Disease-causing mutation in α-actinin-4 promotes podocyte detachment through maladaptation to periodic stretch.

α-Actinin-4 (ACTN4) bundles and cross-links actin filaments to confer mechanical resilience to the reconstituted actin network. How this resilience is built and dynamically regulated in the podocyte, and the cause of its failure in ACTN4 mutation-associated focal segmental glomerulosclerosis (FSGS), remains poorly defined. Using primary podocytes isolated from wild-type (WT) and FSGS-causing point mutant Actn4 knockin mice, we report responses to periodic stretch. While WT cells largely maintained their F-actin cytoskeleton and contraction, mutant cells developed extensive and irrecoverable reductions in these same properties. This difference was attributable to both actin material changes and a more spatially correlated intracellular stress in mutant cells. When stretched cells were further challenged using a cell adhesion assay, mutant cells were more likely to detach. Together, these data suggest a mechanism for mutant podocyte dysfunction and loss in FSGS-it is a direct consequence of mechanical responses of a cytoskeleton that is brittle.

Local Mechanism Governs Global Reinforcement of Nanofiller-Hydrogel Composites.

We reveal the mechanism for the strong reinforcement of attractive nanofiller-hydrogel composites. Measuring the linear viscoelastic properties of hydrogels containing filler nanoparticles, we show that a significant increase of the modulus can be achieved at unexpectedly low volume fractions of nanofillers when the filler-hydrogel interactions are attractive. Using three-dimensional numerical simulations, we identify a general microscopic mechanism for the reinforcement, common to hydrogel matrices of different compositions and concentrations and containing nanofillers of varying sizes. The attractive interactions induce a local increase in the gel density around the nanofillers. The effective fillers, composed of the nanofillers and the densified regions around them, assemble into a percolated network, which constrains the gel displacement and enhances the stress coupling throughout the system. A global reinforcement of the composite is induced as the stresses become strongly coupled. This physical mechanism of reinforcement, which relies only on attractive filler-matrix interactions, provides design strategies for versatile composites that combine low nanofiller fractions with an enhanced mechanical strength.

Microscopic interactions and emerging elasticity in model soft particulate gels.

We discuss a class of models for particulate gels in which the particle contacts are described by an effective interaction combining a two-body attraction and a three-body angular repulsion. Using molecular dynamics, we show how varying the model parameters allows us to sample, for a given gelation protocol, a variety of gel morphologies. For a specific set of the model parameters, we identify the local elastic structures that get interlocked in the gel network. Using the analytical expression of their elastic energy from the microscopic interactions, we can estimate their contribution to the emergent elasticity of the gel and gain new insight into its origin.

Competitive Supramolecular Associations Mediate the Viscoelasticity of Binary Hydrogels.

Supramolecular polymers are known to form strong and resilient hydrogels which can take up large amounts of water while exhibiting ease of processing and self-healing. They also possess similarities with networks of biological macromolecules. The combination of these features makes supramolecular polymers ideal candidates for studying mechanisms and consequences of self-assembly, which are relevant to biological materials. At the same time, this renders investigations of mixed hydrogels based on different supramolecular compounds necessary, since this substantially widens their applicability. Here, we address unusual viscoelastic properties of a class of binary hydrogels made by mixing fibrillar supramolecular polymers that are formed from two compounds: 1,3,5-benzene-tricarboxamide decorated with aliphatic chains terminated by tetra(ethylene glycol) (BTA) and a 20 kg/mol telechelic poly(ethylene glycol) decorated with the same hydrogen bonding BTA motif on both ends (BTA-PEG-BTA). Using a suite of experimental and simulation techniques, we find that the respective single-compound-based supramolecular systems form very different networks which exhibit drastically different rheology. More strikingly, mixing the compounds results in a non-monotonic dependence of modulus and viscosity on composition, suggesting a competition between interactions of the two compounds, which can then be used to fine-tune the mechanical properties. Simulations offer insight into the nature of this competition and their remarkable qualitative agreement with the experimental results is promising for the design of mixed hydrogels with desired and tunable properties. Their combination with a sensitive dynamic probe (here rheology) offer a powerful toolbox to explore the unique properties of binary hydrogel mixtures.