Beyond animal testing: the rise of organs on chips technology

Back in December 2022, President Biden signed a new law stating that novel medicines no longer needed to be tested on animals to receive U.S. Food and Administration (FDA) approval, a change long sought by animal welfare organizations. Drugs can be now cleared for human trials using non-animal technologies developed over the last 10-15 years. However, since these technologies are still relatively new, this change won't revolutionize the drug approval process overnight.

Animal experiments date back to ancient Egyptian and Greek civilizations. They became integral to physiological and pharmacological research during the 19th century and started to be systematically used for drug development during the 20th century. Agencies like the FDA and the European Medicines Agency (EMA) established rigorous guidelines for preclinical testing in animals after disasters such as the 1937 elixir sulfanilamide poisonings or the thalidomide tragedy of the 1950s and 60s (Sántha, 2020). Since then, animal-based testing has been the gold standard for establishing a drug's safety and efficacy.

There are a number of reasons for reducing animal experimentation. On one hand, the cost of preclinical development typically ranges from a few hundred thousand to several million dollars per compound. On the other hand, key differences exist between humans and animal species commonly used in testing, raising concerns about the real world translatability of animal studies, and published studies indicate that in vitro and in silico tests can outperform animal models in predicting certain adverse events. For example, one study demonstrated 89% accuracy of in silico drug trials in populations of human cardiomyocyte models in predicting clinical arrhythmia - versus a 75% accuracy using animal models (Passini, 2017) .

Then, of course, there are the ethical considerations. Great efforts have been made to replace animal experimentation with non-clinical tests in agreement with the Three Rs principle: Replacement, Reduction, and Refinement. Agencies such as the E.U. Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) and the FDA's Advancing Alternative Methods (AAMS) work on the development and promotion of non-animal approaches.

Alternative technologies and methods include system biology studies such as transcriptomics and metabolomics; cell-based assays; engineered tissues such as 3Dbioprinted tissues or organoids, which have shown promising results in predicting, for example, liver and cardiac toxicity; organ-on-chip (OoC) and microphysiological systems (MPS) to mimic human physiology; and computer modeling and simulations (including machine learning and artificial intelligence). Alternative organisms such as zebrafish and c. elegans can also be considered in some cases (U.S. Food and Drug Administration, 2023) .

Organs-on-chips are a type of microphysiological system consisting of a miniaturized physiological environment engineered to yield and/or analyze functional tissue units capable of modeling specified/targeted organ-level responses, usually no larger than a typical microscope slide (R, 2023) . They reproduce the microenvironment of tissues in the human body under regulated dynamic settings. Several distinct types of cells may be required to produce the settings or to research how the cells interact with one another. For example, liver-chip devices may include iPSC-derived hepatocytes, endothelial cells, and Kupffer cells.

Single OoC for most of the organs in the human body have been developed, but they lack the cross-organ communication and systemic dimension to, for example, evaluate PK/PD parameters and further understand diseases caused by multiorgan interactions. Multi-OoC have been created and the ultimate goal is to develop a "body on a chip" technology. This requires considering interorgan scaling, expected flow rate, media, and interrelated functionalities. On the other hand, advancements in artificial intelligence provide more improvements for the experimental design and data interpretation of OoC (Deng, 2023) .

Some studies have shown a higher performance of OoC. A study using a proximal tubular OoC successfully predicted the nephrotoxicity of SPC-5001, which exhibited nephrotoxicity in phase 1 trials, but not in preclinical testing on mice and non-human primates (Nieskens, 2021) . An analysis of 870 Liver-Chips across a set of 27 known hepatotoxic and non-toxic drugs displayed a sensitivity of 87% and a specificity of 100% (Ewart, 2022) . A vessel-chip allowed researchers to evaluate the prothrombotic effects of Hu5c8, a monoclonal antibody against CD40L, though research was terminated in clinical phases due to unexpected thrombotic complications not detected during preclinical testing (Barrile, 2018) .

Today, animal models remain essential for drug development, but non-clinical tests can complement these studies, and new and innovative technologies developed in labs around the world have made the end of animal testing a realistic possibility for the future, although the change may be slow, as the complexity of biological systems makes exceptionally difficult to replicate the intricate interactions within a living organism. The need for considerable research and funding for developing and validating alternative methods may also be an issue (Nuwer, 2022; Anon., 2024).

Cortellis Drug Discovery Intelligence^TM Experimental Models have been expanded to cover non-animal in vitro models such as organoids and organ-on-chips, including detailed information on how they have been used to study the efficacy or safety of a therapeutic agent. If you want to learn more about this solution, please visit Cortellis Drug Discovery Intelligence Platform | Clarivate or contact us.

Works cited

1. Anon., 2024. Animal research is not always king: researchers should explore the alternatives. Nature, 631(8021).
2. Barrile, R., 2018. Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems. Clinical Pharmacology and Therapeutics, 104(6), pp. 1240-1248.
3. Deng, S., 2023. Organ-on-a-chip meets artificial intelligence in drug evaluation. Theranostics, 13(3), pp. 4526-4558.
4. Ewart, L., 2022. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Communications Medicine, 2(1).
5. Nieskens, T. T. G., 2021. Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip. Archives of Toxicology, 95(6), pp. 2123-2136.
6. Nuwer, R., 2022. US agency seeks to phase out animal testing. Nature.
7. Passini, E., 2017. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity. Frontiers in Physiology.
8. R. N., 2023. Organ-On-A-Chip: An Emerging Research Platform. Organogenesis, 19(1).
9. Sántha, M., 2020. Biologia futura: animal testing in drug development-the past, the present and the future. Biologica Futura, 71(4), pp. 443-452.
   U.S. Food and Drug Administration, 2023. About Alternative Methods. [Online]
10. Available at: https://www.fda.gov/science-research/advancing-alternative-methods-fda/about-alternative-methods
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