A / B-三糖表位作为免疫吸附材料的可能性。糖聚合物配备有生物素标签,并沉积在链霉亲和素包被的传感器芯片上。使用表面等离振子共振来定量每单位表面积的抗体去除能力和与固定的糖缀合物结合的抗体的动力学。然后,我们开发了一个简单的数学模型来指导临床BSAF设备的关键设计和操作参数的选择。该模型表明,对于给定的流速和储液器体积,BSAF中的抗体去除速率取决于集总的无量纲参数的大小,该参数表征了珠粒吸收抗体的速率与设备中Starling流速的比值。对于灌注受限方案,预计最高抗体去除率。一旦获得最大限制,抗体去除率的任何进一步提高都只能通过增加装置中的流速来实现。在装有抗A特异性磁珠的BSAF设备中进行的一系列体外单克隆抗A抗体捕获研究中验证了关键模型的预测。验证后,我们使用该模型设计了BSAF设备,该设备将产生临床上相关的抗A去除率。我们制造并测试了按比例缩小的“临床” BSAF设备原型,并显示在通过我们制造的BSAF设备进行全血灌注后两个小时内,IgM和IgG抗A抗体滴度显着降低。

著录项

  • 作者

    Alikhani Azadeh Hajy;

  • 作者单位
  • 年度 2010
  • 总页数
  • 原文格式 PDF
  • 正文语种 en
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