An innovative in silico model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation through epithelium

• DOI: 10.48550/arxiv.2401.14928
• Publication Date: 2024-01-26
• Authors: Sean M. Edwards; Amy L. Harding; Joseph Leedale; S. David Webb; Helen Colley; Craig Murdoch; Rachel N. Bearon
• Keywords: Oral mucosa

In pharmaceutical therapeutic design or toxicology, accurately predicting the permeation of chemicals through human epithelial tissues is crucial, where significantly influenced by tissue's cellular architecture. Current mathematical models for multi-layered epithelium such as oral mucosa only use simplistic 'bricks and mortar' geometries therefore do not account complex architecture these at microscale level, extensive plasma membrane convolutions that define extracellular spaces between cells. Chemicals often permeate via this paracellular route, meaning underestimated. To address this, measurements buccal mucosal tissue were conducted to ascertain width tortuosity across epithelium. Using mechanistic modelling, we show convoluted geometry impacts chemical can be approximated, provided accounted for. We next developed an advanced physically-relevant in silico model using partial differential equations, fitted vitro assays on tissue-engineered mucosa. Tissue measured captured silico, examined predicted with different physicochemical properties. The effect altering space mimic enhancers was also assessed perturbing model. This novel vitro-in approach has potential expedite innovation testing oromucosal permeation, providing a more accurate, physiologically-relevant which reduce animal early screening based