A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process

Abstract

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Establishment and application of a dynamic tumor-vessel microsystem for studying different stages of tumor metastasis and evaluating anti-tumor drugs

“…Viability of liver cancer cells HepG2, breast ones MDA MB 231, and vascular endothelial cells EAhy926 was evaluated aer they were cultivated on the microsystem for 72 h. PDMS has been demonstrated to be a biocompatible material with a vast array of cell types. 21 Consistent with previous studies, 22 our results also conrmed that cancer and endothelial cells showed around 97% viability on the microdevice aer 3 days of cultivation ( Fig. 2A and B), indicating that the laminated PDMS microuidic devices almost had no detrimental effects on cell survival.…”

“…During the proliferative phase of tumor cells, functional vasculature and interstitial uid ow may have major inuence on drug transport. 22 At the stage of tumor cell intravasation, due to the barrier function of vascular endothelial cells 28 and the different invasion style of various tumor cells, 41 the inhibitory effects of drugs on tumor cells intravasation may be different. Therefore, tumor-vascular models such as our dynamic micro-uidic platform may become capable of recapitulating the desired, human-mimicking, and nuanced responses to drug treatment at different phases of tumor metastasis.…”

Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease

“…82,83 An alternate approach, which is currently pursued, is represented by so-called "organ-on-a-chip" models. [97][98][99] Such approaches might be combined or paralleled by in silico approaches. 100,101 Although physiologically based pharmacokinetic modeling approaches involve transport and metabolism 102,103 and are combined with wet lab approaches (e.g., drug sulfonation 104 ), it might be interesting to further evolve such models by taking into account a possible specific special arrangement of transporters and drug-metabolizing enzymes in hepatocytes.…”

Microfluidic-Based Multi-Organ Platforms for Drug Discovery

“…The type of cells (single or multiple origins), the direct microenvironment of cells, the medium preserving differentiated states of different cells, as well as the three-dimensional (3D) configuration of tissues may all impact outcome measures. Further features to consider include dose–response characterizations and the developmental stages of selected cells [ 21 , 22 ].…”