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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. 

Many pathologic conditions lead to the development of tissue scarring and fibrosis, which are characterized by the accumulation of abnormal extracellular matrix (ECM) and changes in tissue mechanical properties. Cells within fibrotic tissues are exposed to dynamic microenvironments that may promote or prolong fibrosis, which makes it difficult to treat. Biomaterials have proved indispensable to better understand how cells sense their extracellular environment and are now being employed to study fibrosis in many tissues. As mechanical testing of tissues becomes more routine and biomaterial tools become more advanced, the impact of biophysical factors in fibrosis are beginning to be understood. Herein, fibrosis from a materials perspective is reviewed, including the role and mechanical properties of ECM components, the spatiotemporal mechanical changes that occur during fibrosis, current biomaterial systems to study fibrosis, and emerging biomaterial systems and tools that can further the understanding of fibrosis initiation and progression. This review concludes by highlighting considerations in promoting wide‐spread use of biomaterials for fibrosis investigations and by suggesting future in vivo studies that it is hoped will inspire the development of even more advanced biomaterial systems.