Low-modulus hydrogels reduce scar formation in wound healing

Pathological scarring following skin trauma remains a formidable clinical challenge. Hydrogel dressings can promote wound closure by providing wet healing environment, yet the role of the dressing's mechanical microenvironment on the scar formation is overlooked. Herein, a series of mechanically-tunable hydrogels were produced from the same concentrations of polyvinyl alcohol (PVA) and poly(polyethylene glycol methacrylate-co-glycidyl methacrylate) (PPG) without or with the addition of hyperbranched poly-l-lysine (HBPL) via a cyclic freeze-thaw method. All the hydrogels could maintain their mechanical strength under physiological conditions. Culture with fibroblasts on the hydrogels in vitro showed that the high-stiffness environment triggered the Piezo1 ion channel (the mechanosensitive ion channel), inducing a calcium influx, conveying severe scarring potential. The low-modulus hydrogels (∼20-29 kPa) significantly reduced scar elevation index, α-smooth muscle actin expression and collagen I/III ratios in a rabbit ear ventral full-thickness wound model in vivo. While the mechanical modulus of the hydrogel played a dominant role in scar suppression, the incorporation of HBPL provided a modest yet synergistic anti‑scarring benefit by effectively adsorbing key inflammatory factors. The material system demonstrated its great potential as a ready-to-use wound dressing for clinical translation. By identifying a mechanical adaptive window for wound dressings, this study provides a framework for the rational design of mechanotherapeutic biomaterials to achieve better scar-less tissue regeneration. STATEMENT OF SIGNIFICANCE: Pathological scarring following skin trauma remains a formidable clinical challenge. Hydrogel dressings can promote wound closure by providing a wet healing environment, yet the role of the dressing's mechanical microenvironment on the scar formation is overlooked. Herein, mechanically-tunable polyvinyl alcohol-based hydrogels with the same chemical compositions were prepared via a cyclic freeze-thaw method. The substrate stiffness modulated the Piezo1 mechanosensitive axis, triggering a stiffness-dependent calcium influx. The low-modulus dressings effectively suppressed pathological hyperplasia with the smallest scar elevation index, downregulated α-smooth muscle actin expression, and a transition toward a regenerative type III/I collagen ratio. By silencing the Piezo1-mediated mechanotransduction pathway through a low-modulus interface, this study provides a robust material design framework that optimizes the regenerative microenvironment, offering a promising dual-strategy approach for clinical wound management and the prevention of pathological fibrosis.