Dynamic Mechanical Stimulation of Thermoresponsive Nanofibers for Activation of Fibroblasts in Skin Repair

Abstract Substrate stiffness regulates fibroblast phenotype through focal adhesion‐mediated mechanotransduction pathways to facilitate tissue repair and regeneration. To analyze the effects of dynamic mechanical stimulation of substrates on cell behavior and skin wound healing, collagen‐like hydrogel nanofibers are fabricated using coaxial electrospinning of gelatin methacryloyl (GelMA) and poly‐L‐lactic acid (PLLA). These nanofibers are then grafted with thermoresponsive poly(N‐vinylcaprolactam) (PNVCL) via dehydration condensation reaction, providing temperature‐dependent mechanical signals. The incorporation of PLLA significantly enhanced the mechanical properties of the GelMA hydrogel nanofibers, while the subsequent grafting of PNVCL effectively reduced the swelling ratio and porosity. Upon exposure to temperatures above the lowest critical solution temperature (LCST), PNVCL molecules underwent a phase transition and self‐contraction, improving mechanical properties by forming robust hydrogen bonds with GelMA and expelling water molecules from the polymer matrix. This dynamic mechanical stimulation further promoted cytoskeletal remodeling of mouse skin fibroblasts (MSFs) without significantly affecting cell proliferation and migration. Additionally, it stimulated the differentiation of fibroblasts into myofibroblasts, thereby enhancing extracellular matrix secretion and skin regeneration in vivo. Overall, the engineering of thermoresponsive hydrogel nanofibers with dynamic mechanical stimulation introduces a novel design paradigm in functional tissue engineering, enabling precise regulation of cellular behaviors for effective skin wound healing.