The beginning
Cell culture was created for the first time during the start of the 20th century. For a long time, it was fairly limited to straightforward small-scale tissue culture propagation techniques used for fundamental research. In parallel, large bioreactors were also in use to produce economically valuable secondary metabolites by using microbial fermentation. By the mid-1950s, huge vaccination campaigns were also implemented, bringing with them the development of industrial-scale cell culture bioreactors. Prior to this, primary cells were cultured for vaccine manufacture on a very small-scale using roller bottles.
Examples of the first cell culture bioreactors, such as plate propagators and packed beds, were made expressly for adherent cells. The first commercially viable suspension cell products – the interferon generated in Namalwa cells and the vaccination for the food-and-mouth disease – spurred the adaptation of homogenous bioreactor systems used for microbial growth, to meet the needs of the mechanically more delicate animal cells.
The development of numerous diverse bioreactors and culture systems suitable for suspension cell culture followed, with a focus on increasing the product yield per unit volume through improved nutrient supply and waste product removal. This was made possible by the emergence of the monoclonal antibody era in the 1970s. These specialized systems include fluidized bed reactors, hollow fiber bioreactors, and other compartmentalized bioreactors based on the perfusion of new media through the cell-containing compartment and the immobilization of cells.
The underlying concept was to create an environment that would enable the cells to continually generate the desired product at high levels while overcoming the two main drawbacks of cell cultivation – slow cell development and low final cell density. Many cell retention technologies for stirred tanks or airlift bioreactors were created concurrently, enabling continuous medium exchange in homogenous systems. In the 1980s, several protein therapies could be produced in mammalian cells thanks to recombinant DNA technology, which is the foundation of contemporary biotechnology. This unique potential also had an influence on the design and refinement of large-scale bioreactors for anchorage-dependent and suspension cells.
Adherent and suspension cell bioreactors
Adherent cell culture technologies such as the fixed-bed bioreactor system offer a large surface area for adherent cell cultivation in a closed and controlled environment. These can be adopted for various applications, and production of extracellular and intracellular viruses and proteins that are grown and produced by the cells attached to a surface.
Suspension bioreactors create a dynamic and controlled culture environment through agitating the fluid with the purpose of keeping the product in suspension. This may be achieved through a few different methods such as mechanical agitation, introduction of gas to keep the liquid turbulent, or by manipulation of the entire vessel.
Bioreactor applications in biotechnology
When considering the applications that use bioreactors, biotechnology is one of the main industries that employ this technology. For example, the growth of cells such as mammalian and insect cells can be performed in mechanically agitated bioreactors with or without microcarriers, rocking platform bioreactors, and rotatory bioreactors. These cells can then be used to produce a range of proteins, like antibodies and enzymes, along with viral vectors without having to remove the cells from the bioreactor. The use of bioreactors is not limited specifically to the biotech industry for therapeutic and medical use. For example, photobioreactors, which utilize a light source and airlift of gassing the solution, are used to culture organisms that use photosynthesis, such as algae and cyanobacteria. These organisms can be further refined into biofuel. Bioreactors, or fermenters, are also used to produce biofuels such as bioethanol from plant products such as corn and sugarcane.
And of course, bioreactors are not limited to biotechnology, we see them used by the food and beverage industry in milk processing and production of yeast and beer.
The future…
Due to the current strong product pipeline for fully human monoclonal antibodies, a bottleneck is predicted for the upcoming decade. To fulfil the projected demand of several kilograms of protein per year, ultra-large-scale bioreactors beyond the 20m2 scale are being suggested. Scaled-down systems are also becoming increasingly crucial to support simultaneous experimental methodologies for cell line and process development. Since the middle of the 1990s, the design of bioreactors for artificial organs and systems for tissue and stem cell cultivation has delved into the existing expertise.