Development of a 3D Model of the Dermal Niche

Human skin is a complex, multilayered organ that is subjected to several mechanical and biochemical stimuli, which can modulate cell activity and affect skin function and disease. [1] In the intermediate layer of the skin or dermis, human dermal fibroblasts are embedded within a three-dimensional matrix that can generate and transmit mechanical forces. Mechanotransduction translates mechanical stimuli into intracellular biochemical signals that, in turn, drive changes in cell function. [2] Notably, mechanical stimulation, such as cyclic stretching, has demonstrated favorable effects on fibroblast proliferation and gene expression, making it useful for therapeutic applications or the production of skin substitutes. [3] Moreover, the mechanical analysis of skin elongation revealed that stretching induces changes in osmotic and hydrostatic pressure within the surrounding environment of the cell through chemomechanical coupling. [4] The effects of osmotic and hydrostatic pressure are thought to be involved in impaired wound repair, inflammation, proliferation and chromatin arrangement, although the underlying mechanotransduction mechanisms remain unclear. [5], [6] To investigate these, two-dimensional cell culture has been widely used; however, it has been recently questioned whether 2D can preserve or replicate the in vivo conditions in which cells are naturally embedded. Indeed, this can cause cells to behave far from how they would behave in the in vivo dermis, which is a soft 3D matrix. [7] Moreover, 2D systems cannot replicate the chemomechanical coupling investigated in skin tissue, as this is inherent to a 3D matrix. The use of 3D hydrogel systems to culture and study cell behavior allows better modeling of the in vivo conditions, permitting to tune the mechanical and morphological properties of the environment, and consequently studying cell response to different stimuli.