A Novel Chitosan-Hydrogel-Based Nanoparticle Delivery System for Local Inner Ear Application

Abstract

Hypothesis A chitosan-hydrogel-based nanoparticle (nanohydrogel) delivery system can be used to deliver therapeutic biomaterials across the round window membrane (RWM) into the inner ear in a mouse model. Background Delivering therapies to the inner ear has always been a challenge for the Otolaryngologist. Advances in biomedical nanotechnology, increased understanding of the RWM diffusion properties, and discovery of novel therapeutic targets and agents, have all sparked interest in the controlled local delivery of drugs and biomaterials to the inner ear using nanoparticles (NPs). Methods Fluorescently-labeled liposomal NPs were constructed and loaded into a chitosan-based hydrogel to form a nanohydrogel, and in vitro studies were performed to evaluate its properties and release kinetics. Furthermore, the nanohydrogel was applied to the RWM of mice, and perilymph and morphologic analysis were performed to assess the NP delivery and distribution within the inner ear. Results NPs with an average diameter of 160nm were obtained. In vitro experiments showed that liposomal NPs can persist under physiologic conditions for at least two weeks without significant degradation, and that the nanohydrogel can carry and release these NPs in a controlled and sustained manner. In vivo findings demonstrated that the nanohydrogel can deliver intact nanoparticles into the perilymphatic system and reach cellular structures in the scala media of the inner ear of our mouse model. Conclusion Our study suggests that the nanohydrogel system has great potential to deliver therapeutics in a controlled and sustained manner from the middle ear to the inner ear without altering inner ear structures.

Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss

“…They have shown that liposomal NPs delivered via nanohydrogel in vitro persisted under physiologic conditions for at least 2 weeks, thus demonstrating sustained release. Furthermore, they found that these NPs could be delivered in vivo across the mouse RWM to reach structures in the scala media [74]. Another unique feature of this delivery approach is that it is noninvasive to the inner ear, which is crucial for clinical application.…”

Inner ear delivery: Challenges and opportunities

“…These liposomes remain in hyaluronic acid adjacent to the RWM, creating a local reservoir that allowed sustained release of dexamethasone into the perilymph over 30 days, with increased conversion of dexamethasone phosphate to active dexamethasone. Likewise, nanohydrogel consisting of liposomal nanoparticles loaded onto a chitosan‐based hydrogel acts as a reservoir to release nanoparticles in a controlled and sustained manner into the perilymphatic system . Nanoparticles have also been introduced directly into the inner ear via cochleostomy, with improved distribution over intratympanic injection alone …”

“…Likewise, nanohydrogel consisting of liposomal nanoparticles loaded onto a chitosan-based hydrogel acts as a reservoir to release nanoparticles in a controlled and sustained manner into the perilymphatic system. 62 Nanoparticles have also been introduced directly into the inner ear via cochleostomy, with improved distribution over intratympanic injection alone. 69,74 More recently, microperforations have been studied in combination with the thermoreversible hydrogel poloxamer 407.…”

“…However, further development was suspended after OTO‐104 failed to demonstrate benefit over placebo. A variety of other hydrogels, including chitosan glycerophosphate and hyaluronic acid, has been studied extensively with similar safety and efficacy …”

Nanomedicine strategy for optimizing delivery to outer hair cells by surface-modified poly(lactic/glycolic acid) nanoparticles with hydrophilic molecules

“…30 We also assessed whether different NPs would induce histological changes in the cochlea through intratympanic administration, as effectively delivering therapeutic agents to the inner ear without damaging the integrity of delicate structures is most challenging. 31 Light microscopy with hematoxylin and eosin-stained paraffin sections did not reveal any inflammation in the inner ear. Individual cochlear tissues, including stria vascularis, spiral ligament, OC, and spiral ganglion cells, barely underwent morphological alterations after application of NPs for 24 h ( Figure S8).…”