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Epithelial tissues are driven out of thermodynamic equilibrium by internally generated forces, causing complex patterns of motion. Even when both the forces and motion are measurable, it is not yet possible to relate the two, because the sources of energy injection and dissipation are often unclear. Here, we study how energy is transferred by developing a method to measure the effective viscosity from the shear stresses and strain rates within an epithelial cell monolayer. Interestingly, there emerged multicellular regions in which the relationship between shear stress and shear strain rate was negatively proportional, indicating a negative effective viscosity. The negative effective viscosity occurred in regions wherein cell stresses were less efficient at producing tissue deformations compared to regions of positive effective viscosity. Regions of negative effective viscosity consistently exhibited greater cell speed and vorticity, and the cells had elevated metabolic activity, reflecting an increased energy demand in these cells. Our study shows that negative effective viscosity is a useful means of quantifying the flow of energy in living matter. 

Effective viscosity in epithelial cell monolayers has a wide distribution, with the width being caused by activity and the mean indicating the resistance of the cell monolayer to flow. 

In tissue formation and repair, the epithelium undergoes complex patterns of motion driven by the active forces produced by each cell. Although the principles governing how the forces evolve in time are not yet clear, it is often assumed that the contractile stresses within the cell layer align with the axis defined by the body of each cell. Here, we simultaneously measured the orientations of the cell shape and the cell-generated contractile stresses, observing correlated, dynamic domains in which the stresses were systematically misaligned with the cell body. We developed a continuum model that decouples the orientations of contractile stress and cell body. The model recovered the spatial and temporal dynamics of the regions of misalignment in the experiments. These findings reveal that the cell controls its contractile forces independently from its shape, suggesting that the physical rules relating cell forces and cell shape are more flexible than previously thought. 

Abstract Soft bioinspired fiber networks offer great potential in biomedical engineering and material design due to their adjustable mechanical behaviors. However, existing strategies to integrate modeling and manufacturing of bioinspired networks do not consider the intrinsic microstructural disorder of biopolymer networks, which limits the ability to tune their mechanical properties. To fill in this gap, we developed a method to generate computer models of aperiodic fiber networks mimicking type I collagen ready to be submitted for additive manufacturing. The models of fiber networks were created in a scripting language wherein key geometric features like connectivity, fiber length, and fiber cross section could be easily tuned to achieve desired mechanical behavior, namely, pretension-induced shear stiffening. The stiffening was first predicted using finite element software, and then a representative network was fabricated using a commercial 3D printer based on digital light processing technology using a soft resin. The stiffening response of the fabricated network was verified experimentally on a novel test device capable of testing the shear stiffness of the specimen under varying levels of uniaxial pretension. The resulting data demonstrated clear pretension-induced stiffening in shear in the fabricated network, with uniaxial pretension of 40% resulting in a factor of 2.65 increase in the small strain shear stiffness. The strategy described in this article addresses current challenges in modeling bioinspired fiber networks and can be readily integrated with advances in fabrication technology to fabricate materials truly replicating the mechanical response of biopolymer networks. 

Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modifiedPIEZO1^−/−OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.