High-Molecular-Weight Hyaluronic Acid Vehicle Can Deliver Gadolinium Into the Cochlea at a Higher Concentration for a Longer Duration: A 9.4-T Magnetic Resonance Imaging Study

Abstract

Intratympanic (IT) gadolinium (Gd) injection is one method of delivering Gd into the inner ear to evaluate the amount of endolymphatic hydrops (EH) using magnetic resonance imaging (MRI). As Gd is usually prepared in a fluid form mixed with saline, Gd injected into the middle ear drains easily through the Eustachian tube within several hours. High-molecular-weight (hMW) hyaluronic acid (HA) is an ideal vehicle for IT Gd due to its viscous and adhesive properties. The present study was performed to elucidate whether novel hMW HA is superior to conventional HA in delivering Gd into the inner ear in the short term. The second aim was to verify the long-term Gd delivery efficiency of hMW HA compared to the standard-of-care vehicle (saline). IT Gd injection and 3D T1-weighted MRI were performed in 13 rats. For the short-term study (imaging after 1, 2, and 3 h), the left ear was treated with hMW HA+Gd and the right ear with conventional HA+Gd. For the long-term study (imaging after 1, 2, 3, and 4 h, 1 – 3 days, and 7 – 10 days), the left ear was treated with hMW HA+Gd and the right ear with saline+Gd. Signal intensities (SIs) in the scala tympani (ST) and scala vestibuli (SV) were quantified. Compared to conventional HA, signal enhancement was 2.3 – 2.4 times greater in the apical and middle turns after hMW HA+Gd injection (SV at 1 h). In comparison to the standard-of-care procedure, the SI was not only greater in the short term but the higher SI also lasted for a longer duration. On days 7 – 10 after IT Gd delivery, the SI in the basal turn was 1.9 – 2.1 times greater in hMW HA+Gd-treated ears than in saline IT Gd-treated ears. Overall, hMW HA may be a useful vehicle for more efficient IT Gd delivery. Gd enhancement in the cochlea improved approximately two-fold when hMW HA was used. In addition, this greater enhancement lasted for up to 7 – 10 days. Repeated MRI of EH may be possible for several days with a single IT hMW HA+Gd delivery.

Biosafety and potency of high-molecular-weight hyaluronic acid with intratympanic dexamethasone delivery for acute hearing loss

“…The minute gaps between the ossicles and the round window niche might serve as crucial anatomical sites where HHA remains for extended durations, subsequently acting as a reservoir for D. Consequently, the concentration of D phosphate in the cochlear perilymph was about double that of the saline + D group. In previous research, the concentration of gadolinium was also observed to be 1.9–2.1 times higher in the HHA group compared to the saline group ( Hwang et al, 2021 ). We speculate that the elevated drug concentration in the cochlea is attributable to the extended residence of the HHA vehicle within the middle ear.…”

“…Compared to conventional HA (molecular weight ≤3 MDa), HHA is more robust and adhesive ( Figure 1 ). Prior research has highlighted the differences in physical properties and 9.6T MR imaging-based pharmacokinetics between HHA and conventional HA ( Hwang et al, 2021 ). HHA demonstrated the ability to deliver higher gadolinium concentrations to the cochlea over an extended period without adverse effects.…”

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“…Our micro-CT data showed that the dual vehicle stayed in the middle ear for several weeks. This residual volume of drug/vehicle can provide a continuous drug supply to the inner ear (Hwang et al, 2021). When conventional HA was used as a vehicle, the vehicle stayed in the middle ear for only 2 days and the treatment effect was limited (Park et al, 2020).…”