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Lab-On-a-Chip drug testing in Microfluidics

Introduction

Microfluidics has emerged as a powerful tool in the field of drug testing, offering unique advantages over traditional methods. This technology involves the precise manipulation of fluids at the microscale level, enabling researchers to conduct experiments with minimal sample volumes and high throughput. By leveraging the principles of microfluidics, drug testing processes can be streamlined, leading to faster results, reduced costs, and improved accuracy. In this review, we explore the fundamental principles of lab-on-a-chip and their applications in drug testing.1

Principle

A Lab-On-a-Chip (LOC) device allows for multiple laboratory-based analytical techniques to be miniaturized by incorporating microfluidic methodology. Microfluidics involves the manipulation of fluids within channels on a micrometer scale.2

Microfluidic system with cell culture chambers.
Figure 1: Microfluidic system with cell culture chambers.³

LOCs, also known as micro physiological systems or tissue chips (Fig. 1), are used to model tissues and organs by simulating physiological and pathological tissue components and arrangement, structural composition, and dynamic components (gas, blood, force, etc.).3 These chips are designed to position cells in a three-dimensional structure that mimic the function of organs of the body, and react in a physiological manner to exposure to drugs, hormones, cell signaling molecules and biomechanical stressors.4

The drug development pipeline has well-documented high failure rates and is expensive and time-consuming. When a drug reaches the clinical trials stage, the probability of clinical success is around only 12%.5 The ability to recreate functional human (and animal) organs in vitro has transformed the drug discovery process, and opened new avenues for the study of physiology and disease pathology in both humans and animals.4

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Applications

Microfluidics has gained significant attention in the field of drug testing due to its numerous applications and advantages. One key area where microfluidics is extensively utilized is in drug toxicity testing, offering high-throughput capabilities. Furthermore, microfluidic devices have been successfully employed in cancer diagnosis, metastasis studies, drug delivery, and tissue engineering within the biomedical field.6-8 Herein, we review a few examples where microfluidics has been applied to drug testing/development.

Drug Screening and drug development

Scheme of organ-on-a-chip for drug screening and application.
Figure 2: Scheme of organ-on-a-chip for drug screening and application.⁹

The screening of compounds in drug development is essential for narrowing down the selection of molecules to “hit” and “lead” compounds. Initially, high-throughput methods using simple 2D cellular models are employed to assess toxicity and eliminate obviously toxic compounds.4 2D cell culture and animal models exhibit limited predictability for drug discovery, and therefore, there is an urgent need to find better models for efficient and reproducible drug screening. On the other hand, the ethical rules governing the experiments involving laboratory animals became more and more restrictive, limiting the in vivo preclinical analysis extent.10

As the development pipeline progresses, more complex three-dimensional organ systems can provide valuable insights, especially for drugs with borderline toxicity profiles. These systems offer a more comprehensive understanding of the interactions between different tissue types and can provide physiologically relevant outcomes for compounds of interest.4

Microfluidic LOCs have the potential to be used as drug testing platforms, to model various diseases, to understand different cellular and molecular mechanisms, or for biomarker identification, with the eventual aim of replacing animals in preclinical tests.10

Drug-drug interaction toxicity

The study by Deng et al. aimed to develop a microfluidic liver model using cell lines to investigate hepatotoxicity resulting from drug-drug interactions (Fig. 3). This research is significant in the field of liver-on-a-chip platforms, which aim to mimic liver functions for various biomedical applications. The use of cell lines in this microfluidic liver model allows for the simulation of liver functions and the study of how drug combinations interact and potentially lead to liver damage. The study likely involved assessing parameters such as cell viability, enzyme activity, or gene expression to evaluate the hepatotoxic effects of different drug combinations. This work contributes to the understanding of how drug-drug interactions can induce hepatotoxicity, providing insights that could aid in predicting and preventing adverse effects in clinical settings.11

Microfluidic LOC for hepatotoxicity induced by drug-drug interaction
Figure 3: Microfluidic LOC for hepatotoxicity induced by drug-drug interaction.¹¹

Anticancer drug screening

Although a variety of treatments is currently available, there is no technique for rapidly evaluating the response of cancer patients to the drug. Microfluidic devices that are being designed to address current challenges in chemotherapy, such as drug resistance, combinatorial drug therapy, personalized medicine, and cancer metastasis are also reviewed in detail. We provide a perspective on how personalized ‘tumor-on-chip’, as well as high-throughput microfluidic platforms based on patient-specific tumor cells, can potentially replace the more expensive and ‘non-human’ animal models in preclinical anticancer drug development.12 A vascularized OOC platform for large-scale drug screening was proposed to mimic the complexity of in vivo physiology. Thus, several arrays of vascularized micro-tumors were created and tested against up to twelve FDA-approved anti-cancer drugs, revealing the successful identification of both anti-angiogenic and antitumor drugs.10 Zervantonakis and Arvanitis investigated the potential of the combination of focused ultrasound (FUS) and nanomedicine drugs to improve the treatment of glioblastoma (Fig. 4). For that purpose, an acoustofluidic platform was developed to culture glioblastoma cells in a 3D environment and to apply the FUS treatment. Nanoparticles of doxorubicin (DOX) encapsulated in temperature-sensitive liposomes were used, and the heat generated by FUS contributed to a higher uptake of the drug by the cells resulting in an increase in cell death and a reduction of cell proliferation when compared to the isolated treatments.
Schematic microfluidic device for glioblastoma 3D cell culture.
Figure 4: Schematic microfluidic device for glioblastoma 3D cell culture.¹³

Li et.al. presented an innovative approach to evaluating the toxicological effects of anticancer drugs. The study utilized an integrated microchip system to assess the oxygen-dependent cytotoxicity and genotoxicity of anticancer drugs, specifically tirapazamine (TPZ) and bleomycin (BLM). Through single-cell loading, cultivation, drug treatment, and in situ analysis, the researchers demonstrated the application and performance of this microchip system in evaluating the effects of these drugs on cells.14

In a separate study, Madaboosi et al. introduce an innovative approach to detecting prostate cancer biomarkers. The research integrates microfluidic ELISA with a-Si:H p-i-n photodiodes to develop a highly sensitive detection system for prostate cancer biomarkers. This integrated system shows promise for point-of-care applications by detecting a variety of biomarkers for prostate cancer, even at very low levels that are typically difficult to detect using traditional methods. Through the utilization of a sandwich assay in the microfluidic ELISA and photodiode detection, the system can be further improved with suitable amplification strategies to enable the multiplexing of biomarkers for prostate cancer.15

Antibiotic susceptibility and toxicity testing

Microfluidics has emerged as a powerful tool for antibiotic susceptibility and toxicity testing (Fig. 5), offering rapid and precise analysis at the single-cell level.17 This technology allows for the investigation of antibiotic susceptibility not only in bulk cultures but also at the single-cell level, providing insights into microbial sensitivity and resistance.18 By utilizing microfluidic platforms, researchers have been able to conduct phenotypic antibiotic susceptibility tests in less than 30 minutes, enabling quick and efficient evaluation of bacterial responses to antibiotics.19 These ‘lab-on-a-chip’ platforms have shown promise in facilitating antibiotic susceptibility and toxicity testing, offering a versatile and adaptable approach for assessing antimicrobial effectiveness.20

Microfluidics for Antibiotic Susceptibility and Toxicity Testing
Figure 5: Microfluidics for Antibiotic Susceptibility and Toxicity Testing.¹⁶

Forensic chemistry

Using a Lab-on-a-Chip approach offers the potential for rapid, cost-effective, and portable detection systems in clinical and forensic environments. LOC devices for detection of drugs of abuse is still a rapidly evolving field, with 42% of articles published since 2019. A total of 28 different drugs of abuse were investigated, with cocaine the most widely studied (58%). The LOC devices were capable of accepting a wide range of biological and non-biological samples. A total of 18 countries have been involved in LOC research into detection of drugs of abuse, with locations generally following local trends in drug use. LOC devices employed a range of detection methods with immunoassays most commonly incorporated (34%).2

Take home message

Microfluidic systems have played a crucial role in advancing drug discovery processes by allowing for more accurate modeling of physiological conditions, facilitating systematic high-volume testing for different aspects of drug development.21 These systems also offer great potential for drug screening in a high-throughput manner through perfusion cell culture.22 Microfluidic platforms have been shown to perform rapid antibiotic susceptibility tests, evaluating the efficacy of antimicrobial drugs efficiently.16

In drug testing applications, microfluidic devices are tailored to replicate the physiological conditions of biological systems, offering a more realistic representation of drug interactions. These systems are equipped with cell culture chambers, perfusion systems, and integrated sensors that enable real-time monitoring of drug responses. Moreover, the miniaturization of these devices facilitates simultaneous testing of multiple drugs or concentrations on a single platform, thereby streamlining processes and reducing costs associated with conventional drug screening methods.

References
  1.         Toh Y-C, Lim TC, Tai D, Xiao G, van Noort D, Yu H. A microfluidic 3D hepatocyte chip for drug toxicity testing. 10.1039/B900912D. Lab on a Chip. 2009;9(14):2026-2035. doi:10.1039/B900912D
  2.         McNeill L, Megson D, Linton PE, et al. Lab-on-a-Chip approaches for the detection of controlled drugs, including new psychoactive substances: A systematic review. Forensic Chemistry. 2021/12/01/ 2021;26:100370. doi:https://www.sciencedirect.com/science/article/abs/pii/S2468170921000667
  3.         Luo Y, Li X, Zhao Y, Zhong W, Xing M, Lyu G. Development of Organs-on-Chips and Their Impact on Precision Medicine and Advanced System Simulation. Pharmaceutics. Aug 7 2023;15(8)doi:10.3390/pharmaceutics15082094
  4.         Low LA, Tagle DA. Tissue chips – innovative tools for drug development and disease modeling. Lab Chip. Sep 12 2017;17(18):3026-3036. doi:10.1039/c7lc00462a
  5.         Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. Jul 2022;12(7):3049-3062. doi:10.1016/j.apsb.2022.02.002
  6.         Wu M-H, Huang S-B, Lee G-B. Microfluidic cell culture systems for drug research. 10.1039/B921695B. Lab on a Chip. 2010;10(8):939-956. doi:10.1039/B921695B
  7.         Kang L, Chung BG, Langer R, Khademhosseini A. Microfluidics for drug discovery and development: From target selection to product lifecycle management. Drug Discovery Today. 2008/01/01/ 2008;13(1):1-13. doi:https://www.sciencedirect.com/science/article/abs/pii/S1359644607004175
  8.         Han SJ, Park H-K, Kim KS. Applications of Microfluidic Devices for Urology. Int Neurourol J. 4 2017;21(Suppl 1):S4-9. doi:10.5213/inj.1734838.419
  9.         Wang Y, Gao Y, Pan Y, et al. Emerging trends in organ-on-a-chip systems for drug screening. Acta Pharmaceutica Sinica B. 2023/06/01/ 2023;13(6):2483-2509. doi:https://www.sciencedirect.com/science/article/pii/S2211383523000333
  10.     Staicu CE, Jipa F, Axente E, Radu M, Radu BM, Sima F. Lab-on-a-Chip Platforms as Tools for Drug Screening in Neuropathologies Associated with Blood-Brain Barrier Alterations. Biomolecules. Jun 21 2021;11(6)doi:10.3390/biom11060916
  11.     Deng J, Zhang X, Chen Z, et al. A cell lines derived microfluidic liver model for investigation of hepatotoxicity induced by drug-drug interaction. Biomicrofluidics. 2019;13(2):024101. doi:10.1063/1.5070088
  12.     Dhiman N, Kingshott P, Sumer H, Sharma CS, Rath SN. On-chip anticancer drug screening – Recent progress in microfluidic platforms to address challenges in chemotherapy. Biosensors and Bioelectronics. 2019/07/15/ 2019;137:236-254. doi:https://www.sciencedirect.com/science/article/abs/pii/S0956566319302209
  13.     Maia I, Carvalho V, Rodrigues R, et al. Organ-on-a-Chip Platforms for Drug Screening and Delivery in Tumor Cells: A Systematic Review. Cancers. 02/13 2022;14:935. doi:10.3390/cancers14040935
  14.     Li L, Li Y, Shao Z, Luo G, Ding M, Liang Q. Simultaneous Assay of Oxygen-Dependent Cytotoxicity and Genotoxicity of Anticancer Drugs on an Integrated Microchip. Analytical Chemistry. 2018/10/16 2018;90(20):11899-11907. doi:10.1021/acs.analchem.8b02070
  15.     Madaboosi N, Pedrosa CR, Reis MF, Soares RRG, Chu V, Conde JP. Microfluidic ELISA for sensing of prostate cancer biomarkers using integrated a-Si:H p-i-n photodiodes. 2014:881-884.
  16.     Dai J, Hamon M, Jambovane S. Microfluidics for Antibiotic Susceptibility and Toxicity Testing. Bioengineering. 2016;3(4). doi:10.3390/bioengineering3040025
  17.     Kamiński TS, Scheler O, Garstecki P. Droplet Microfluidics for Microbiology: Techniques, Applications and Challenges. Lab on a Chip. 2016;doi:10.1039/c6lc00367b
  18.     Zhang K, Qin S, Wu S, Liang Y, Li J. Microfluidic Systems for Rapid Antibiotic Susceptibility Tests (ASTs) at the Single-Cell Level. Chemical Science. 2020;doi:10.1039/d0sc01353f
  19.     Baltekin Ö, Boucharin A, Tano E, Andersson DI, Elf J. Antibiotic Susceptibility Testing in Less Than 30 Min Using Direct Single-Cell Imaging. Proceedings of the National Academy of Sciences. 2017;doi:10.1073/pnas.1708558114
  20.     Benková M, Soukup O, Marek J. Antimicrobial Susceptibility Testing: Currently Used Methods and Devices and the Near Future in Clinical Practice. Journal of Applied Microbiology. 2020;doi:10.1111/jam.14704
  21.     Neužil P, Giselbrecht S, Länge K, Huang TJ, Manz A. Revisiting lab-on-a-chip technology for drug discovery. Nature Reviews Drug Discovery. 2012/08/01 2012;11(8):620-632. doi:10.1038/nrd3799
  22.     Sung JH, Kam C, Shuler ML. A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip. 10.1039/B917763A. Lab on a Chip. 2010;10(4):446-455. doi:10.1039/B917763A
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