According to Florian Wurm, PhD, professor at the Swiss Federal Institute, Lausanne, advances in cell culture media have been responsible for most of the productivity gains in batch-fed mammalian cell culture-based biomanufacturing. With dozens of stock, off-the-shelf basal media to choose from investigators can, through design-of-experiment type investigation, determine which additives and feeds best suit their process.

One could say that industry has this aspect of upstream processing down to a science, if only for monoclonal antibody production. Similar opportunities exist to optimize cell culture media for mammalian cell lines suitable for use in preclinical studies and basic research.

Today’s biotech is slowly breaking out of that paradigm with the introduction of novel vaccines, gene and cell therapies, and other complex “advanced therapies.” 3D cell cultures (spheroids, organoids, organ-chips, etc.) are part of that iconoclasm. Because they are thought to be more “patient-like,” 3D cultures or co-cultures are now standard in some drug discovery assays. Their relevance stems from the incorporation of cell-cell and cell-matrix interactions, which are assumed to be more predictive of in vivo responses.

How does this affect choice of cell culture medium for growing 3D cell cultures? “It is well known that chemical and physical cues can modulate cell differentiation,” says Evelyn Aranda, PhD, senior research scientist at Xylyx Bio. “Every cell type has basal and specific nutrient requirements. Consequently, choosing the right specific cell culture media is essential for cell cultures to survive and grow.”

What about the significance of serum-free and chemically-defined media? Are they as important for 3D cultures as they are for manufacturing processes? “Serum is normally required for cell growth. However, the composition of serum is not consistent, resulting in high levels of variability between experiments,” she adds. “Even though serum-free cell cultures show slower growth rate, working with them in experimental situations can help to standardize cell responses.”

As with early-stage production media, the choice to work with off-the-shelf media or design a unique medium depends on specific needs. “Ready-to-use media are convenient. They save time, have a long shelf life, and their formulations are reliable,” according to Aranda. “Most researchers today start with ready-to-use media and supplement them with specific nutrients if needed.”

The major difference between ordinary 2D or suspension cultures and 3D is the extracellular matrix (ECM), which holds the cells together and confers biological relevance.

“ECM provides structural support and facilitates activation of signaling pathways that modulate adhesion, proliferation, and cell morphology,” Aranda says. “An ideal 3D model would include tissue-specific ECM and cell culture media supplemented with specific nutrients that help sustain proliferation and maintain cell metabolism closer to in vivo conditions. As those models are evolving, more component combinations are needed to better recapitulate in vivo microenvironments.”

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