Collaborative Research: The Role of Tension in the Digestion of Blood Clots

Blood clots form in response to an injury and stop the flow of blood during the wound healing process. The structural scaffold of a blood clot is a mesh of fibers, composed of a biomaterial called fibrin. These fibers trap blood cells and other blood components during the clotting process. When wound healing is complete, the fibers must be digested by enzymes in the blood in order to prevent significant risks from a blocked blood vessel such as strokes and heart attacks. During the digestion process, flowing blood and blood cells subject the fibers to significant tension. However, it is not well understood how these forces on fibrin impact the digestion process. The aim of this research is to test several hypotheses about how tension could regulate the breakdown of blood clots. Results from this research will yield a deeper understanding of the causes that lead to increased risk of strokes and/or heart attacks due to improper blood clot digestion, providing avenues for improved national health. In addition, studying the blood clotting and breakdown processes involves collaborative research in biochemistry, medicine, engineering, mathematics, and physics, thus providing a robust training atmosphere for student researchers. This project will support a diverse group of undergraduate and graduate researchers at three different institutions, providing them with a multidisciplinary training environment. Moreover, the lead investigators will develop curricular materials to teach principles about tension and blood clot digestion to elementary school students using LEGO® during a 1-week STEM summer camp. During blood clot formation, fibrin polymerizes into a 3-dimensional gel wherein the fibers have inherent tension. After polymerization, clots are subject to applied tension, which originates from numerous sources including platelet contraction and blood hemodynamics. The fibrin network must withstand vascular forces during wound healing but then, to avoid blood vessel occlusion, must be dissolved through a process called fibrinolysis. A key knowledge gap lies in understanding the extent to which, and the mechanisms by which, inherent and applied tension regulate the fibrinolytic process. This project extends initial findings that inherent tension accelerates lysis while applied tension hinders lysis to perform the first multiscale study correlating amounts of fiber and clot tension with fibrinolytic rates. Each aim of this project centers on testing one hypothesized mechanism of how tension affects lysis: 1) causing structural rearrangements in the gel prior to lysis, shrinking the volume and expelling lytic enzymes; 2) altering the binding kinetics of enzymes to fibrin; and 3) causing structural rearrangements within the fibers and network structure during lysis, thereby clearing the fibrin more rapidly from the clot volume. Each hypothesis will be tested using a multidisciplinary research approach across three different institutions involving tensile testing, time-resolved microscopy, and mathematical modeling. This work will result in a combinatorial multiscale mathematical and experimental model that can predict lytic outcomes as a function of mechanical forces. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.