Assistant Professor New Jersey Institute of Technology, United States
Introduction: In the microcirculation, red blood cells (RBCs) interact hydrodynamically with circulating cells (CCs), such as leukocytes or cancer cells, causing these cells to move alongside the vessel wall. This process, known as margination, is crucial for the extravasation of cells from the bloodstream into surrounding tissues. Traditionally, our understanding of the fluid mechanics behind margination has been based on straight tube flow, where CCs do not marginate without the presence of RBCs. Recent research has uncovered that at low Reynolds numbers, deformable cells can move toward the vessel wall due to vessel curvature. This suggests that margination can occur even in the absence of RBCs in tortuous microvessels, which are commonly found in vivo with their back-and-forth bending patterns. In a first-of-its-kind study, this work utilizes high-fidelity 3D cell-resolved simulations to reveal and quantify the margination behavior of a CC flowing through a tortuous microvessel digitally reconstructed from in vivo images.
Materials and
Methods: This work involves modeling a digitally reconstructed 1 mm long segment of a 20 µm diameter in vivo vessel with notable tortuosity (Fig 1A). 3D computational fluid dynamics simulations are conducted using an approach based on the immersed boundary method to model biophysical flows in complex geometries. The model has been extensively validated in prior works against experimental data. For the current work, blood is simulated as a suspension of three-dimensional RBCs and a CC flowing alongside plasma. The simulations consider a wide range of microcirculation conditions by systematically varying hematocrit, effective shear rate, and initial cell position.
Results, Conclusions, and Discussions: This study is the first to investigate CC margination in an in vivo tortuous microvessel using 3D cell-resolved hemodynamics, unlike previous research on straight tubes. We analyzed complex output data using a local margination plane (Fig 1C), allowing us to quantify CC margination behavior in a time-averaged manner across various conditions (Fig 1E). Our findings showed that regardless of the initial position, CCs tend to marginate by the time they reach the end of the vessel. We identified a crucial distinction between margination to the cell-free layer (CFL) and near-wall regions, which has often been overlooked in previous studies. This differentiation is significant because the distance between the cell surface and vascular walls can influence adhesion, depending on the cell type, organ, or other physiological factors. We observed that once CCs marginate to the CFL in a tortuous vessel, they tend to stay marginated (Fig 1F), a behavior distinctly different from that in straight tubes. By comparing behavior under various conditions with margination in equivalent straight tubes, we showed that vessel tortuosity can either enhance or reduce margination residence time. Specifically, tortuosity can enable margination at low hematocrit levels, which would not occur in a straight vessel. Conversely, at higher hematocrit levels or low shear rates, where margination typically occurs in straight vessels, tortuosity can reduce this behavior by temporarily pulling CCs away from the walls. The findings have important implications for understanding the margination mechanism in vessel morphologies more physiologically realistic than idealized straight tubes. Given the central role played by CC margination in cancer metastasis or leukocyte extravasation, this study lays the groundwork for predicting metastatic attachment sites or developing new treatments to augment the body’s response to infection.
Acknowledgements (Optional):
References: Balogh et. al, JCP., 2017.
Funding and Support: NSF CBET 2309559, and Expanse at the San Diego Supercomputer Center per NSF Accelerate Award BIO230073.
