Generation of Tetrafluoroethylene–Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies

Sano, Emi; Deguchi, Sayaka; Matsuoka, Naoki; Tsuda, Masahiro; Wang, Mengyang; Kosugi, Kaori; Mori, Chihiro; Yagi, Kiyoshi; Wada, Aya; Yamasaki, Shinsuke; Kawai, Takeshi; Yodogawa, Masahide; Mizuguchi, Hiroyuki; Nakazawa, Norihito; Yamashita, Fumiyoshi; Torisawa, Yu-suke; Takayama, Kazuo

doi:10.1021/acsomega.1c03719

Cited by 10 publications

(5 citation statements)

References 19 publications

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“…For instance, culture of hepatic cell lines or primary hepatocytes in tetrafluoroethylene-propylene or glass-based devices reduced absorption of small hydrophobic molecules, increased the amount of detectable metabolites and sensitized 2D hepatocyte cultures to coumarin cytotoxicity. [53,54] However, there are typically tradeoffs for the use of materials with decreased compound absorption, such as unfavorable mechanical or optical properties, reduced ease of prototyping or higher fabrication costs.…”

Section: Discussionmentioning

confidence: 99%

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Kemas,

Zandi Shafagh,

Taebnia

et al. 2023

Adv Healthcare Materials

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Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000‐fold between polymers with polydimethyl siloxane (PDMS) being most absorptive, whereas polytetrafluoroethylene (PTFE) and thiol‐ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations, whereas isogenic cultures in PDMS devices are resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability.

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Section: Discussionmentioning

confidence: 99%

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Kemas,

Zandi Shafagh,

Taebnia

et al. 2023

Adv Healthcare Materials

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“…It is known that the porous structure of PDMS allows small hydrophobic molecules to diffuse in. [15][16][17] Although alternative materials have been explored to avoid or reduce this problem, [18][19][20] we investigated the effect of albumin that is known to improve sink conditions and solubilize hydrophobic drugs. 21) It has been reported that the addition of albumin to the basal fluid remarkably increases the absorptive transport of hydrophobic compounds across Caco-2 cell monolayers cultured in the Transwells, owing to prevention of their adsorption onto the plastic surface.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Permeability of Drugs in Caco-2 Cells Cultured in Microfluidic Devices

Sasaki

Tatsuoka

Tsuda

et al. 2022

Biological & Pharmaceutical Bulletin

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Microfluidic devices are attracting attention for their ability to provide a biomimetic microenvironment wherein cells are arranged in a particular pattern and provided fluidic and mechanical forces. In this study, we evaluated drug transport across Caco-2 cell layers in microfluidic devices and investigated the effects of fluid flow on drug transport and metabolism. We designed a microfluidic device that comprises two blocks of polydimethylsiloxane and a sandwiched polyethylene terephthalate membrane with pores 3.0 µm in diameter. When cultured in a dynamic fluid environment, Caco-2 cells were multilayered and developed microvilli on the surface as compared with a static environment. Drugs with higher lipophilicity exhibited higher permeability across the Caco-2 layers, as well as in the conventional method using Transwells, and the fluidic conditions had little effect on permeability. In the Caco-2 cell layers cultured in Transwells and microfluidic devices, the basal-to-apical transport of rhodamine 123, a substrate of P-glycoprotein, was greater than the apical-to-basal transport, and the presence of tariquidar, an inhibitor of P-glycoprotein, completely diminished asymmetric transport. Furthermore, fluidic conditions promoted the metabolism of temocapril by carboxylesterases. On the other hand, we showed that fluidic conditions have little effect on gene expression of several transporters and metabolic enzymes. These results provide useful information regarding the application of microfluidic devices in drug transport and metabolism studies.

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“…For instance, these systems enable the simulation of tissue structures and fluid dynamics, which closely resemble physiological conditions. We are actively developing and characterizing an organ-on-a-chip that mimics various organs (e.g., the liver, − kidney, , intestine, and tumors to assess ADME/Tox and drug delivery systems. Current research has not only pivoted to replicate the physiological functions of individual organs but also to explore interorgan interactions facilitated by microfluidic channels. ,,− The gut-liver-on-a-chip has been used to examine drug metabolism − and the intricate network of inflammatory intertissue crosstalk. − The use of small-volume microfluidic channels to connect cells provides the distinct advantage of reducing the dilution of secreted humoral factors in the culture medium, which influences cellular function.…”

Section: Introductionmentioning

confidence: 99%

Perfluoropolyether-Based Gut-Liver-on-a-Chip for the Evaluation of First-Pass Metabolism and Oral Bioavailability of Drugs

Wang,

Sasaki,

Sakagami

et al. 2024

ACS Biomater. Sci. Eng.

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In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.

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Generation of Tetrafluoroethylene–Propylene Elastomer-Based Microfluidic Devices for Drug Toxicity and Metabolism Studies

Cited by 10 publications

References 19 publications

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Intestinal Permeability of Drugs in Caco-2 Cells Cultured in Microfluidic Devices

Perfluoropolyether-Based Gut-Liver-on-a-Chip for the Evaluation of First-Pass Metabolism and Oral Bioavailability of Drugs

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