The lymphatic vasculature is crucial to many physiologic functions of the body including returning fluid and proteins from various tissues back to the venous circulation, absorbing most dietary fat from the intestine, and providing a route for immune cells to be transported to the lymph nodes. To perform these tasks, the lymphatic system relies on the coordinated pumping of lymphatic vessels, and the presence of valves that separate each pumping unit, to move fluid through the lymphatic system. Interestingly the most common genetic defects that produce significant lymphatic pathologies, are those that alter lymphatic valves. However, in spite of their importance, very little is known regarding the mechanical properties of these valves, and how subtle alterations in these properties compromise the performance of the lymphatic system. Thus, computational modeling will be used together with mechanical testing of lymphatic valves from a variety of species to determine how alterations in lymphatic valve geometries and mechanical properties influence lymphatic function of in individual vessel as well as across a lymphatic network.
This project will advance our fundamental understanding of how lymphatic valve structure is designed to achieve optimal performance in a variety of conditions. An intrinsic trade-off exists between the valves ability to prevent backflow under an adverse pressure gradient, and the resistance the valve provides to flow in the forward direction. Atomic force microscopy will be utilized to probe the mechanical stiffness of valve leaflets isolated from various regions in the body while geometric data will be obtained from vessel dissections and histology. Valve kinematics will be ascertained through high speed spinning-disk confocal microscopy. A fluid structure interaction (FSI) model of a lymphangion and valve will be created using the lattice-Boltzmann method (LBM) to model fluid mechanics, whereas a nonlinear finite element model (FEM) will be harnessed to represent the nonlinear behavior of the biological tissues. The valve kinematics produced with this FSI model will be compared to the experimentally measured values. The single vessel model will then be coupled into a lumped-parameter model of a chain of lymphatic vessels to determine how changes in individual valves alter bulk lymphatic flow at larger length scales. This combined modeling and experimental approach is expected to yield unique mechanistic insights into lymphatic valve optimization and morphogenesis in vivo.
