Microfluidic devices are an extremely useful tool to explore in vitro the pathophysiology of many different cardiovascular diseases. In this work, we designed two microfabricated platforms, one for the study of RBCs transmigration through the spleen and to characterize three dimensional forces exerted by cells. Red blood cells (RBCs) are cleared from the circulation when they become damaged or display aging signals targeted by macrophages. This process occurs mainly in the spleen, where blood flows through submicrometric constrictions called inter-endothelial slits (IES), subjecting RBCs to large-amplitude deformations. In this work, RBCs are circulated through microfluidic devices containing microchannels that replicate the IES. The cyclic mechanical stresses experienced by the cells affect their biophysical properties and molecular composition, accelerating cell aging. Specifically, RBCs quickly transition to a more spherical, less deformable phenotype that hinders microchannel passage, causing hemolysis. This transition is associated with the release of membrane vesicles, which self-extinguishes as the spacing between membrane-cytoskeleton linkers becomes tighter. Proteomics analysis of the mechanically aged RBCs reveals significant losses of essential proteins involved in antioxidant protection, gas transport, and cell metabolism. Finally, it is shown that these changes make mechanically aged RBCs more susceptible to macrophage phagocytosis. These results provide a comprehensive model explaining how physical stress induces RBC clearance in the spleen. The data also suggest new biomarkers of early "hemodamage" and inflammation preceding hemolysis in RBCs subjected to mechanical stress. Force exertion is an integral part of cellular phenotype regulating important cell functions and fate. In order to quantify mechanical forces at the cellular scale, traction force microscopy has traditionally been considered a standard when quantification of forces at the cell-substrate interface are required. However, quantification of compressive and shear stresses in three dimensions have been elusive due to the lack of experimental and computational techniques appropriate for this sizable challenge. This dissertation presents a novel methodology to produce photo-initiated elastic round microgels that can be functionalized and embedded in three dimensional tissues for force quantification.