Advisor: Dr. Wilbur Lam (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University)

Committee Members:

Dr. David Myers (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University)

Dr. Tara Deans (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University)

Dr. Todd Sulchek (George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology)

Dr. Ovijit Chaudhuri (Department of Mechanical Engineering, Stanford University)

Dynamics of Blood Clot Viscoelasticity Mediates Clot Maturation via Platelet Mechanotransduction

Clot formation is an essential step in hemostasis and needs to be precisely regulated. Dysfunctional clot growth can manifest in different cardiovascular conditions. Excessive clotting can lead to thrombosis, while insufficient clotting can cause hemorrhagic disorders. While clot initiation has been extensively studied and well-characterized, clot cessation represents a critical gap in our understanding of the hemostatic process.  Clots represent a highly dynamic environment, rapidly transitioning from a liquid-like, viscous material to a solid-like elastic material. Platelets have been known to sense their mechanical environments, specifically substrate stiffness. I extend this reasoning to substrate viscoelasticity and hypothesize that clot viscoelasticity is a mechanical regulator of clot growth arrest. To test this, I will use tunable interpenetrating networks (IPNs) to investigate how substrate viscoelasticity regulates platelet activation at the molecular level, and how physiological shear stresses interact with clot mechanics to govern clot cessation. Aim 1 will establish physiological viscoelastic relevance of the IPNs by comparing their viscoelastic properties of the IPNs to whole blood clots and contrived spatial clot models. Aim 2 will be to investigate platelet response to viscoelastic microenvironments in both 2D and 3D environments and elucidate the molecular mechanisms that govern platelet activation through integrin-driven signaling pathways. Aim 3 will extend these findings to physiological flow conditions using microfluidic platforms, determining the synergistic effect of hemodynamic shear and clot viscoelasticity on platelet mechanotransduction. These studies will uncover viscoelastic mechanosensing as a previously unrecognized regulator of clot cessation, generating a new mechanobiological perspective for understanding hemostasis and thrombosis with direct implications for the development of precision therapies for both thrombotic and hemorrhagic disorders.