Real-time drug release monitoring from acoustically responsive scaffolds

Acoustically responsive scaffolds (ARSs), composite hydrogels containing phase-shift droplets that are activated by ultrasound, enable on-demand drug delivery with spatiotemporal precision. Yet, real-time monitoring of drug release from ARSs remains limited. Here, we studied the dynamics of the ultrasound-based activation mechanism, acoustic droplet vaporization (ADV), in fibrin-based ARSs containing perfluorohexane droplets. We investigated how initial droplet concentration, acoustic pressure, and burst number affect droplet dynamics, bubble cloud evolution, acoustic emissions, and drug release efficiency. Optical imaging, at 5 million frames per second (Mfps) and 50 fps, revealed that ADV-induced bubble cloud morphologies were concentration dependent. At high concentrations and pressures, bubble clouds expanded significantly beyond the ultrasound focal region by up to 300%. ADV generated distinct low-frequency (LF) emissions that progressively decreased over repeated bursts by ≈30 dB, indicating a reduction in the number of vaporized droplets within the focal region. The burst number at which LF emissions plateaued (e.g., 51 bursts at 0.1% (v/v), 6.2 MPa) correlated with the burst number at which payload release reached its maximum value (57 bursts), demonstrating that LF emissions provide real-time, non-invasive feedback on ADV-mediated drug delivery. These results establish a direct correlation between LF emissions and ADV, and underscore their potential for real-time monitoring of drug release in ARSs.