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Preclinical research has never been perfect. Although one third of all R&D costs occur pre-clinic (1), the animal studies that characterize this phase are poor predictors of success: more than 90% of drugs that succeed in animal trials fail in subsequent human trials (2).
Shifting opinions on the ethics of animal testing and the rapid progress of alternative technologies prompted congress to pass the FDA Modernization Act 2.0 in December 2022. This piece of legislature lifted the requirement of animal testing to get a drug approved for clinical trials, paving the way for other “advanced technologies.” Organs-on-chips (OoCs) are at the forefront of these new technologies, promising to usher in a new era of efficient, patient-centric, and highly accurate preclinical drug development.
What are Organs-on-Chips?
Organs-on-chips are micro-engineered devices that mimic the physiological functions of human organs, providing a realistic environment for studying disease, drug responses, and toxicity without the use of animal models. These clear, polymer-based chips contain living human cells and networks of <1mm hollow channels that control fluids to mimic physiological processes.
Organs-on-chips are similar to another advanced tissue engineering technology often used in biomedical research: organoids. Organoids consist of 3D miniaturized and simplified versions of organs grown in vitro from stem cells. While organoids grow more organically and unpredictably, OoCs are precisely engineered to have controlled structures and functionalities. This level of precision makes OoCs suitable for advanced imaging and analysis techniques.
Organs-on-chips can also simulate fluid flow and mechanical cues, which are crucial for understanding how cells interact with forces like fluid shear stress and compression. For example, a lung-on-a-chip can mimic breathing motions.
Impact on Preclinical Drug Development
Given their high clinical relevance and comparatively low cost, organs-on-chips have the potential to improve many stages of the development process, from early drug discovery to preclinical translation. In the discovery stage, OoCs can be used to model diseases in controlled conditions. For instance, cancer-on-chip models can simulate tumor environments to validate therapeutic targets.
Given their high clinical relevance and comparatively low cost, organs-on-chips have the potential to improve many stages of the development process, from early drug discovery to preclinical translation.
Organs-on-chips can also be used to evaluate the toxicity of drug candidates on different organ systems. In fact, many OoC startups have focused their efforts on developing liver tissue chips to evaluate liver toxicity (fig. 1), which accounts for 22% of failures in clinical trials and around 1 in 3 post-approval withdrawals caused by adverse drug reactions (3). Organs-on-chips could save the industry $3 billion annually on liver toxicity studies alone (4).
Organs-on-chips seem particularly promising for pharmacokinetic and pharmacodynamic (PK/PD) studies, especially with multi-organ chips that allow systematic testing across different human organs. Eventually, OoCs could drive precision medicine, enabling the creation of patient-specific tissue chips to guide personalized treatments.
Figure 1: Selected OoC companies and their tissue models
Barriers to Widespread Adoption
Despite the great promise offered by OoCs, uptake has been slow. Understandably, drug developers are cautious about replacing traditional animal trials due to the risk of FDA rejection. The industry is looking for more efficacy validation to de-risk the technology before integrating it into their workflows. Emulate, the most well-funded OoC startup with over $220M raised to date, is leading these efforts. It has collaborated with pharmaceutical companies like AstraZeneca and Merck to incorporate OoCs into their R&D programs and with the FDA to evaluate the safety of COVID-19 therapeutics using their Lung Chips (5).
The FDA is also working to qualify OoCs and other advanced technologies for regulatory use through their New Alternatives Methods (NAM) Program. Meanwhile, the National Institute of Standards and Technology has recently established a working group for developing guidelines and standards for OoC research, bringing together global leaders from industry, academia, and government agencies.
Scalability also remains a challenge, because current OoC fabrication and experimentation is generally low throughput. Startups such as Vivodyne are addressing this issue by using robotics to automate experiments on thousands of tissues simultaneously (6). Additionally, 3D bioprinting could enhance the throughput of OoC manufacturing (7).
In parallel, it is critical that industry-wide standards be established for OoC to ensure consistent quality and seamless collaboration. This work is underway at the International Organization for Standardization with ISO 22916:2022, which has set minimum specifications for interoperability of OoC components (8).
The View from the Crow’s Nest
Organs-on-chips represent a significant advancement in tissue engineering and will play an important role in the transition towards highly predictive, non-animal methods of preclinical research. The applications of OoCs are relevant to all stages of drug development, from discovery through PK/PD.
Despite how impactful this tech could be, adoption is still scant as it represents an unknown for drug developers. While investors and the FDA have endorsed the technology, more collaboration is needed among stakeholders to set industry standards and conduct the kind of validation studies that will convince drug developers to transition away from traditional animal testing.
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Sources:
1. Innovation in the pharmaceutical industry: New estimates of R&D costs (https://pubmed.ncbi.nlm.nih.gov/26928437/)
2. Why 90% of clinical drug development fails and how to improve it? (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293739/)
3. Drug safety sciences and the bottleneck in drug development (https://pubmed.ncbi.nlm.nih.gov/21593756/)
4. Human organs-on-chips for disease modelling, drug development and personalized medicine (https://www.nature.com/articles/s41576-022-00466-9)
5. 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 (https://emulatebio.com/press/fda-organ-chip-crada-2020/)
6. Vivodyne (https://www.vivodyne.com/platform)
7. Organ-on-a-Chip: A new paradigm for drug development (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990030/)
8. Microfluidic devices — Interoperability requirements for dimensions, connections and initial device classification (https://www.iso.org/obp/ui/#iso:std:iso:22916:ed-1:v1:en)
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