Strain history dependence of the nonlinear stress response of fibrin and collagen networks

Abstract

We show that the nonlinear mechanical response of networks formed from un-cross-linked fibrin or collagen type I continually changes in response to repeated large-strain loading. We demonstrate that this dynamic evolution of the mechanical response arises from a shift of a characteristic nonlinear stress-strain relationship to higher strains. Therefore, the imposed loading does not weaken the underlying matrices but instead delays the occurrence of the strain stiffening. Using confocal microscopy, we present direct evidence that this behavior results from persistent lengthening of individual fibers caused by an interplay between fiber stretching and fiber buckling when the networks are repeatedly strained. Moreover, we show that covalent cross-linking of fibrin or collagen inhibits the shift of the nonlinear material response, suggesting that the molecular origin of individual fiber lengthening may be slip of monomers within the fibers. Thus, a fibrous architecture in combination with constituents that exhibit internal plasticity creates a material whose mechanical response adapts to external loading conditions. This design principle may be useful to engineer novel materials with this capability.ECM | nonlinear rheology | factor XIII | blood clot N etworks of stiff biopolymer fibers are a major component of the structural architecture of multicellular organisms; their unique material properties provide rigidity and protect structural integrity. These networks are particularly important in the extracellular matrix (ECM) where they provide mechanical support to living cells and form many of the load-carrying structures in the body. One important example is fibrin, which forms the underlying scaffold of blood clots and the provisional matrix (1). Another important example is collagen type I, the major structural constituent of all connective tissue, tendons, ligaments, and bone (2). Because the in vivo structure of these fiber networks is so complex, investigations of in vitro networks of both proteins have been used to explore their structure and unique mechanical properties, and to elucidate their underlying design principles. Interestingly, fibrin and collagen exhibit many similar features: Both proteins self-assemble into thick, hierarchically ordered, rather stiff fibers through electrostatic and hydrophobic interactions (3, 4); these fibers associate into sparse, 3D networks that possess unusual mechanical properties not seen in synthetic polymers. In both cases, these networks display highly nonlinear mechanics and stiffen significantly as the strain increases (5-8). In addition, they are both also viscoelastic: They partially store elastic energy and partially relax internal stress through dissipative processes (9-12). All of these properties are delicately influenced by the structure of the networks, by the molecular interactions between monomers, and by the addition of covalent cross-links (7,13,14). This creates a delicate interplay between the viscoelastic and nonlinear mechanical properties of these ne...

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

“…We must point out that local fiber recruitment is closely related to the inelastic (history-dependent) bulk response of biopolymer networks (27)(28)(29). In particular, mechanical straining accelerates the dissociation of weak cross-links (30), leading to macroscale plastic deformation of the matrix.…”

“…In particular, mechanical straining accelerates the dissociation of weak cross-links (30), leading to macroscale plastic deformation of the matrix. It had been shown that such an effect is more prominent at long timescales (27) and large strains (28,29), whereas it diminishes with the addition of permanent covalent cross-links (28,29). In contrast, networks that only have weak crosslinks are more dissipative and undergo larger stress relaxations (29).…”

Modeling the formation of cell-matrix adhesions on a single 3D matrix fiber

“…For example, collagen type I exhibits a viscoelastic behavior, they store elastic energy and partially relax internal stress through dissipative process [33]. The fiber crosslinkers exhibit a complex behavior and when they are subjected to a high level of force they can break down.…”

The application of large amplitude oscillatory stress in a study of fully formed fibrin clots

“…9 Thus, it is important to consider the effects of both the vast range and progressive increase in stress experienced by fully formed clots. Marked changes in the structure and rheological properties of the clot can arise as a consequence of shear stress through several different mechanisms including strain-stiffening of the fibrin network, 11 strain-stiffening of individual fibrin fibres, 12,13 protein unfolding of stretched fibres, 14 unfolding of fibrin monomers, 15 yielding of branching points, 16 slippage of protofibrils within fibres, 17 and breakage of individual fibrin fibres. 18,19 The propensity of the formed blood clot to macroscopically fracture may be influenced by all of the aforementioned mechanisms.…”

“…Large Amplitude Oscillatory Shear (LAOS) has been used in a controlled strain manner to perform repeated large strain loadings on fibrin clots and the data were presented using Lissajous-Bowditch curves. 17,25 Using repeated cyclic strain loadings, Münster et al 17 showed the ability of un-crosslinked fibrin clots to adapt to stress through the slippage of protofibrils. Moreover, the LAOS studies of van Kempen et al 25 revealed several nonlinear features of fibrin clots, including time-dependent softening, intra-cycle strain stiffening, and increased viscous dissipation with increased strain, illustrating the usefulness of LAOS in capturing rich nonlinear behaviour.…”