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

用于在体外治疗期间选择性去除无细胞血浆血红蛋白的血液吸附装置。

• 批准号: 10527451
• 负责人: William J. Federspiel
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527451
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Affinity; Anticoagulation; Binding; Biochemical; Biological Availability; Biomedical Engineering; Blood; Blood Circulation; Blood flow; Cardiopulmonary Bypass; Cells; Clinical; Clinical Trials; Complex; Complication; Country; Creatinine; Critically ill children; DNA Nucleotidylexotransferase; Development; Device Designs; Devices; Disease; Doctor of Philosophy; Dose; Elements; Engineering; Environment; Epithelial; Excision; Exhibits; Extracorporeal Membrane Oxygenation; Foundations; Functional disorder; Funding; Future; Goals; Haptoglobins; Hemadsorption; Hemoglobin; Hemolysis; Histologic; Immobilization; In Vitro; Injury to Kidney; Institutes; Intensive Care Units; Interdisciplinary Study; Kidney; Kinetics; Knowledge; LCN2 gene; Label; Length of Stay; Liquid substance; Measures; Modeling; Molecular Weight; Monitor; Nitric Oxide; Organ; Outcome; Oxidative Stress; Pathology; Patient Care; Patients; Periodic acid Schiff stain method; Perioperative; Peroxidases; Physiological Processes; Plasma; Plasma Exchange; Play; Polymers; Positioning Attribute; Postoperative Period; Pre-Clinical Model; Principal Investigator; Proteins; Rattus; Regenerative Medicine; Research; Resources; Reticuloendothelial System; Risk Factors; Rodent Model; Role; Serum; Sickle Cell; Stains; Surface; Technology; Theoretical model; Therapeutic; Toxic effect; Treatment Efficacy; Tubular formation; University resources; Urine; Whole Blood; Work; adverse outcome; base; clinical implementation; clinically relevant; design; evidence base; experience; experimental study; hemocompatibility; improved; in vivo; injury prevention; interest; interstitial; kidney dysfunction; method development; mortality; novel; organ injury; post gamma-globulins; pre-clinical; prevent; prototype; rat KIM-1 protein; scale up

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.

抽象的 体外疗法（ECT），包括心肺旁路（CPB）和体外膜 多年来，氧合（ECMO）已经进行了完善，但不利的结果，例如急性肾脏损伤 （AKI）继续发生，并与死亡率和长时间的重症监护室和医院长度有关 住宿。 CPB和ECMO期间溶血中无细胞的血浆血红蛋白（PHB）增加了 被确定为在这种功能障碍中起着核心作用，因此是一个明显的临床靶标。尽管如此，那里 在ECT期间没有选择性去除PHB的临床可用疗法。该提议的重点是 开发一种新型的体外吸收吸附装置，以作为易于实现的疗法 在ECT期间有选择地删除PHB。吸血器设备将使用一个基于珠的基质，其中包含 固定的Haptoglobin（HP），一种具有高亲和力结合的天然蛋白，可有选择地去除PHB 从全血流。 已经进行了初步工作，以确定拟议方法的基础可行性。 这包括开发产生HP修饰珠的方法，确认这些珠子的能力 珠子结合PHB，表明基于珠的柱可容纳全血流的能力， 以及基于模型的证据证明临床合理设备流速获得治疗性PHB的能力 移动。此外，我们已经建立了一个ECT诱导的AKI大鼠模型，以在体内使用 评估拟议方法。 提出的两个目标将（i）制造功能性的，缩放的原型并表征PHB结合 台式研究期间的动力学在全血流量和（ii）使用大鼠模型评估器件的可行性 ECT期间的实施及其预防ECT诱发的肾脏损伤的能力。因此，拟议的工作 涉及设计和制造体外血液接触设备的元素，多孔培养基流体 动力学，基于血液的传质，血流相容性，肾脏损伤，溶血相关病理和 ECT的临床实施。 由主要研究人员Nahmah Kim-Campbell，医学博士和William领导的研究团队 Federspiel，PhD具有高度追求这一高度的独特工程和临床专业知识 多学科研究。结合大学的丰富研究环境和资源 匹兹堡和麦克高万再生医学研究所，该团队有能力成功地 开发这种机械支持的方法，以改善ECT的不良结果。