‘Organ on a chip’: The new lab setup scientists are using instead of animals to test new drugs

Experts expect this state-of-the-art technology to be used as drug test-beds in India within a few years to a decade.

Updated - February 28, 2023 11:04 am IST

Published - February 26, 2023 03:30 pm IST - Bengaluru

A device for studying wound infections using a chip setup.

A device for studying wound infections using a chip setup. | Photo Credit: Special arrangement

The recent U.S. Food and Drug Administration Modernization Act 2.0 brought cheer to animal rights activists and drug developers alike. By approving the Act, the US government green-lit computer-based and experimental alternatives to animals to test new drugs.

The move is expected to boost the research and development of organ chips – small devices containing human cells that are used to mimic the environment in human organs, including blood flow and breathing movements, serving as synthetic environments in which to test new drugs.

For more than a decade, scientists, pharmaceutical companies, and animal activists have been pushing regulators to include synthetic setups that mimic human diseases, in addition to using animals, as drug testbeds, with arguments rooted in science, commerce, and ethics.

Lab to market

Bringing a new drug into the market is a long, expensive, and challenging process ridden with failure. First, researchers identify chemical compounds (including biological molecules) that can be used to treat a condition using modelling, among other techniques. Then, they pick a shortlist of options that perform well and test them on cells grown on plastic dishes in the lab – or on animals that can mimic the disease in certain conditions.

At this stage, called the preclinical trial, scientists determine whether these drugs are toxic and if they can efficaciously treat the mimicked condition. Animals used here include mice, rats, hamsters, and guinea pigs, depending on the drug being tested. Researchers also use pigs when testing implant devices like stents.

Before the new Act, researchers had to demonstrate the safety and efficacy of a drug in an animal model of the disease before moving to human clinical trials.

Human clinical trials have four well-known phases: checking for drug safety; for safety and efficacy; for safety and efficacy compared to the current treatment standard; and post-marketing surveillance.

As of today, fewer than 10% of new drugs complete preclinical studies and fewer than 50% of these eventually enter the market. Some researchers believe that the use of animal models in preclinical studies could be to blame for this enormous failure rate.

A 2013 study by researchers at Stanford University found that mice models “poorly” mimic human inflammatory diseases. But in a 2015 study, researchers at the Japan Science and Technology Agency reanalysed the same data and reported the diametric opposite: that mice models “greatly” mimic human inflammatory diseases.

The data pertained to how acute inflammatory conditions in humans, such as trauma, burns, and the presence of lipopolysaccharide in the blood, affected one’s genes. (Lipopolysaccharide is a component of the outer membrane covering a certain type of bacteria; it is deadly when it enters the human bloodstream.) The researchers compared this data with that of genetic changes in mice that modelled these conditions.

On February 2, researchers from the U.S. and Canada again analysed the same data and struck a balance: they assessed six human inflammatory diseases and reported that mice could mimic two; couldn’t mimic two; and the results from two were inconclusive.

This outcome mirrors the current scientific consensus: animals mimic some human diseases well but not others. In cases where they can’t mimic a condition, a new drug that seems promising in preclinical studies is almost certainly bound to fail in human clinical trials.

These challenges have led scientists to look for alternative models that mimic human diseases. One such is the organ-on-chip model, which has garnered a lot of attention in the last decade.

Donald E. Ingber, a professor of bioengineering and director of the Wyss Institute at Harvard University, and his colleagues developed the first human organ-on-chip model in 2010. It was a ‘lung on a chip’ that mimicked biochemical aspects of the lung and its breathing motions. Ingber’s group went on to develop more human organs-on-chips.

An organ-on-a-chip device setup with flow of media and cells present to study wound infections.

An organ-on-a-chip device setup with flow of media and cells present to study wound infections. | Photo Credit: Special arrangement

In 2014, members of Wyss Institute launched a start-up called Emulate Inc. to commercialise their technology. The group has since created several different chips, including of the bone marrow, epithelial barrier, lung, gut, kidney, and vagina.

Several research groups across the world followed suit as well. Scientists also formed consortia to encourage research in this field, such as the European Organ-on-Chip Society.

In many cases like that of Emulate, academic research groups have joined forces with tech start-ups to commercialise the technology. In a recent success, Emulate’s liver chips could successfully predict the ability of drugs to cause liver injury with 87% sensitivity and 100% specificity. The researchers used liver chips to evaluate the toxic effects of 27 drugs known to be either safe or cause liver injury in humans. Their paper was published in Communications Medicine in December 2022.

Organs on a chip in India

A few research groups in India have been developing organ-on-chip models over the last few years.

Prajakta Dandekar-Jain, an assistant professor of pharmaceutical sciences and technology at the Institute of Chemical Technology, Mumbai, told The Hindu there are “diffuse efforts in this direction”.

Dr. Dandekar-Jain’s group has developed a skin-on-chip model together with the team of Abhijit Majumdar, an associate professor of chemical engineering at IIT Bombay. The model is currently being tested for studying skin irritation and toxicity. The two groups are also developing a retina-on-chip model together.

Dr. Majumdar and his team are also separately developing a placenta-on-chip model with Debjani Paul, a professor of bioscience and bioengineering at IIT Bombay, and Deepak Modi, a scientist at the ICMR-National Institute for Research in Reproductive and Child Health, Mumbai.

All these individuals agree that these models are great tools to mimic human organs and their diseases. “Since we use human cells in these organ-on-chip models, they are more human-relevant than animal models,” Dr. Majumdar said. “Moreover, they are free from ethical issues associated with [the use of] animal models.”

According to him, these are also better at predicting the treatment outcomes than conventional cell culture systems – where researchers grow cells in plastic dishes in the lab – as they model different aspects of the human body, such as its three-dimensional geometry or the flow of fluids like blood and lymph.

Apart from organs, researchers are also trying to mimic different disease states using chips. This is what Kaushik Chatterjee, an associate professor of materials engineering, and Deepak K. Saini, a professor of developmental biology and genetics at the Indian Institute of Science, Bengaluru, are doing vis-à-vis the lung.

(Note: The author is affiliated with the Indian Institute of Science, Bengaluru.)

Dr. Chatterjee explained that while several groups worldwide have developed lung-on-chip devices to mimic lung function, few have been able to capture the biological aspects of different lung diseases, including those caused by air pollution and COVID-19. “We hope to [recreate] such conditions using our lung-on-chip platform,” he said.

The group of Karishma Kaushik, an assistant professor of biotechnology at the Savitribai Phule Pune University (SPPU), has developed an infection-on-chip model to recreate a human skin wound infection state. The goal: to mimic an infection that doesn’t heal despite prolonged and repeated antibiotic treatment.

Left to right: Nizam Shaikh, Karishma Kaushik, and Shreeya Mhade.

Left to right: Nizam Shaikh, Karishma Kaushik, and Shreeya Mhade. | Photo Credit: Special arrangement

According to Dr. Kaushik, the model can be used to study different features of clinical wounds, investigate how bacteria stick to each other (forming layers called biofilms where they are shielded from treatment), and test the effects of antibiotics or new treatment methods on biofilms.

“There has been a push towards studying wound infections, developing new treatments, and evaluating combinations of treatments. The wound infection on-chip model developed in our research group” is a part of it, Dr. Kaushik said.

“If the cells are isolated from patients and used to create the biomimetic tissues, the resulting organ chips can be used to develop personalised therapies for individual patients,” Dr. Dandekar-Jain said.

The technology is inherently interdisciplinary, so “one needs to establish highly interdisciplinary research and product development teams that can design and create microfluidic devices that can be used for biological and diagnostic applications with reproducible results,” she added.

Some of these organs-on-chips that Indian scientists have developed are ready for use as drug test-beds in lab settings, but they could be a decade away from featuring in preclinical trials, with a push, according to Dr. Kaushik.

“The next step would be to formalise their place as preclinical screening tools, and possibly as alternatives to animal testing. As with the case across the world, this would require modifications to the [Rules] for drug evaluation processes,” she said.

On the other hand, Dr. Dandekar-Jain said it should only be a matter of a couple years before industry takes these technologies up, provided it can forge good collaborations with academia, access training programmes to popularise the technology, and get government support. But she also said “there is still a reluctance on the part of the industries in [using this] for preclinical research due to the lack of experienced personnel”.

While scientists and institutions are rooting for, and regulators are acquiring a sense of, interdisciplinary research, “a large part of the challenge remains in fostering regular and seamless crosstalk, unlike short-term conferences or specific collaborations, between scientists, clinicians, engineers, and pharmacologists,” Dr. Kaushik said.

Dr. Dandekar-Jain agreed. According to her, India’s regulators lack exposure to researchers’ issues while academicians don’t fully understand regulatory requirements. There are bureaucratic hurdles as well. Dr. Dandekar-Jain invoked the examples of the “inflexible heads of expenditures in government grants” and the delay in releasing money for sanctioned grants.

These researchers hope to see larger consortia with diverse experts from academia, industries, and regulators come together to be able to compare India’s organ-on-chip efforts with those of the West. The Centre for Predictive Human Model Systems, Hyderabad, is building a database of researchers working in different areas of alternatives to animal models, including organ chips.

Academic research groups, start-ups, and biomedical companies in the West have also switched gears to build larger human-on-chip models. These are assemblies of different organ chips containing nutrients for the cells flowing across them, mimicking the flow of blood and nutrients across different organs in the body. The idea is to predict the efficacy of a drug against a particular disease in the presence of messy organ interactions instead of cleanly isolated systems.

Note: The name of the institute in Hyderabad was corrected to the Centre for Predictive Human Model Systems, from the Centre for Predictive Human Relevant Microphysiological Systems, at 8:56 am on February 27, 2023.

Joel P. Joseph is a freelance science journalist and researcher who works with 3D cell-culture systems.

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