Platelet Adhesion and Activation in an ECMO Thrombosis-on-a-Chip Model.

Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis-on-a-chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real-time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P-selectin activation compared to connector material, polycarbonate. This ECMO thrombosis-on-a-chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti-thrombotic biomaterials to ultimately reduce medical device thrombosis, anti-thrombotic drug use and therefore bleeding complications, leading to safer blood-contacting medical devices.

Biomaterial Wettability Affects Fibrin Clot Structure and Fibrinolysis.

Thrombosis on blood-contacting medical devices can cause patient fatalities through device failure and unstable thrombi causing embolism. The effect of material wettability on fibrin network formation, structure, and stability is poorly understood. Under static conditions, fibrin fiber network volume and density increase in clots formed on hydrophilic compared to hydrophobic polystyrene surfaces. This correlates with reduced plasma clotting time and increased factor XIIa (FXIIa) activity. These structural differences are consistent up to 50 µm away from the material surface and are FXIIa dependent. Fibrin forms fibers immediately at the material interface on hydrophilic surfaces but are incompletely formed in the first 5 µm above hydrophobic surfaces. Additionally, fibrin clots on hydrophobic surfaces have increased susceptibility to fibrinolysis compared to clots formed on hydrophilic surfaces. Under low-flow conditions, clots are still denser on hydrophilic surfaces, but only 5 µm above the surface, showing the combined effect of the surface wettability and coagulation factor dilution with low flow. Overall, wettability affects fibrin fiber formation at material interfaces, which leads to differences in bulk fibrin clot density and susceptibility to fibrinolysis. These findings have implications for thrombus formed in stagnant or low-flow regions of medical devices and the design of nonthrombogenic materials.

Evaluating medical device and material thrombosis under flow: current and emerging technologies.

Although blood-contacting medical devices are used widely, blood clot formation (thrombosis) leads to device failure and potentially catastrophic adverse thrombotic events for patients, such as stroke or pulomonary embolism. Systemic anti-thrombotic drugs aimed at reducing these complications do not always prevent device thrombosis and can cause increased bleeding risks. Therefore, our understanding of material thrombosis mechanisms needs to be improved in order to develop next generation blood-contacting medical devices and materials. Medical device development requires material thrombogenicity evaluation according to the International Standards 10993-4 Biological evaluation of medical devices-Selection of tests for interactions with blood, which highlights that one of the key aspects for testing is a clinically relevant flow system. In this review, we first provide an overview of the current knowledge regarding material thrombosis and important physical and biological aspects of blood flow in relation to thrombus formation. We then examine commonly used in vitro flow systems to evaluate material and medical device thrombosis, focusing on their capabilities, advantages and disadvantages. Finally, we explore recent advances in technology that will aid in improving the design and fabrication of flow systems, mechanistic analysis and computational modelling.