Intrinsic mechanism and pharmacologic treatments of noise-induced hearing loss

Abstract

Noise accounts for one-third of hearing loss worldwide. Regretfully, noise-induced hearing loss (NIHL) is deemed to be irreversible due to the elusive pathogenic mechanisms that have not been fully elucidated. The complex interaction between genetic and environmental factors, which influences numerous downstream molecular and cellular events, contributes to the NIHL. In clinical settings, there are no effective therapeutic drugs other than steroids, which are the only treatment option for patients with NIHL. Therefore, the need for treatment of NIHL that is currently unmet, along with recent progress in our understanding of the underlying regulatory mechanisms, has led to a lot of new literatures focusing on this therapeutic field. The emergence of novel technologies that modify local drug delivery to the inner ear has led to the development of promising therapeutic approaches, which are currently under clinical investigation. In this comprehensive review, we focus on outlining and analyzing the basics and potential therapeutics of NIHL, as well as the application of biomaterials and nanomedicines in inner ear drug delivery. The objective of this review is to provide an incentive for NIHL's fundamental research and future clinical translation.

Keywords: drug delivery systems; nanoparticles; noise-induced hearing loss; pharmacologic strategies.

Figure 1

The anatomy of the human ear. (A) Schematic representation of ear anatomy. The ear consists of three parts: the outer, middle, and inner ear. The outer and middle ear are separated by the tympanic membrane. Sound waves are transduced through tympanic membrane to the chain of three tiny bones (the ossicles) in middle ear cavity, which is attached to the oval window membrane, leading to fluid vibrations in the inner ear. The inner ear is responsible for hearing (cochlea) and balance (vestibule). (B) The cochlea is divided into three fluid-filled membranous tube coiling around the modiolus: the scala tympani, scala vestibuli, and scala media. The fluid vibrations create a traveling wave along the basilar membrane, in which hair cells generate the electrical signals and pass them to the spiral ganglion cells. (C) High-intensity sound waves travel through the cochlear duct, causing damage to three key functional areas: the organ of Corti, the SGNs and the stria vascularis. Hair cells, supporting cells and SGNs go through morphological changes and eventual apoptosis in extreme cases. Loss of tight junctions, malfunction of endothelial cells and surrounding cell types contribute to the BLB disruption. Abbreviations: SV: scala vestibuli; SM: scala media; ST: scala tympani; SCs: supporting cells; OHCs: outer hair cells; IHC: inner hair cell; BLB: blood-labyrinth barrier. Created with BioRender (www.biorender.com).

Figure 2

Illustration of the contributing factors to NIHL and their interactions with each other. Noise-related disfunction of the stria vascularis leads to ischemia reperfusion injury, which increases the level of ROS in the cochlea. The overproduction of ROS and cochlear inflammation are two biochemical events that promote each other. With excessive calcium influx triggering the glutamate neurotoxicity at the ribbon synapses, both hair cells and the synaptic structures are damaged. Intrinsic or extrinsic pathways of apoptosis are activated by the resulting injuries. Abbreviations: ROS: reactive oxygen species; GluR: glutamate receptor.

Figure 3

Illustration of relatively recent findings on molecular pathways underlying NIHL as potential therapeutic opportunities. Signaling pathways involved in (A) inflammation, (B) energy metabolism, (C) oxidative stress, (D) programmed cell death and (E) excitotoxicity and autophagy are illustrated in separated regions. Protective responses are shown in green. Adverse cellular events are shown in red. Pharmacological interventions are shown in purple. Created with BioRender (www.biorender.com).

Figure 4

Molecular structures of the clinical candidates for NIHL therapy. A non-exhaustive list of evaluated drugs in preclinical studies is illustrated in the blue region. Drugs that have entered clinical trials are illustrated in separated regions according to the stage of clinical trials they are in.

Figure 5

Summary of different drug delivery routes to the inner ear. Abbreviations: CCA: common cochlear artery; CNS: central neural system; IHCs: inner hair cells; OC: organ of Corti; OHCs: outer hair cells; OW: oval window; RW: round window; SM: scala media; SP: spiral prominence; ST: scala tympani; SV: scala vestibuli.

Figure 6

Potential future strategies for drug delivery across the BLB that have been discussed in this review. Multiple strategies including receptor-mediated transcytosis, cell-mediated drug delivery, nanoparticle-facilitated drug delivery and exploiting certain conditions to open the barrier are illustrated. The image of cochlear blood supply by ink perfusion was reproduced under the terms of the CC-BY Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) . Copyright 2018, the authors, published by Elsevier. Abbreviations: EC: endothelial cells; LRP-1: low-density lipoprotein receptor-related protein 1; NPs: nanoparticles; PC: pericyte; PVM/M: perivascular resident macrophage type-melanocyte; TJ: tight junction; SM: scala media; ST: scala tympani; SV: scala vestibuli. Created with BioRender (www.biorender.com).

Figure 7

Advanced strategies for intratympanic drug delivery across the RWM that have been discussed in this review. Nanoparticulate systems can penetrate the tissue barrier via both paracellular and transcellular pathways. CPEs can be used to decrease the tight junctions to improve drug penetration. Gelling systems maintain close attachment to the RWM for prolonged drug delivery. Abbreviations: CPE: chemical permeation enhancers; CT: connective tissue; OE: outer epithelium; RWM: round window membrane; SE: squamous epithelium; TDNs: tetrahedral DNA nanostructures. Created with BioRender (www.biorender.com).

Figure 8

Targeted drug delivery strategies for NIHL treatment. (A) Schematic of the A666 peptide-conjugated nanodelivery system targeting prestin on OHCs . (B) Schematic of the Tet1 functionalized polymersome targeting the trisialoganglioside clostridial toxin receptors on SGNs . Created with BioRender (www.biorender.com). (C) Four candidate BLB targeting peptides and their uptake in mouse cochleae by ex vivo fluorescence imaging. Reproduced under the terms of the CC-BY Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) . Copyright 2022, The authors, published by Springer Nature. (D) The ability of IETP2 to cross the BLB in vivo. Reproduced under the terms of the CC-BY Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) . Copyright 2022, The Authors, published by Springer Nature. Abbreviations: OHCs: outer hair cells; SGNs: spiral ganglion cells; LRP1: low-density lipoprotein receptor-related protein 1

Figure 9

Schematics of the ultraviolet polymerized GelMA microgels for prolonged drug delivery of dexamethasone sodium phosphate for NIHL therapy. Reproduced with permission . Copyright 2022, American Chemical Society.

Figure 10

(A) Schematic of ultrasound-induced microbubble cavitation to increase the permeability of the RWM. Reproduced under the terms of the CC-BY Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) . Copyright 2020, The Authors, published by The American Society for Clinical Investigation. (B) Concentration of IGF-1 in the cochleae after the IGF-1 treatment with and without microbubble irradiation. Reproduced under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/) . Copyright 2021, by The Authors, published by MDPI. (C) ABR threshold shift of guinea pigs after the IGF-1 treatment with and without microbubble irradiation. Reproduced under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/) . Copyright 2021, by The Authors, published by MDPI. Abbreviations: MBs: microbubbles; RWS, round window soaking; USM, ultrasound microbubble treatment.

Figure 11

(A) Schematics of the ROS-Responsive nanoparticle (PL-PPS/BBR) delivery system which disassembled in a ROS-rich lymph for berberine release. (B) Comparison of OHC loss at basal turn in each group. (C) Schematics of the anti-inflammatory and antioxidant effects of PL-PPS/BBR on OHCs. (D) SEM images of OHCs and their stereocilia in each group. Reproduced with permission . Copyright 2021, American Chemical Society.

Figure 12

Summary of drug development and drug delivery for NIHL. Pathological mechanism studies of NIHL are the basics of preclinical drug development. More efficient drug delivery into the inner ear will be propelled by an advanced understanding of the main patterns of substance transport across the biological barriers, with the combined efforts of fast-developing nanotechnology. Those factors also contribute to the clinical translation of drug candidates. Created with BioRender (www.biorender.com).