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.

尽管接触血液的医疗设备(BCMD)已经成为器官的救命替代品 对于许多移植患者来说，血栓和出血事件仍然是最常见的术后事件 并发症往往是毁灭性的，往往危及生命。设备引起的止血功能障碍 通常被认为是这些并发症的罪魁祸首，与血小板活化和 非生理性切应力(NPSS)引起的受体脱落相关功能障碍 设备。多年来，计算流体力学(CFD)辅助的模拟和分析得到了广泛的应用 为实现设备引起的血小板功能障碍的重大研究工作而采用的。借助CFD 该技术可以准确地识别血流路径中异常NPSS和停滞血流的区域，以评估 此外，设备中存在血栓形成和出血的潜在风险。然而，现有的CFD模型用于预测 剪切诱导的血小板活化和受体脱落以及相关的止血并发症(血栓和 出血)，主要基于经验模型，从设备设计的角度来看，成功有限。 这项建议旨在开发一种新的血小板激活模型，该模型基于对 血小板在激活时的基本形态变化。它将被纳入到CFD的发展中 能够评估体外和体内设备诱导的血小板功能障碍和相关黏附的模型 对底物的容量。将开发数值算法和实现方案来连接剪切力。 将诱导血小板损伤模型转化为CFD变量以预测设备诱导的血小板功能障碍。量化 设备损伤的血小板对胶原、vWF和纤维蛋白原的黏附能力可以用来代表 血栓形成和出血的设备相关电位。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SHEEP研究，以测试体内CFD模型 预测性建模。CFD模型将结合绵羊特定的血液特性、设备几何形状、设备 用于预测体内设备诱导的血小板的操作条件、血小板消耗和生成模型 绵羊在VADS和ECMO载体上的功能障碍和黏附能力的改变。圆满完成 该项目的实施将产生基于CFD的预测工具。这些工具可用于提供定量评估 对BCMD的性能和体内生物相容性进行研究，并帮助开发和优化新的 具有改进的功能特性和生物相容性的BCMD。