Interplay between viscoelasticity and topography regulates fibroblast mechanoresponse and activation

The extracellular matrix's topographies influence cell behavior and tissue function. Anisotropic topographies promote cell elongation and alignment, while isotropic cues, often found in diseased tissues, induce random cell orientation that may lead to undesirable cell mechanoresponses, such as the persistent activation of fibroblasts. Viscoelasticity has increasingly been recognized to also affect cell behavior. Yet, understanding the effects of both physiologically relevant cues remains challenging. Here, we address this by using a digital UV-light microsculpting approach to create viscoelastic polyacrylamide hydrogels (elastic modulus=13 kPa, half relaxation time: Ƭ 1/2 = 0.03 s) with various surface topographies (linear or crosshatch ∼250-nm-high microtopographies), mimicking healthy and diseased microenvironments. By combining viscoelastic and topographical cues in one system, our study reveals a dominant role for substrate viscoelasticity in fibroblast activation. This finding highlights the need to study cell mechanoresponses in multi-cue environments while offering an intriguing role of viscoelasticity in regulating fibroblast phenotype.