Janus acoustically responsive scaffolds for sequential drug release with phase-programmed steady and pulsatile kinetics.

Achieving precise temporal control over drug release kinetics, including sequential delivery with varied profiles, is crucial for optimizing therapeutic outcomes. However, engineering systems capable of sequential release combining distinct kinetics (e.g., steady and pulsatile) remains challenging. Here we developed a novel Janus acoustically responsive scaffold (ARS) for achieving precisely controlled sequential drug release using ultrasound. The Janus ARS is a composite hydrogel containing fibrin and different phase-shift emulsions within each half. Upon exposure to ultrasound, drug release is triggered by acoustic droplet vaporization (ADV), which induces bubble formation within the dispersed, liquid perfluorocarbon phase of each emulsion. We characterized release kinetics and morphological changes in ARSs with emulsions containing perfluorohexane or perfluorooctane. ARSs with perfluorohexane emulsion exhibited a triphasic release profile with bubbles retained in the fibrin hydrogel and steady release occurring over days. Contrastingly, ARSs with perfluorooctane emulsion exhibited a biphasic profile with macropore formation and pulsatile release following ultrasound exposure. Sequential release of two payloads was successfully achieved by leveraging the distinct properties of the two emulsion types and their frequency-dependent ADV behavior. In addition, quantitative models describing release from both sides of the Janus ARS were developed and validated. These results demonstrate the potential of Janus ARSs to provide advanced drug delivery solutions for complex therapeutic challenges currently unmet by conventional single-profile controlled release systems, offering a versatile platform for sophisticated temporal drug presentation.