“Fluctuating Hemorheology and Its Impact on Molecular and Cellular Mechanobiology in Thrombosis and Hemostasis”

Dept: Chemical & Biomedical Engineering

Chair: Zixiang Leonardo Liu, Ph.D.

Abstract

Blood exhibits complex rheological behavior as a concentrated suspension of cells and molecules. It is well recognized that blood is a non-Newtonian (shear-thinning) fluid, as reflected in its bulk rheology; however, bulk hemorheology often fails to explain what happens at the cellular and subcellular scales, such as platelet migration and margination, which are driven by subcellular scale hydrodynamic interactions that are essential to thrombosis and hemostasis. Despite their central importance in blood-related diseases, the transport, adhesion, and biogenesis or lysis of proteins and cells, driven by micro-hemorheology, remain poorly understood. The primary goal of this dissertation is to investigate how hemorheology influences and regulates molecular and cellular biological responses, aiming to bridge the fields of biorheology and mechanobiology. By exploring the interplay between hemorheology and molecular/cellular function, this work aims to elucidate the critical role of hemorheological forces in mechanobiological processes and to highlight their implications for health and disease.

First, through direct numerical simulation of cellular blood flows in a viscometric flow setting, we examine the micro-flow statistics in concentrated cellular or particle suspensions. Our study shows that particle suspension induces hydrodynamic stress fluctuations that can increase the local stress magnitude by up to 3-fold. Moreover, we observed pure elongational flow structures arising from local confinement-induced acceleration-deceleration flows, which are absent in single-phase flow systems. Next, by combining multiscale simulations and in vitro rheometer tests, we examine how fluctuations and cellular-level interactions regulate Von Willebrand factor (VWF) activation and cleavage. For the first time, we show that the presence of RBCs creates local elongational flow, resulting in an instantaneous elevation of VWF tension and enhanced VWF cleavage. This work highlights the overlooked mechanical role of RBCs in enhancing the mechano-activation of VWF, opening a completely new mechanical pathway for regulating thrombosis and hemostasis. Lastly, we combine computational and experimental microfluidics to develop shear-responsive RBCs for targeted drug delivery. We demonstrate that the shear-responsive RBC drug carrier locally releases its cargo at sites of stenosis where shear is high. We demonstrate that the release kinetics of sr-RBCs are directly controlled by the RBC tank-treading-induced instantaneous pore-opening.

The findings presented in this dissertation provide mechanistic insight into the relationship between complex micro-hemorheology and molecular and cellular biological responses, thereby furthering understanding of the bleeding and thrombotic complications associated with cardiovascular and hematological diseases.