Computational Modeling of Device-Induced Platelet Activation and Receptor Shedding Relevant to Thrombosis and Bleeding in Device-Assisted Circulation

与装置辅助循环中血栓形成和出血相关的装置诱导血小板激活和受体脱落的计算模型

• 批准号: 10582083
• 负责人: Zhongjun Jon Wu
• 金额: $ 51.28万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582083
• 关键词: Adhesions; Adopted; Affect; Agonist; Algorithms; Animals; Anticoagulation; Assisted Circulation; Biocompatible Materials; Biology; Biomechanics; Blood; Blood Cells; Blood Coagulation Factor; Blood Platelets; Blood Preservation; Blood flow; Calibration; Capsid Proteins; Characteristics; Chemicals; Coagulation Process; Collagen; Computer Models; Consumption; Coupled; Development; Device Designs; Device or Instrument Development; Devices; Disease; Event; Extracorporeal Membrane Oxygenation; Fibrinogen; Functional disorder; Generations; Geometry; Hemodialysis; Hemolysis; Hemorrhage; Hemostatic Agents; Hemostatic function; In Vitro; Injury; Laws; Life; Link; Liquid substance; Mechanical Stress; Medical Device; Modeling; Morphology; Organ; Organ Transplantation; Patients; Pattern; Performance; Platelet Activation; Postoperative Complications; Property; Proteins; Quantitative Evaluations; Research; Risk; Scheme; Self-Help Devices; Sheep; Structure; Surface; Techniques; Testing; Thrombosis; Transplantation; Trauma; VWF gene; biomaterial compatibility; biomechanical model; experimental study; improved; in vivo; in vivo Model; in vivo evaluation; indexing; innovation; novel; predictive modeling; predictive tools; prototype; receptor; shear stress; sheep model; simulation; success; surface coating; thrombotic; tool; ventricular assist device; virtual

Although blood-contacting medical devices (BCMDs) have become lifesaving alternatives to organ transplantation for many patients, thrombotic and bleeding events remain the most common postoperative complications that tend to be devastating and often life-threatening. Device-induced hemostatic dysfunction is commonly believed to be the culprit of these complications and is directly related to platelet activation and receptor shedding associated dysfunction caused by the non-physiological shear stress (NPSS) in these devices. Over the years, computational fluid dynamics (CFD)-aided simulation and analysis have been widely adopted to achieve significant research efforts on device-induced platelet dysfunction. With the help of the CFD technique, regions of abnormal NPSS and stagnant flow in blood flow paths can be precisely identified to assess further the potential risk of thrombosis and bleeding in devices. However, the existing CFD models for predicting shear-induced platelet activation and receptor shedding and related hemostatic complications (thrombotic and bleeding), mainly based on the empirical models, have limited success from the device design perspective. This proposal aims to develop a novel platelet activation model based on the art-of-state interpretation of the platelet’s fundamental morphological change upon activation. It will be incorporated in the development of CFD models capable of assessing in-vitro and in-vivo device-induced platelet dysfunction and associated adhesion capacities to substrates. Numerical algorithms and implementation schemes will be developed to link shear- induced platelet damage models to CFD variables to predict device-induced platelet dysfunction. Quantitative adhesion capacities of device-damaged platelets to collagen, vWF, and fibrinogen could be used to represent device-associated potentials for thrombosis and bleeding. Experiments will then be performed to validate the CFD-based predictive modeling. Finally, a sheep study will be performed to test the CFD models for in-vivo predictive modeling. CFD models will incorporate sheep-specific blood properties, device geometry, device operating conditions, platelet consumption, and generation models to predict the in-vivo device-induced platelet dysfunction and altered adhesion capacities of sheep on VADs and ECMO support. The successful completion of this project will result in CFD-based predictive tools. These tools can be used to provide quantitative evaluation of the performance and in-vivo biocompatibilities of BCMDs and aid the development and optimization of new BCMDs with improved functional characteristics and biocompatibility.

尽管接触血液接触的医疗设备（BCMD）已成为组织的救生替代品 许多患者的移植，血栓形成和出血事件仍然是最常见的术后 往往是毁灭性且常常威胁生命的并发症。设备引起的止血功能障碍是 通常认为是这些并发症的罪魁祸首，与血小板激活直接相关 接收器脱落相关的功能障碍是由非生理剪切应力（NPS）引起的 设备。多年来，计算流体动力学（CFD）辅助模拟和分析已广泛 通过用于实现设备引起的血小板功能障碍的重大研究工作。在CFD的帮助下 可以精确鉴定出技术，异常NPS的区域和血液流动路径中停滞的流量以评估 进一步，设备中血栓形成和出血的潜在风险。但是，用于预测的现有CFD模型 剪切诱导的血小板激活和受体脱落以及相关的止血并发症（血栓形成和 从设备设计的角度来看，主要基于经验模型的出血）取得了有限的成功。 该提案旨在基于国家艺术的解释开发一种新型的血小板激活模型 血小板激活后的基本形态变化。它将纳入CFD的开发 能够评估体外和体内设备诱导的血小板功能障碍以及相关粘合剂的模型 底物的能力。将开发数值算法和实施方案，以链接剪切 诱导CFD变量的血小板损伤模型预测设备诱导的血小板功能障碍。定量 可以使用胶原蛋白，VWF和纤维蛋白原的设备损伤血小板的粘附能力来代表 与设备相关的血栓形成和出血的潜力。然后将进行实验以验证 基于CFD的预测建模。最后，将进行一项绵羊研究以测试Vivo的CFD模型 预测建模。 CFD型号将结合特定的血液特性，设备几何形状，设备 操作条件，血小板消耗和生成模型，以预测体内设备引起的血小板 在VAD和ECMO支持上的绵羊的功能障碍和改变的广告能力。成功完成 该项目将导致基于CFD的预测工具。这些工具可用于提供定量评估 BCMD的性能和体内生物相容性，并有助于新的发展和优化 具有改善功能特征和生物相容性的BCMD。