Search

We present a new model and extensive computations that explain the dramatic remodelling undergone by a fibrous collagen extracellular matrix (ECM), when subjected to contractile mechanical forces from embedded cells or cell clusters. This remodelling creates complex patterns, comprising multiple narrow localised bands of severe densification and fiber alignment, extending far into the ECM, often joining distant cells or cell clusters (such as tumours). Most previous models cannot capture this behaviour, as they assume stable mechanical fiber response with stress an increasing function of fiber stretch, and a restriction to small displacements. Our fully nonlinear network model distinguishes between two types of single-fiber nonlinearity: fibers that undergo stable (supercritical) buckling (as in previous work) versus fibers that suffer unstable (subcritical) buckling collapse. The model allows unrestricted, arbitrarily large displacements (geometric nonlinearity). Our assumptions on single-fiber instability are supported by recent simulations and experiments on buckling of individual beams with a hierarchical microstructure, such as collagen fibers. We use simple scenarios to illustrate, for the first time, two distinct compressive-instability mechanisms at work in our model: unstable buckling collapse of single fibers, and snap-through of multiple-fiber groups. The latter is possible even when single fibers are stable. Through simulations of large fiber networks, we show how these instabilities lead to spatially extended patterns of densification, fiber alignment and ECM remodelling induced by cell contraction. Our model is simple, but describes a very complex, multi-stable energy landscape, using sophisticated numerical optimisation methods that overcome the difficulties caused by instabilities in large systems. Our work opens up new ways of understanding the unique biomechanics of fibrous-network ECM, by fully accounting for nonlinearity and associated loss of stability in fiber networks. Our results provide new insights on tumour invasion and metastasis.

We present a new model and extensive computations that explain the dramatic remodelling undergone by a fibrous collagen extracellular matrix (ECM), when subjected to contractile mechanical forces from embedded cells or cell clusters. This remodelling creates complex patterns, comprising multiple narrow localised bands of severe densification and fiber alignment, extending far into the ECM, often joining distant cells or cell clusters (such as tumours). Most previous models cannot capture this behaviour, as they assume stable mechanical fiber response with stress an increasing function of fiber stretch, and a restriction to small displacements. Our fully nonlinear network model distinguishes between two types of single-fiber nonlinearity: fibers that undergo stable (supercritical) buckling (as in previous work) versus fibers that suffer unstable (subcritical) buckling collapse. The model allows unrestricted, arbitrarily large displacements (geometric nonlinearity). Our assumptions on single-fiber instability are supported by recent simulations and experiments on buckling of individual beams with a hierarchical microstructure, such as collagen fibers. We use simple scenarios to illustrate, for the first time, two distinct compressive-instability mechanisms at work in our model: unstable buckling collapse of single fibers, and snap-through of multiple-fiber groups. The latter is possible even when single fibers are stable. Through simulations of large fiber networks, we show how these instabilities lead to spatially extended patterns of densification, fiber alignment and ECM remodelling induced by cell contraction. Our model is simple, but describes a very complex, multi-stable energy landscape, using sophisticated numerical optimisation methods that overcome the difficulties caused by instabilities in large systems. Our work opens up new ways of understanding the unique biomechanics of fibrous-network ECM, by fully accounting for nonlinearity and associated loss of stability in fiber networks. Our results provide new insights on tumour invasion and metastasis. Author summary: Living tissue often comprises a complex network of fibrous collagen and other proteins called the Extracellular Matrix, or ECM, containing embedded cells at various distances from one another. Cells can interact with their environment and communicate with peers by exerting mechanical forces onto the ECM, which acts as a medium for signalling, migration and invasion. Observed mechanical response of the ECM to forces from contracting cells is unexpected. Distinctive patterns of narrow bands emerge, where fibers are collapsed and aligned, extending unusually far into the ECM, often joining distant cells or cell clusters, such as tumours. These bands serve as conduits for mechanical signalling or highways for cell migration, tumour invasion and cancer metastasis. We hypothesise that the formation of these striking patterns results from the inability of fibers to resist compression, much like rubber bands, and the fact that in a network, there is room for fibers to rotate, buckle and collapse. Our computations successfully predict the emergent striking patterns of ECM pathways consisting of densified aligned fibers and confirm our hypothesis that multiple compressive instability mechanisms are behind the phenomenon. This brings new understanding of the role of unstable mechanical behaviour of the ECM in aiding and abetting tumour invasion and metastasis. [ABSTRACT FROM AUTHOR]

We consider a model of energy minimization arising in the study of the mechanical behavior caused by cell contraction within a fibrous biological medium. The macroscopic model is based on the theory of non rank-one convex nonlinear elasticity for phase transitions. We study appropriate numerical approximations based on the discontinuous Galerkin treatment of higher gradients and used succesfully in numerical simulations of experiments. We show that the discrete minimizers converge in the limit to minimizers of the continuous problem. This is achieved by employing the theory of\Gamma-convergence of the approximate energy functionals to the continuous model when the discretization parameter tends to zero. The analysis is involved due to the structure of numerical approximations which are defined in spaces with lower regularity than the space where the minimizers of the continuous variational problem are sought. This fact leads to the development of a new approach to\Gamma-convergence, appropriate for discontinuous finite element discretizations, which can be applied to quite general energy minimization problems. Furthermore, the adoption of exponential terms penalizing the interpenetration of matter requires a new framework based on Orlicz spaces for discontinuous Galerkin methods which is developed in this paper as well. [ABSTRACT FROM AUTHOR]