Experiment-based multi-scale modeling of the tensile and compressive deformations of fibrin

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Experiment-based multi-scale modeling of the tensile and compressive deformations of fibrin Prashant K. Purohit and John W. Weisel University of Pennsylvania, Philadelphia, PA 19104. Abstract: The research objective of this proposal is to measure, model and predict the tensile and compressive response of fibrin clots at the molecular and continuum scales. This is important because there are no comprehensive models that link the molecular mechanics to the macroscopic deformation of clots and thrombi, even though they experience deformation/alteration at all scales during their normal function in hemostasis and in pathological situations of thrombosis. We have shown that macroscale fibrin clots can be stretched to three or four times their original length in uniaxial tension due to mechanical unfolding of fibrin monomers at the nanometer scale. In compression, we have shown that the deformation of a clot is analogous to that of a foam and proceeds by the motion of a compression front, behind which the network densifies due to buckling of fibers and creation of inter-fiber contacts. These features are captured in our models that can quantitatively describe and predict how molecular and fiber level mechanics has implications for the macroscopic response of clots. Our models allow us to tune the macroscale mechanical behavior of clots by altering the molecular building blocks and the structural parameters of the network. This idea will be put to the test when we (a) modulate the equilibrium tensile response of clots by altering the network structural parameters, and (b) investigate how cross-linking of oligomers affects the dependence of the tensile response on the strain rate. We can also alter the nanoscale structure of fibrin and use our model to predict the consequences for macroscopic clots. Our target is the  C region of fibrin, which is known to vary depending on the species and has been shown to play a part in controlling the tensile stiffness and extensibility of single fibrin fibers as well fibrin clots. For compression, we will show that the deformation of platelet-poor plasma clots, platelet-rich plasma clots, whole blood clots and thrombi is also foam-like, and then predict and measure their response to localized loads. Such localized loads could be encountered in clinical situations, such as the interaction of catheters or bubbles with thrombi. We will also investigate the effect of the  C region on the compression response of clots. Our models are based on continuum mechanical principles for the study of polymeric materials and foams, as well as statistical mechanics models describing forced unfolding of single protein molecules. The proposed experiments cover the whole gamut of macroscopic uniaxial tension tests, atomic force microscopy experiments including stretching of oligomers and indentation of clots, rheometry to measure the storage and loss moduli in compression, electron microscopy as well as fluorescence microscopy to visualize the structure of fibrin clots. Our models and experiments will help answer clinically important questions, such as why is there a strong correlation between clot structure/mechanical properties and cardiovascular disease, and also help design biomaterials with unique mechanical properties by altering the structure of fibrin at the nanoscale.