The Structural Hierarchy and Mechanical Properties of Fibrin Described with a Multi-scale Model Public Deposited

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  • March 22, 2019
Creator
  • Hudson, Nathan E.
    • Affiliation: College of Arts and Sciences, Department of Physics and Astronomy
Abstract
  • Fibrin networks form the structural scaffold of blood clots during hemostasis. To survive in the dynamic environment of the vasculature, these networks have a diverse set of mechanical and dynamical properties. In this work, a series of experiments and molecular dynamics simulations bridge the gap between the mechanical properties of fibrin networks and the origins of those properties at the fiber and molecular scales. Mechanical measurements on individual fibrin fibers indicated that fibrin fibers are soft in stretching, strain stiffen, and exhibit an increased stiffness when ligated by transglutaminase FXIIIa. We hypothesized that these properties derived from one particular part of the fibrin molecule, the alpha-C region and developed a mechanical model for the fiber based on the extension of the alpha-C region. Measurements on the recoil dynamics of fibrin fibers indicated that they recoil on microsecond timescales and regain their full tension within a few ms of relaxation in agreement with the alpha-C model. In spite of the success of the alpha-C extension model, the fibrin molecule is complex and several other regions including the coiled coil region and the gamma-nodule have previously been implicated as potential sources of extension. To test these hypotheses we ran constant force Steered Discrete Molecular Dynamics Simulations on each region of the fibrin molecule. The simulations confirmed that the alpha-C region is the most likely to extend at forces as low as 10pN, but implicated other regions of the molecule as well. This led a more complete model for the mechanical properties of individual fibrin fibers dubbed the SLaCK model. Finally, to probe how the mechanical properties of individual fibrin fibers affect network strength, 2-D fibrin networks suspended between channels were stretched to failure using and Atomic Force Microscope. The strain of individual fibers in the network was tracked, and it was shown that fibrin network strength is enhanced by the strain stiffening of individual fibrin fibers. This work provides a framework for a predictive model in which the affects from alterations at the molecular level could be observed in the mechanical properties of the higher levels of the hierarchy.
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  • In Copyright
Advisor
  • Superfine, Richard
Degree
  • Doctor of Philosophy
Graduation year
  • 2011
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