# In Silico Investigation of the RBC Velocity Fluctuations in Ex Vivo Capillaries
## 5 Pathophysiological Relevance  
Understanding the physical principles behind the RBC flow dynamics in individual capillaries is necessary for a better understanding of microcirculatory dysfunction in the central nervous system. Our findings indicate slight but persistent temporal fluctuations in RBC velocity, which are influenced by the level of hematocrit and capillary lumen irregularity. Although direct in vivo measurements of capillary velocity at the spatiotemporal resolution of our simulations is highly challenging, self-fluctuation of the RBC flux and velocity has been experimentally shown in brain capillaries in a recent study [61], underscoring the applicability of our findings to in vivo conditions. Such similar fluctuations in RBC flow were previously attributed to variations in cell size and rheological features, changes in capillary wall tonus, or the presence of leukocytes [62], while under high-hematocrit conditions, the underlying heterogeneity of the capillary luminal profile can be sufficient to trigger oscillations even with the uniform type of flowing RBCs. Our reported temporal fluctuations are small in absolute measurements. However, because the central nervous system contains a dense, interconnected network of capillaries, even minor velocity changes in individual vessels can build up cumulatively to affect blood flow dynamics at macroscopic levels. It has been shown in computational models that flow abnormality in a capillary can readily affect nearby interconnected capillaries; for example, a block can increase the probability of blocks in the nearby capillaries, spatially expanding the abnormality [63]. Therefore, small but repetitive fluctuations at multiple adjacent capillaries can, in theory, synchronize and amplify over time and space, leading to spontaneous oscillations in blood flow. If these fluctuations rise to a certain level, they can lead to the formation of capillary stalls, causing RBCs to come to a temporary halt in a capillary segment [64; 65; 66]. This is analogous to slight velocity disturbances in rapidly moving traffic dramatically escalating to a full traffic jam [67]. Although RBC stalls can occur to some extent in physiological situations, the number and frequency of capillary stalls increase prominently under acute and chronic neurological disorders like cerebral ischemia, epilepsy, Alzheimer's disease, sepsis, and even SARS-CoV-2 infection [60; 68; 69; 70; 71; 72]. The exact physical causes of capillary stalls are currently under active investigation, and our work and the future research on spontaneous capillary RBC velocity fluctuations can contribute to an understanding of these dynamic flow interruptions. It is now well established that the level of oxygen extraction in the central nervous system depends not only on the level of blood flow but also almost equally on the distribution of blood flow velocity across capillaries over space and time [73]. If this distribution is highly heterogeneous (i.e., high CTTH is present), oxygenated RBCs either shunt rapidly across low-resistance paths without delivering their oxygen to the tissue [74] or end up in very long anomalous transport routes [75], traveling in the tissue without benefits after being deprived of their oxygen content. Microcirculatory dysfunction due to excessive capillary transit time heterogeneity is found to be responsible for the pathophysiology of ischemic stroke, Alzheimer's disease, subarachnoid hemorrhage, traumatic brain injury, and many other debilitating conditions [76; 77; 78; 79]. Therefore, the spontaneous oscillations of RBC flow can have profound effects on tissue health and viability. Our results point to a strong contributing effect of high capillary hematocrit in the temporal velocity fluctuations of RBCs. Capillary hematocrit is dependent on arterial or venous hematocrit levels, which are measured routinely in clinical studies.