Reversible opening of the blood-labyrinth barrier by low-pressure pulsed ultrasound and microbubbles for the treatment of inner ear diseases

Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases. However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig's inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin. Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe