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 体外治疗（ECT），包括体外循环（CPB）和体外膜 氧合 (ECMO) 多年来已得到完善，但仍存在急性肾损伤等不良后果 （AKI）持续发生，并与死亡率、重症监护病房时间和住院时间延长相关 的住宿。 CPB 和 ECMO 期间溶血导致无细胞血浆血红蛋白 (PHb) 增加 被认为在这种功能障碍中发挥着核心作用，因此是一个明显的临床目标。尽管如此，有 临床上尚无用于在 ECT 期间选择性去除 PHb 的疗法。该提案的重点是 开发一种新型体外血液吸附装置作为一种易于实施的治疗方法 在 ECT 期间选择性去除 PHb。血液吸附装置将使用基于珠子的基质，其中包含 固定化触珠蛋白 (Hp)，一种与 PHb 具有高亲和力结合的天然蛋白质，可选择性去除 PHb 来自全血流。 已开展初步工作以确定所提议方法的基本可行性。 这包括开发生产 Hp 修饰珠子的方法，确认这些珠子的能力 珠子结合 PHb，证明基于珠子的柱容纳全血流的能力， 以及基于模型的证据，证明临床上合理的设备流速能够达到治疗性 PHb 移动。此外，我们还建立了 ECT 诱导的 AKI 大鼠模型，用于体内实验 对拟议方法的评估。 拟议的两个目标将 (i) 制造功能性的、按比例缩小的原型并表征 PHb 结合 全血流台式研究中的动力学，以及 (ii) 使用大鼠模型评估装置的可行性 ECT 期间的实施及其预防 ECT 引起的肾损伤的能力。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、血液传质、血液相容性、肾损伤、溶血相关病理学以及 ECT的临床实施。 该研究小组由首席研究员 Nahmah Kim-Campbell（医学博士、理学硕士）和 William 领导 Federspiel 博士拥有追求这一高度所需的独特工程和临床专业知识 多学科研究。结合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，该团队处于有利地位，可以成功 开发这种机械支持的方法来改善 ECT 的不良后果。