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How to optimize your cell culture media for cultivated meat

Cell culture media is used to sustain cellular growth ex vivo. Without it, growing cells in an artificial environment would not be possible, which makes it arguably the most critical factor in cell cultivation.

Although its a mainstay in scientific research and industrial bioprocessing, significant opportunities remain to optimize its use for the alternative protein industry.

Developing industry-standard cell culture media will greatly support manufacturers to reduce costs, increase viable yields, and achieve price parity.

In this week’s article, we’ll discuss the fundamentals of cell culture media, an overview of prevalent ingredients and preparation types, and actionable steps on how to develop industry-standard optimized media that works well across several cell types and species.

The fundamentals of cell culture media

To optimize your media, it’s important to understand the basics, including its usage, the essential components, and the different preparation types.

What is cell culture media?

Cell culture media is the gel or liquid that supplies the necessary nutrients and environment (e.g. pH and osmolality) to support the growth and function of ex vivo cell cultures, including those used as biomass for 3D printed steak and other cultivated products.

Different cell types often require distinct growing environments, which is important to consider when designing your cell culture media.

Common cell culture media ingredients

Cell culture media has evolved significantly following the invention of Ringer’s Solution in 1882 (the first documented instance of ex vivo cell culturing). Since then, media has been continuously tweaked and optimized using a trial and error approach, with additions such as chemical-based synthetic ingredients, sera, and other naturally-derived products.

Varying the components helps to promote the cell survival, proliferation, and cellular function of different cell types and species. However, despite the diverse formulations, the essential components of cell culture media remain relatively constant:

  1. Amino acids
  2. Buffering systems
  3. A carbon-based energy source (e.g. glucose, mannose, etc.)
  4. Inorganic salts
  5. Serum (or its essential components, including growth factors, hormones, lipids, proteins, and trace elements)
  6. Vitamins and minerals
  7. Treated water

Types of cell culture media preparation

It is possible to purchase working media solutions in pre-made liquid form. Manufacturers then have the option to add further ingredients to tailor the media toward a chosen species or cell type. However, while pre-made media may be easier to use, they are more difficult to transport and store in large quantities and tend to be more expensive.

You may wish to add your own components to the pre-made media used in animal cell culture

Powdered or concentrated media preparations are cheaper and generally have a longer shelf-life. They can also offer greater control of the components and efficient development of optimized media, although they must be prepared on-site; sterilizing and preparing media for cell culture can be complex and time-consuming.

How to develop an industry-standard optimized media

Developing an industry-standard media which can be tailored according to different cell lines and stages of cell line growth is a crucial step to achieving mass-market penetration.

This can be accomplished through the trial and error approach mentioned earlier; monitoring changes after adding individual components and analyzing the results will yield custom formulations for each stage.

1. Start with a basal medium (optional)

It’s typical of biopharmaceutical companies to begin with an established basal medium and to add their own components, according to cell line needs. Alternative protein manufacturers may wish to follow this example and start by using a common mammalian media formula, such as Dulbecco’s Modified Eagle Medium (DMEM).

2. Seek serum-free media for cell culture

Animal sera, particularly fetal bovine serum (FBS), are commonly used in cell culture media. The natural cocktail of ingredients is able to emulate a proliferative environment (e.g. growth factors, proteins, hormones, lipids, vitamins, etc.)

Despite its widespread usage, FBS is expensive, has never been fully characterized, and has a number of documented issues. For example, while serum is a byproduct of the meat processing industry, there is a limited supply. Competition from a number of well-established and prosperous industries, as well as a surge in cell therapies and stem cell research, has meant that the current demand for stem cell culture media and other FBS formulations exceeds availability.

Moreover, FBS is prone to viral and bacterial contamination and exhibits immense variability, which is hardly conducive to an industry-standard optimized media. It also harbors ethical and environmental concerns since the use of fetal calves opposes the whole concept of cultivated meat.

While there is still a way to go before a viable serum-free media for cell cultures is established, there are already a number of promising FBS alternatives actively employed in stem cell culture and cultivated meat production, human platelet lysates (HPL) being one prime example.

Replacing FBS with HPL allows for optimization and potential food-grade production of animal cells by eliminating the transmission of bovine prions and other xenogeneic risks

3. Source food-grade, non-animal ingredients

Discovery platforms and databases powered by machine learning (e.g. Flourish) are valuable in the search for molecularly-identical plant compounds to replace serum and provide food-grade media components.

Peptides, peptones, small molecules, and less-refined hydrolysates from various edible plants (e.g. garlic, onion, soybeans, chickpeas) can potentially provide flavor and/or antimicrobial components, while also promoting robust growth and/or differentiation of the cells.

If sourcing from upcycled or recycled streams, these ingredients must be determined safe (pathogen and chemical-residue-free) by target market regulatory authorities.

4. Pursue high-yielding media at reduced costs

When designing their industry-standard optimized media process, manufacturers may wish to consider different host cells to increase the yield of microbial proteins dedicated to cell culture media. For example, Vibrio natriegens grows rapidly and is less contaminant-prone than its conventional alternatives. In this case, GRAS certification or safety screening is necessary.

Another option would be to pursue plant molecular farming, which has been shown to produce large amounts of bioactive, recombinant growth factors.

Plant molecular farming shows potential as a cost-effective and low-resource alternative to producing recombinant growth factors for cell growth medium.

You may also wish to consider pairing with a bioreactor company to investigate the ideal parameters on your behalf, which can also offer cost-reduction benefits.

5. Explore promising media standardization technologies

The most useful technology for media optimization is high throughput screening of cell cultures, which should include image analysis (potentially automated) to assess cell phenotype and viability.

Automation monitoring, amino acid consumption testing, and other metabolomic methodologies may also be worth exploring.

Future opportunities for cell culture media

The optimization of different types of animal cell culture media is an ongoing journey but its importance for cell cultivation technologies can not be understated.

Unique opportunities lie in serum-free formulation, particularly in the search for types, concentrations, and combinations of the various growth factors and small molecules required for the differentiation of different cell types.

Moreover, progressive technology, such as machine learning and high-throughput screening, continues to enhance the efficiency of media optimization.

Still unsure?

We can help you achieve clarity regarding the entire supply chain of cultivated meat, including specific support in designing your cell culture media. Get in touch with Bright Green Partners today.

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