Advances in Cell Culture for Drug Development

Advances in cell culture technology enhance many applications in drug development, but more work lies ahead. “One of the biggest challenges when using cell cultures for drug development is the lack of more predictive preclinical models,” says Chris Suarez, PhD, senior scientific applications manager at Corning Life Sciences. “As more physiologically relevant model systems are developed, the success rate of translation into clinical approval may be improved.”

Creating models that generate a more physiologically relevant environment for the cells takes work. First, organisms exist in three dimensions, and most cultures over the years have limited cells to two-dimensional monolayers. As Suarez explains, “The use of 2D cell culture has not provided a predictive preclinical model when utilized in the drug-development process based on several factors.” As an example, he points out that cells in 2D get more exposure to surrounding fluids than they might in an organism’s 3D structure, which can have a “significant impact when utilized in drug studies as the treatment may show increased efficacy compared to cultures grown in 3D that are more representative of in vivo conditions.”

As a result, many scientists and companies involved in drug development might prefer 3D cultures—but it’s not a simple transition. As Suarez mentions, “The ability to scale and execute high-throughput screening for cells grown in 3D are areas for improvement as this model system continues to be more broadly adopted to replace screening in 2D.”

Accelerating the transition

Factors outside of cell culture technology influence the transition to 3D cultures. In 2022, for example, President Biden signed the FDA Modernization Act 2.0, which decreases the reliance on animal models in drug development. So, drug developers can replace some animal testing with faster and less expensive culture-based methods. As a result, “dimensionality has become forefront in the cell-culture conversation,” Suarez says.

That conversation includes the search for consistency in some complex 3D approaches to culturing, such as organoids, which are 3D cultures of stem cells intended to mimic an organ’s structure and function. To make use of such advanced methods, “assay miniaturization and automation are important success metrics to consider in using cell cultures for drug development,” says Suarez. “Both bioprinting and microfluidic chip technologies facilitate better 3D-model generation, which allows cross talk of various tissue types as well as fluid flow that mimics the role of vasculature in human physiology—all of which are required in drug development.”

As more physiologically relevant model systems are developed, the success rate of translation into clinical approval may be improved.

Similarly, Shaimaa M. Badr-Eldin, PhD, professor of pharmaceutics at the King Abdulaziz University in Saudi Arabia, and her colleagues pointed out: “It is anticipated that these 3D cell culture methods will bridge the translation of data from 2D cell culture to animal models.”¹ Nonetheless, these scientists echoed Suarez’s comments about the need to improve the reproducibility of 3D cell cultures. As Badr-Eldin and her colleagues put it: “Slight variations in the culture of 3D models can produce some modifications in permutations which can affect the reproducibility of results in them.”

When it comes to drug development, inconsistent results must be resolved before 3D cultures can replace animal models.

Integrating technologies

While some scientists work on the reproducibility of 3D cell cultures and the resulting data, others explore new approaches to creating more physiologically accurate conditions.

As one example, Valerie Speirs, PhD, chair in molecular oncology at the University of Aberdeen in the UK, and her colleagues reported that most 3D cell culture models of cancer have “failed to incorporate the biochemical and biophysical stimuli from fluid flow.”² So, Speirs and her colleagues made 3D cultures of breast cancer cells, added perfusion, and tested the impact of tamoxifen—a common drug used in breast cancer patients. The breast cancer cells lived for more than three weeks in this experimental set-up and showed improved cell viability compared to 3D cultures of these cells without perfusion. The scientists concluded that this technique “supported examining the effect of tamoxifen on breast cancer cell lines and in primary patient-derived breast cancer samples.”

If a scientist cultures an organoid and adds perfusion, it is called an organ-on-a-chip or simply, organ chip. As explained by Donald E. Ingber, MD, PhD, founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, these “devices represent one of the recent successes in the search for in vitro human microphysiological systems that can recapitulate organ-level and even organism-level functions.”³

One kind of organ chip can be linked with others to work toward a body-on-chip. As Ingber noted, “Multi-organ human body-on-chip systems have been created to study multi-organ physiology and whole-body level drug responses.”

Other technologies can also be combined. One interesting example comes from Amgen and Fluidform, who teamed up to 3D bioprint human tonsil tissue.⁴ These 3D tissues will be used as a model of the human immune system, which can be used in drug testing.

Better models ahead

In looking ahead, “the key theme will be the development and early inclusion of models that are more relevant and representative of humans,” says Alejandro Montoya, senior product manager, advanced cell culture, Corning Life Sciences. “This includes healthy and diseased states.”

Although Montoya mentions the advances in culturing and engineering primary cells—even multiple cell types and various forms of 3D cell culture—he adds, “The destination has been set, but the path is being paved.”

Parts of that path even lead into outer space. UC San Diego’s Astrobiotechnology Hub runs stem cell studies on NASA’s International Space Station.⁵ That environment can accelerate cell aging, which could be useful in drug development for neurodegenerative diseases.

The future goal for using cell cultures in drug development, Montoya says, “is to be able to obtain and mimic throughout the drug-development process more physiologically relevant data, models, and responses.” To achieve that, he says, cell culture models of healthy and diseases tissues need to be “more robust, standardized, reproducible, accessible, and acceptable.” Reaching those goals will take more time and investment.

References:

1. “Three-Dimensional In Vitro Cell Culture Models for Efficient Drug Discovery: Progress So Far and Future Prospects”. https://www.mdpi.com/1424-8247/15/8/926.
2. “Validation of a 3D perfused cell culture platform as a tool for humanised preclinical drug testing in breast cancer using established cell lines and patient-derived tissues”. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0283044.
3. “Human organs-on-chips for disease modelling, drug development and personalized medicine”. https://www.nature.com/articles/s41576-022-00466-9.
4. “3D Tissue Models Mimic the Human Immune System to Inform Drug Development”. https://www.amgen.com/stories/2023/02/3d-tissue-models-mimic-the-human-immune-system-to-inform-drug-development.
5. “UC San Diego’s Astrobiotechnology Hub to Drive Drug Discovery in Space”. https://today.ucsd.edu/story/uc-san-diegos-astrobiotechnology-hub-to-drive-drug-discovery-in-space.