Tissue fibrosis is a leading cause of mortality and is characterized by excessive protein deposition and altered tissue mechanical properties. In pathological fibrosis, as well as cancer related fibrosis, tissue pericytes and fibroblasts transition from a quiescent to a myofibroblastic phenotype. In vitro models are needed to better understand how these cells are influenced by their local microenvironment. Here, we developed a fibrous network platform to mimic the structure of the extracellular matrix, where fibers consist of cross-linked hyaluronic acid hydrogels with controlled cross-link density and mechanical properties. As a model myofibroblast precursor, primary hepatic stellate cells were seeded onto fibers with either low (soft) or high (stiff) cross-link density, either directly after isolation (quiescent) or following preculture on tissue culture plates (activated). In general, both quiescent and activated cells showed an increase in spreading, alpha smooth muscle actin expression, and the formation of multicellular clusters on soft fibers when compared to stiff fibers. Further, inhibition of alpha smooth muscle actin decreased activation of cells on soft fibers. This is likely due to fiber recruitment in soft fibers that increased local fiber density, whereas stiff fibers resisted recruitment. This work emphasizes the importance of substrate topography on cell–material interactions and shows that tunable fibrous hydrogels are a relevant culture platform for studying fibrosis and mechanotransduction in disease.

The extracellular matrix (ECM) has force‐responsive (i.e., mechanochemical) properties that enable adaptation to mechanical loading through changes in fibrous network structure and interfiber bonding. Imparting such properties into synthetic fibrous materials will allow reinforcement under mechanical load, the potential for material self‐adhesion, and the general mimicking of ECM. Multifiber hydrogel networks are developed through the electrospinning of multiple fibrous hydrogel populations, where fibers contain complementary chemical moieties (e.g., aldehyde and hydrazide groups) that form covalent bonds within minutes when brought into contact under mechanical load. These fiber interactions lead to microscale anisotropy, as well as increased material stiffness and plastic deformation. Macroscale structures (e.g., tubes and layered scaffolds) are fabricated from these materials through interfiber bonding and adhesion when placed into contact while maintaining a microscale fibrous architecture. The design principles for engineering plasticity described can be applied to numerous material systems to introduce unique properties, from textiles to biomedical applications.

Congenital clubfoot is a complex pediatric foot deformity, occurring in approximately 1 in 1000 live births and resulting in significant disability, deformity, and pain if left untreated. The Ponseti method of manipulation is widely recognized as the gold standard treatment for congenital clubfoot; however, its mechanical aspects have not yet been fully explored. During the multiple manipulation-casting cycles, the tendons and ligaments on the medial and posterior aspect of the foot and ankle, which are identified as the rate-limiting tissues, usually undergo weekly sequential stretches, with a plaster of Paris cast applied after the stretch to maintain the length gained. This triggers extracellular matrix remodeling and tissue growth, but due to the viscoelastic properties of tendons and ligaments, the initial strain size, rate, and loading history will affect the relaxation behavior and mechanical strength of the tissue. To increase the efficiency of the Ponseti treatment, we discuss the theoretical possibilities of decreasing the size of the strain step and interval of casting and/or increasing the overall number of casts. This modification may provide more tensile stimuli, allow more time for remodeling, and preserve the mechanical integrity of the soft tissues.

In article number 1905719, Jason A. Burdick and co‐workers describe the development of adhesive fibrous hydrogel networks where force induces chemical bonding between mixed fiber populations containing complementary chemical groups. This mechanochemical behavior can be applied to numerous material systems to introduce unique properties, from textiles to biomedical applications.

The Ponseti method corrects a clubfoot by manipulation and casting which causes stress relaxation on the tendons. Here, we examined the effect of long-term stress relaxation on tendon extracellular matrix (ECM) by (1) an ex vivo stress relaxation test, (2) an in vitro tenocyte culture with stress relaxation and (3) an in vivo rabbit study. Time-dependent tendon lengthening and ECM alterations including crimp angle reduction and cleaved elastin were observed, which illustrated the mechanism of tissue lengthening behind the treatment—a material-based crimp angle reduction resulted from elastin cleavage. Additionally, in vitro and in vivo results observed restoration of these ECM alterations along with increased elastin level after 7 days of treatment, and the existence of neovascularization and inflammation, indicating the recovery and adaptation from the tendon in reaction to the treatment. Overall, this study provides the scientific background and information that helps explain the Ponseti method.