Ultrasound-Mediated Piezoelectric Microneedles Regulating Macrophage Polarization and Remodeling Pathological Microenvironment for Lymphedema Improvement

Lymphedema, a severe and complex inflammatory disease caused by lymphatic system insufficiency and impeded lymphatic drainage that causes an enormous physical and psychological burden on patients and may even lead to death, has long been a challenging issue in the medical field. Clinically, conventional approaches including surgical treatment and conservative treatment have been employed for lymphedema therapy, but their curative effect is still unsatisfactory because of high operational difficulty, high cost, and long-term reliance. In this study, a novel kind of piezoelectric microneedle driven by ultrasound (US) is proposed to regulate macrophage polarization and remodel the pathological inflammatory microenvironment in a noninvasive manner, thereby promoting lymphatic regeneration and improving lymphedema. US-mediated piezoelectric microneedles can significantly enhance the anti-inflammatory M2-type polarization of macrophages while suppressing pro-inflammatory M1-type polarization in vitro. Enhancements in macrophage M2 polarization can trigger increased secretion of anti-inflammatory factors (e.g., IL-4, IL-10, and Arg-1) that promote inflammatory microenvironment remodeling and immune rebalancing. In a mouse-tail lymphedema model, a higher proportion of M2 macrophage polarization marker CD206 is observed accompanied by normal lymphangiogenesis and lymphedema subsiding following piezoelectric microneedles with US stimulation treatment. Additionally, based on RNA sequencing and mechanistic investigation, it was revealed that US-mediated piezoelectric microneedles can activate signaling pathways related to M2 macrophage polarization that regulate inflammatory responses and improve lymphatic function, consequently alleviating lymphedema. Collectively, this study provides a new strategy for lymphedema therapy in a noninvasive and drug-free manner as well as a potent tool to manipulate macrophages for other immunological diseases.