A Wearable Ultrasound-Assisted Microneedle System for the Treatment of Poorly Permeable Skin Lesions.

Abstract

Poorly permeable skin lesions (e.g., hypertrophic scars and psoriasis) exhibit impaired barrier function, making it difficult for drugs to penetrate to deeper layers. Microneedles (MNs) have emerged as a promising strategy to bypass the stratum corneum, but their efficacy in poorly permeable lesions is restricted by excessive insertion force, insufficient penetration depth, and limited drug diffusion. Herein, we develop a wearable ultrasound-assisted microneedle system (WUAMS) that integrates low-frequency ultrasound with titanium nanotubes (TNTs)-functionalized MNs for poorly permeable skin lesions to realize low-force insertion and rapid deep drug delivery. Compared with MNs, the WUAMS reduces the insertion force by approximately 1.86-fold in rat skin, 3.28-fold in porcine skin, 2.54-fold in rabbit skin, and 5.94-fold in rabbit ear scar skin, minimizing insertion discomfort and improving compliance for long-term use. In vitro studies demonstrate that WUAMS achieves rapid deep drug delivery of Rhodamine B within 3 min, 10 times faster than MNs, with a penetration depth 1.62-fold greater than MNs patch, 3.79-fold greater than ultrasound, and 15.02-fold greater than passive diffusion. In a rabbit ear hypertrophic scar model, the WUAMS enhances intralesional drug deposition, suppresses fibroblast activation, and downregulates TGF - β1/Col I signaling pathway, resulting in significant scar remodeling. In a psoriasis mouse model, the WUAMS alleviates abnormal keratinization and inhibits Th17 - related inflammatory responses. As a platform technology, the WUAMS offers a minimally invasive and personalized therapeutic approach for poorly permeable skin lesions, promoting the advancement of transdermal treatment towards higher efficiency and clinical translatability. STATEMENT OF SIGNIFICANCE: • The WUAMS platform highly integrates the ultrasonic driving circuit with the ultrasonic microneedle transducer, with a compact size of Ф37 × 21 mm³. • Compared with microneedles, WUAMS reduces the puncture force by 5.94 times in scar tissue. The drug delivery depth of rhodamine B was 1.62 times greater than that of microneedles, while the drug delivery time was significantly shortened from 30 min to 3 min. • The WUAMS is demonstrated as a generalizable platform technology rather than a disease-specific solution, with its therapeutic efficacy systematically validated in two representative models. In a rabbit ear hypertrophic scar model, WUAMS enhanced intralesional drug deposition, inhibited fibroblast activation and down-regulated TGF-β1/Col I pathway. In a psoriasis mice model, the system effectively alleviated abnormal keratinization and suppressed Th17-related inflammatory responses.