Microphysiological systems can be used with the aim of providing a more precise replica of human physiology in vitro and can be a more efficient alternative to the use of animal models, he explains. Dr. Audrey Dubourg.
Billions are invested in drug discovery every year, but most drugs never reach the market. Why? Because experiments fail to accurately predict human responses, including drug safety and efficacy, leading to frequent, costly, and late-stage failures of clinical trials.
Standard in vitro 2D cell culture does not provide insight into the complex and multifaceted interactions that take place in a living body. This has led to a reliance on animal models to provide these critical and complex insights from whole living systems. However, animal testing is time-consuming, expensive, and requires cross-species translation to extrapolate predictions to humans.
In addition, it entails important ethical considerations. Translating the findings to these critical in vivo settings remains challenging due to inherent differences between species and insufficient understanding of the underlying pathophysiology of human disease.
In June 2022, the FDA Modernization Act of 2021 passed the US House of Representatives, ending the outdated mandate that all drugs must be tested on animals. The door is now open for innovative and human-relevant new alternative methodologies (NAMs), such as Organ-on-a-chip (OOC), to help provide safer and more effective medicines. Experts suggest that bridging the gap with OOC technology will increase new drug development success rates and significantly reduce research costs, with the market size estimated to grow to $1.6 billion USD by 2030 at a rate CAGR of 31.1% .
The goal of OOC, also known as a microphysiological system (MPS), is to more accurately replicate human physiology in vitro to overcome relevance limitations of current approaches. By recreating 3D mimics of organs and tissues in the lab, the technology enables researchers to recreate 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 deliver nutrients and mimic blood flow, as well as the ability to attach organs to simulate more complicated processes, for example drug absorption and metabolism, organ-to-organ interactions and systemic effects, such as inflammation, a key driver of the disease . By interconnecting individual organs or microtissues, these sophisticated models allow researchers to generate translationally relevant preclinical data in areas such as bioavailability, where estimates are required to guide the drug development process and form the basis for establishing safe and effective doses in the clinic. .
Therefore, its accuracy is related to the success or failure of clinical trials. Despite such importance, this key parameter has, to date, been derived primarily from animal models.
Opportunities are being explored to use OOC to replace animal models in modalities that rely on human-specific modes of action, for example, cell and gene therapy, where the technology is demonstrating its ability to predict clinical outcomes that animal testing cannot. .
OOC technology provides researchers with high-quality, human-relevant data to facilitate more informed decisions about which drugs to bring to the clinic, delivering significant savings in R&D time and costs. Opportunities are being explored to use OOC to replace animal models in modalities that rely on human-specific modes of action, for example, cell and gene therapy, where the technology is demonstrating its ability to predict clinical outcomes that animal testing cannot. .
These advanced MPS systems clearly improve physiological relevance and culture longevity compared to standard 2D in vitro approaches. However, there are important considerations surrounding substitution for in vivo experiments. While ethically desirable and a goal for those working in the field, complete replacement of animal models is unlikely to happen overnight as there is so much to prove. Right now, incorporating OOC into strategic-stage drug development offers tremendous benefits for cross-validation and complementation of data sets to fill key knowledge gaps and make clinical decisions with greater confidence.
We, and other vendors, are building the body of evidence for these disruptive technologies so that they can be increasingly trusted as we move away from reliance on animal models.
There is an exponential growth in the number of publications citing the use or development of OOC technology and a collection of well-established companies designing and producing commercially viable research systems and services. Leading pharmaceutical and biotech companies are showing a greater appetite to bring new drugs to market more efficiently, and more importantly, there is genuine interest from regulators. Here, strong collaborations are essential and significant progress has already been made with regulatory authorities recognizing the potential of MPS and investing in initiatives to help demonstrate its robustness, reliability and performance, paving the way for OOC data to be included. in IND submissions. The first joint publication between FDA scientists and an MPS developer (CN Bio), evaluating their Liveron-a-Chip MPS, was an important milestone for the validation of the technology. .
OOC technology has already proven to be a reliable and accurate tool to help reduce, refine and supplement existing tests, available for use in today’s laboratory workflows. Where animal testing captures the complexity of a living organism, OOC demonstrates how the effects of drugs or the mechanism of a disease will differ in a human setting. Combining the two provides a much stronger and broader view that aids translational research and hopefully paves the way for successful new therapies to come to market.
As these advanced in vitro models continue to increase in sophistication toward a human body on a chip in the lab, the future vision is more firmly focused on helping reduce and replace our reliance on animal models where better performance has been shown.
CN Bio’s Product Manager for its PhysioMimix™ Organ-On-Chip Laboratory Benchtop Platform, Dr. Audrey Dubourg has significant experience in 3D cell culture using MPS technologies and postdoctoral training in microbiology cn-bio.com
1 https://www. allied market research. com/press-release/organ-on-chip-market. html
2 CN Bio’s PhysioMimix™ OOC range of single-organ and multi-organ microphysiological systems: https://cn-bio.com/ fisiomimixooc/
3 A. Rubiano, A. Indapurkar, R. Yokosawa, A. Miedzik, B. Rosenzweig, A. Arefin, CM Moulin, K. Dame, N. Hartman, DA Volpe, Matta , MK, Hughes, DJ, Strauss, DG, Kostrzewski, T. and Ribeiro, AJS (2021). Characterization of reproducibility in the use of a hepatic microphysiological system to analyze the toxicity, metabolism and accumulation of drugs. Clinical and Translational Science, 14(3), pgs. 1049–1061. doi:10.1111/cts.12969