Vascular-targeted particle binding efficacy in the presence of rigid red blood cells: Implications for performance in diseased blood.

The field of drug delivery has taken an interest in combating numerous blood and heart diseases via the use of injectable vascular-targeted carriers (VTCs). However, VTC technology has encountered limited efficacy due to a variety of challenges associated with the immense complexity of the in vivo blood flow environment, including the hemodynamic interactions of blood cells, which impact their margination and adhesion to the vascular wall. Red blood cell (RBC) physiology, i.e., size, shape, and deformability, drive cellular distribution in blood flow and has been shown to impact VTC margination to the vessel wall significantly. The RBC shape and deformability are known to be altered in certain human diseases, yet little experimental work has been conducted towards understanding the effect of these alterations, specifically RBC rigidity, on VTC dynamics in physiological blood flow. In this work, we investigate the impact of RBCs of varying stiffnesses on the adhesion efficacy of particles of various sizes, moduli, and shapes onto an inflamed endothelial layer in a human vasculature-inspired, in vitro blood flow model. The blood rigid RBC compositions and degrees of RBC stiffness evaluated are analogous to conditions in diseases such as sickle cell disease. We find that particles of different sizes, moduli, and shapes yield drastically different adhesion patterns in blood flow in the presence of rigid RBCs when compared to 100% healthy RBCs. Specifically, up to 50% reduction in the localization and adhesion of non-deformable 2 μm particles to the vessel wall was observed in the presence of rigid RBCs. Interestingly, deformable 2 μm particles showed enhanced vessel wall localization and adhesion, by up to 85%, depending on the rigidity of RBCs evaluated. Ultimately, this work experimentally clarifies the importance of considering RBC rigidity in the intelligent design of particle therapeutics and highlights possible implications for a wide range of diseases relating to RBC deformability.