Academic Journal
Synergistic impact of 3D multicellular architecture and capillary-like flow on intestinal drug permeability.
| Title: | Synergistic impact of 3D multicellular architecture and capillary-like flow on intestinal drug permeability. |
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| Authors: | Dias S; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228 4050-313 Porto, Portugal., Costa S; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228 4050-313 Porto, Portugal., Barros S; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228 4050-313 Porto, Portugal., Leite Pereira C; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal. Electronic address: catarina.pereira@i3s.up.pt., Sarmento B; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208 4200-135 Porto, Portugal; IUCS-CESPU - Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317 4585-116 Gandra, Portugal. |
| Source: | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2026 Aug 01; Vol. 223, pp. 107576. Date of Electronic Publication: 2026 Jun 04. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science B.V Country of Publication: Netherlands NLM ID: 9317982 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0720 (Electronic) Linking ISSN: 09280987 NLM ISO Abbreviation: Eur J Pharm Sci Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Science B.V Original Publication: Amsterdam ; New York : Elsevier, c1993- |
| MeSH Terms: | Atenolol*/metabolism , Intestinal Mucosa*/metabolism , Intestinal Absorption*, Metoprolol/metabolism ; Colchicine/metabolism ; Fibroblasts/metabolism ; Humans ; Caco-2 Cells ; Permeability ; HT29 Cells ; Intestinal Barrier Function ; Coculture Techniques ; Models, Biological |
| Abstract: | Understanding intestinal drug permeability requires in vitro systems capable of reproducing both the structural complexity and the dynamic fluidic environment of the human gut. Traditional two‑dimensional (2D) models, although widely used in Absorption, Distribution, Metabolism and Excretion (ADME) screening, offer limited physiological relevance and often fail to predict in vivo absorption. Three‑dimensional (3D) models and microfluidic technologies have emerged as promising tools to address these limitations by incorporating multiple cell types, extracellular matrix components, and biomechanical cues. In this study, we compared the permeability of three model drugs, metoprolol (high permeability), atenolol (moderate permeability), and colchicine (low permeability), across a 2D Caco‑2/HT29‑MTX coculture and an advanced 3D intestinal model composed of the same epithelial cells, stromal fibroblasts embedded in a collagen-alginate matrix, and a basolateral endothelial layer mimicking the vascular compartment. Both systems were evaluated under static conditions and under dynamic basolateral flow using the PDMS‑free MIVO® millifluidic platform designed to reproduce capillary‑like fluid dynamics. Permeability and TEER measurements revealed consistently higher transport across the 3D model than the 2D system, confirming its enhanced physiological relevance. Dynamic flow further increased permeability in both models, with the most pronounced effect observed for metoprolol, whose permeation was highest under dynamic 3D conditions. Flow also accelerated TEER decline in the 3D setup, suggesting increased barrier stress associated with elevated transport. Overall, integrating 3D multicellular architecture with physiologically relevant flow substantially improves the predictive capacity of intestinal in vitro models. These findings support dynamic 3D systems as advanced tools for drug permeability assessment and early‑stage drug development. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: 3D intestinal model; Caco-2; Fluid dynamics in vitro; Intestinal permeability; Millifluidics |
| Substance Nomenclature: | GEB06NHM23 (Metoprolol) 50VV3VW0TI (Atenolol) SML2Y3J35T (Colchicine) |
| Entry Date(s): | Date Created: 20260605 Date Completed: 20260613 Latest Revision: 20260615 |
| Update Code: | 20260616 |
| DOI: | 10.1016/j.ejps.2026.107576 |
| PMID: | 42248264 |
| Database: | MEDLINE |
| ISSN: | 1879-0720 |
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| DOI: | 10.1016/j.ejps.2026.107576 |