arXiv subjects

Ayelet Lesman

Publications and source records attributed to Ayelet Lesman.

7 recordsLinked to original sources

arXiv2026

Local Strain-Dependent Anisotropy in Fibrous Networks

Cells in connective tissues reside within the extracellular matrix (ECM), which consists of a fibrous mesh that exhibits non-linear strain-stiffening behavior, driven by a transition from bending-to-stretching-dominated deformation. While bulk rheology captures macroscopic mechanical properties, cells actively sense and respond to local microscale heterogeneities and stiffness anisotropy in their environment. Characterizing ECM micromechanics is therefore essential for understanding the mechanical cues experienced by cells. This study quantifies local stiffness anisotropy in stretched fibrous gels by combining experimental and numerical approaches. Experimentally, we utilized optical tweezers microrheology to measure local stiffness in fibrin gels subjected to uniaxial stretch. The gels demonstrated gradual local stiffening along both the tensile and perpendicular axes, with a more profound increase along the tensile axis, resulting in local anisotropy. To investigate the physical parameters driving this phenomenon, we developed a 3D finite element model of a discrete random fiber network, successfully replicating the experimental local stiffening and anisotropy. Numerical analysis further revealed that within the sub-isostatic region, both fiber thickness and network connectivity strongly influence local anisotropy: slender fibers and higher connectivity amplify the anisotropy by up to an order of magnitude. This contributes to the formation of a highly anisotropic local environment, thereby playing a significant role in directing mechanically driven biological processes, such as cell migration and durotaxis. Our simulations also indicate that local micromechanical responses may differ from the material's global stiffening behaviors, highlighting the need for characterization at the microscopic scale.

cond-mat.soft↗

arXiv2026

Micromechanical statistical model links induced nematic order to mechanical response in fiber networks

Contractile cells and external loads reorganize the fibrous extracellular matrix, aligning and compacting fibers over distances far exceeding a cell's size, strongly affecting bioprocesses such as wound healing, angiogenesis and tumor invasion. We develop a continuum micromechanical theory that links, at every material point, the load-induced orientational order to the mechanical response that the reoriented network then exhibits. The network is described statistically, by the probability density of fiber orientations, and deforms affinely, so that a single-fiber stress-strain law is carried into the network stress, with the deformation set self-consistently by mechanical equilibrium. Critical to realistic biological relevant conditions, this theory allows both geometrical and material nonlinearities. Applied to a two-dimensional network under uniaxial stretch, the theory collapses onto a single anisotropy parameter that governs the orientation distribution, the nematic order, the Poisson ratio, and the densification of fibers. Our theory reveals that induced order and densification are highly positively correlated, and in the case of uniaxial stretch they collapse onto a nearly universal curve, independent of the single-fiber stiffness behavior. For a contracting cell, we find that buckling controls how far nematic orientational order and densification propagate. We find an algebraic decay of deformations with distance and solve for the dependence of the power-law exponent on the buckled-reduced stiffness of a single fiber. We validate our theory by comparison with non-affine discrete fiber-network simulations.

cond-mat.soft↗

arXiv2020

Target finding in fibrous biological environments

We use a lattice model to study first-passage time distributions of target finding events through complex environments with elongated fibers distributed with different anisotropies and volume occupation fractions. For isotropic systems and for low densities of aligned fibers, the three-dimensional search is a Poisson process with the first-passage time exponentially distributed with the most probable finding time at zero. At high enough densities of aligned fibers, elongated channels emerge, reducing the dynamics dimensionality to one dimension. We show how the shape and size of the channels modify the behavior of the first-passage time distribution and its short, intermediate, and long time scales. We develop an exactly solvable model for synthetic rectangular channels, which captures the effects of the tortuous local structure of the elongated channels that naturally emerge in our system. For arbitrary values of the nematic order parameter of fiber orientations, we develop a mapping to the simpler situation of fully aligned fibers at some other effective volume occupation fraction. Our results shed light on the molecular transport of biomolecules between biological cells in complex fibrous environments.

cond-mat.stat-mech↗

arXiv2019

Mechanical Interaction Between Cells Facilitates Molecular Transport

In vivo, eukaryotic cells are embedded in a matrix environment, where they grow and develop. Generally, this extracellular matrix (ECM) is an anisotropic fibrous structure, through which macromolecules and biochemical signaling molecules at the nanometer scale diffuse. The ECM is continuously remodeled by cells, via mechanical interactions, which lead to a potential link between biomechanical and biochemical cell-cell interactions. Here, we study how cell-induced forces applied on the ECM impacts the biochemical transport of molecules between distant cells. Experimentally, we observe that cells remodel the ECM by increasing fiber alignment and density of the matrix between them over time. Using random walk simulations on a 3D lattice, we implement elongated fixed obstacles that mimic the fibrous ECM structure. We measure both diffusion of a tracer molecule and the mean first-passage time a molecule secreted from one cell takes to reach another cell. Our model predicts that cell-induced remodeling can lead to a dramatic speedup in the transport of molecules between cells. Fiber alignment and densification cause reduction of the transport dimensionality from a 3D to a much more rapid 1D process. Thus, we suggest a novel mechanism of mechano-biochemical feedback in the regulation of long-range cell-cell communication.

physics.bio-ph↗

arXiv2019

Elastic Anisotropy Governs the Decay of Cell-induced Displacements

The unique nonlinear mechanics of the fibrous extracellular matrix (ECM) facilitates long-range cell-cell mechanical communications that would be impossible on linear elastic substrates. Past research has described the contribution of two separated effects on the range of force transmission, including ECM elastic non-linearity and fiber alignment. However, the relation between these different effects is unclear, and how they combine to dictate force transmission range is still elusive. Here, we combine discrete fiber simulations with continuum modeling to study the decay of displacements induced by a contractile cell in fibrous networks. We demonstrate that fiber non-linearity and fiber reorientation both contribute to the strain-induced anisotropy of the elastic moduli of the cell local environment. This elastic anisotropy is a parameter that governs the slow decay of the displacements, and it depends on the magnitude of applied strain, either an external tension or an internal contraction as a model of the cell. Furthermore, we show that accounting for artificially-prescribed elastic anisotropy dictates the displacement decay induced by a contracting cell. Our findings unify previous single effects into a mechanical theory that explains force transmission in fibrous networks. This work provides important insights into biological processes that involve the coordinated action of distant cells mediated by the ECM, such that occur in morphogenesis, wound healing, angiogenesis, and cancer metastasis. It may also provide design parameters for biomaterials to control force transmission between cells, as a way to guide morphogenesis in tissue engineering.

physics.bio-ph↗

arXiv2018

Nonlinear elasticity of the extracellular matrix fibers facilitates efficient inter-cellular mechanical communication

Biological cells embedded in fibrous matrices have been observed to form inter-cellular bands of dense and aligned fibers, through which they mechanically interact over long distances. Such matrix-mediated cellular interactions have been shown to regulate a variety of biological processes. The current study was aimed at exploring the effects of elastic nonlinearity of the fibers contained in the extracellular matrix (ECM) on the transmission of mechanical loads between contracting cells. Based on our biological experiments, we developed a finite-element model of two contracting cells embedded within a fibrous network. The individual fibers were modeled as showing either linear elasticity, compression-microbuckling, tension-stiffening or both of the latter. Compression-buckling resulted in smaller loads occurring in the ECM, but these were more directed toward the neighboring cell. The latter decreased with increasing cell-to-cell distance; when cells were >15 cell-diameters apart, no such inter-cellular interaction was observed. Tension-stiffening further contributed to directing the loads toward the neighboring cell, though to a smaller extent. The contraction of two neighboring cells resulted in mutual attraction forces, which were considerably increased by tension-stiffening, and decayed with increasing cell-to-cell distances. Nonlinear elasticity contributed also to the onset of force polarity on the cell boundary. The density and alignment of the fibers within the inter-cellular band were considerably greater when fibers buckled under compression, with tension-stiffening further contributing to this structural remodeling. Our model demonstrates the contribution of nonlinear elasticity of biological gels to directionality and efficiency of mechanical-signal transfer between distant cells.

physics.bio-ph↗

arXiv2015

Microbuckling of Fibrin Provides a Mechanism for Cell Mechanosensing

Biological cells sense and respond to mechanical forces, but how such a mechanosensing proccess takes place in a nonlinear inhomogeneous fibrous matrix remains unknown. We show that cells in a fibrous matrix induce deformation fields that propagate over a longer range than predicted by linear elasticity. Synthetic, linear elastic hydrogels used in many mechanotransduction studies fail to capture this effect. We develop a nonlinear microstructural finite element model for a fiber network to simulate localized deformations induced by cells. The model captures measured cell- induced matrix displacements from experiments and identifies an important mechanism for long range cell mechanosensing: loss of compression stiffness due to microbuckling of individual fibers. We show evidence that cells sense each other through the formation of localized intercellular bands of tensile deformations caused by this mechanism.

physics.bio-ph↗