Vital erythrocyte phenomena: what can theory, modeling, and simulation offer?

We overview recent advances in the theoretical modeling, in particular via numerical simulation, of various vital human erythrocyte phenomena. The review is novel in how it interconnects a range of analysis within a coherent framework and focuses on extracting from them specific suggestions for experimental studies focused on, either validation of the analysis' mechanistic basis, or uncovering heretofore unrecognized effects and mechanistic understanding. In some cases, new analysis is described to fill in gaps and expand on previously published findings. Moreover, the presentation makes clear what new knowledge is required to further advance what is envisioned to be a truly quantitative approach to understanding the human blood cell. The entire treatment is based on, and designed to directly couple to, experimental observations. A specific goal is to point to a more quantitative and predictive approach to understanding human erythrocyte phenomena and their connectivity. Among the phenomena analyzed are: (1) membrane skeletal dynamics, per se, and how it is involved in (2) transmembrane molecular transport, e.g., glucose uptake; (3) red cell vesiculation, especially as it may occur during splenic flow; and (4) how skeletal dynamics affects both phenomena. Red cell flow is analyzed in complex flows such as oscillatory shear flow and during cell passage through splenic-like venous slits. We show, and perhaps remarkably, that the deformation modes that develop during both, apparently disparate, flows are actually quite similar. This finding suggests a novel methodology for experimentally studying splenic-like vesiculation. Additional analysis is presented that examines the effect of skeletal defects, including disruptions in its membrane connectivity, on molecular transport and vesiculation. As an example, we explore a reported effect of skeletal disruptions at the anion transporter, Band 3, on glucose uptake and efflux at the GLUT1 which are connected via the spectrin skeleton.