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Eric Gottwald: innovative 3D cell culture systems for pharmaceutical testing

Realistic alternatives to animal testing are more in demand than ever, especially in the drug development field. One possible solution is 3D cell cultures that possess the characteristics of the tissue from which they originate. Such systems were already developed at the Karlsruhe Institute of Technology (KIT) many years ago. Due to the huge demand for such systems, Prof. Dr. Eric Gottwald and two of his colleagues founded a company called 300MICRONS GmbH, which develops and markets 3D cell culture systems for different applications. The company will soon be able to produce large quantities of such cell culture systems.

Prof. Dr. Eric Gottwald heads up the 3D Cell Culture group at the Karlsruhe Institute of Technology (KIT) and is also the CEO and co-founder of 300MICRONS GmbH. © 300MICRONS

Prof. Dr. Eric Gottwald started focusing on the development of an artificial liver when he was a post-doc at the Karlsruhe Institute of Technology (KIT). His work was crowned with success: together with some of his colleagues, the biologist developed a system for cultivating liver cells. Back then, such a system was truly unique. "It was a purely academic project in which we created just a handful of items," explains the professor. "However, demand in the pharmaceutical industry for a wide range of cultured cells has risen considerably and stimulated the development of manufacturing techniques for large-scale cell cultivation. Although animal experiments are true 3D systems, the use of animals means that the tests are not actually being done in humans for whom the medicines are being developed. Such tests therefore cannot be readily used to predict human response to drugs. In addition, animal tests are very expensive. However, the pharmaceutical industry urgently needs tests that reliably provide information on new active ingredients. A golden mean is the use of cell cultures that have a tissue-like function through their three-dimensional arrangement, but are much less complex than a whole animal."

Glossary

  • Stem cells are cells from the embryo, fetus or adult that that have the ability to divide for indefinite periods in culture and give rise to specialized cells. In Germany it is illegal to extract the stem cells from embryos.
  • A cell culture is a pool of uniform cells which were isolated from multicellular organisms and are cultivated on an artificial nutrition medium (in vitro) for experimental research.
  • Blood capillaries are very small blood vessels in the periphery of the body, in which mass transfer with the surrounding tissue takes place.
  • Physiology is the study of the biochemical and physical processes in cells, tissues and organs of creatures.
Microscope image of bone marrow stem cells in co-culture with human cells in a microwell array. © 300MICRONS

The basis for 3D test systems was thus established with the KIT's artificial liver around 20 years ago. The developers thought about commercialising the system, but a market study they had commissioned suggested to not set up a company. “The project was therefore put on hold,” says Gottwald. “However, huge progress was made in the 3D cell culture field and the field of stem cells in the following years. We also focused increasingly on stem cells as we were no longer able to carry out our work with our artificial liver: the EU banned the use of porcine hepatocytes for health reasons. Thus, we made a virtue out of necessity and started using our microwell arrays for stem cells as well and developing artificial stem cell niches. At the same time, the demand for 3D systems grew, so we then started to think about cheaper manufacturing processes that would enable us nonetheless to commercialise our technology, despite the earlier recommendation not to spin out a company.

Huge worldwide demand for 3D cell culture systems

Over the following years, the KIT scientists were able to produce culture systems more and more cost-effectively. And so the idea of establishing a company came up again. “The demand for 3D culture systems was there,” says Gottwald. “This is why we made use of a Helmholtz Association of German Research Centres programme in 2013, which helped us develop the business idea and turn our ideas into reality. In 2015, we finally had the necessary confidence to start company establishment, making use of our large support network.” Since then, the company founders Prof. Eric Gottwald, Prof. Stefan Giselbrecht and Prof. Roman Truckenmüller have been the managing directors of 300MICRONS GmbH. Gottwald continues to carry out research at the KIT, while Giselbrecht and Truckenmüller are based at the University of Maastricht.

The microwells are of a size that helps simulate the natural conditions of cell as effectively as possible. © 300MICRONS

The young company develops and produces novel 3D cell culture systems for biological and pharmaceutical research and industry. For this purpose, 300MICRONS has developed a special microthermal technique and the machines required to produce polymer films with extremely thin-walled microwells of the order of magnitude of natural biological structures: for example, the maximum distance between two blood capillaries in a typical animal tissue is no more than 300 μm - hence the company name, 300MICRONS. The cells are arranged on films that serve as a supporting framework. They can be cultivated three-dimensionally such that their organotypic properties are retained over a prolonged period of time. This works for many cells, including stem cells, which need an environment that is as close as possible to the physiological condition in the human body.

Part-time professor and company founder

Gottwald reports that the real motivation for establishing a company was to harvest the fruits of their work that had led to the development of a marketable product. And he adds: “Being able to do this in one’s own company is great fun. It is a whole different world and a fantastic challenge. You get to know completely different people, gain new skills and be much closer to real life. You see the proverbial ivory tower of science through completely different eyes, and realize that it is actually a tower.”

After the establishment of 300MICRONS, Gottwald reduced his research commitments at the KIT: in the morning, he works at the KIT where he heads up the 3D Cell Culture group, and he then spends his afternoons in the company. “This works excellently,” Gottwald says. “And the reason it works so well is thanks to the KIT management who gave us every imaginable kind of support, including allowing Gottwald and his colleagues to work flexible hours. The KIT is always interested in spin-offs as it is considered an excellent start-up incubator, and wants to carry on playing this kind of role in the future.” Gottwald also points out that there have been no problems with patents: “As the patents required for company foundation were filed by the KIT, and the KIT therefore owns the patents, 300MICRONS had to license them. This asset is extremely important for the company and was brought on board through an exclusive licensing agreement, which gives 300MICRONS the necessary freedom to operate.”

The 3D cell cultures can be used in industrial standard formats, for example in microtitre plates used for high-throughput screening. © 300MICRONS

As far as the compatibility between research and teaching is concerned, Gottwald believes that there is a certain conflict of interest: “But this was discussed openly with the KIT from the word go. In fact, the term is not really appropriate, and somewhat unfair, because university start-ups are important and much-needed, but also dependent on science for their future existence. This works quite well, because university start-offs have one foot in the academic world and one in the world of entrepreneurship and, as is the case here, the two are in close vicinity to one another. Companies that permanently depend on cooperation partners find it difficult to survive in the long run.” Gottwald adds: “However, our university teaching benefits from our outside experience, for example, when we give lectures and hands-on seminars using information about brand new developments or when we involve students in our work.”

Large quantities with self-built machines

In the year the company was founded, business volume was deliberately kept low. “We still don't have regular orders,” says the scientist. “But we have not yet started to market our systems. We do not yet have the manufacturing capacity to deal with large orders. If a large pharmaceutical company placed a large order, say about 100,000 items, we would not be able to deliver it.” However from mid-2017, we will be able to deliver these kinds of quantities. The company founders have specifically developed the necessary machines, which will soon be installed in 300MICRONS’ production facility. Then there will be nothing to stop us from professionally marketing 3D systems for a broad range of different applications.

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