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“To make cultured meat a reality, small-scale proof-of-concept demonstrations must be scaled up to reproducible and economically viable processes.”
Israeli biotech Future Meat just announced the opening of the world’s first cultured meat manufacturing plant. The plant can produce up to 500 kg of cultured meat products per day, equivalent to approximately 5,000 hamburgers. Although the details of their and other cultured meat manufacturers’ processes have not been disclosed, there has been a surge of reports looking at improvements in cell sourcing, tissue scaffolds, cell culture media, and bioprocess design. Here we will briefly look at standard bioprocess designs for cellular agriculture.
To make cultured meat a reality, small-scale proof-of-concept demonstrations must be scaled up to reproducible and economically viable processes. Most early studies and evaluations of cultivated meat used conventional tissue-culture flasks. A recent review article summarized that the bioprocess design of cultured meat must start with the intended final product in mind, whether it is processed or a whole cut of meat. The authors note that it takes approximately 2.9 x 1011 muscle cells to produce 1 kg of meat. Given typical cell densities and cell culture processes, it would take hundreds, if not thousands, of flasks filled with a total of 2,900 L of tissue culture to make just 1 kg of meat. That is not a scalable approach. Thus, using scalable bioreactors is integral to the manufacturing process. Additionally, bioreactors are easy to maintain, highly automated, compatible with necessary process analytics, and can have integrated filtration and media recycling mechanisms to keep manufacturing costs low.
Fortunately, companies are building on many decades of advancements in bioreactor design in the biopharma industry. Stirred-tank bioreactors are used frequently for recombinant protein production because they can culture cells that do not require a scaffold. However, unlike cell lines adapted to grow in suspension, myocyte precursor cells in cultured meat need a scaffold or anchored support. One approach that is being explored is growing these shear-sensitive cells in suspension via aggregates or spheroids. This technique has some commonalities with the burgeoning allogeneic cell therapy market. Aside from potentially using stirred-tank bioreactors, other bioreactors that may be effective in growing skeletal muscle cells are high aspect ratio vessels like rotating wall bioreactors, spinner flasks, and hollow fiber bioreactors, among others.
Recently, a team in Birmingham, UK, demonstrated using spinner flasks for the scalable production of cultivated meat. The group used bovine adipose-derived stem cells and seeded them at different densities (e.g., 1,500, 3,000, and 6,000 cells/cm2) of the microcarrier surface. The lowest seeding density consistently provided the highest cell proliferation, specific growth rate, and the shortest doubling time. They also looked at the role of the cell media feeding strategy, specifically the media exchange protocol. Alpha-modified Eagle’s media (supplemented with glucose and alanyl-glutamine) with 10% (v/v) fetal bovine serum was replaced at a 50-80% exchange rate starting on day 3 of the cultures and every other day thereafter. The 80% media exchange provided the highest number of cells throughout the culture by at least 2.5x compared to the next highest growing culture using a 50% exchange rate, and it improved specific growth rates and doubling times.
Using more mainstream stirred-tank bioreactors, which enable larger volumes and better analytics integration, the same team explored these bioreactors in a subsequent study. Starting the cultures first in spinner flasks (100- and 500-mL volumes), the group intensified the process to 3 L benchtop bioreactors (1 L working volume) via increased surface-area expansion bead-to-bead microcarrier transfer and media exchange processes. Comparing baseline to intensified processes in the bioreactors, there were 3.3x more cells, a 31% higher specific growth rate, and a 24% faster doubling time in the intensified processes. In addition, glucose concentrations in the intensified processes reached deficient levels. In contrast, lactate levels increased dramatically. Both readings suggest that higher culture volumes or more frequent media replacement protocols may keep the cultures healthier. Finally, when calculating the volume of media required to produce one million cells, only 4.9 mL was needed in the intensified bioreactor processes compared to 9.9 mL in the baseline conditions of the same bioreactor. That 50% reduction in media costs could significantly lower manufacturing costs if the costs continue to scale with intensified processes.
A vital component to these two studies was optimizing the scaffolds (e.g., microcarriers), cell media protocols, and analytics of the processes. Parts 3 through 5 of this series will cover these topics as they are critical to the cultured meat industry.
Cell-Based Meat Process Development Series
- Part 1: An Introduction to the Cell-Based Meat Revolution
- Part 2: The Variety of Process Considerations in Cell-Based Meat Production
- Part 3: How Cell Proliferation for Cultured Meat Production Relies on the Appropriate Microcarrier or Scaffold Selection
- Part 4: The Importance of Cell Culture Media Optimization for Cost and Productivity Considerations in Cell-Based Meat Processes
- Part 5: The Role of Analytics in Cell-Based Meat Production
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