The passage of the Federal Food, Drug, and Cosmetic Act in 1938 mandated animal testing for the development of safe and effective drugs for human use. Now, the FDA Modernization Act 2.0 permits the use of alternative models to animal studies in drug development, shifting the landscape of drug and chemical safety. Researchers can now access a broader range of new approach methodologies (NAMs) — such as cell-based assays, 3D organoids, organ-on-a-chip, or computer in-silico modeling — to investigate drug safety and efficacy. This was the topic of conversation in our recent panel discussion with Dr. Stephen Ferguson, scientist at the National Institute of Environmental Health Sciences; Jim Finley, Principal Scientist of Investigative Toxicology at Pfizer; and Marc Ferrer, Director of 3D Tissue Bioprinting Laboratory at the National Center for Advancing Translational Sciences. The panelists also discussed technical and experimental challenges associated with microphysiological systems (MPS) and balanced out its advantages and limitations.
Most popular cell models and applications
As many of the panel discussion attendees indicated, 2D cell culture models are still relied upon for many research purposes. Compared to more advanced technologies, 2D models are well-known, less expensive, reproducible, easy to analyze, and do not require extensive, specialized training to use in biological research. The main and critical disadvantage of 2D cell systems is that they do not mimic the way cells grow and function in the animal body.
In response to this disadvantage, 3D cell culture systems were developed as more realistic representations of the in vivo conditions of different organ systems, offering more realistic cell polarities and cell-environment interactions and preserving molecular mechanisms. Dr. Ferguson provided an excellent example regarding ADME, an acronym for absorption, distribution, metabolism, and excretion – the concepts that underlie pharmacokinetics, “I think there are certain use cases like barrier function and ADME type properties where you're worried about how much chemicals [are] getting into the cell from basolateral or apical exposure. And those are where these more complex systems really begin to shine because they can just integrate a greater complexity of biology and tissue functionality that lets you ask different kinds of questions.” Ultimately, the goal of these new technologies is to offer a more accurate representation of physiological responses to drugs and toxins that could ultimately lead to reduced reliance on animal models.
As our panelists astutely pointed out, the initial hurdle is choosing the technology that best suits the scientific question and goal at hand. As Dr. Ferrer explained, “Engineering is ahead of the biology.” Researchers face a number of options including multicellular spheroids, organoids, organ-on-a-chip, hanging drop, microtissues, and 3D bioprinting. Dr. Ferrer goes on to advise researchers to, “Arrive at a model that you can benchmark and validate and shows predictability.”
Overcoming challenges of using physiological cell models
For many researchers, making the jump to more complex 3D cell models is limited by the additional cost needed for specialized reagents, cells, and equipment. As Finley noted, “Materials costs are high, your cell costs are high, your license costs.” Making this move to 3D models also demands the technical expertise required to run more complex procedures. For example, 3D cell models are grown in a gel-like matrix or solid scaffold in order to mimic in vivo environments more closely. However, the physical nature of these matrices may mean cultures form more slowly, or that collecting cells or secreted factors for assays are more challenging, all of which call for greater handling skills for 3D cell models. The jump to 3D models also means 3D cultures are more difficult to analyze by microscopy, necessitating the need for specialized 3D imaging and microscopy capabilities, such as confocal microscopy.
Future outlook on replacement of animal models by complex models
The final question posed to our panelists: are we there yet? Meaning, are the MPS models able to meet the promise of replacing animal models? Our panelists indicated that one major hurdle toward that goal is the lack of standardization of protocols across models, making it hard to compare data. “You work in the GI organoid models, you'll talk to 12 different people”, as Finley explained. “You find 12 different ways of culturing and plating them. It's whatever works for that lab. That's what they use.” Validation of the use of 3D models as animal surrogates will require large-scale evaluation of multiple devices of the same design implemented using the same protocols. It will also be necessary to have critical design and performance parameters in place in order to qualify models being evaluated. In response to these critical needs, the panelists highlighted promising initiatives such as the IQMPS consortium of pharmaceutical and biotechnology companies working to standardize MPS protocols and models so that they can be validated and used across multiple labs.
So, while our panelists agreed that animal models still provide a broader perspective, tools such as organ-on-a-chip models are within a rapidly evolving space, making MPS and the collection of technologies discussed here the future mainstays for targeted studies.
To learn more from our panelists and their predictions about the future of replacing animal models by organ-on-chip/organoids or other complex models, you can now watch the full discussion.
For research use only. Not for use in diagnostic procedures.
The views expressed during this panel discussion belong solely to the speakers and may not necessarily reflect those of their respective companies.
