An advanced in silico model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation.

Autor: Edwards SM; Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, United Kingdom., Harding AL; School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, United Kingdom., Leedale JA; Syngenta, Jeallott's Hill International Research Centre, Bracknell RG42 6EY, United Kingdom., Webb SD; Syngenta, Jeallott's Hill International Research Centre, Bracknell RG42 6EY, United Kingdom., Colley HE; School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, United Kingdom., Murdoch C; School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, United Kingdom. Electronic address: c.murdoch@sheffield.ac.uk., Bearon RN; Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, United Kingdom; Department of Mathematics, King's College London, London WC2R 2LS, United Kingdom.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Dec 05; Vol. 666, pp. 124827. Date of Electronic Publication: 2024 Oct 14.
DOI: 10.1016/j.ijpharm.2024.124827
Abstrakt: Accurately predicting the permeation of chemicals through human epithelial tissues is crucial for pharmaceutical therapeutic design and toxicology. Current mathematical models of multi-layered stratified squamous epithelium such as those in the oral cavity use simplistic 'bricks and mortar' geometries that do not fully account for the complex cellular architecture that may affect chemical permeation in these tissues. Here we aimed to develop a new, advanced mechanistic mathematical model of the human epithelium that more accurately represents chemical tissue permeation. Using measurements of cell size and tortuosity from micrograph images of both human oral (buccal) and tissue-engineered buccal mucosa along with mechanistic mathematical modelling, we show that the convoluted geometry of the extracellular spaces within the epithelium significantly impacts chemical permeation. We next developed an advanced histologically and physiologically-relevant in silico model of buccal mucosal chemical permeation using partial differential equations, fitted to chemical permeation from in vitro assay data derived from tissue-engineered buccal mucosal models and chemicals with known physiochemical properties. Our novel in silico model can predict epithelial permeation kinetics for chemicals with different physicochemical properties in the absence or presence of permeability enhancers. This in vitro - in silico approach constitutes a step-change in the modelling of chemical tissue permeation and has the potential to expedite pharmaceutical innovation by improved and more rapid screening of chemical entities whilst reducing the need for in vivo animal experiments.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Craig Murdoch reports financial support, article publishing charges, and travel were provided by National Centre for the Replacement Refinement and Reduction of Animals in Research. Steve Webb and Joseph Leedale reports a relationship with Syngenta that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper].
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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