Structural Hierarchy Governs Fibrin Gel Mechanics

Abstract

Fibrin gels are responsible for the mechanical strength of blood clots, which are among the most resilient protein materials in nature. Here we investigate the physical origin of this mechanical behavior by performing rheology measurements on reconstituted fibrin gels. We find that increasing levels of shear strain induce a succession of distinct elastic responses that reflect stretching processes on different length scales. We present a theoretical model that explains these observations in terms of the unique hierarchical architecture of the fibers. The fibers are bundles of semiflexible protofibrils that are loosely connected by flexible linker chains. This architecture makes the fibers 100-fold more flexible to bending than anticipated based on their large diameter. Moreover, in contrast with other biopolymers, fibrin fibers intrinsically stiffen when stretched. The resulting hierarchy of elastic regimes explains the incredible resilience of fibrin clots against large deformations.

Fibrin network adaptation to cell-generated forces

“…In our study, G 0 of fibrin networks followed a power-law in concentration with an exponent of 1.5. This exponent is in good agreement with prior measurements on fibrin networks where G 0 followed a power-law in concentration with an exponent of nearly 2.0 and 2.3 measured by macrorheology (Jansen et al 2013;Piechocka et al 2010). The magnitude of the moduli measured by macrorheology is greater than our measurement.…”

“…The magnitude of the moduli measured by macrorheology is greater than our measurement. Fibrin networks were prepared under similar fibrin conditions, but in our study, the fibrinogen concentration range was small, i.e., 1 to 3 mg/ml, compared to other studies where the range was 0.1 to 6 mg/ml (Jansen et al 2013) and 0.1 to 8 mg/ml (Piechocka et al 2010). The difference in magnitude of the moduli can be explained by the smaller range of fibrinogen concentration used in our study.…”

“…These forces lead to reorganization of the matrix fibers around them (Notbohm et al 2015). Reorganization is the first stage of the matrix remodeling process and takes place over a few hours to a few days (Piechocka et al 2010). Structural remodeling of fibrin networks due to cellular traction forces is a complex process, in part because fibrin networks are not linearly elastic, exhibiting strain-stiffening when subjected to large deformations (Piechocka et al 2010).…”

“…Reorganization is the first stage of the matrix remodeling process and takes place over a few hours to a few days (Piechocka et al 2010). Structural remodeling of fibrin networks due to cellular traction forces is a complex process, in part because fibrin networks are not linearly elastic, exhibiting strain-stiffening when subjected to large deformations (Piechocka et al 2010). The differences found in cellular shape between the dilute fibrin networks with 1 or 2 mg/ml fibrinogen and the denser fibrin network with 3 mg/ml fibrinogen 1 day after cell seeding indicate differences in reorganization.…”

“…Cells in dilute fibrin networks are elongated and extend several thin protrusions into the network, while cells in denser fibrin networks remain round and extend short and thin protrusions into the network (Jansen et al 2013). Since mesh size decreases with the square-root of fibrinogen concentration (Piechocka et al 2010), the smaller mesh size in dense fibrin networks can constrain the cell body and can impede the extensions of protrusions. Fibrin's plasticity can direct and control cell morphology and migration (Notbohm et al 2015).…”