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

Liao, Ai‐Ho; Wang, Chih‐Hung; Weng, Ping-Yu; Lin, Yi‐Chun; Wang, Hao; Chen, Hang-Kang; Liu, Hao-Li; Chuang, Ho‐Chiao; Shih, Cheng‐Ping

doi:10.1172/jci.insight.132880

Cited by 24 publications

(37 citation statements)

References 47 publications

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“…Our previous study first demonstrated the feasibility and supported the potential clinical application of US-mediated MB cavitation via the external auditory canal to facilitate drug delivery into the inner ear (Liao et al, 2020). We also assessed the usefulness of US plus US contrast agent MBs in agarose gels for enhancing transdermal drug delivery (Liao, Lu, Hung, et al, 2016).…”

Section: Introductionmentioning

confidence: 83%

Development of thermosensitive poloxamer 407-based microbubble gel with ultrasound mediation for inner ear drug delivery

Liao

Shih

et al. 2021

Drug Delivery

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Our previous study first investigated feasibility of applying ultrasound (US) and microbubbles (MBs) via external auditory canal to facilitate drug delivery into inner ear. However, most drugs are in aqueous formulae and eliminated via Eustachian tubes after drug application. In this study, feasibility of sustained release of thermosensitive poloxamer 407 (P407)-based MB gel for US mediation-enhanced inner ear drug (dexamethasone, DEX) delivery was investigated. The sol-to-gel transition temperature showed that mixture of DEX and only 10% and 12.5% P407 in MBs can be used for in vitro and in vivo drug delivery experiments. In in vitro Franz diffusion experiments, the release rates of 12.5% P407-MBs þ US groups in the model using DEX as the delivered reagent at 3 h resulted in values 1.52 times greater than those of 12.5% P407-MBs groups. In guinea pigs, by filling tympanic bulla with DEX in 12.5% P407-MBs (DEX-P407-MBs), USMB applied at post-treatment days 1 and 7 induced 109.13% and 66.67% increases in DEX delivery efficiencies, respectively, compared to the group without US. On the 28th day after US-mediated P407-MB treatment, the safety assessment showed no significant changes in the hearing thresholds and no damage to the integrity of cochlea or middle ear. These are the first results to demonstrate feasibility of US-modified liquid form DEX-P407-MB cavitation for enhancing permeability of round window membrane. Then, a gel form of DEX-P407-MBs was generated and thus prolonged the release of DEX in middle ear to maintain the therapeutic DEX level in inner ear for at least 7 days.

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Section: Introductionmentioning

confidence: 83%

Development of thermosensitive poloxamer 407-based microbubble gel with ultrasound mediation for inner ear drug delivery

Liao

Shih

et al. 2021

Drug Delivery

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“…Hence, an additional amount of salicylate could enter the ST down its concentration gradient when the salicylate concentration in the immediate vicinity of the inner surface of the RW dropped due to enhanced mixing because of the vortex formation described above and because the RW permeability increased during its mechanical stimulation (e.g. Park & Moon, 2014;Liao et al, 2020). This facilitated additional influx of salicylate could increase its concentration at the cochlear base, which is indicated by higher basal CAP threshold elevations observed in our experiments (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…A few relatively non-invasive techniques for assisting substance mixing along the cochlea have been suggested recently that utilise low-frequency pressure stimulation (Lukashkin et al, 2020), stimulation at acoustic frequencies (Park & Moon, 2014;Shokrian et al, 2020) and ultrasound (Liao et al, 2020) which cause reciprocated movement of the stapes and RW. While the later method relies on the formation of ultrasound-induced microbubbles which can act directly on the RW (Liao et al, 2020), the other techniques require the mobility of the ossicular chain. If the ossicular chain is immobile or malformed then these techniques become nonapplicable.…”

Section: Introductionmentioning

confidence: 99%

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations

Flaherty

Russell

Lukashkin

2021

Preprint

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The cochlea's inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method of local drug delivery to the cochlea presented here could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.

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“…Since the drug delivery enhancement is related to the destruction efficacy of MBs ( Liao et al, 2020a ; Liao et al, 2020b ). As illustrated in Figure 2 , each well of a 24-well plate was filled with about 4 ml of MBs (1.4 × 10 7 , 0.7 × 10 7 , or 0.35 × 10 7 MBs/ml) while ensuring that no air bubbles were trapped when the cover was placed.…”

Section: Methodsmentioning

confidence: 99%

Minoxidil-Coated Lysozyme-Shelled Microbubbes Combined With Ultrasound for the Enhancement of Hair Follicle Growth: Efficacy In Vitro and In Vivo

et al. 2021

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Lysozyme (Lyz) is an antimicrobial peptide, a safe adjunct, and it has been indicated that Lyz can promote vibrissae follicle growth by enhancing the hair-inductive capacity of dermal papilla cells in mice. The present study produced a new type of minoxidil (Mx)-coated antifungal Lyz-shelled microbubble (LyzMB) for inhibiting bacteria and allergies on the oily scalp. The potential of Mx-coated LyzMBs (Mx-LyzMBs) combined with ultrasound (US) and the role of LyzMB fragments in enhancing hair follicle growth were investigated. Mx grafted with LyzMBs were synthesized and the loading efficiency of Mx on cationic LyzMBs was 20.3%. The biological activity of Lyz in skin was determined using an activity assay kit and immunohistochemistry expression, and the activities in the US+Mx-LyzMBs group were 65.8 and 118.5 μU/mL at 6 and 18 h, respectively. In hair follicle cell culture experiments, the lengths of hair follicle cells were significantly enhanced in the US+Mx-LyzMBs group (108.2 ± 11.6 μm) compared to in the US+LyzMBs+Mx group (44.3 ± 9.8 μm) and the group with Mx alone (79.6 ± 12.0 μm) on day 2 (p < 0.001). During 21 days of treatment in animal experiments, the growth rates at days 10 and 14 in the US+Mx-LyzMBs group increased by 19.4 and 65.7%, respectively, and there were significant differences (p < 0.05) between the US+Mx-LyzMBs group and the other four groups. These findings indicate that 1-MHz US (applied at 3 W/cm2, acoustic pressure = 0.266 MPa) for 1 min combined with Mx-LyzMBs can significantly increase more penetration of Mx and LyzMB fragments into skin and enhance hair growth than Mx alone.

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

Cited by 24 publications

References 47 publications

Development of thermosensitive poloxamer 407-based microbubble gel with ultrasound mediation for inner ear drug delivery

Development of thermosensitive poloxamer 407-based microbubble gel with ultrasound mediation for inner ear drug delivery

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations

Minoxidil-Coated Lysozyme-Shelled Microbubbes Combined With Ultrasound for the Enhancement of Hair Follicle Growth: Efficacy In Vitro and In Vivo

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