Authors: Dr. Boštjan Vihar and Luka Banović
Collaboration between research and technology providers is the new norm for rapid multi-disciplinary innovation, which IRNAS is actively working on. Following these principles, New Harvest, a research institute dedicated to accelerating the pace of innovation in cellular agriculture, and IRNAS, a custom technology provider, have formed a partnership in 2018 in order to co-develop a modular bioreactor system. A news article about the idea and project development was published by Massive Science, as well as in one of our recent blog posts.
Successful partnerships are based on short feedback loop cycles between researchers and engineers making systems under development as useful as possible, as fast as possible. Simultaneously, we are exploring new workflows and conditions for effective engineering of larger tissue constructs. With the prototype just entering the first round of biocompatibility testing, the value of the technological-scientific partnership is already paying its dividends. With infrastructure available at IRNAS new adaptations are made on a weekly basis and immediately tested just down the road in a lab. We are excited to keep you posted about our progress!
* Dr. Ivana Gadjanski – Assistant director for science at BioSense – Development of sensors for bioreactors
* Dr. Jan Saam – CEO at OSPIN GmbH – Modular Bioreactor Design
* Scott Allan – Research Fellow and PhD student – Ellis Lab, University of Bath
* Luka Banović – Engineering Project Manager at IRNAS – Applied Custom Hardware Development
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The perks of bioprocessing
While the bioprocess of cell culture proteins will likely vary, depending on the desired end product, production of whole cuts of cultured meat is expected to require at least two main stages:
- cell multiplication – in which the total number of muscle cells is increased and
- tissue maturation – where the cells fuse together and form a structured and tissue
At least for cell multiplication, the process design can draw heavily from insights of the pharmaceutical, dairy and other biotechnological industries. There the technology is already adapted for a wide range of production scales. For tissue maturation, where perfusion bioreactors come into play, the current development stage is not entirely clear. In the academic world, the set-ups are suitable for small, laboratory-scale experiments with small tissue sizes (in the millimetre range). Scaling up from there is not as simple as just multiplying the same process to the desired volume.
Culture of animal cells has been around for decades, however, until recently it was all limited to cellular monolayers on flat plastic or glass surfaces. This way full complexity of spatial interaction, morphology and function of the native environment are hard to recapitulate. Having said that, cell monolayers are great for experimentation. They provide sharp images under the microscope and since all cells are exposed to very similar conditions, evaluation of morphology, metabolic activity, and other parameters produces highly reproducible results.
Shifting cell culture into the third dimension vastly increases not only the complexity of cell behaviour and interaction, but also the ways to study emerging phenomena as well as the total number of experiments.
The introduction of perfusion into the culture opens many new questions that need to be addressed before optimisation of growth and development conditions can even be attempted. How does the created shear stress impact the cells? How are things like attachment to the surface, division, mobility influenced? It is important to explore the impact of the higher concentration gradients of nutrients, the continuous removal of signalling molecules and waste products. And finally, how many times can the same batch of medium be cycled if at all? How fast is the ideal flow rate? Is it continuous, pulsed or follows another function? The shape and size of culturing containers will vary with scaffold geometry, direction and rate of perfusion. Depending on the utilisation of the culturing medium it’s recycling, replenishment and complexity of monitoring could also change. Perhaps medium composition and uptake can be optimised to a degree where recycling is not necessary at all (E.g. the way a bird’s egg can provide complete and waste-free nutrition for the embryo).
A bit about the future
There is an infinite number of questions to be answered. For that, we need to design the studies and think about how can we get to the answers we need and what kind of equipment is necessary. A lot will depend on the type and size of samples to study. Undoubtedly, things will change on all levels as we go along the process, as well as when we attempt to scale things up.
The one clear thing at the moment is that the science, engineering and ultimately production of cultured meat and cellular agriculture, in general, are going to change significantly in the coming years. The only way this high level of complexity can be tackled is through coevolution of research and technology.
To spark up some constructive debate on this topic we have invited some of the most experienced people from the field to join us in a webinar session. We would like to invite you to join us in further exploration of custom technology for bioprocessing.