Sequential Macrophage Polarization Mediated by a Biphasic Cold Plasma Pen for Oral Ulcer Therapy

The clinical management of recurrent aphthous stomatitis, commonly known as oral ulcers, remains a significant challenge. Existing topical pharmacotherapies─although capable of providing temporary symptomatic relief─are frequently limited by inadequate bioadhesion, short therapeutic duration, and critically, an inability to correct the immune dysregulation inherent in the healing process. To address these limitations, this study developed a hand-held cold atmospheric plasma jet device, termed the “Biphasic Unity Pen” (BU Pen). The device introduces an innovative “Demon Sphere–Spiritual Sphere” biphasic immunomodulation strategy, designed to achieve intelligent, stage-dependent, and time-regulated therapy for oral ulcers. The BU Pen stably generates reactive oxygen and nitrogen species, enabling sustained immunomodulation within the humid oral environment without reliance on physical adhesion. In vitro, the device sequentially induces M1 macrophage polarization to support inflammatory clearance (the “Demon Sphere”), followed by a timely transition to M2 polarization to facilitate anti-inflammatory repair (the “Spiritual Sphere”). Additionally, the BU Pen enhances epithelial cell and fibroblast migration and promotes basement-membrane assembly and cytoskeletal reorganization. In a rat oral-ulcer model, treatment with the BU Pen achieved healing rates of up to 92.9%, restored feeding behavior and body weight, and promoted collagen deposition and angiogenesis through the M1-to-M2 macrophage transition. Overall, this study presents a novel and intelligent physical-therapy strategy for oral ulcers and other inflammatory oral diseases, offering substantial potential for clinical translation.