A Multifunctional Injectable Nanocomposite Hydrogel for Precision Keloid Therapy via ECM Remodeling and Local Pruritus Relief

Keloids are fibroproliferative dermal tumors resulting from dysregulated wound healing characterized by excessive extracellular matrix (ECM) deposition, persistent fibroblast activation, chronic inflammation, and intense pruritus. Current clinical treatments, including corticosteroid injections, surgery, cryotherapy, and laser therapy, often demonstrate high recurrence rates ranging from ۴۵% to ۸۰% and fail to effectively control both fibrotic progression and itch-related symptoms. Therefore, the development of multifunctional therapeutic platforms capable of targeting multiple pathogenic mechanisms simultaneously is highly desirable. In this study, we developed a multifunctional injectable nanocomposite hydrogel designed for precision keloid therapy by combining ECM remodeling, anti fibrotic drug delivery, and local antipruritic action. The hydrogel matrix consisted of a gelatin methacrylate (GelMA) and chitosan composite network incorporating pirfenidone loaded PLGA nanoparticles (PFD NPs) and lidocaine loaded lipid nanocarriers (LID LNCs). The resulting system demonstrated excellent injectability, shear thinning rheological properties, and rapid in situ gelation within ۶۰ seconds under physiological conditions. Nanoparticles exhibited an average diameter of ۱۴۲ ± ۱۱ nm with encapsulation efficiency of ۸۳.۶ ± ۳.۲%. The nanocomposite hydrogel provided sustained drug release over ۲۱ days, with cumulative release of ۷۸.۴% for pirfenidone and ۷۲.۹% for lidocaine. In vitro studies using human keloid fibroblasts showed significant reductions in cell proliferation (۴۸.۶%), collagen I expression (۵۷.۹%), collagen III expression (۵۱.۴%), and α smooth muscle actin (۶۲.۷%) compared with untreated controls (p < ۰.۰۰۱). In vivo evaluation in a rabbit ear hypertrophic scar model demonstrated that hydrogel treatment reduced scar elevation index (SEI) by ۵۲.۴%, collagen density by ۴۶.۷%, and pruritic scratching behavior by ۶۲.۳% relative to control groups (p < ۰.۰۰۱). Immunohistochemical analysis confirmed significant downregulation of TGF β۱, α SMA, and IL ۳۱ expression. Collectively, these findings demonstrate that the multifunctional nanocomposite hydrogel provides a promising minimally invasive therapeutic strategy for precision treatment of keloids through combined ECM remodeling and local pruritus suppression.

کلیدواژه ها:

ECM remodeling ، Pirfenidone ، Lidocaine ، TGF β signaling ، Pruritus therapy