Cationic Polylysine-Compensated Hydrogels Reduce Scar Formation of Scar-Prone Wounds via Immunomodulation and ECM Remodeling.

Abnormal wound healing in scar‑prone sites remains a clinical challenge, primarily due to excessive inflammation and disorganized extracellular matrix (ECM) remodeling. Herein, we developed an injectable, enzyme‑crosslinked hydrogel by incorporating cationic polylysine (PLys) into a transglutaminase‑crosslinked gelatin matrix. Mechanistically, the inclusion of PLys not only accelerated gelation kinetics but also enhanced mechanical performance via macromolecular crosslinking, while concurrently imparting self-healing capacity, robust tissue adhesion, and inherent antibacterial activity to the hydrogel. In vitro characterization demonstrated the hydrogel exhibited satisfactory biocompatibility, promoted fibroblast adhesion and spreading, and modulated ECM remodeling by upregulated expression of matrix metalloproteinase (MMPs). Furthermore, the hydrogel exerted significant immunomodulatory effects, as evidenced by increased expression of anti-inflammatory cytokines (IL-10, TGF-β, Arg-1) and pro-inflammatory mediators (TNF-α, IL-6), consistent with a controlled early inflammatory stimulus that promotes subsequent resolution. In a rabbit ear hypertrophic scar model, the hydrogel effectively improved scar outcome in scar-prone wounds, as reflected by reduced scar elevation, better-organized collagen architecture, suppressed myofibroblast accumulation, and favorable modulation of both inflammation-related and matrix-remodeling signaling pathways. Collectively, these findings indicate that cationic PLys-compensated hydrogels represent a promising therapeutic strategy for improving wound repair in scar‑prone tissues, acting through the coordinated regulation of key cellular and molecular processes.