Blood vessels of a piece of pig’s intestine are used as carrier material for the IGB’s liver model and the cells seeded on the blood vessels stem from human biopsies. Dr. Johanna Schanz from the Fraunhofer IGB used this combination to produce her doctoral thesis which led to impressive results: a functional system of blood vessels in a biological carrier structure. Schanz’s outstanding thesis results have led to the creation of a liver model for testing drugs that can replace animal experiments. In 2009, the liver model was awarded two research prizes.
"A human being is not a 70 or 80 kg rat." Speaking at Biotechnica 2009, Dr. Johanna Schanz highlighted the advantages of alternative drug testing systems. Apart from ethical concerns related to the use of experimental animals, doubts can sometimes arise when transferring findings from animals to the situation in humans, said the researcher. Since the human metabolism is different from that of rats, many side effects only become clear in clinical studies involving human subjects.
"Alternative artificial test systems often fail due to the complexity of human tissue, in particular due to the complexity of the liver that can only be copied with extreme difficulty. "The liver is one of the metabolic giants of the human body," said Schanz, who goes on to underline that metabolic enzymes often pose a huge problem. It is still impossible to artificially maintain the enzymes' interactions, variety and multifunctionality. Sustaining the supply of nutrients in a blood vessel system is hugely problematic in cultivated tissue and effective vascularisation has only partially been achieved in tissue engineering. Vascularisation was the starting point for Schanz and her boss, Prof. Dr. Heike Walles, at the Stuttgart-based Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB).
Schanz and Walles have been working together successfully for many years. Schanz studied biology at the University of Hanover where she met Walles, her future supervisor, and started working with her on the development of cell systems. When Prof. Walles (known then by the name of Mertsching) decided to move to Stuttgart at the end of 2004, Schanz followed her supervisor and began her doctoral thesis in 2005 in the IGB’s Department of Cell Systems. “It was then that we started our preliminary work on the vascularised liver test system,” said Schanz who had completed her doctoral thesis by December 2007, taking less than three years for the experiments and analyses. In addition to receiving her doctoral degree, Schanz had also made a considerable contribution to advancing and further developing the seeding of cells on organic matrices.
The liver model is a product of state-of-the-art biotechnology: it combines state-of-the-art cell culture and process engineering techniques with tissue engineering. The concept behind the model was that if it is impossible to produce the complex system that is the liver, then the next best thing is to use biological structures. The IGB team uses blood vessels from a pig's intestines. "The long small intestines of pigs provide sufficient material and connection points. In addition, they are easy to prepare. Following the removal of all the pig cells, the blood vessels are preserved, and, as they are easily visible to the naked eye, they can easily be manipulated with Braun's cannules," said Schanz highlighting the practical advantages of using a piece of pig's intestine.
Schanz can prepare up to eight segments from one single pig's intestine. "We prefer to use the sections that are close to the stomach, as this is where vessel density is the highest." The intestine pieces are washed to remove the pig cells. "The intestinal tube is rinsed with tenside and salt solutions. This procedure leaves us with pure connective tissue structures that consist mainly of collagen," said Schanz explaining that human endothelial cells and hepatocytes are seeded onto the structure, which is then put into a computer-controlled bioreactor with a flexible tube pump that enables the nutrient solution to be fed in and carried away just like in veins and arteries in humans.
In the reactor, the hepatocytes work in a similar way to those in the human body. They break down and convert drug components. The human endothelial cells cover the porcine blood vessels, just as in the human body, they give off nutrients to the hepatocytes and remove degradation products. The flow of the blood through the computer-controlled reactor is maintained by a tube pump. Schanz has made good progress with the model and the cells remain active for up to three weeks. However, the potential is still not fully exploited.
Dr. Schanz has since become deputy head of the Department of Cell Systems and is concentrating all her efforts on developing the model further and optimising it for a range of different issues. In principle, the model can be used for multiple applications, and Schanz's objective is to optimise it for use in long-term studies. Up until recently, the liver reactor project was exclusively funded by the Fraunhofer IGB. However, the project has since attracted the attention of the pharmaceutical industry. "Novartis has been interested in the liver model for quite some time and is now providing financial support for the project," said the scientist, delighted with this development. Novartis is paying the costs of a doctoral student. "The company sees it as an investment in the development of new technologies; one of the long-term goals is to use the liver model for toxicity tests," said Schanz.
The attention of the pharmaceutical industry was attracted in large part by the two prizes that were awarded to the liver model in 2009. In June 2009, Walles and Schanz were awarded the Fraunhofer Society “Technik für den Menschen” (Technology for People) Prize with a purse of 10,000 euros. In October 2009, Schanz was awarded the German government’s “Research Prize for Alternatives to Animal Experiments” with a purse of 15,000 euros. Schanz received the prize from State Secretary Gerd Lindemann at a symposium organised by the Central Clearing Office for the Registration and Assessment of Replacement and Supplementary Methods for Animal Experiments (ZEBET).Rather than spending the prize money on a new car or something similar, the frugal Schanz chose to invest it in a bank savings account. “I have never been able to save any money before, and I see the prize money as my financial foundations, particularly with regard to retirement arrangements,” said Schanz who used part of the money to buy the best sewing machine on the market – a Pfaff with embroidery unit. I have always dreamt of owning a machine like this and it has been very useful for making Christmas presents,” said the amateur dressmaker.
Further information:Fraunhofer Institute for Interfacial Engineering and Biotechnology IGBDr. Johanna SchanzNobelstraße 1270569 StuttgartTel.: +49 (0)711 970-4073Fax: +49 (0)711 970-4200E-Mail: johanna.schanz[at]igb.fraunhofer.de