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How did the use of bioreactors evolve through time

Bioreactors provide a controlled environment for the chosen production organism to achieve optimal growth and product formation. The bioreactor can be thought of as the heart of the bioprocess!

When thinking about bioreactors the first thing that comes to mind is big shiny steel machines. 

However, the beginnings go as far back as ancient times (2000 to 3000 B.C) when a simple clay pot did the job of a bioreactor! Clay pots were used by Greeks and Romans (as well as many other civilizations at that time) to create anaerobic conditions for the fermentation of wine, beer and vinegar.

Figure 1. Ancient clay pots used for the production of wine.

Bioreactor evolved together with the human needs for certain products! For a long time, only anaerobic conditions for producing food products were used in so-called fermentors.  

In the 1900s, they grew living organisms under aerobic conditions and produced metabolites, such as glycerine, citric acid, lactic acid. This is how aerobic bioreactors were born. Achieving aerobic conditions in a bioreactor brought its own challenges, as maintaining adequate aeration and ensuring sufficient mixing meant needing more complex equipment than before. During the first world war, a British scientist named Chain Weizmann developed a fermentor for the production of acetone.

Figure 2. During World War I, a British scientist named Chain Weizmann developed a fermenter for the production of acetone.

As the importance of aseptic conditions was being recognized, Strauch and Schmidt patented a system in 1934 in which the aeration tubes were introduced with water and steam for cleaning and sterilization.

Figure 3. Strauch and Schmidt patented a system in which aeration tubes were introduced with water and steam to clean and sterilize fermenters.

In the 1940s suddenly a large need for antibiotics arose, mainly due to the second world war. The development of the antibiotic industry led to the rapid development of the bioreactor. The focus was mainly on increasing the efficiency and the size of the bioreactor, since having a bigger reactor meant you could produce more product in one run.

In 1944 De Beeze and Liebmann used the first large scale (20 litres) fermentor for the production of yeast. The fermentor consisted of a large cylindrical tank with air introduced at the base via a network of perforated pipes. In later modifications, mechanical impellers were implemented to increase the rate of mixing and to disperse the air bubbles, increasing the aeration efficiency. 

Figure 4. De Beeze and Liebmann using the first large-scale fermenter for yeast production.

At that time, the famous bioreactor equipment international manufacturers were: West German’s Braun Company, American N.B.S, and Japan’s Marubishi Corporation. They contributed a lot to the advancement of bioreactors in the industry.

In the 1950-1960s, a lot of new developments hit the bioreactor market. With the rapid innovation now the world’s first commercial fermentors – single vessel and multi-vessel systems were available. In addition, a 40-litre pilot plant fermentor and a continuous culture apparatus were introduced. Additional equipment, such as autoclaves for vessel sterilization, freeze dryers, and the first tissue culture roller drums, was becoming available as well. 

The second major influence on the importance and development of the bioreactor came in the 1970s when the success of DNA recombination technology marked the era of modern biotechnology. In 1978, researchers at Genentech found a human gene for insulin and put it into a strain of E. coli bacteria. The human insulin-producing bacteria was the first example of successful recombinant DNA engineering. The human insulin hit the market soon after, in 1982,  under the name Humulin.

Aseptic conditions, good aeration and agitation were essential for carefully designed and purpose-built fermentation vessels.

Up until the 1990s, the bioreactors were built and adapted mainly for growing bacterial cultures. That all changed when the use of the bioreactor became more diverse and included culturing of mammalian cells, and later on insect cells and algae as well.

In 2002, researchers, developed a new low-cost method of producing a human rabies vaccine, helping to prevent a disease that kills an estimated 59,000 people annually. The production process, using a 30L bioreactor produced a million doses of the vaccine! This further proved the significance of bioreactors and the change they facilitate in the world.

Currently, we are looking at a new trend, that is shaping the bioreactor future, where disposable bioreactors are becoming more popular due to the ease of use and lower operating and validation costs. 

In addition, bioreactors are becoming more and more advanced, with the implementation of online monitoring tools and automatic sampling devices. With increasing automatization the bioreactor industry is moving more and more towards bioprocessing 4.0. - if you don't know what that is or you'd like to know more about it, we highly advise you to check out our blog post on Bioprocessing 4.0.

A group of people in white lab coats in a room with computers

Description automatically generated with low confidenceFigure 5. Automation of modern bioreactors.


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