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1.I.4.  The Round Window Membrane (RWM) Family  

The round window is one of the two openings into the cochlea from the middle ear. The round window membrane (RWM) vibrates with an opposite phase to acoustic vibrations entering the cochlea through the stapes at the oval window, another opening of the cochlea to the middle ear. The RWM is the most common entryway for local drug and gene delivery into the inner ear (Zhang et al. 2016), but its permeability can change the treatment outcome. Various types of nanoparticles have been used for gene (Jero et al. 2001) and drug (Yang et al. 2018) delivery. The ultrastructure of the RWMs of humans, monkeys, felines, and rodents discloses three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium (Goycoolea and Lundman 1997). Interspecies variations are mainly in terms of thickness, being thinnest in rodents and thicker in humans. Morphologic evidence suggests that the layers of the round window participate in absorption and secretion of substances to and from the inner ear, and that the entire membrane could play a role in the defense system of the ear. Different substances, including antibiotics, local anesthetics, and tracers such as cationic ferritin, horseradish peroxidase, and 1 mu latex microspheres, are placed in the middle ear side traverse the membrane. Cationic ferritin and 1 micron microspheres placed in perilymph become incorporated by the inner epithelial cells of the membrane. Permeability is selective; factors include size, concentration, liposolubility, electrical charge, and thickness of the membrane. Passage of substances through the RWM is by different pathways, the nature of which is seemingly decided at the outer epithelium of the round window membrane (Goycoolea and Lundman 1997). The application of liposomes to inner ear drug delivery has been reviewed (Mohammadian et al. 2017).

The round window membrane (RWM) is permeable to certain biological substances because they can  pass through the RWM (Juhn et al. 1989).  They have the potential to cause inner ear damage, leading to functional disturbances. The RWM is permeable to water, and the existence of osmotically active substances in the middle ear cavity can induce an alteration of inner ear fluid osmolality, leading to membrane displacement. However, several limiting factors exist that prevent free passage of substances from the middle ear to the inner ear. These include the morphological barrier of the three-layered RWM, the molecular weight of the substances, and the nature and concentration of substances in the middle ear cavity. The degree and duration of the inflammation in the middle ear cavity, as well as the morphological integrity of the RWM, also play an important role in controlling the passage of noxious substances into the inner ear. Further characterization of the factors involved in RWM permeability, and clarification of the mechanisms of the inner ear damages caused by substances passing into the inner ear through the RWM, will be necessary for an understanding of the inner ear dysfunction caused by middle ear inflammation (Juhn et al. 1989).

The round-window membrane (RWM) is extremely thin and is the only soft-tissue barrier between the middle ear and the inner ear (Hellström et al. 1997). Under inflammatory conditions of the middle ear, the various layers of the triple-layered RWM undergo characteristic changes parallel to the changes of the middle-ear mucosa. Bacterial products, exo- and endotoxins from bacteria, invading the middle ear may result in inflammatory changes in the inner ear, followed by damage to inner-ear function. Hellström et al. 1997 summarized experimental and clinical observations on bacterial products in interactions between the middle and inner ear, focused on: 1. Bacteria and bacterial products in an inflamed middle ear that may influence inner-ear function; 2. RWM structure and RWM permeability under the influence of bacteria and bacterial products, and 3. Morphological and functional inner-ear effects of bacterial infection of the middle ear.

 Lin et al. 2019 demonstrated an approach using ultrasound-aided microbubble (USMB) cavitation to enhance the permeability of the RWM, and they investigated the safety of USMB exposure and the association between temporal changes in RWM permeability and ultrastructure. Guinea pigs were divided into two treatment groups, a control group receiving round window soaking (RWS) with MBs and a treatment (USM) group undergoing 3 (USM-3) or 5 (USM-5) consecutive USMB exposures (1 min/exposure) at an acoustic intensity of 3 W/cm(2) and 1 MHz frequency. The trans-RWM delivery efficiency of biotin-fluorescein isothiocyanate conjugates, used as permeability tracers, revealed a greater than 7-fold higher delivery efficiency for the USM groups immediately after 3 or 5 exposures than for the RWS group. After 24 h, the delivery efficiency was 2.4-fold higher for the USM-3 group but was 6.6-fold higher for the USM-5 group (and 3.7-fold higher after 48 h), when compared to the RWS group. Scanning electron microscopy images of the RWM ultrastructure revealed USMB-induced sonoporation effects that could include the formation of heterogeneous pore-like openings with perforation diameters from 100 nm to several micrometers, disruption of the continuity of the outer epithelial surface layer, and loss of microvilli. These ultrastructural features were associated with differential permeability changes that depended on the USMB exposure course. Fourteen days after treatment, the pore-like openings had significantly decreased in number, and the epithelial defects were healed, either by cell expansion or by repair by newly migrated epithelial cells. The auditory brainstem response recordings of the animals following the 5-exposure USMB treatment indicated no deterioration in the hearing thresholds at a 2-month follow-up and no significant hair cell damage or apoptosis, based on scanning electron microscopy, surface preparations, and TUNEL assays. USMBs therefore appear to be safe and effective for inner ear drug delivery. The mechanism of enhanced permeability may involve a disruption of the continuity of the outer RWM epithelial layer, which controls transmembrane transport of various substances (Lin et al. 2019).


References associated with 1.I.4 family:

Goycoolea, M.V. and L. Lundman. (1997). Round window membrane. Structure function and permeability: a review. Microsc Res Tech 36: 201-211. 9080410
Hellström, S., P.O. Eriksson, Y.J. Yoon, and U. Johansson. (1997). Interactions between the middle ear and the inner ear: bacterial products. Ann. N.Y. Acad. Sci. 830: 110-119. 9616671
Jero, J., A.N. Mhatre, C.J. Tseng, R.E. Stern, D.E. Coling, J.A. Goldstein, K. Hong, W.W. Zheng, A.T. Hoque, and A.K. Lalwani. (2001). Cochlear gene delivery through an intact round window membrane in mouse. Hum Gene Ther 12: 539-548. 11268286
Juhn, S.K., Y. Hamaguchi, and M. Goycoolea. (1989). Review of round window membrane permeability. Acta Otolaryngol Suppl 457: 43-48. 2648755
Lin, Y.C., H.C. Chen, H.K. Chen, Y.Y. Lin, C.Y. Kuo, H. Wang, C.L. Hung, C.P. Shih, and C.H. Wang. (2019). Ultrastructural Changes Associated With the Enhanced Permeability of the Round Window Membrane Mediated by Ultrasound Microbubbles. Front Pharmacol 10: 1580. 32047431
Mohammadian, F., A. Eatemadi, and H. Daraee. (2017). Inner ear drug delivery using liposomes. Cell Mol Biol (Noisy-le-grand) 63: 28-33. 28234628
Yang, K.J., J. Son, S.Y. Jung, G. Yi, J. Yoo, D.K. Kim, and H. Koo. (2018). Optimized phospholipid-based nanoparticles for inner ear drug delivery and therapy. Biomaterials 171: 133-143. 29689410
Zhang, Y., H. Su, L. Wen, F. Yang, and G. Chen. (2016). Mathematical modeling for local trans-round window membrane drug transport in the inner ear. Drug Deliv 23: 3082-3087. 26934165