New ‘liver-on-a-chip’ device could make drug safety testing more reliable

Creating a drug that might help treat or cure a health condition in humans is a long, complex process. After developing a candidate drug that shows potential — a process that, in and of itself, can take decades — scientists often spend years testing the safety of new medications in cells, animals and then in humans.

But modern methods to determine the safety of new medicines aren’t perfect — especially when it comes to predicting potential unwanted side effects.

It can be especially challenging to predict how new drugs will affect the liver, the body’s primary organ for processing medications and removing toxins. If a medicine turns out to be harmful to the liver, it can cause a condition known as drug-induced liver injury, which is one of the most common reasons a new drug may never reach patients, even if it may have promising anti-disease properties.

Traditionally, scientists use cells in a dish, followed by tests in animals, to determine the safety of new medications, but the many anatomical and physiological differences between humans and the animals used for safety experiments, especially concerning the liver, make this an often-unreliable process.

In a recent study, Dr. Chander Negi, a postdoctoral research associate in the lab of Texas A&M University professor Dr. Ivan Rusyn, investigated how an emerging “liver-on-a-chip” technology compares with traditional testing methods used in drug safety evaluation.

Using three drugs with documented differences in toxicity across species, the researchers evaluated whether one of these “liver-on-a-chip” devices called the PhysioMimix LC12 — which is manufactured by the United Kingdom-based company CN Bio — could reproduce species-specific drug toxicities, which is a long-standing challenge in preclinical research.

Their findings suggest that despite some limitations, the PhysioMimix LC12 offers a more predictive and physiologically relevant approach for assessing drug-induced liver injury compared to conventional in vitro (“cells in a dish”) models.

Replicating a large organ on a small chip

The liver is a large, complex, multifunctional organ, so trying to create an accurate and functional version on a tiny chip is a challenge.

In recent years, several companies have developed liver microphysiological systems (MPS), also known as organ-on-a-chip technologies, designed to mimic key aspects of human liver structure and function. These systems aim to improve human-relevant predictions while reducing reliance on animal testing.

However, widespread adoption of these technologies has been limited by a lack of independent external validation, particularly with respect to reproducibility, robustness and cross-species performance.

To address these gaps, Negi — under the supervision of Rusyn and with guidance from academic and industry collaborators within the Texas A&M Tissue Chip Validation (TEX-VAL) Consortium — evaluated the performance of the PhysioMimix LC12 by testing primary functional cells from the livers of humans, monkeys, rats and dogs.

“The LC12 platform contains 12 independent culture wells and is designed to re-create key liver features, including cell-to-cell interactions and the continuous flow of nutrients, allowing liver cells to behave more like they do in vivo (within a living organism),” Negi said.

The results showed that the effects of the three tested drugs in the LC12 system produced more consistent, robust and biologically relevant responses.

“Importantly, the liver-on-a-chip model more accurately reflected known species-specific toxicities,” Negi said. “One of the most significant advantages of the LC12 was its ability to support long-term liver cell culture, which remained viable and metabolically active for up to 14 days, with better preservation of liver-specific gene expression.

“This long-term stability is particularly valuable for detecting delayed or cumulative drug-induced liver injury, which is difficult to capture using standard in vitro approaches,” he said. “An additional practical consideration of the LC12 is its relatively large media volume, which enables multiple analyses and repeated sampling from the same chips, allowing for paired analyses across timepoints. This longitudinal assessment is essential for detecting drug-induced liver injury and for establishing relationships between drug exposure and toxicity.”

Limitations of the new system

While the “liver-on-a-chip” technology could outperform the standard in vitro testing platforms, it’s not without limitations.

The system can process more samples than many existing organ-on-a-chip technologies, but it is not designed for very large-scale screening. Higher-throughput versions are in development, though they are not yet widely available.

Cost is another consideration.

“The system is more expensive than conventional cell culture (in-a-dish) models; however, the improved accuracy and human relevance may justify this investment by reducing late-stage drug failures,” Negi said. “Additionally, the inability to perform real-time imaging of cells during ongoing experiments presents a practical challenge, as visual assessment of cell morphology is often important during toxicity studies.”

“In addition to cost and throughput, all organ-on-a-chip devices are yet to achieve full complexity of the human tissues,” said Rusyn, a professor in the Texas A&M College of Veterinary Medicine and Biomedical Sciences. “Inclusion of the immune systems and also testing cells from different individuals is the next frontier for the biomedical engineering to address.”

Finally, the complexity of the new system means that it would need to be automated and standardized before it could be used for large-scale drug testing and generating data that would be acceptable by the regulatory bodies.

Directions for future research

Looking ahead, to more fully validate the liver-on-a-chip technologies, the team plans to expand its studies to include additional drugs, particularly those associated with more complex or delayed liver toxicity. It also aims to explore how advanced systems like PhysioMimix LC 12 can be  integrated with other in vitro models to strengthen safety assessments during drug development.

In addition, the team is working to integrate these organ-on-a-chip devices with advanced molecular analysis tools. By combining them with technologies that measure gene activity, proteins and metabolic changes, scientists aim to gain a clearer understanding of how drugs can potentially damage the liver.

These pipelines will help to link the molecular changes to functional liver outcomes and support more predictive, personalized and mechanistically informed drug testing.

“Although additional research and regulatory evaluation are still needed, this study represents an important step toward more predictive, human-relevant drug testing,” Negi said. “With continued development and validation, the MPS systems — including the PhysioMimix LC12 liver-on-a-chip system — could play a key role in making future medications safer for both humans and animals.”