ABSTRACT The extracellular matrix changes dramatically during the progression of diseases like cancer. These complex, tissue‐specific changes are not adequately replicated by most current biomaterial disease models. This work demonstrates, for the first time, a biomaterial system allowing combined, independent control over stiffness, extracellular matrix composition and 3D collagen architecture. Defined hydrogel formulations are successfully perfused into ice‐templated collagen scaffolds, controlling the composition of these hybrid scaffolds at constant stiffness. The Young's moduli of these hybrid scaffolds can also be tuned independently of composition via chemical cross‐linking. Encapsulation of human dermal fibroblasts reveals that fibroblast morphology depends on hybrid scaffold composition and on viscoelasticity, highlighting the importance of a system that decouples biophysical from biochemical properties. Finally, these hybrid scaffolds are successfully applied to exert combined control over biochemical and biophysical drivers of cell growth and invasion, focusing on breast cancer as proof‐of‐concept. The results reveal that collagen fiber patterning enhances breast cancer cell proliferation, also directing the invasion of patient‐derived breast cancer cells. These hybrid scaffolds are therefore promising new tools for dissecting the diverse but complementary roles played by the extracellular matrix in regulating cell phenotype, in a range of healthcare applications.
Song et al. (2025) studied this question.