Dataset Information

Development and Characterization of an In Vitro Round Window Membrane Model for Drug Permeability Evaluations.

ABSTRACT: Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. This often leads to failed advancement in the market of effective therapeutics. In this context, especially for inner ear-specific pathologies, the availability of an in vitro, physiologically relevant, round window membrane (RWM) model could enable rapid, high-throughput screening of potential topical drugs for inner ear and cochlear dysfunctions and could help accelerate the advancement to clinic and market of more viable drug candidates. In this study, we report the development and evaluation of an in vitro model that mimics the native RWM tissue morphology and microenvironment as shown via immunostaining and histological analyses. The developed three-dimensional (3D) in vitro model was additionally assessed for barrier integrity by transepithelial electrical resistance, and the permeability of lipophilic and hydrophilic drugs was determined. Our collective findings suggest that this in vitro model could serve as a tool for rapid development and screening of topically deliverable oto-therapeutics.

SUBMITTER: Singh R

PROVIDER: S-EPMC9504332 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Development and Characterization of an In Vitro Round Window Membrane Model for Drug Permeability Evaluations.

Singh Ruby R Birru Bhaskar B Veit Joachim G S JGS Arrigali Elizabeth M EM Serban Monica A MA

Pharmaceuticals (Basel, Switzerland) 20220905 9

Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. This often leads to failed advancement in the market of effective therapeutics. In this context, especially for inner ear-specific pathologies, the availability of an in vitro, physiologically rel ...[more]

PMID: 36145326

Similar Datasets

Project description:The round window membrane (RWM) covers an opening between the perilymph fluid-filled inner ear space and the air-filled middle ear space. As the only non-osseous barrier between these two spaces, the RWM is an ideal candidate for aspiration of perilymph for diagnostics purposes and delivery of medication for treatment of inner ear disorders. Routine access across the RWM requires the development of new surgical tools whose design can only be optimized with a thorough understanding of the RWM's structure and properties. The RWM possesses a layer of collagen and elastic fibers so characterization of the distribution and orientation of these fibers is essential. Confocal and two-photon microscopy were conducted on intact RWMs in a guinea pig model to characterize the distribution of collagen and elastic fibers. The fibers were imaged via second-harmonic-generation, autofluorescence, and Rhodamine B staining. Quantitative analyses of both fiber orientation and geometrical properties of the RWM uncovered a significant correlation between mean fiber orientations and directions of zero curvature in some portions of the RWM, with an even more significant correlation between the mean fiber orientations and linear distance along the RWM in a direction approximately parallel to the cochlear axis. The measured mean fiber directions and dispersions can be incorporated into a generalized structure tensor for use in the development of continuum anisotropic mechanical constitutive models that in turn will enable optimization of surgical tools to access the cochlea. STATEMENT OF SIGNIFICANCE: The Round Window Membrane (RWM) is the only non-osseous barrier separating the middle and inner ear spaces, and thus is an ideal portal for medical access to the cochlea. An understanding of RWM structure and mechanical response is necessary to optimize the design of surgical tools for this purpose. The RWM geometry and the connective fiber orientation and dispersion are measured via confocal and 2-photon microscopy. A region of the RWM geometry is characterized as a hyperbolic paraboloid and another region as a tapered parabolic cylinder. Predominant fiber directions correlate well with directions of zero curvature in the hyperbolic paraboloid region. Overall fiber directions correlate well with position along a line approximately parallel to the central axis of the cochlea's spiral.

Project description:IntroductionCannabinoids including cannabidiol (CBD) have attracted enormous interest as bioactive ingredients for various dermatological and/or cosmeceutical uses. However, topical applications of cannabinoids might be limited without a fundamental understanding of their skin permeability. Herein, we aimed to evaluate the skin permeability of CBD and its topical formulations using artificial skin membrane assays. The solubility and stability of CBD in various surfactants that are commonly used in topical applications were also evaluated.MethodsCBD and two CBD-incorporated topical formulations (cream and gel) were prepared for this study. Computational predictions (SwissADME and DERMWIN™) and the parallel artificial membrane permeability assay (PAMPA) were used to evaluate the skin permeability of CBD isolate. The Franz cell diffusion (in vitro release testing) assay was used to evaluate the skin permeability of CBD formulations. The solubility and stability of CBD in surfactants were assessed by high-performance liquid chromatography and mass spectrometry analysis.ResultsCBD isolate showed favorable skin permeability in the SwissADME and DERMWIN™ predictions (-Log Kp of 3.6 and 5.7 cm/s, respectively) and PAMPA (-LogPe value of 5.0 at pH of 6.5 and 7.4). In addition, CBD had higher solubility (378.4 μg/mL) in surfactant Tween 20 as compared to its solubility in polyisobutene. In an acidic environment (pH 5 and 6), Tween 20 maintained the CBD content at 81% and 70% over 30 days, respectively. CBD in the formulations of cream and gel also had moderate skin permeability in the Franz cell diffusion assay.ConclusionData from artificial membrane-based assays support that CBD is a skin permeable cannabinoid and the permeability and stability of its formulations may be influenced by several factors such as surfactant and pH environment. Findings from our study suggest that CBD may have suitable skin permeability for the development of dermatological and/or cosmeceutical applications but further studies using in vivo models are warranted to confirm this.

Dataset Information

Development and Characterization of an In Vitro Round Window Membrane Model for Drug Permeability Evaluations.

Publications

Development and Characterization of an In Vitro Round Window Membrane Model for Drug Permeability Evaluations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets