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Many biological materials contain fibrous protein networks as their main structural components. Understanding the mechanical properties of such networks is important for creating biomimicking materials for cell and tissue engineering, and for developing novel tools for detecting and diagnosing disease. In this work, we develop continuum models for isotropic, athermal fibrous networks by combining a single-fibre model that describes the axial response of individual fibres, with network models that assemble individual fibre properties into overall network behaviour. In particular, we consider four different network models, including the affine, three-chain, eight-chain, and micro-sphere models, which employ different assumptions about network structure and kinematics. We systematically investigate the ability of these models to describe the mechanical response of athermal collagen and fibrin networks by comparing model predictions with experimental data. We test how each model captures network behaviour under three different loading conditions: uniaxial tension, simple shear, and combined tension and shear. We find that the affine and three-chain models can accurately describe both the axial and shear behaviour, whereas the eight-chain and micro-sphere models fail to capture the shear response, leading to unphysical zero shear moduli at infinitesimal strains. Our study is the first to systematically investigate the applicability of popular network models for describing the macroscopic behaviour of athermal fibrous networks, offering insights for selecting efficient models that can be used for large-scale, finite-element simulations of athermal networks. 

Abstract Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduced levels of pGSN. Therefore, using an in vitro system, we investigated whether pGSN could attenuate increased permeability of the blood–brain barrier (BBB) during its exposure to the portion of the SARS-CoV-2 spike protein containing the receptor binding domain (S1 subunit). Materials and methods Two- and three-dimensional models of the human BBB were constructed using the human cerebral microvascular endothelial cell line hCMEC/D3 and exposed to physiologically relevant shear stress to mimic perfusion in the central nervous system (CNS). Trans-endothelial electrical resistance (TEER) as well as immunostaining and Western blotting of tight junction (TJ) proteins assessed barrier integrity in the presence of the SARS-CoV-2 spike protein and pGSN. The IncuCyte Live Imaging system evaluated the motility of the endothelial cells. Magnetic bead-based ELISA was used to determine cytokine secretion. Additionally, quantitative real-time PCR (qRT-PCR) revealed gene expression of proteins from signaling pathways that are associated with the immune response. Results pGSN reversed S1-induced BBB permeability in both 2D and 3D BBB models in the presence of shear stress. BBB models exposed to pGSN also exhibited attenuated pro-inflammatory signaling pathways (PI3K, AKT, MAPK, NF-κB), reduced cytokine secretion (IL-6, IL-8, TNF-α), and increased expression of proteins that form intercellular TJ (ZO-1, occludin, claudin-5). Conclusion Due to its anti-inflammatory and protective effects on the brain endothelium, pGSN has the potential to be an alternative therapeutic target for patients with severe SARS-CoV-2 infection, especially those suffering neurological complications of COVID-19. 

Electrical stimulation (ES) within a conductive scaffold is potentially beneficial in encouraging the differentiation of stem cells toward a neuronal phenotype. To improve stem cell‐based regenerative therapies, it is essential to use electroconductive scaffolds with appropriate stiffnesses to regulate the amount and location of ES delivery. Herein, biodegradable electroconductive substrates with different stiffnesses are fabricated from chitosan‐grafted‐polyaniline (CS‐g‐PANI) copolymers. Human mesenchymal stem cells (hMSCs) cultured on soft conductive scaffolds show a morphological change with significant filopodial elongation after electrically stimulated culture along with upregulation of neuronal markers and downregulation of glial markers. Compared to stiff conductive scaffolds and non‐conductive CS scaffolds, soft conductive CS‐g‐PANI scaffolds promote increased expression of microtubule‐associated protein 2 (MAP2) and neurofilament heavy chain (NF‐H) after application of ES. At the same time, there is a decrease in the expression of the glial markers glial fibrillary acidic protein (GFAP) and vimentin after ES. Furthermore, the elevation of intracellular calcium [Ca²⁺] during spontaneous, cell‐generated Ca²⁺transients further suggests that electric field stimulation of hMSCs cultured on conductive substrates can promote a neural‐like phenotype. The findings suggest that the combination of the soft conductive CS‐g‐PANI substrate and ES is a promising new tool for enhancing neuronal tissue engineering outcomes.

 

Sponges are animals that inhabit many aquatic environments while filtering small particles and ejecting metabolic wastes. They are composed of cells in a bulk extracellular matrix, often with an embedded scaffolding of stiff, siliceous spicules. We hypothesize that the mechanical response of this heterogeneous tissue to hydrodynamic flow influences cell proliferation in a manner that generates the body of a sponge. Towards a more complete picture of the emergence of sponge morphology, we dissected a set of species and subjected discs of living tissue to physiological shear and uniaxial deformations on a rheometer. Various species exhibited rheological properties such as anisotropic elasticity, shear softening and compression stiffening, negative normal stress, and non-monotonic dissipation as a function of both shear strain and frequency. Erect sponges possessed aligned, spicule-reinforced fibres which endowed three times greater stiffness axially compared with orthogonally. By contrast, tissue taken from shorter sponges was more isotropic but time-dependent, suggesting higher flow sensitivity in these compared with erect forms. We explore ecological and physiological implications of our results and speculate about flow-induced mechanical signalling in sponge cells. 

Cells can sense and respond to mechanical forces in fibrous extracellular matrices (ECMs) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing the intensity of collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen–GAG cogels. We found significantly lower intensities of aligned collagen in collagen–GAG cogels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The role of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs. 

Cells can respond to signals generated by other cells that are remarkably far away. Studies from at least the 1920's showed that cells move toward each other when the distance between them is on the order of a millimeter, which is many times the cell diameter. Chemical signals generated by molecules diffusing from the cell surface would move too slowly and dissipate too fast to account for these effects, suggesting that they might be physical rather than biochemical. The non-linear elastic responses of sparsely connected networks of stiff or semiflexible filament such as those that form the extracellular matrix (ECM) and the cytoskeleton have unusual properties that suggest multiple mechanisms for long-range signaling in biological tissues. These include not only direct force transmission, but also highly non-uniform local deformations, and force-generated changes in fiber alignment and density. Defining how fibrous networks respond to cell-generated forces can help design new methods to characterize abnormal tissues and can guide development of improved biomimetic materials.