Middle‐ear dexamethasone delivery via ultrasound microbubbles attenuates noise‐induced hearing loss

Abstract

Objectives/Hypothesis In this study, we expanded our previous investigation by testing the efficiency of trans–round window membrane dexamethasone (DEX) delivery mediated by ultrasound (US)‐aided microbubbles (MBs) and its preventive effects regarding noise exposure in animal models. Study Design Live animal model. Methods Forty‐two pigmented male guinea pigs were divided into the following three groups: an US‐MBs (USM) group, in which the tympanic bulla was filled with DEX and MBs and exposed to US; a round window soaking (RWS) group, without the US irradiation; and a control group. The above‐mentioned manipulations were performed 2 hours prior to white noise exposure. The cochlear damage, including auditory threshold shifts, hair cell loss, and expression of cochlear HMGB1, was evaluated. Results The enhanced DEX delivery efficiency of the USM group was approximately 2.4× to 11.2× greater than that of the RWS group. After the noise exposure, the RWS group showed significant cochlear protection compared with the control group, and more significant and dominant protective effects were demonstrated in the USM group. Conclusions The application of US‐MBs provides a safe and more effective approach than spontaneous diffusion, which is commonly used in clinical practice; thus, this technique holds potential for future inner‐ear drug delivery. Level of Evidence NALaryngoscope, 129:1907–1914, 2019

Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles

“…The ultrasound device (ST2000V, Nepa Gene, Chiba, Japan) equipped with a 6mm-diameter transducer was used for irradiation. The optimal US exposure settings had been predetermined in our previous report (Shih et al, 2019). Briefly, the mode was set as follows: frequency 1 MHz, burst rate 250 Hz, burst duration 2 ms, acoustic intensity 3 W/cm 2 (mechanical index [MI] = 0.254) for three or five consecutive 1-min courses; and a 50% duty cycle.…”

“…As described and schematically illustrated in our previous study (Shih et al, 2019), guinea pigs were administered xylazine i.m. (Rompun; Bayer, Leverkusen, Germany) at 10 mg/kg and ketamine (Imalgene; Merial, Lyon, France) at 80 mg/kg.…”

“…For example, intratympanic injections of corticosteroids are effective for treating sudden sensorineural hearing loss, and aminoglycoside injection is used to treat Meniere's disease (Jackson and Silverstein, 2002;Rauch et al, 2011;Li et al, 2017). These injection procedures are minimally invasive; however, effective therapeutic outcomes may require repeated injections, avoidance of swallowing by the patient, or placing the patient's head slightly lower than the body because medications in the middle ear cavity usually drain out through the Eustachian tube (Shih et al, 2019). To overcome the short residence times for contact with the RWM, several delivery devices, such as the MicroWick, microcathers, and osmotic pumps, have been developed to prolong the duration of medication contact with the RWM.…”

“…Furthermore, in 2014, we demonstrated that USMBs were effective at facilitating gene transfer to auditory cells in vitro (Liao et al, 2014) and that the size-dependent MB oscillation behavior in the presence of US plays a role in enhancing gene transfer. In addition, dexamethasone delivery to the round window of animals with the aid of USMBs has a greater efficacy in protecting the inner ear from noise-exposed injury when compared to a simple soaking with the drug (Shih et al, 2019).…”

Ultrasound-induced microbubble cavitation via a transcanal or transcranial approach facilitates inner ear drug delivery

“…Our previous study demonstrated the practical application of using USMB to increase the permeability of the RWM, in which a surgical technique was used to remove the temporal bone and expose the membrane (17). We subsequently expanded that technique to explore the delivery of dexamethasone mediated by USMB and its protective effects against noise exposure in animal models (18). In clinical practice, the transcanal approach is often indicated for transtympanic injections of drugs to treat various inner ear diseases and is applied to most patients undergoing endoscopic ear surgery (19).…”