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

摘要 体外治疗(ECT)包括体外循环(CPB)和体外膜 多年来，氧合作用(ECMO)已经得到了改进，但结果不佳，如急性肾损伤 (AKI)继续发生，并与死亡率和延长的重症监护病房和住院时间有关 留下来。CPB和ECMO期间因溶血而导致的游离血浆血红蛋白(PHB)增加 被确定为在这种功能障碍中发挥核心作用，因此是一个明显的临床靶点。尽管如此，还有 在ECT中选择性去除PHB尚无临床可用的治疗方法。这项提议的重点是 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过程中有选择地清除PHB。血液吸附装置将使用基于珠子的基质，其中包含 与PHB高亲和力结合的天然蛋白--固定化结合珠蛋白选择性去除PHB 从全血中流出来。 已经开展了初步工作，以确定拟议办法的基本可行性。 这包括开发生产HP修饰的珠子的方法，确认这些 结合PHB的珠子，展示了基于珠子的柱容纳整个血液流动的能力， 和基于模型的证据，证明临床合理的装置流速能够实现治疗性PHB 移走。此外，我们还建立了一种ECT诱导的AKI大鼠模型，用于体内实验 对提议的方法进行评估。 这两个拟议的目标将(I)制造功能性的、按比例缩小的原型并表征PHB结合 全血流量台式研究中的动力学和(Ii)使用大鼠模型评估该装置的可行性 ECT中的实施及其预防ECT所致肾损伤的能力。因此，拟议的工作 涉及体外血液接触装置、多孔介质流体的设计和制造要素 动力学、基于血液的传质、血液相容性、肾脏损伤、溶血相关病理以及 ECT的临床应用。 研究小组由首席调查员Nahmah Kim-Campbell，医学博士，MS和William领导 费德斯佩尔博士拥有高度追求这一目标所需的独特的工程和临床专业知识 多学科研究。结合北京理工大学丰富的科研环境和资源 匹兹堡和麦高恩再生医学研究所，这个团队处于有利地位，能够成功 开发这种机械支持的方法，以改善ECT的不良后果。

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.