Fibroblasts are cells present throughout the human body that are primarily responsible for the production and maintenance of the extracellular matrix (ECM) within the tissues. They have the capability to modify the mechanical properties of the ECM within the tissue and transition into myofibroblasts, a cell type that is associated with the development of fibrotic tissue through an acute increase of cell density and protein deposition. This transition from fibroblast to myofibroblast—a well-known cellular hallmark of the pathological state of tissues—and the environmental stimuli that can induce this transition have received a lot of attention, for example in the contexts of asthma and cardiac fibrosis. Recent efforts in understanding how cells sense their physical environment at the micro- and nano-scales have ushered in a new appreciation that the substrates on which the cells adhere provide not only passive influence, but also active stimulus that can affect fibroblast activation. These studies suggest that mechanical interactions at the cell–substrate interface play a key role in regulating this phenotype transition by changing the mechanical and morphological properties of the cells. Here, we briefly summarize the reported chemical and physical cues regulating fibroblast phenotype. We then argue that a better understanding of how cells mechanically interact with the substrate (mechanosensing) and how this influences cell behaviors (mechanotransduction) using well-defined platforms that decouple the physical stimuli from the chemical ones can provide a powerful tool to control the balance between physiological tissue regeneration and pathological fibrotic response.

Adherent cells residing within tissues or biomaterials are presented with 3D geometrical cues from their environment, often in the form of local surface curvatures. While there is growing evidence that cellular decision‐making is influenced by substrate curvature, the effect of physiologically relevant, cell‐scale anisotropic curvatures remains poorly understood. This study systematically explores the migration behavior of human bone marrow stromal cells (hBMSCs) on a library of anisotropic curved structures. Analysis of cell trajectories reveals that, on convex cylindrical structures, hBMSC migration speed and persistence are strongly governed by the cellular orientation on the curved structure, while migration on concave cylindrical structures is characterized by fast but non‐aligned and non‐persistent migration. Concurrent presentation of concave and convex substrates on toroidal structures induces migration in the direction where hBMSCs can most effectively avoid cell bending. These distinct migration behaviors are found to be universally explained by the cell‐perceived substrate curvature, which on anisotropic curved structures is dependent on both the temporally varying cell orientation and the 3D cellular morphology. This work demonstrates that cell migration is dynamically guided by the perceived curvature of the underlying substrate, providing an important biomaterial design parameter for instructing cell migration in tissue engineering and regenerative medicine.

Bundles of polymer filaments are responsible for the rich and unique mechanical behaviors of many biomaterials. We show that the extraordinary strain-stiffening response of networks of fibrin fibers important for blood clotting reflects the fiber's hierarchical architecture.

The intrinsic architecture of biological tissues and of implanted biomaterials provides cells with large-scale geometrical cues. To understand how cells are able to sense and respond to complex structural environments, a deeper insight into the cellular response to multi-scale and conflicting geometrical cues is needed. In this study, we subjected human bone marrow stromal cells (hBMSCs) to mesoscale cylindrical surfaces (diameter 250–5000 µm) and nanoscale collagen fibrils (diameter 100–200 nm) that were aligned perpendicular to the cylinder axis. On flat surfaces and at low substrate curvatures (cylinder diameter d > 1000 µm), cell alignment and migration were governed by the nanoscale collagen fibrils, consistent with the contact guidance effect. With increasing surface curvature (decreasing cylinder diameter, d < 1000 µm), cells increasingly aligned and migrated along the cylinder axis, i.e. the direction of zero curvature. An increase in phosphorylated myosin light chain levels was observed with increasing substrate curvature, suggesting a link between substrate-induced cell bending and the F-actin–myosin machinery. Taken together, this work demonstrates that geometrical cues of up to 10× cell size can play a dominant role in directing hBMSC alignment and migration and that the effect of nanoscale contact guidance can even be overruled by mesoscale curvature guidance.

Geometrical cues provided by the intrinsic architecture of tissues and implanted biomaterials have a high relevance in controlling cellular behavior. Knowledge of how cells sense and subsequently respond to complex geometrical cues of various sizes and origins is needed to understand the role of the architecture of the extracellular environment as a cell-instructive parameter. This is of particular interest in the field of tissue engineering, where the success of scaffold-guided tissue regeneration largely depends on the formation of new tissue in a native-like organization in order to ensure proper tissue function. A well-considered internal scaffold design (i.e., the inner architecture of the porous structure) can largely contribute to the desired cell and tissue organization. Advances in scaffold production techniques for tissue engineering purposes in the last years have provided the possibility to accurately create scaffolds with defined macroscale external and microscale internal architectures. Using the knowledge of how cells sense geometrical cues of different size ranges can drive the rational design of scaffolds that control cellular and tissue architecture. This concise review addresses the recently gained knowledge of the sensory mechanisms of cells towards geometrical cues of different sizes (from the nanometer to millimeter scale) and points out how this insight can contribute to informed architectural scaffold designs.