Microphysiological systems can be employed with the aim of providing a more accurate replication of human physiology in vitro and can prove a more effective alternative to the use of animal models, explains Dr Audrey Dubourg.
Billions are invested into drug discovery annually, yet most drugs never reach the market. Why? Because experiments fail to accurately predict human responses, including drug safety and efficacy, leading to frequent, late-stage and expensive clinical trial failures.
Standard in vitro 2D cell culture fails to provide insights to the complex, multifaceted interactions taking place in a living body. This has led to a dependence on animal models to provide these critical and complex insights obtained from whole, living systems. However, animal experimentation is slow, expensive and requires cross-species translation to extrapolate predictions to humans.
Furthermore, it carries important ethical considerations. Translating findings to these critical in vivo settings remains a challenge due to inherent differences between species and an insufficient understanding of the underlying pathophysiology of human diseases.
In June 2022, the FDA Modernization Act of 2021 was passed in the US House of Representatives, ending the outdated mandate that all drugs must be tested on animals. The door is now open for innovative, humanrelevant, new alternative methodologies (NAMs), such as Organ-on-a-chip (OOC), to help deliver safer and more efficacious medicines. Experts suggest that bridging the gap with OOC technology will increase the success rates of new drug development and significantly reduce research costs, with the market size estimated to grow to $1.6 billion USD by 2030 at a CAGR of 31.1% .
The aim of OOC, also known as microphysiological system (MPS), is to more accurately replicate human physiology in vitro to overcome the relevance limitations of current approaches. By re-creating 3D organ and tissue mimics in the lab, the technology enables researchers to re-create human physiology and disease in an MPS that functions and responds to drugs as it would in humans.
The field is progressing at a rapid pace, with next-generation MPS featuring fluid circulation to provide nutrients and mimic blood flow, plus the ability to link organs together to simulate more complicated processes, for example drug absorption and metabolism, inter-organ interactions and systemic effects, such as inflammation – a key disease driver . By interconnecting individual organs, or microtissues together, these sophisticated models enable researchers to generate translationally-relevant pre-clinical data in areas such as bioavailability, where estimations are required to guide the drug development process and form the basis for setting safe and efficacious doses in the clinic.
Their accuracy is therefore linked to the success, or failure, of clinical trials. Despite such importance, this key parameter, to-date, is principally derived from animal models.
Opportunities to use OOC to replace animal models in modalities which rely on human-specific modes of action are being explored, for example cell and gene therapy, where the technology is demonstrating its ability to predict clinical outcomes that animal experimentation cannot
OOC technology provides researchers with high quality, human-relevant data to facilitate more informed decisions about which medicines to take into the clinic, thereby offering significant savings in R&D costs and time. Opportunities to use OOC to replace animal models in modalities which rely on human-specific modes of action are being explored, for example cell and gene therapy, where the technology is demonstrating its ability to predict clinical outcomes that animal experimentation cannot.
These advanced MPS systems clearly improve physiological relevance and culture longevity compared with standard 2D in vitro approaches. However, there are significant considerations surrounding the replacement of in vivo experiments. Whilst ethically desirable and an aim for those working in the field, realistically, the complete replacement of animal models is unlikely to happen overnight as there is much to prove. Right now, incorporating OOC into drug development at strategic stages offers huge benefits for crossvalidating and supplementing data sets to fill key knowledge gaps and make more confident clinical decision making.
We, and other providers, are building the body of evidence for these disruptive technologies so they can be increasingly relied on as we move away from a dependence on animal models.
There is exponential growth in the number of publications that cite the use of, or development of, OOC technology and a collection of well-established companies that design and produce commercially viable systems and research services. Major Pharma and Biotech are showing an increased appetite to bring new medicines to market more efficiently and, importantly, there is genuine interest from the regulators. Here, strong collaborations are essential, and significant progress has already been made with regulatory authorities acknowledging the potential of MPS and investing in initiatives to help demonstrate their robustness, reliability, and performance, paving the way for OOC data to be included in IND submissions. The first co-publication between FDA scientists and a MPS developer (CN Bio), assessing its Liveron- a-Chip MPS, was a significant milestone for validation of the technology .
Already, OOC technology has proven itself as a reliable and accurate tool to help reduce, refine, and complement existing tests, available for use in today’s laboratory workflows. Where animal experimentation captures the complexity of a living organism, OOC demonstrate how drug effects or a disease mechanism will differ in a human setting. The combination of the two gives a much stronger and broader insight that aids translational research and, hopefully, paves the way for successful new therapeutics to make it to market.
As these advanced in vitro models continue to increase in sophistication towards a human body-on-a-chip in the lab, the future vision is more firmly focused on helping to reduce and replace our reliance on animal models where improved performance is proven.
CN Bio’s Product Manager for its PhysioMimix™ Organ-On-Chip lab benchtop platform, Dr Audrey Dubourg has significant experience in 3D cell culture using MPS technologies and a post-doctoral background in microbiology cn-bio.com
2 CN Bio’s PhysioMimix™ OOC range of single and multi-organ microphysiological systems: https://cn-bio.com/physiomimixooc/
3 Rubiano, A., Indapurkar, A., Yokosawa, R., Miedzik, A., Rosenzweig, B., Arefin, A., Moulin, C.M., Dame, K., Hartman, N., Volpe, D.A., Matta, M.K., Hughes, D.J., Strauss, D.G., Kostrzewski, T. and Ribeiro, A.J.S. (2021). Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism, and accumulation. Clinical and Translational Science, 14(3), pp.1049–1061. doi:10.1111/cts.12969