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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
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Pumpless, unidirectional microphysiological system for testing metabolism-dependent chemotherapeutic toxicity
Danielle J LaValley1, Paula G Miller1, Michael L Shuler1,2
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
Biotechnology Progress
|December 4, 2020
Summary
This study introduces a novel pumpless, multiorgan body-on-a-chip system for preclinical drug testing. The platform accurately predicts anticancer drug efficacy and identifies off-target toxicity, improving drug development.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Oncology
Background:
- Preclinical drug development models often fail to predict human responses accurately.
- Microphysiological systems (MPS), including body-on-a-chip (BOC) devices, offer improved prediction of drug efficacy and safety.
- Existing BOC systems often require pumps, complicating their design and operation.
Purpose of the Study:
- To design and validate the first pumpless, unidirectional, multiorgan body-on-a-chip system.
- To assess the efficacy and toxicity of anticancer drugs using this novel platform.
- To establish a physiologically-based pharmacokinetic drug screening tool for cancer drug development.
Main Methods:
- Development of a pumpless microfluidic device with interconnected organ chambers for unidirectional perfusion.
- Culture of HCT-116 colon cancer spheroids, HepG2/C3A hepatocytes, and HL-60 promyeloblasts in distinct tissue compartments.
- Application of the system to test the metabolism-dependent toxic effects of Tegafur-uracil on cancer cells and normal tissues.
Main Results:
- The pumpless system achieved unidirectional perfusion at physiologically realistic ratios.
- Tegafur-uracil treatment demonstrated significant cytotoxicity in HCT-116 colon cancer cells, with reduced efficacy in multicellular spheroids due to drug penetration limits.
- Off-target toxicity was observed in HL-60 cells, highlighting the system's ability to detect dose-limiting side effects.
Conclusions:
- The developed pumpless multiorgan body-on-a-chip system is a viable platform for physiologically-based pharmacokinetic drug screening.
- This microscale cell culture analog can enhance the prediction of anticancer drug efficacy and safety in preclinical studies.
- The system provides valuable insights into both therapeutic effects and potential dose-limiting toxicities, supporting informed cancer drug development.
