Hemoadsorption Device for Selective Removal of Cell-Free Plasma Hemoglobin During Extracorporeal Therapies.

摘要 体外循环治疗（ECT），包括心肺转流（CPB）和体外膜 多年来，体外膜肺氧合（ECMO）已得到完善，但不利的结果，如急性肾损伤 (AKI)持续发生，并与死亡率、重症监护室延长和住院时间相关 留下来。CPB和ECMO期间溶血导致的无细胞血浆血红蛋白（PHb）增加， 被鉴定为在这种功能障碍中起核心作用，因此是明显的临床靶点。尽管如此，在 在ECT期间，没有临床上可用于选择性去除PHb的疗法。本提案的重点是 开发一种新的体外血液吸附装置，作为一种易于实施的治疗方法， 在ECT期间选择性地去除PHb。血液吸附装置将使用基于珠粒的基质， 固定化结合珠蛋白（Hp），一种与PHb具有高亲和力结合的天然蛋白质，以选择性地去除PHb 从整个血液流动。 已经进行了初步工作，以确定拟议方法的基本可行性。 这包括开发生产Hp修饰的珠粒的方法，确认这些珠粒的能力， 珠粒结合PHb，证明基于珠粒的柱能够容纳全血流量， 以及基于模型的证据，证明临床合理的器械流速能够实现治疗性PHb 的拔除.此外，我们还建立了一种用于体内研究的ECT诱导的阿基大鼠模型， 对拟议办法的评估。 这两个拟议的目标将（i）制造功能，按比例缩小的原型和表征PHb结合 在全血流动的实验室研究期间的动力学和（ii）使用大鼠模型来评估装置的可行性 在ECT过程中的实施和它的能力，以防止ECT诱导的肾损伤。因此，拟议的工作 涉及体外血液接触装置、多孔介质流体 动力学、基于血液的质量转移、血液相容性、肾损伤、溶血相关病理学，以及 ECT的临床应用 该研究小组由主要研究人员Nahmah Kim-Campbell，MD，MS和William领导 Federspiel博士拥有独特的工程和临床专业知识，可以追求这一高度 多学科研究。结合大学丰富的研究环境和资源 匹兹堡和麦高恩再生医学研究所，这个团队是很好的定位，成功地 开发这种机械支持的方法来改善ECT的不良结果。

ABSTRACT Extracorporeal therapies (ECT) including cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been refined over the years, yet unfavorable outcomes such as acute kidney injury (AKI) continue to occur and are associated with mortality and prolonged intensive care unit and hospital length of stay. Increased cell-free plasma hemoglobin (PHb) from hemolysis during CPB and ECMO has been identified as playing a central role in such dysfunction and is thus an obvious clinical target. Despite this, there are no clinically available therapies for the selective removal of PHb during ECT. The focus of this proposal is to develop a novel extracorporeal hemoadsorption device to serve as an easily implementable therapy to selectively remove PHb during ECT. The hemoadsorption device will use a bead-based matrix containing immobilized haptoglobin (Hp), a native protein with high-affinity binding for PHb, to selectively remove PHb from whole blood flow. Preliminary work has been conducted to establish the foundational feasibility of the proposed approach. This includes the development of methods to produce Hp-modified beads, confirmation of the ability of these beads to bind PHb, demonstration of the ability of a bead-based column to accommodate whole blood flow, and model-based evidence of the ability for clinically reasonable device flow rates to achieve therapeutic PHb removal. In addition, we have established a rat model of ECT-induced AKI to be used during in vivo assessment of the proposed approach. The two proposed Aims will (i) fabricate functional, scaled-down prototypes and characterize PHb binding kinetics during benchtop studies in whole blood flow and (ii) use a rat model to evaluate the feasibility of device implementation during ECT and its ability to prevent ECT-induced renal injury. Thus, the proposed work involves elements of design and fabrication of extracorporeal blood-contacting devices, porous media fluid dynamics, blood-based mass transfer, hemocompatibility, kidney injury, hemolysis-associated pathology, and clinical implementation of ECT. The research team, led by principal investigators Nahmah Kim-Campbell, MD, MS and William Federspiel, PhD, possesses the unique engineering and clinical expertise necessary to pursue this highly multidisciplinary research. Combined with the rich research environment and resources of the University of Pittsburgh and the McGowan Institute of Regenerative Medicine, this team is well positioned to successfully develop this mechanistically-supported approach to improve adverse outcomes in ECT.