Low-modulus hydrogels reduce scar formation in wound healing.

Area of Science:

• Biomaterials Science
• Tissue Engineering
• Wound Healing

Background:

• Pathological scarring after skin trauma is a significant clinical issue.
• Hydrogel dressings promote wound healing but their mechanical properties' impact on scar formation is understudied.
• The mechanical microenvironment of wound dressings can influence cellular responses and subsequent scarring.

Purpose of the Study:

• To develop mechanically tunable hydrogels for scar reduction.
• To investigate the role of substrate stiffness and the Piezo1 ion channel in scar formation.
• To evaluate the anti-scarring efficacy of low-modulus hydrogels in a preclinical wound model.

Main Methods:

• Fabrication of polyvinyl alcohol (PVA) and poly(polyethylene glycol methacrylate-co-glycidyl methacrylate) (PPG) hydrogels with varying mechanical properties using a cyclic freeze-thaw method.
• In vitro fibroblast culture on hydrogels to assess mechanotransduction via the Piezo1 ion channel and calcium influx.
• In vivo evaluation of hydrogel dressings in a rabbit ear full-thickness wound model to measure scar characteristics.

Main Results:

• High-stiffness hydrogels induced Piezo1 activation and calcium influx, correlating with severe scarring.
• Low-modulus hydrogels (20-29 kPa) significantly reduced scar elevation index, α-smooth muscle actin expression, and normalized collagen I/III ratios.
• Hyperbranched poly-L-lysine (HBPL) incorporation provided a synergistic anti-scarring effect by adsorbing inflammatory factors.

Conclusions:

• Substrate stiffness is a critical factor in controlling scar formation, with low-modulus hydrogels offering significant therapeutic benefits.
• The Piezo1 mechanotransduction pathway is a key mediator of stiffness-dependent scarring.
• This study provides a framework for designing mechanotherapeutic biomaterials for scar-less tissue regeneration and clinical wound management.