Soft Matter

We experimentally assess the nonlinear rheology of composite biopolymer hydrogels composed of thiolated hyaluronic acid, poly(ethylene glycol) diacrylate (PEGDA), and laminin-111 in varied concentrations. We focus in particular on the influence of laminin on the mechanics of the assembled hydrogels, reporting nonlinear rheological measurements for gels under applied shear and compressive load. We find that increasing the concentration of laminin in the synthesized gels reduces the linear shear modulus and gives rise to a mild strain softening regime at intermediate strains prior to the onset of strain stiffening. In the stiffening regime, we find that all gels exhibit stress-controlled mechanics with K {propto}{sigma} a, with an apparent stiffening exponent of a {approx} 1, in agreement with observations of a variety of other reconstituted biopolymer gels. We discuss the possible implications of this nonlinear mechanical behavior on mechanotransduction and organoid development in biomimetic extracellular matrices.

Flow and extensional deformation of mucin networks are fundamental in mucus biophysics, governing how mucus functions as a protective and lubricating, and transport-facilitating layer. While the shear and oscillatory rheology of mucin solutions have been characterized in considerable detail, their behavior under extensional deformation remains comparatively understudied. Here, we report a concentration-dependent transition in extensional flow response of mucin solutions using a bespoke dripping-onto-substrate extensional rheometer. We show that mucin solutions at the lower concentrations undergo linear filament thinning, whereas semidilute mucin solutions form highly extensible filaments, with radius decaying exponentially in time, consistent with the elastocapillary thinning observed in solutions of high molecular weight synthetic polymers. Remarkably, at higher mucin concentrations inter-chain mucin associations produce a sudden reduction in the apparent elastocapillary relaxation time. We demonstrate how increasing macromolecular concentration redistributes the balance between viscous and elastic stresses during capillary thinning in a biopolymer network and reveal a concentration-driven reduction in mucin filament extensibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/725541v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1f593acorg.highwire.dtl.DTLVardef@1b23686org.highwire.dtl.DTLVardef@119add3org.highwire.dtl.DTLVardef@e31908_HPS_FORMAT_FIGEXP M_FIG C_FIG

Vertebrate gastrulating mesoderm is a prototypic example of a mesenchymal-like tissue undergoing extensive remodelling. While the tissue may be globally represented as a viscoelastic material, the actual biological material is intrinsically complex. To get to a real understanding of its properties, one needs to move to the mesoscale, linking cellular properties to collective phenomena. Vertebrate embryos also display a remarkable variability in mechanical properties, despite which they robustly complete gastrulation. This study attempts to explore these aspects by dissecting Xenopus mesoderm cell behaviour in a minimal system, using aspiration through a microfluidic system to impose controlled stress to a mesoderm aggregate. We show that beyond estimating global rheology at the tissue scale, it is possible to infer a wealth of information based on cell morphology and dynamics. Our data are consistent with collective behaviour being mostly dictated by the balance between the capacity of cells to stretch and the resistance to cell-cell contacts, which limits cell-cell intercalation and thus tissue remodelling. Importantly, tissues are not only able to transmit stress over a distance, they also clearly react to it through actively reinforcing cell-cell mechanical coupling. This adaptative property is found through a broad range of tissue stiffness, and adhesion strength appears to scale with the elastic modulus, suggesting that cell stiffness may ultimately be the key parameter setting mesoderm rheology and accounting for the large differences observed between embryo batches.

Plant-derived extracellular vesicles (PDEVs) have emerged as superior candidates for oral drug delivery, exhibiting a gastrointestinal survivability that significantly exceeds that of mammalian exosomes or synthetic liposomes. However, the biophysical rules governing how plant genomic regulation translates into this exceptional mechanical resilience remain unknown. Here, we present a predictive multiscale model of plant-derived extracellular vesicles, linking a parameterised genetic state space to emergent mesoscale mechanics via supra-molecular coarse-grained molecular dynamics (SCG-MD). We demonstrate that the upregulation of sterol methyltransferases (SMT) during the plants theoretical Defence state drives the formation of a phase-separated composite architecture, where rigid domains occupying approximately 36% of the membrane surface area effectively arrest crack propagation. This state achieves a critical rupture tension of 367.0 {+/-} 0.7 mN m-1 corresponding to a 39% increase over the wild-type Ripening state. Crucially, we find that chemical composition alone is insufficient for this reinforcement; vesicles with actively sorted lipid domains (Seeded topology) outperform randomised mixtures (Spontaneous topology) by 23% at identical concentrations. Furthermore, while fluid vesicles stiffen reactively under gastric acid shock (pH 2.5) due to the steric jamming of thermodynamically neutralised headgroups, the Defence state exhibits mechanical homeostasis. These findings suggest that PDEVs function as genetically tunable composite materials, offering a design blueprint for next-generation bio-inspired drug delivery vectors. Ultimately, these theoretical indices provide a predictive biophysical framework awaiting empirical confirmation via in vitro nanomechanical assays.

Lipid droplets (LDs) are cellular organelles responsible for lipid storage and metabolism. The mechanism of biogenesis of LDs involves phase separation of neutral lipids from the surrounding phospholipids, which generates oil lenses embedded in lipid bilayers, also known as nascent LDs. As nascent LDs grow, at some point they bud out of the bilayer, forming nearly spherical droplets. Nascent LDs have different propensity to bud, and it has been proposed that their shape provides information on such propensity; however, LD shape is difficult to determine experimentally. Here we studied the shape of lipid droplets using MD simulations at the coarse-grained level, and compared it to the predictions by an established theory. Our general system setup features an oil lens embedded into a flat, periodic bilayer. We found that the shape of simulated nascent LDs resembles a spherical cap (i.e., it has constant curvature over most of the surface), in excellent agreement with the theory, already for very small droplet sizes. The aspect ratio (height/radius) of nascent LDs increases with increasing LD volume, increasing membrane softness, and increasing surface tension between oil and water, also in agreement with theoretical predictions; however, it remains lower than 1 (i.e., the ratio for a sphere) for LDs of up to 40 nm in diameter. Fitting the simulated LD shapes with a theoretical shape equation suggests that a non-zero surface tension is present in both the monolayer and in the bilayer region. The existence of a relatively high surface tension in the bilayer region is confirmed by local stress calculations, and indicates that the periodic system setup does not reproduce the properties of nascent LDs in the endoplasmic reticulum, where the bilayer tension is two orders of magnitude lower. However, the simulations provide a microscopic view into the properties of droplet embedded vesicles.

Poly-L-Lysine (PLL) mediates the non-specific adhesion of cells and is commonly used in Atomic Force Microscopy (AFM) measurements, to ensure that cells remain attached to the substrate. However, it is acknowledged that adhesion affects the measured mechanical properties, in particular in the case Red Blood Cells (RBCs). This results in a wide range of Youngs modulus E reported in the literature. The present study aims at providing a systematic approach to the impact of non-specific adhesion on the rheology of RBCs. It provides a correlation between the topography profile of adherent RBCs and their rheology, from weak (cPLL = 10-3 mg/mL) to strong-adhesion (cPLL = 100 mg/mL) regimes. Using RICM and AFM, we find that there is a continuum of RBC shapes promoted by adhesion, from concave to dome-shaped, as predicted by the theory of vesicle adhesion. Their elastic properties discriminate them into two populations depending on adhesion strength, where stiffer RBCs (E {gtrsim} 100 Pa) correlate with dome-shaped cells. These findings are supported by rheology measurements of the dynamic complex shear modulus G*(f): while the storage modulus increases with cell-substrate adhesion, reflective of an increased membrane shear modulus, the loss modulus remains unchanged. Finally, further analysis inspired by membrane theory shows that different deformation modes may be triggered during indentation of either weakly or strongly adhering RBCs, illustrating the limits of the Hertz model.

In mammalian cells, lipid monolayers support the integrity of lipid droplets (LDs), organelles that function as storage for neutral lipids. Liver-targeting illnesses such as liver cancer interrupt normal LD metabolism and prompt changes in the chemical content of these organelles, which can have effects on structural and organizational behavior of the lipids. In LDs, liver cancer induces concentric crystalline phases of cholesteryl esters (CEs) and triglycerides near the NL-monolayer interface, which become more pronounced as CE concentration increases. Yet, there is little known about how this phenomenon may link to persistence of undigested LDs in liver cancer patients. To shed light on this, all-atom molecular dynamics simulations were used to model LD micropipette aspiration experiments and gain insight into the effect of CE concentration on partitioning, structural, and mechanical properties of LDs. We successfully model micropipette aspiration by application of constant surface tension laterally, which stretches lipid bilayers and monolayers as the magnitude increased. The results show increased phospholipid packing due to insertion of CE fatty tails into the monolayer. Increasing CE concentration induces a non-linear change in surface packing defects on the LDs, notable rigidification, and stiffness. Taken together, these insights improve our understanding of the physical properties at the LD monolayer-core interface during liver cancer progression.

Liquid-liquid phase separation of proteins has been observed to occur on biological membranes, where it is thought to play a role in diverse cellular behaviors. Recent work has demonstrated colocalization between protein condensates on opposing leaflets of the bilayer, suggesting that protein phase separation may be coupled across the bilayer. However, the mechanism behind this coupling phenomenon remains poorly understood. Here we seek to understand the protein-protein and protein-membrane interactions that give rise to transbilayer coupling of protein condensates. We perform coarse-grained molecular dynamics simulations of a bilayer with a disordered protein condensate tethered to each leaflet surface. In this system, we observe stable, coupled diffusion of the condensates across the membrane. We find that increasing the protein-protein interaction strength leads to decoupling, driven by competing membrane curvatures induced by each condensate. However, by applying membrane tension we suppress curvature and restore coupling even at higher protein interaction strengths. Under coupling conditions, we find that lipid entropy is reduced upon direct contact with proteins, but this effect is not transferred to the opposing leaflet. Interestingly, further analysis reveals increased transverse lipid packing (interdigitation) beneath the condensates relative to protein-free regions. Based on these observations, we propose that enhanced lipid interdigitation mediates interleaflet communication and serves as the primary mechanism driving transbilayer coupling of condensates in this system. This work provides insight into a potential physical mechanism for transmembrane communication in cellular contexts and suggests directions for future investigation. Significance StatementLiquid-like condensates are active participants at cellular membranes, where they act as organizers and catalysts for various cellular processes. Recent work has demonstrated that protein condensates can couple across the bilayer; however, the molecular mechanism of this transbilayer coupling remained unknown. Here, we investigate the molecular basis of transmembrane condensate coupling through detailed analysis and propose a mechanism for the phenomenon. This work advances our understanding of how information is transmitted across the bilayer, with implications in cellular requiring coordination across the membrane, such as signaling, and more broadly in the field of membrane biophysics.

The cytoplasm is a crowded and dynamic fluid within which cellular building blocks such as mRNA, proteins, or organelles undergo transport and mixing. Although small things like proteins can eventually mix through diffusion, the high viscosity of cytoplasm means that it should be difficult to obtain significant mixing for structures in the size range of mRNA, multi-protein complexes or organelles. In large amoeboid cells, the cytoplasm undergoes active streaming coupled to cell motility, but this streaming is laminar flow which should not be effective for mixing. In this work we used a combination of live cell tracking of injected beads and computational analysis of motion and mixing in giant amoeba Chaos carolinensis with the initial goal of testing the possibility that large-scale cellular deformations during pseudopod formation might implement chaotic mixing by a Baker-transform like process. Instead, we found that Chaos carolinensis accelerates cytoplasmic mixing using a novel cytoplasmic gel state capture and release strategy. While it was previously thought that the amoeba sol to gel state transitions only occur at the trailing and leading edge of the cell body, our work indicates that these transitions occur frequently throughout the mid-cell region, driving the cytoplasmic mixing of beads and organelles. These results indicate that amoeba achieves nearly complete mixing between 1 and 2 cytoplasmic stream/flow cycle, effectively approximating the Bernoulli mixing regime and thus representing one of the theoretically fastest possible mixers.

An e-GLUE is a polymer network containing interpenetrating polycations, which can bond the anionic network of mucosa through interfacial polycation bridging under an electric field. Such an electroadhesion involves electrophoresis of polycations, ionic complexation between polycations and the anionic network, and polycation-network entanglement, yet their quantitative understanding is lacking. Here, we formulate a theoretical model to describe electroadhesion of polymer networks by polycation interfacial bridging. We use a diffusion-drift model coupled with a Bell-like field-dependent chain friction to describe the sticky electrophoresis of polycations in an anionic sea. The formation of ionic bonds is determined by local availability of cations and anions over the penetration depth. To debond, a force must either pull polycations out from the e-GLUE network or first dissociate them from ionic complexes and then pull out from the anionic network. We model chain pullout from the bulk networks to the interface as a viscous drag against water. The adhesion strength is calculated by summing the debonding force for each polycation per unit area across all chains. Our model quantitatively links electric field strength, applied duration, polycation chain length, and cation concentration to polycation electrophoresis kinetics, ionic bond formation, and adhesion strength. We further conduct electroadhesion tests, and our model predicts well with the experimental data. Lastly, we discuss the use of the model to guide the e-GLUE design. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/730541v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@16524c6org.highwire.dtl.DTLVardef@15163aeorg.highwire.dtl.DTLVardef@673949org.highwire.dtl.DTLVardef@e207a0_HPS_FORMAT_FIGEXP M_FIG C_FIG For Table of Contents use only

Significant cellular processes, including protein sorting, signal transduction, and pathogen entry, amongst others, are associated with membrane microdomains, also known as lipid rafts. Lipid rafts, due to their unique biophysical properties compared to their surrounding environment, which stem from their distinct lipid and protein profiles, have garnered interest in methods and techniques that tune their coexisting liquid-ordered/liquid-disordered state, aiming to disrupt or destabilize them. Since cholesterol stabilizes the membrane domain, cholesterol-depleting compounds like cyclodextrin can be used to destabilize and disrupt the membrane rafts. Overall, given the membrane rafts importance in biological processes, it is crucial to understand the biophysical factors that influence its stability. In this study, we present a new method for disrupting and dissolving lipid rafts in a model system of phase-separated supported lipid bilayer (SLB) patches composed of DOPC, DPPC, and cholesterol. Using fluorescence microscopy to monitor the liquid ordered (Lo) and liquid disordered (Ld) phases of the SLB patches, we observed that adding DOPC liposomes causes a transformation of the co-existing Ld and Lo phases into a single-phase bilayer. On the other hand, adding liposomes that match the lipid content of the phase-separated SLB patch increase the areas of the existing Ld and Lo phases. This work also offers a new method for redistributing raft-localized molecules, confirmed by tracking the redistribution of cholera toxin bound to GM1 after domain dissolution with DOPC liposomes. The work describes an alternative method for dynamically altering membrane composition and dissolving domains via liposome addition, rather than lipid depletion or exchange.

Biomolecular condensates that form via liquid-liquid phase separation (LLPS) of, most prominently, intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotic cells and responsible for regulating a plethora of biological functions. Amongst these, they contribute to regulating cell motility, either individually within an extracellular matrix or collectively within confluent epithelial tissue. In this computational study we focus on the latter with the aim of investigating whether the mutual exertion of mechanical forces during collective migration in an epithelium can principally trigger cytoplasmatic LLPS. Since present models for confluent epithelial motility have so far only considered cells that are devoid of phase separating (protein) solutes, we extend a common multiphase approach for 2D cell motility with a mixing contribution including any number of protein solutes. Our model considers the phase behavior in both intracellular and extracellular regions and determines to what extend the membrane is permeated by the solutes under the influence of mechanical and osmotic forces. Our initial calculations unlock a very rich behavior involving formation and dissolution of condensates during migration, as well as an impact of LLPS on the very nature of the motility itself, through feedback mechanisms which may bear biological relevance.

Enveloped viruses can enter host cells by fusing their membrane with that of the host cell, a process known as membrane fusion. This process depends on specific fusion proteins located on the viral particle surface, which contain a short, relatively hydrophobic segment called "fusion peptide" that binds to the host membrane. To investigate the fusion efficiency of various fusion peptides, we create simplified non-infectious virus like particles decorated with different fusion peptides and fuse them with an artificial cell membrane. For this purpose, microfluidic devices are used to create supported lipid bilayers while the result of the fusion process is studied by fluorescence microscopy. Our study provides structural insights into the interactions between virus particles and cell membranes, which can facilitate the development of new therapeutic strategies and more effective viral vectors for therapeutic applications.

Auxetic metamaterials exhibit negative Poisson's ratio behaviors due to their architecture of periodically arranged unit cells. Although mechanical metamaterials are well established at the macroscale, programmable auxetic units remain scarce at the nanoscale. DNA origami offers a promising platform to bridge this gap, but design principles for dynamically deformable 3D auxetic nanostructures remain largely unexplored. Here, we develop design strategies for such 3D auxetic metastructures built from wireframe DNA origami. As a model system, we use a 3D re-entrant triangular unit composed of double-stranded DNA (dsDNA) bundle edges connected by single-stranded DNA (ssDNA) joints. Using coarse-grained molecular dynamics (MD) and umbrella-sampling free-energy simulations, we examine how edge design and joint-connection scheme govern auxetic responses and the energetics of the structural transformation. Our results show that auxetic performance and deformation energetics emerge from the coupled effects of DNA bundle rigidity and connector mechanics at the joints. This study provides mechanistic insights and design guidelines for programmable auxetic motion and energetics in 3D DNA origami metamaterials, advancing the development of stimuli-responsive nanomechanical devices.

Spiral geometries commonly occur in natural and engineered systems and are fundamentally described by curvature and torsion. In deformation-dominated systems, these variables evolve dynamically, requiring a continuum mechanical framework to link geometry and deformation. This study focused on refractile bodies (R-bodies), protein supramolecular assemblies that undergo reversible roll-spiral transformations in response to stimuli such as pH changes. Although multiple R-body types with distinct morphologies and unrolling behaviours were experimentally identified, their deformation mechanisms lack quantitative theoretical descriptions. We proposed a deformation-gradient-tensor-based continuum model incorporating geometrical mapping from the rolled to spiral state within a unified framework. The model successfully reconstructed macroscopic deformation behaviours of types 51, 7, and Pa R-bodies by capturing differences in unrolling behaviours, tapered geometry, and spatio-temporal evolution. The analysis revealed that deformation proceeds through a coupled process in which the curvature decreases via straightening, while the torsion increases by twisting. Importantly, the framework connected the macroscopic morphology with microscopic lattice deformation, enabling quantitative inference of lattice intervals and angles. The proposed comprehensive geometric model of the R-body roll-spiral transformation offers a general mathematical foundation for understanding deformation-driven spiral transformations in soft matter systems.

Bridging molecular and emergent properties is essential for designing soft matter. Synthetic DNA materials are attractive in this context because their sequence design space supports a wide range of material properties. Targeted design of DNA materials is hindered by scale differences and manual exploration of vast design spaces. We address this challenge with a computational workflow that links sequence-level design to rheological material properties. Concretely, we use machine learning to parametrise scalable, DNA-sequence-aware simulations, which we then evaluate using graph-based rheology. In our example, we study materials composed of self-interacting, multivalent DNA nanostars assembled from single strands. Structure and flexibility of nanostars are quantified with nucleotide-level oxDNA simulations, enabling Bayesian optimisation of a more coarse-grained bead-spring model. The bead-spring model allows efficient simulation of network formation between nanostars, governed by hybridisation free energies, which are computed with oxDNA and NUPACK. Nanostar valency and network connectivity are translated into rheological material properties with a graph-based method that we extend to include hydrodynamic interactions, yielding good agreement with experimental reference data. We generalise our findings by analysing theoretical graph representations of DNA materials and show how machine learning can optimise sequence affinities to produce desired rheological responses. Our work illustrates how machine learning can bridge scales and automate coarse-graining to facilitate targeted design of DNA materials through sequence-property relationships. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/728076v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@20b8c6org.highwire.dtl.DTLVardef@42f843org.highwire.dtl.DTLVardef@b90119org.highwire.dtl.DTLVardef@1f72d66_HPS_FORMAT_FIGEXP M_FIG C_FIG

Budding yeast septins assemble into filamentous networks bound to the inner plasma membrane. In situ or in vitro, septins are implicated in membrane deformations. We therefore suspected that septins might alter membrane mechanical properties both directly or indirectly. To decipher whether septins directly tune the rigidity of membranes, we used a cell free in vitro approach. To this end, using AFM, we measured the mechanical response of reconstituted GUVs pre-incubated with septins. Unexpectedly, we find that large GUVs (typically tens of {micro}m diameter size) are more deformable in the presence of septins. Theoretical modeling suggests that this peculiar behavior is likely due to initial micrometer membrane "wrinkled" deformations imposed by septins. Conversely, small GUVs (1 to 2 microns in diameter) cannot undergo any micrometric deformations and are thereby less deformable with septin filaments bound. Our findings suggest that, in specific cellular context, septins could provide a membrane reservoir and eventually facilitate membrane deformations. Significance statementFilamentous cytoskeletal septins, interacting with membranes would be expected to enhance membrane rigidity. Upon mechanical stress, GUVs larger than tens of microns appear, more deformable in the presence of septins. Septins initial membrane reshaping is responsible for this unexpected behavior, as shown by theoretical modeling. However smaller non deformable vesicles are more rigid, with septins bound.

Antimicrobial peptides (AMPs) act at the membrane interface, where they remodel lipid packing defects and redistribute lateral stresses, yet a quantitative, dose-dependent understanding of how they alter membrane mechanical properties remains incomplete. We use coarse-grained MARTINI 3 molecular dynamics simulations to systematically characterize the mechanical and microstructural response of a 70:30 POPE:POPG bilayer to three AMPs spanning distinct structural classes: aedesin (alpha-helical, 2MMM), arenicin-1 (beta-hairpin, 2JSB), and indolicidin (disordered, 1G89). For each peptide we vary the surface loading from one to four peptides per leaflet and extract the bending modulus Kc, the area compressibility modulus KA, peptide localization depth, bilayer thickness, peptide-lipid and peptide-peptide spatial organization, and leaflet-resolved lipid packing defect distributions. All three peptides soften Kc monotonically with loading, but at per-peptide rates that span a threefold range and order systematically by structural class: - 1.39 {+/-} 0.09, - 0.66 {+/-} 0.04, and - 0.44 {+/-} 0.01 kBT per peptide for aedesin, arenicin-1, and indolicidin, respectively. The tilt and twist moduli remain invariant across all conditions, indicating that the perturbation operates selectively on long-wavelength collective deformation modes. KA softens for the two structured peptides but is statistically indistinguishable from the control for indolicidin, a dissociation we trace to a supraphosphate adsorption versus interfacial insertion dichotomy: structured peptides sit above the phosphate plane and act as supraphosphate wedges, while the disordered peptide threads into the interface without coherently displacing lipids. Independent geometric, spatial-organization, and microstructural observables corroborate this framework, with the deep versus shallow defect remodeling asymmetry providing a clean microstructural counterpart to the Kc-KA dichotomy. Acyl chain order parameters resolve the per-lipid splay from the bilayer-averaged response and show that the per-lipid perturbation tracks conformational state rather than peptide length: the two structured peptides impose comparable per-lipid chain disordering despite differing in length, while the disordered peptide imposes far less. These findings establish a quantitative connection between peptide-induced defect remodeling and the elastic response of the bilayer, and suggest a design principle in which conformational restriction maximizes the per-peptide membrane perturbation, motivating experimental tests on stapled-peptide AMP analogs.

Mechanical properties of epithelial tissues play essential roles in morphogenesis and physiological function. In this study, we analytically derived the in-plane bulk modulus, shear modulus, and Poissons ratio of a three-dimensional cell vertex model of epithelial monolayers. We showed that the model can robustly reproduce a near-zero in-plane Poissons ratio, a mechanical feature reported in cultured epithelial tissues. Numerical simulations further confirmed that the theoretically predicted Poissons ratio accurately describes the response of the model under finite, biologically relevant strains. In addition, the model exhibits not only morphological bistability between squamous-like and columnar-like states, but also mechanical bistability characterized by distinct elastic responses. Together, these results provide a minimal three-dimensional framework that links cell-scale mechanical interactions and epithelial morphology to tissue-scale elastic properties.

Cell migration plays a central role in numerous physiological and pathological processes and emerges from the coordinated interplay between intracellular force generation, adhesion dynamics, and mechanical interactions with the environment. A minimal, mechanistically grounded understanding of these processes is required to disentangle the respective contributions of cell-intrinsic and environmental cues. Here, a two-dimensional in silico cell motility model is introduced to describe mesenchymal migration driven by intracellular traction forces generated within actin-rich protrusions anchored to a substrate. The model explicitly accounts for adhesion nucleation, maturation, force buildup and rupture, and relies on a small set of physically interpretable parameters. A systematic mechanical analysis identifies parameter regimes that permit effective cell translocation and delineates conditions leading to stalled or mobile cells. Within motile regimes, the model reproduces a broad spectrum of cell morphologies and migratory behaviours. In particular, cell trajectories exhibit the statistical features of a persistent random walk, with a crossover from ballistic to diffusive motion that arises solely from adhesion dynamics and force balance, without imposing polarization or directional bias. Cell morphology is shown to strongly regulate migration speed, persistence, and pausing behaviour. Altogether, this model provides a minimal reference framework for cell migration on non-deformable substrates and establishes a baseline for future studies of mechanically driven guidance. By construction, it is well suited for extension to deformable fibrous substrates, where cell-induced matrix remodeling and stiffness feedback are expected to bias migration and regulate cell encounters relevant to tissue morphogenesis and anastomosis.