Next‐Generation Oral Ulcer Management: Integrating Cold Atmospheric Plasma (CAP) with Nanogel‐Based Pharmaceuticals for Inflammation Regulation

Oral ulcers are induced at three sites in the same rat using acetic acid. Different treatments elicited distinct immune responses. In the no-treatment group, excessive inflammation and CD15+ infiltration left large ulcers on Day 10. The Watermelon Frost (WF) group showed insufficient inflammation and slow healing, while the Cold Atmospheric Plasma+GOx-CAT nanogel (CAP+GCN) group activated Epidermal Growth Factor Receptor (EGFR) expression, promoting fast recovery.

Abstract

Oral ulcers, affecting 27.9% of adults, can lead to malnutrition and dehydration, especially in individuals with diabetes, cancer, viral infections, and autoimmune diseases. Existing treatments—including oral films, sprays, frosts, and powders—often fail to be effective due to rapid dilution and clearance in the moist oral environment. This study is the first to investigate the use of Cold Atmospheric Plasma (CAP) for treating oral ulcers and its underlying molecular mechanisms. A novel high-bioavailability, mucoadhesive therapy combining handheld three dimensions (3D) multi-microhole CAP is developed with a nanogel-based pharmaceutical system containing glucose oxidase (GOx) and catalase (CAT), termed GCN. These results showed that both CAP alone and CAP combined with GCN significantly accelerate oral ulcer healing, modulate immune responses, and activate the Epidermal Growth Factor Receptor (EGFR) in acetic acid-induced oral ulcers, outperforming untreated controls and the conventional medication, Watermelon Frost (WF). Furthermore, the CAP+GCN combination enhances therapeutic effects by promoting fibroblast generation. CAP pretreatment also enhances cell permeability and nanoparticle uptake, improving tissue adhesion. These findings are validated in primary Human Gingival Fibroblasts (HGF) and Human Periodontal Ligament Stem Cells (PDLSC) from healthy donors, as well as an oral ulcer model in rats, demonstrating superior biocompatibility and safety.