Experimental modeling of blood rheology and hemolysis in adult and pediatric blood

This cumulative dissertation focuses on the experimental modeling of blood rheology and shear stress-induced hemolysis in adult and pediatric blood in the context of mechanical circulatory support devices. These devices are an established, life-saving treatment option for advanced heart failure. However, their clinical use is limited due to severe adverse events. One of the main complications is hemolysis, the mechanically induced damage to red blood cells as a result of non-physiological fow conditions and increased shear stresses within the devices. Blood is a two-phase, non-Newtonian fuid whose rheological behavior is largely determined by the mechanical properties of red blood cells. Under realistic conditions, however, direct optical analysis of fow properties is almost impossible because whole blood is optically opaque. Furthermore, experimental investigation of shear stress-induced hemolysis with human blood is severely limited due to ethical, logistical, and regulatory restrictions. In particular, there are only a few studies that investigate hemolysis under precisely defned shear stresses and systematically take biological variability into account. This cumulative dissertation addresses three central research questions. The frst research question concerns the development of an experimental blood model for the optical analysis of blood fow in complex geometries. Since whole blood does not allow direct visualization of cell movement, cell deformation, and local fow phenomena due to its opacity, there is a fundamental need for transparent substitute models. The aim is to develop a two-phase blood model that reproduces the central rheological and mechanical properties of blood while enabling optical investigation of cell-scale processes. The dissertation shows that a transparent model with deformable red blood cell analogs allows qualitative investigation of migration, deformation, and the formation of cell-free layers under physiologically relevant shear conditions. This creates an experimental approach to analyzing potentially blood-damaging fow mechanisms in mechanical circulatory support devices, which cannot be achieved with real blood. At the same time, the conceptual and biological limitations of such models are critically evaluated in comparison to real blood. The second research question examines the extent to which existing empirical models for predicting shear stress-induced hemolysis can be experimentally validated under controlled conditions. Power law models are often used in the numerical design of mechanical circulatory support devices to describe hemolysis as a function of shear stress and exposure time. However, the parameters underlying these models originate from highly heterogeneous experiments with diferent species, shear geometries, and experimental conditions. The dissertation addresses this problem by performing systematic hemolysis measurements with adult and pediatric blood under precisely defned shear conditions in a Couette shear device. The results show that the predictions of the established parameter sets vary considerably and are only transferable to a limited extent. This makes it clear that existing hemolysis models without experimental validation have only limited validity for real mechanical circulatory support fows. The work thus makes an important contribution to classifying the applicability and limitations of power law hemolysis models. The third research question addresses the biological variability of human blood, particularly agerelated diferences between pediatric and adult blood. Clinical observations indicate an increased risk of hemolysis in pediatric mechanical circulatory support patients, but no experimental comparisons under identical shear conditions have been published to date. The dissertation shows that pediatric and adult blood respond diferently in terms of their susceptibility to hemolysis under identical, precisely controlled shear stresses. These diferences are interpreted in the context of age-related changes in the red blood cell population, cell age structure, and mechanical properties of the cell membrane. Experimentally, hemolysis was lower in pediatric blood than in adult blood, whereas clinically the opposite is observed, suggesting that this is primarily due to device-and operationspecifc stresses. The results of this dissertation demonstrate that improved experimental modeling of blood fow and hemolysis is only possible through a combination of transparent blood models, strictly controlled shear experiments, and systematic consideration of biological variability. The fndings contribute signifcantly to the further development of experimental test methods and to the more critical application of numerical hemolysis models, and form a basis for the age-appropriate optimization of future mechanical circulatory support devices.