Diabetes-mediated changes in red blood cell biomechanics reorganize capillary network hemodynamics through altered...

Diabetes alters shape and deformability of red blood cells (RBCs), thereby potentially modifying their transport through capillary networks. Microvascular dysfunction-including impaired capillary perfusion, endothelial dysregulation, and vascular remodeling-is a hallmark of diabetes. However, the contribution of altered RBC biomechanics to network-scale changes in capillary hemodynamics and the cellular-scale mechanisms underlying such changes remain poorly understood. Current in vivo imaging techniques cannot directly quantify critical hemodynamic parameters including endothelial mechanical load, capillary pressure, and the cell-free layer in vessels less than 10 microns in diameter. Nor can they identify the cellular-scale mechanisms responsible for network-scale hemodynamic changes. To bridge these gaps, we combined anatomically reconstructed human retinal capillary networks with a high-fidelity three-dimensional fluid-structure interaction model that fully resolves RBC deformation and transport. The simulations predict that diabetes-mediated alterations in RBC shape and deformability redistribute capillary hemodynamics with bidirectional, highly localized, and spatially heterogeneous changes. Compared to healthy RBCs, diabetic RBCs resulted in hematocrit changes by ±40%, RBC velocity by -30% to +40%, vessel pressure drop by twofold, and local wall shear stress nearly fourfold. Diabetic RBCs also shifted the Fåhræus relationship where the concentration of cells decreases with vessel diameter through diameter-dependent changes in the cell-free layer. Analysis of individual bifurcations identified three cellular-scale mechanisms underlying these network-scale changes: reduced lingering, capillary obstruction, and slower lateral migration of diabetic RBCs that altered their partitioning into downstream vessels. Together, these mechanisms reorganized downstream cellular trafficking and redistributed capillary hemodynamics throughout the network. These findings establish how diabetes-mediated alterations in RBC biomechanics give rise to localized microvascular dysfunction by linking single-cell biomechanics to altered cellular trafficking and emergent capillary network hemodynamics.