A Novel In Vitro Membrane Permeability Methodology Using Three-dimensional Caco-2 Tubules in a Microphysiological System Which Better Mimics In Vivo Physiological Conditions

Hagiwara, Yuki; Kumagai, Harumi; Ouwerkerk, Niels; Gijzen, Linda; Annida, Rumaisha; Bokkers, Marleen; Vught, Remko van; Yoshinari, Kouichi; Katakawa, Yoshifumi; Motonaga, Kei; Tajiri, Tomokazu

doi:10.1016/j.xphs.2021.11.016

Cited by 10 publications

(3 citation statements)

References 59 publications

(50 reference statements)

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“…Design features of MAPs were varied as followed: flat‐tipped microposts with cubic arrangement (Flat‐Cub), flat‐tipped microposts with hexagonal arrangement (Flat–Hex), round‐tipped microposts with cubic arrangement (Roun–Cub), and round‐tipped microposts with hexagonal arrangement (Roun–Hex) (Figure 2e,g,f ). Intestinal peristaltic shears range from 2×10 −8 to 3.5×10 −4 N cm −2 [ 36 , 37 , 38 , 39 ] while the contact forces varies along the gut due to its variable diameter and is estimated to be between 0.9 and 2.9 N cm −2 . [ 40 , 41 ] In the view of this variability, in our simulations we utilized the knowledge of estimated shear stress experienced by bolus, which is ≈1 N cm −2 [ 17 , 42 ] as our reference and subjected MP‐V and MAP‐VP simulation models to a peristaltic shear of 0.01 and 0.1 N cm −2 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices

et al. 2023

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Intestinal retentive devices have applications ranging from sustained oral drug delivery systems to indwelling ingestible medical devices. Current strategies to retain devices in the small intestine primarily focus on chemical anchoring using mucoadhesives or mechanical coupling using expandable devices or structures that pierce the intestinal epithelium. Here, the feasibility of intestinal retention using devices containing villi‐inspired structures that mechanically interlock with natural villi of the small intestine is evaluated. First the viability of mechanical interlocking as an intestinal retention strategy is estimated by estimating the resistance to peristaltic shear between simulated natural villi and devices with various micropost geometries and parameters. Simulations are validated in vitro by fabricating micropost array patches via multistep replica molding and performing lap‐shear tests to evaluate the interlocking performance of the fabricated microposts with artificial villi. Finally, the optimal material and design parameters of the patches that can successfully achieve retention in vivo are predicted. This study represents a proof‐of‐concept for the viability of micropost‐villi mechanical interlocking strategy to develop nonpenetrative multifunctional intestinal retentive devices for the future.

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Section: Resultsmentioning

confidence: 99%

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices

et al. 2023

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“…As shown by Trietsch et al, culture of adenocarcinoma-derived Caco-2 cells in the OrganoPlate more closely resembles the differentiation, polarization, and gene expression profiles of the intestine than Transwell systems 27 . Further studies also showed how the platform can effectively mimic intestinal inflammatory disease conditions and can be used to assess intestinal drug permeability 29 , 30 . More recently, Pöschl et al reported the use of the platform to examine the effects of deoxynivalenol on barrier permeability, being the first to study enterotoxin toxicity using a high-throughput in vitro model with flow 31 .…”

Section: Introductionmentioning

confidence: 99%

A high-throughput gut-on-chip platform to study the epithelial responses to enterotoxins

Morelli,

Cabezuelo Rodríguez,

Queiroz

2024

Sci Rep

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Enterotoxins are a type of toxins that primarily affect the intestines. Understanding their harmful effects is essential for food safety and medical research. Current methods lack high-throughput, robust, and translatable models capable of characterizing toxin-specific epithelial damage. Pressing concerns regarding enterotoxin contamination of foods and emerging interest in clinical applications of enterotoxins emphasize the need for new platforms. Here, we demonstrate how Caco-2 tubules can be used to study the effect of enterotoxins on the human intestinal epithelium, reflecting toxins’ distinct pathogenic mechanisms. After exposure of the model to toxins nigericin, ochratoxin A, patulin and melittin, we observed dose-dependent reductions in barrier permeability as measured by TEER, which were detected with higher sensitivity than previous studies using conventional models. Combination of LDH release assays and DRAQ7 staining allowed comprehensive evaluation of toxin cytotoxicity, which was only observed after exposure to melittin and ochratoxin A. Furthermore, the study of actin cytoskeleton allowed to assess toxin-induced changes in cell morphology, which were only caused by nigericin. Altogether, our study highlights the potential of our Caco-2 tubular model in becoming a multi-parametric and high-throughput tool to bridge the gap between current enterotoxin research and translatable in vivo models of the human intestinal epithelium.

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“…The exclusion of the mucus barrier, villi topography, and fluidic forces can distort fundamental assumptions about nanocarrier-tissue interactions, leading to inaccurate assessments of drug bioavailability. Strategies to overcome these limitations comprise the integration of mucus producing cell types, induced pluripotent stem cells or patient-derived material, and their cultivation in microfluidic chips, resulting in the formation of complex threedimensional micro-tissues [30][31][32][33][34][35] . While these approaches offer the potential to create test systems with improved physiological relevance, they require a high level of expertise in the fields of cell biology as well as engineering and are currently limited by high production costs and low throughput.…”

Section: Introductionmentioning

confidence: 99%

Predicting nanocarrier permeation across the human intestinein vitro: Model matters

Jung,

Schreiner,

Baur

et al. 2024

Preprint

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For clinical translation of oral nanocarriers, simulation of the complex intestinal microenvironment is crucial to evaluate interactions and transport across the intestinal mucosa for predicting the drug’s bioavailability. However, permeation studies are often conducted using simplistic cell culture models, overlooking key physiological factors such as tissue composition, morphology, and additional diffusion barriers as constituted by mucus. This oversight may potentially lead to an incomplete evaluation of the nanocarrier-tissue interactions and an overestimation of permeation. In this study, we systematically investigated different 3D tissue models of the human intestine under static cultivation and dynamic flow conditions with respect to tissue morphology, mucus production, and their impact on nanocarrier permeation. Our results revealed that the cell ratio between the different cell types (enterocytes and goblet cells), as well as the choice of culture conditions, had a notable impact on tissue layer thickness, mucus secretion, and barrier impairment, all of which were increased under dynamic flow conditions. Permeation studies with polymeric nanocarriers (PLGA and PEG-PLGA) elucidated that the amount of mucus present in the respective model was the limiting factor for the permeation of PLGA nanocarriers, while tissue topography represented the key factor influencing PEG-PLGA nanocarrier permeation. Furthermore, both nanocarriers exhibited diametrically opposite permeation kinetics in a direct comparison to soluble compounds. In summary, these findings reveal the critical role of the implemented test systems on permeation assessment and emphasize that, in the context of preclinical nanocarrier testing, the choice ofin vitromodel matters.

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A Novel In Vitro Membrane Permeability Methodology Using Three-dimensional Caco-2 Tubules in a Microphysiological System Which Better Mimics In Vivo Physiological Conditions

Cited by 10 publications

References 59 publications

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices

Villi Inspired Mechanical Interlocking for Intestinal Retentive Devices

A high-throughput gut-on-chip platform to study the epithelial responses to enterotoxins

Predicting nanocarrier permeation across the human intestinein vitro: Model matters

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