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Discovery & Development Drug Discovery, COVID-19

When the Chips Are Down

Organ-on-a-chip is considered an important emerging technology for research and development because it can show how a candidate drug might react in human tissue structures – as opposed to traditional animal models – long before it enters the clinic. Here, we speak with Lorna Ewart, Executive Vice President, Science of Emulate, to learn more.

How do organ-on-chip platforms accurately mimic human organs?

Organ-on-a chip technologies use microscale engineering technologies combined with cultured living human cells to create an experimental platform that recapitulates the physiological and mechanical microenvironment of whole living organs. These microphysiological systems (MPS) enable the study of complex human physiology and pathology in an organ-specific context. These specialized in vitro human disease models can revolutionize drug discovery and development by helping researchers better predict human responses to medicines, including safety and efficacy. 

Organ-on-a-chip technology can be designed to fully recreate the complex, dynamic state in which living cells function within a human organ – a so-called “home away from home” for human cells. Such an environment involves modelling complex interactions, often in three dimensions. This starts with the extracellular matrix (ECM), which is optimized for organ-relevant composition, stiffness, and cell attachment. Homotypic and heterotypic cell-cell interactions are recreated. And finally, the model seeks to create oxygen, nutrient, and chemical gradients that provide the complete set of cues cells need to behave and function accurately – just as they would in the human body.

As an example, Emulate Organ-Chips are composed of a transparent, flexible silicone polymer (polydimethylsiloxane (PDMS)) about the size of an AA battery. Each chip has two parallel, fluidically independent channels separated by a flexible membrane, with pores seven microns in diameter. The membrane is coated with an optimized ECM before the channels are lined by living human epithelial cells on the upper channel and living human organ-specific endothelial cells on the lower channel. Such an arrangement recreates the essential tissue-to-tissue interface found in every organ. The channels are flanked by vacuum channels that can provide tissue-relevant mechanical forces for organs to mimic processes such as breathing in the lung.

How well used is organ-on-a-chip technology in drug discovery and the pharma industry today?

We’re working with around 19 of the top 25 pharmaceutical companies as defined by their R&D spend. In my view, the industry should always be considering the adoption of new technologies that can reduce the long, costly drug discovery and development process, or improve confidence in how a medicine will perform in human trials.

Organ-on-a-chip technology can develop human-relevant data for drug candidates and also offer a sustainable, ethical research model by relying less on animal models – which are frequently shown to poorly recreate the human pathophysiological phenotype.

Organ-on-a-chip technology is barely a decade old, so the pharma industry is still in the testing and evaluation phase. Around 23 pharmaceutical companies have established an MPS affiliate under the IQ Consortium – which aims to advance innovation and quality in the biopharmaceutical industry. The goal of this MPS affiliate is to define the criteria of use for new, sophisticated in vitro models, such as organ-on-chip and, to this end, a series of organotypic manuscripts have been published to guide technology innovators, such as ourselves, toward building organ-models to address the key safety- or ADME-related questions relevant in drug development (1). The affiliate is also closely aligned with the FDA, thereby ensuring consistency of direction and approach for advancing this new technology. 

In my experience, customers are really interested in using organ-on-a-chip technology for internal decision-making purposes within the preclinical safety testing or target validation stages of the drug discovery and development process. One notable example is the human Blood Vessel-Chip developed by Emulate in collaboration with Janssen Pharmaceuticals, which was able to recreate the thrombotic toxicities of a monoclonal antibody drug that led to its failure in human clinical trials (2). The ultimate goal of some pharma companies is to include organ-on-a-chip data within their regulatory filings for new drugs, to augment the results from animal data or to strengthen a weight-of-evidence argument. 

What is necessary to promote greater uptake?

Promoting greater adoption of organ-on-a-chip technology is likely to result from progress in several areas. These have been discussed in greater detail by in Nature Reviews Drug Discovery (3).

First, adoption will be driven by a move toward technology standardization. Because this is still a developing field, there are multiple MPS platforms and approaches. As leading technologies are further industrialized, they will become standardized, enabling broader inter-laboratory comparisons, technology adoption for key applications, and more widespread use. 

Second, regulatory acceptance will trigger technology adoption, especially relating to robustness and reproducibility (both inter- and intra-laboratory) of the technology. This is a central component of the Cooperative Research and Development Agreement (CRADA) between Emulate and the FDA. For example, if organ-on-a-chip technology is proposed to replace an existing approach, regulators will want to see concordance of data between the organ-on-a-chip model and the animal model that it intends to replace. In other cases, if the use is related to a greater understanding of mechanism of action, the user needs to articulate which regulatory question is being answered. A good example of this could be explaining species differences with respect to toxicological outcome, as has been nicely described in a paper where the Emulate Liver-Chip was used to understand drug toxicity (4). 

Third, significant progress is underway in demonstrating confidence in new organ-on-a-chip models, as well as translational qualification. Importantly, the work of the IQ MPS affiliate is designed to articulate new roadmaps that are sound and relevant for enabling organ-on-a-chip innovators to navigate towards faster development and broader adoption. Essential criteria to be fulfilled include the ability to reproduce functionality within and across laboratories, execute with good experimental design, knowledge of model stability over time and donor variability, and qualification of supporting analytical methods.

Lastly, successful proliferation of organ-on-a-chip technology – and the experimental results they produce – within pharmaceutical organizational hierarchies and cultures will lead to the continuing growth trajectory of adoption. 

What can you tell us about the new CRADA with the FDA?

The first FDA-Emulate CRADA was in 2017 and was focused on toxicology. Our new multi-year CRADA expands beyond toxicology and is agency-wide, meaning that divisions throughout the FDA will be able to use Emulate products for programs that address some of the most challenging areas, including Alzheimer’s disease, the intestinal microbiome, liver toxicity, and, importantly, COVID-19 (5).

Toxicology leaders at the FDA have been involved in collaborative research with our technology since before we commercialized it – back in 2010 when it was in development at the Wyss Institute for Biologically Inspired Engineering at Harvard University. In 2017, after years of being connected with our technology, the FDA established an initial CRADA focused on using Emulate Organ-Chips for toxicology applications within the regulatory process. It was designed so the FDA could gain first-hand experience with our Human Emulation System, working alongside our scientists to generate data together. It is beneficial for the FDA to have a Human Emulation System in their laboratories, and it will pave the way for qualifying the use of our technology and integrating it within the existing regulatory framework for product testing.

The FDA seeks to engage with alternative methods not only to reduce the risk of products reaching the market with toxicological consequences, but also to ensure that regulated products reach the market faster and with improved efficacy (6).

The first FDA-Emulate CRADA was in 2017 and was focused on toxicology. Our new multi-year CRADA expands beyond toxicology and is agency-wide, meaning that divisions throughout the FDA will be able to use Emulate products for programs that address some of the most challenging areas, including Alzheimer’s disease, the intestinal microbiome, liver toxicity, and, importantly, COVID-19 (5).

Toxicology leaders at the FDA have been involved in collaborative research with our technology since before we commercialized it – back in 2010 when it was in development at the Wyss Institute for Biologically Inspired Engineering at Harvard University. In 2017, after years of being connected with our technology, the FDA established an initial CRADA focused on using Emulate Organ-Chips for toxicology applications within the regulatory process. It was designed so the FDA could gain first-hand experience with our Human Emulation System, working alongside our scientists to generate data together. It is beneficial for the FDA to have a Human Emulation System in their laboratories, and it will pave the way for qualifying the use of our technology and integrating it within the existing regulatory framework for product testing.

The FDA seeks to engage with alternative methods not only to reduce the risk of products reaching the market with toxicological consequences, but also to ensure that regulated products reach the market faster and with improved efficacy (6).

The first FDA-Emulate CRADA was in 2017 and was focused on toxicology. Our new multi-year CRADA expands beyond toxicology and is agency-wide, meaning that divisions throughout the FDA will be able to use Emulate products for programs that address some of the most challenging areas, including Alzheimer’s disease, the intestinal microbiome, liver toxicity, and, importantly, COVID-19 (5).

Toxicology leaders at the FDA have been involved in collaborative research with our technology since before we commercialized it – back in 2010 when it was in development at the Wyss Institute for Biologically Inspired Engineering at Harvard University. In 2017, after years of being connected with our technology, the FDA established an initial CRADA focused on using Emulate Organ-Chips for toxicology applications within the regulatory process. It was designed so the FDA could gain first-hand experience with our Human Emulation System, working alongside our scientists to generate data together. It is beneficial for the FDA to have a Human Emulation System in their laboratories, and it will pave the way for qualifying the use of our technology and integrating it within the existing regulatory framework for product testing.

The FDA seeks to engage with alternative methods not only to reduce the risk of products reaching the market with toxicological consequences, but also to ensure that regulated products reach the market faster and with improved efficacy (6).

In what ways can organ-on-a-chip technology be used in the fight against COVID-19?

The COVID-19 pandemic has required scientists to improve the predictive nature of preclinical models to accelerate therapeutics and vaccines entering the clinic. Species differences – including differences in viral pathogenesis, immune response and immune system interactions, inflammatory response, pharmacokinetics, and drug action – are known to impact successful translation of preclinical data to the clinic. More human-relevant alternatives, such as organ-on-a-chip technology can be adopted to accelerate discovery and development efforts in COVID-19 (7).

Historically, animal alternatives for studying respiratory viruses have involved conventional in vitro models that use cell lines (such as Vero, A549, or MDCK cells.) These approaches are poor predictors of human outcomes, most likely due to the simple culture conditions that lack the in vivo relevance and biological complexity required to model viral pathogenesis. In contrast, Emulate Lung-Chips can more faithfully recreate human biology and pathophysiology observed in vivo, including mucociliary clearance, lung inflammation, immune cell recruitment, cytokine production, viral infection, and pulmonary edema (4, 8, 9, 10, 11, 12).

Emulate Lung-Chips have been shown to support key hallmarks of the cytopathology and inflammatory responses observed in human airways after viral infection with human rhinovirus, influenza, and SARS-CoV-2 viral particles that express the SARS-CoV-2 spike protein, as well as relevant levels of angiotensin converting enzyme-2 (ACE-2) and TMPRSS2 protease. Emerging evidence also suggests that the endothelial tissue plays a critical role in SARS-CoV-2 pathogenesis (13) – and some organ-on-a-chip products can incorporate this cell layer. Overall, Emulate Organ-Chips can enable more rapid insights into COVID-19 and other human diseases – and precisely predict human response to vaccines and drug candidates.

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  1. IQ Microphysiological Systems Affiliate, “Publications” (2020). Available at www.iqmps.org/publications
  2. R Barrile et al., “Organ-on-Chip Recapitulates Thrombosis Induced by an anti-CD154 Monoclonal Antibody: Translational Potential of Advanced Microengineered Systems,” Clin. Pharmacol. Ther., 104 (2018). DOI: 10.1002/cpt.1054
  3. L Ewart, A Roth, “Opportunities and challenges with microphysiological systems: a pharma end-user perspective,” Nature Reviews Drug Discovery (2020). DOI: 10.1038/d41573-020-00030-2
  4. K-J Jang et al., “Reproducing human and cross-species drug toxicities using a Liver-Chip,” Sci. Trans. Med., 11 (2019). DOI: 10.1126/scitranslmed.aax5516
  5. Emulate, “Emulate Signs Collaborative Agreement with the FDA to Apply Lung-Chip to Evaluate Safety of COVID-19 Vaccines and Protective Immunity Against SARS-CoV-2,” (2020). Available at https://bit.ly/3srvr8j
  6. FDA, “Advancing Alternative Methods at FDA,” (2021). Available at: https://bit.ly/3de1xQa
  7. Emulate, “How Organs-on-Chips Technology is being used to Provide Scientific Insights into COVID-19,” (2020). Available at https://bit.ly/31i7Mve
  8. D Huh et al., “Reconstituting organ-level lung functions on a chip,” Science, 328 (2010). DOI: 10.1126/science.1188302
  9. D Huh et al., “A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice,” Sci. Transl. Med., 4, (2012). DOI: 10.1126/scitranslmed.3004249
  10. M Kasandra et al., “Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model,” eLife (2020). DOI: 10.7554/eLife.50135
  11. J. Nawroth et al., “A Micro-Engineered Airway Lung-Chip Models Key Features of Viral-Induced Exacerbation of Asthma,” [preprint] (2020). DOI: 10.1101/2020.02.02.931055
  12. L Si et al., “Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics,” [preprint] (2020). DOI: 10.1101/2020.04.13.039917
  13. Z Varga et al., “Endothelial cell infection and endotheliitis in COVID-19,” The Lancet, 395 (2020). DOI: 10.1016/S0140-6736(20)30937-5

About the Author

Stephanie Sutton

Making great scientific magazines isn’t just about delivering knowledge and high quality content; it’s also about packaging these in the right words to ensure that someone is truly inspired by a topic. My passion is ensuring that our authors’ expertise is presented as a seamless and enjoyable reading experience, whether in print, in digital or on social media. I’ve spent seven years writing and editing features for scientific and manufacturing publications, and in making this content engaging and accessible without sacrificing its scientific integrity. There is nothing better than a magazine with great content that feels great to read.

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