The capture of circulating cells such as lymphocytes and metastatic tumor cells to the blood vessel wall is a complex process. Cell adhesion to the vascular endothelium depends on the forces of adhesion, the fluid dynamics, and the kinetics of adhesion molecule association-dissociation in the contact region. As a cell interacts with the surface, the participation of various adhesion molecules is determined by the force of contact (which must overcome surface protein electrostatic repulsive forces to bring the receptor-ligand pair into close proximity) and the time of contact (which must be long enough to allow at least one bond formation). Even though RBCs constitute 95% of the particles in blood and 30-45% of the total volume, they have largely been ignored as contributors to the process of adhesion. Since erythrocytes may increase both the contact force and contact time, studies performed in the absence of these cells may be inadequate for extrapolating the in vivo flow. For example, a receptor-ligand pair that does not extend very far above the glycocalyx (the glycoprotein-rich envelope surrounding the cell) may not be able to engage in saline solution, but with the additional forces imparted by RBCs, the cell membranes may come into closer contact, allowing bond formation. Also, larger contact forces should result in larger contact areas, thereby increasing the number of adhesion molecules available for binding; this would increase the probability of cell arrest. The presence of RBCs may also change the spatial distribution of leukocytes in the flow stream, pushing them from the bulk toward the wall. The proposed study will quantify the physical forces and rheological characteristics an adhering cell experiences in the bloodstream. The resulting information will be invaluable in 1) the extrapolation of flow chamber studies to in vivo adhesion, 2) the development of more physiologic blood substitutes, 3) explaining and overcoming immune surveillance by solid tumors and 4) formulation of novel strategies for prevention of atherosclerosis.
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