Impact of Blood Rheology on Chronic and Systemic Effects in Sickle Cell Disease

Abstract

In sickle cell disease, blood rheological changes driven by oxygen-dependent effects in red blood cell mechanics and vascular biology are critical to understanding the complex patient pathophysiology. Existent research has focused on the contributions of rheological and single cell changes to disease pathology however their emphasis has been on acute, proximal effects leaving systemic, chronic issues unaddressed. In addition, the methodology of many of these studies has lacked physiological relevance and model systems that offer the tunability and observational capacity to collect the necessary information to understand the fundamental mechanisms of the anomalous rheological behavior sickle cell disease patients express. To solve many of these issues, we present a series of studies with the main goals of: 1) developing model systems to characterize the physiologically relevant behaviors of sickle rheology, 2) quantification of different features of rheological behavior and their physiological relevance for patients, and 3) identification of biomarkers that offer clinical course predictability and evaluation of patient complications and treatment regimens. To accomplish these goals, we develop a microfluidic platform to mimic physiologically relevant features of blood flow in the vasculature. The platform allows detailed data collection of multiple rheological features allowing a thorough analysis of patient rheological behavior. Using this methodology, we report on the oxygen-dependent velocity and viscosity changes sickle rheology expresses and understand the types of fluid behaviors and transitions expressed by sickle patients. Via the application of computer vision and computational fluidic models, we also identify patient-specific rheological parameters whose physiological relevance offer insights into the contributions rheological abnormalities have on the complications for sickle cell disease patients. These parameters also highlight the systemic alterations sickle blood flow displays and identifies the increased risk these patients have for vascular complications. Next, associated biomarkers are preliminarily implemented and utilized as clinical predictors to determine their potential as predictive tools for patient-specific care utilizing vascular representations directly obtained from patients. Finally, a model system for evaluation of single cell characteristics is introduced and used to reveal the heterogenous nature of red blood cells and their impact on whole blood rheology.