Despite existing since 400 BCE, animal testing may finally be at an end due to organ on a chip tech.
Organ on a chip. It is an interesting concept and something that could be first seen as “Star Trekian”. However, it is not so futuristic that only science fiction authors can write about it. In fact, it is technology that medical and clinical researchers are beginning to use in the real world more often. Fresh off a podcast conversation with Jan Turner from Safer Medicines, and Prof. Alice White and Dr. Christos Michas from Boston University — which will air in September, this article covers the development of organ on a chip (OOAC) technology, and why the industry may see the growing use of these tiny units of packaged biological circuitry.
Organ-on-a-chip: what is that?
Organ-on-a-chip technology is a 3D platform, the size of a USB, where a miniature model of tissues, organoids, or cells are used for preclinical testing of drugs. This is a platform that draws from the interdisciplinary fields of engineering, biology, and additive manufacturing. These chips have been developed so that you can put human cells into small channels and observe the interplay of in-development drugs on cells and tissues.
Fluids flow through these channels as well as culture medium or even, in some cases, a blood-like medium to recreate what would happen in a normal organ system. The responses of the cells allow researchers to delve much deeper into the biology of cellular mechanisms, and also the interplay between different cell types and different tissue types. This platform allows the testing for human response to drugs without putting patients at risk and reducing the need for animal testing.
Spot the difference: animal and human models
The animal model has long been used to promote human health. It has a far longer history than you may expect. Some ancient Greek works by Aristotle and Erasistratus detail that they were among the first to perform experiments on living animals.[1] Due to the rules of Hypocrites banning human cadaver dissections, a second-century Roman physician, Galen, performed post-mortem dissections of pigs and goats in an attempt to understand the anatomy of the human body.
So, for almost 3000 years, animal testing has been the norm in understanding human medicine. Yet, only in the past century have we managed to accumulate detailed scientific evidence of its shortcomings as a research practice. The main issue is translating the response seen in the animal model, usually in mice or rats, into what that means in humans. Our anatomy and physiology are partially incompatible in terms of how our cells communicate with one another and react to foreign agents. And this incompatibility adds an element of unpredictability in whether preclinical testing of drugs will elicit the same reaction in human cells.
As a result, according to Jan Turner, it is not surprising that cures have been discovered for over 30 types of cancer in mice, but these same cures are ineffective against cancer in humans. That’s a major misprediction of animal tests. And yet, nearly 79.9 million animals are used in testing, half of which are used in either basic research or regulated preclinical testing.[2] OOAC technology has the potential to replace animal testing and therefore bears benefits for both human medicine and animal welfare.
The need for OOACs is further underlined if we consider that around 10 000 deaths a year are recorded from adverse reactions to therapeutic drugs.[3] This number relates to those drugs on the market. We must remember that 90% of therapeutic drugs do not even make it this far.[4] The human and financial cost cannot be sustained this way.
So, by using an organoid on a chip to measure the response to external inputs, researchers would not have to be concerned with the ‘if’ in terms of whether it would work for humans, rather the researchers could spend time tailoring it to a human. It should save time, resources, and lives.
Improved testing: speed, standardization, and cost
Organ on a chip technology has more than one advantage. When it comes to actually addressing the ever-increasing cost and demands on modern drug manufacturing, these platforms could be a way of speeding up and cheapening the process, while also being more standardized because they are made following protocols and more precise specs.
The nature of OOACs, as expendable tools that are made and discarded on demand, helps increase the speed with which a drug can be tested.
Reports of the cost of testing and launching a new drug vary from $161 million to $4.54 billion a year.[5] Imagine the cost savings these chips could generate. Furthermore, researchers would only need to sustain a minimum amount of living tissue, not an entire animal that requires space and food. Achieving the end goal of having a non-toxic therapeutic is a long process as submissions to clinical trials are a necessary but long-winded endeavour. So, if found to be toxic on these OOACs, the manufacturers and researchers could pivot, preventing fruitless testing and clinical trials that would otherwise run.
However, this does not mean that OOAC-tested drugs would avoid adequate regulation. In fact, it’s the opposite. With OOACs being made following protocols and precise specifications, they are more “standardized” as opposed to animals, who cannot be trusted to have the same response each time. Thereby these chips could outmanoeuvre risks to regulations.
Innovation at its heart: the miniPUMP
OOACs can be any organ: brain, liver, heart, and so on. The heart is an important organ in clinical research as, globally, 7 million people die a year from cardiac arrest.[6] Clearly, something must be done.
Alice White and Christos Michas, researchers at Boston University, have developed a tiny living heart chamber replica to more accurately mimic the real organ, which is part of a larger project at CELL-MET, a multi-institutional research center, to create patches of human heart tissue to repair those damaged by heart attacks.
The heart acts differently than other organs. There is huge interest in understanding how heart disease emerges, and how to develop therapeutics to treat it. Prof. White and Dr. Michas’ OOAC can be a research tool to enable these discoveries to happen. Additionally, something that is also a little bit special about the heart is that if a patient has a healthy heart, but they have a disease in another organ, when we introduce drugs for other organs it’s likely that they will interact with the heart in a negative and harmful manner. In fact, more likely than with the majority of other organs. So, this chip could be used to predict what the side effects of drugs are on the heart will be.
A heart on a chip could be more versatile in how it could be used and in what type of research. As this particular heart on a chip could actually recapitulate some of the functional properties of a heart, not just the tissue but the function, it could potentially enable researchers to study how high blood pressure impacts heart tissue.
Michas theorised and built this chip as part of his PhD research and combined multiple disciplines to envision and produce his creation. This chip, known as the miniPUMP, is a scaffold created through a very special kind of 3D printing, direct laser writing (DLW). Prof. Alice White’s expertise on two photon direct laser writing to create structures of interest truly came in handy for the OOAC. DLW has a beam of photons focused at exactly the right place inside a liquid drop of photosensitive resin to make the resin solid. The coming together of two photons is what exposes the resin. So, the resin is transparent to the single photon, but solidifies at the focal point, and the size of the focal point is determined by the two-photon cross section.
So, if a heart is to be modelled on a chip, the pressure patterns that the heart experiences, like the flow of the blood, will also need to be modelled. The entire device is smaller than a coin, so the structural components that replicate the function of the mechanical elements must be done in very fine resolution. In order to do this, the team added a 3D cylindrical scaffold on the chip that supports the heart tissue, which can contract as well as store and propel blood. This fine resolution also allows for the creation of valves that control the flow.
OOAC technology can clearly be used to replicate the various elements of an organ, which means that the future of drug discovery looks promising.
SUMMARY
So, we have come a long way from the 4th century BCE. The mutually beneficial move away from animal testing could be sooner than we think. Thanks to passionate interdisciplinary work, researchers at Boston University have potentially shown how to find treatment or cures for human heart disease more effectively.
But one question remains, how will organ on a chip technology continue to advance, and will we move towards a place where drug development is wholly tested on these OOAC platforms? Will we see all organs on this platform? The possibilities are endless.
For more information on organ on a chip technology:
· Listen to our podcast episode on Discovery Matters in September
· Read this article on the miniPUMP at Boston University
“If you have always done it that way, it is probably wrong.” — Charles Kettering, inventor of the electric starter motor which eliminated the need for hand cranking.
References:
[1] History of Animal Testing | ProCon.org
[2] Taylor K, Alvarez LR. An Estimate of the Number of Animals Used for Scientific Purposes Worldwide in 2015. Altern Lab Anim. 2019 Nov-Dec;47(5–6):196–213. doi: 10.1177/0261192919899853.
[3] The Danger in Taking Prescribed Medications (usnews.com)
[4] Duxin Sun, Wei Gao, Hongxiang Hu, Simon Zhou, ‘Why 90% of clinical drug development fails and how to improve it?’, Acta Pharmaceutica Sinica B, Volume 12, Issue 7, 2022, p.3049–3062. https://doi.org/10.1016/j.apsb.2022.02.002
[5] Schlander, M., Hernandez-Villafuerte, K., Cheng, CY. et al. How Much Does It Cost to Research and Develop a New Drug? A Systematic Review and Assessment. PharmacoEconomics 39, 1243–1269 (2021). https://doi.org/10.1007/s40273-021-01065-y
