Sequential Drug Release from Dual-Responsive Scaffold with Ultrasound-Enhanced Efficacy for Infectious Oral Ulcer Therapy

Abstract Oral aphthous ulcers are among the most prevalent mucosal disorders, with infectious oral ulcers severely compromising patients’ quality of life. This study introduces a dual-responsive (ultrasound- and pH-sensitive) hydrogel–microsphere scaffold for their precise, staged management. The scaffold, composed of a pH-sensitive chitosan (CS) hydrogel and ultrasound-responsive sodium alginate (SA) microspheres, demonstrated injectability, biocompatibility, and sequential drug release. Specifically, ultrasound enhanced drug release and tissue penetration, improving therapeutic efficacy. The pH-responsive mechanism enabled targeted release of lidocaine (LID) and curcumin (CUR) at inflamed sites, which is expected to provide local anesthesia while promoting epithelial regeneration. Mechanistically, ultrasound stimulation activated PI3K-Akt and ECM-receptor interaction pathways, which were associated with enhanced cell migration, proliferation, and drug responsiveness. These effects not only enhanced the therapeutic efficacy, but also established a microenvironment favorable for tissue repair. Our platform integrates multimodal functionalities, including rapid release of the analgesic drug LID, followed by the sustained effects of CUR. Crucially, ultrasound facilitate this release process and enhance the therapeutic efficacy. This comprehensive approach modulates the local wound microenvironment, thereby creating favorable conditions for accelerating tissue repair. This work expands new avenues for stimulus-responsive drug delivery systems in the treatment of oral diseases and holds potential for clinical translation.