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Innovative 3D bioreactors for higher cell and tissue quality

Two projects from Baden-Württemberg were among the winners of the 12th Medical Technology Innovation Competition organised by the German BMBF. One project consists of a new bioreactor technology developed at the Institute of Anatomy of the Centre for Regenerative Biology and Medicine (ZRM) in Tübingen, which seeks to improve the supply of cells and tissue with nutrients and oxygen by cultivating them in aerosols.

In Germany, around 6,000 to 8,000 people require a cornea substitute in order to regain their sight. However, there are far too few donor corneas available. A reason for the scarcity of suitable corneas is the fact that the quality of around 15 per cent of donor corneas decreases when the tissue is cultivated in bioreactors, thus making them unsuitable for transplantation. Dr. Lothar Just and Dr. Timo Schmidt at the Centre for Regenerative Biology and Medicine at the University of Tübingen have developed a completely new bioreactor technology for the cultivation and growth of tissue. In contrast to other methods, Schmidt and Just’s method involves the supply of nutrients by way of aerosols. The droplets are produced by an ultrasound vaporiser and the researchers believe that aerosol vaporisation is gentler on the tissue and a lot more efficient than traditional methods in supplying the tissue with nutrients and oxygen. The researchers will now use this new technique to improve the quality of cornea transplants by cultivating and quality-assuring them prior to transplantation.

The next step involves the development of a bioreactor for the cultivation of cornea transplants and artificial corneas in cooperation with doctors from the University Eye Hospital in Tübingen, researchers from Hanover and industrial partners from Göttingen and Soest. This will enable the researchers to develop greater numbers of corneas for transplantation.

Promising aerosols

Schematic representing the cultivation of cornea transplants: 1. aerosol and cultivation zone; 2. cornea transplant © ZRM Tübingen

Schmidt and his colleagues have already tested six prototypes, the construction and reconstruction of which is supported by funds from industrial partners. "We work with Sartorius AG, which is one of the largest bioreactor manufacturers in the world. Sartorius supports us in the development of the control unit." Cooperations with worldwide leading companies support the professional development of devices. However, a great deal of development work is still required if the prototypes are to become marketable commodities. Since winning the BMBF's competition, the researchers now have around 400,000 euros available for their investigations and developments. The BMBF funds will be divided among the project partners, including the ZRM, the University Eye Hospital in Tübingen and a research group at the University of Hanover.

Prof. Dr. Thomas Scheper from the Institute of Technical Chemistry at the Leibniz University in Hanover focuses on the modification of the bioreactors. "Our partners in Hanover have access to excellent workshops and outstanding experience in biochemical engineering. They will manufacture the bioreactor based on our construction plans," said Schmidt. In addition, the Hanover researchers will analyse the effects ultrasound vaporisation has on the proteins in the nutrient media. They have already identified the lead proteins for these analyses. "We initially looked at the big proteins that are most likely to be inactivated during the process," said Schmidt. The team from Tübingen is investigating the effects of vaporisation on the cell level by analysing cell vitality and functionality.

It was not possible to simply purchase the ultrasound vaporiser off-the-shelf. Boga Gerätetechnik GmbH adapted their vaporisers to the requirements of the Tübingen team. "The energy influx into the original devices was too high, which is why we had to adjust the input of energy. The researchers and industrial partners need to take great care to adapt voltage, frequency and vaporisation performance to the highest level of stability of the culture medium. This is quite difficult and represents one of the greatest challenges posed by the ultrasound system," explained Schmidt highlighting that his team has already managed to improve the length of time that the media remain stable from two hours to several days, and they will continue to optimise the system further. "We still have a lot of scope. We also want the device to be extremely economical, which means that it must use the smallest quantity of medium possible," said Schmidt.

Immediate objective: stastically evaluable improvements

Donor cornea after transplantation © University Eye Hospital Tübingen

The culture area of the bioreactor will also be improved. A number of quantitative investigations are still missing, but these will now be carried out thanks to the BMBF funds. The next, and rather costly, objective is to manufacture an optimised prototype in which the temperature and O2 and CO2 concentrations can be precisely controlled. Once the project has been positively evaluated, the researchers will be able to apply for follow-up funding in order to develop a marketable product, which might also involve the establishment of a company. Since the technology can in principle be used to cultivate any tissue or cell besides corneas, the team plans to reduce the culture area of the bioreactor and test different pressures.

"Our researchers are currently working principally on the cornea, but the new bioreactor has far greater potential. We believe that the bioreactor can also be used to efficiently transfect and genetically modify tissue. Another possibility is the integration of a camera in order to carry out real-time biological investigations," said Schmidt referring to another of the Tübingen team's projects focusing on the development of a moisture-storing collagen membrane that can be seeded on either side with cells. "Such membranes can then be cultivated along the length in the aerosol of the bioreactor, which will most likely expand the application spectrum of this technology even more," said Schmidt.

Further information:

University of Tübingen
ZRM Centre for Regenerative Biology and Medicine
Institute of Anatomy
PD. Dr. Lothar Just
Dr. Timo Schmidt
Österbergstraße 3
72074 Tübingen
Tel.: +49 (0)7071 29-72176
E-mail: timo.schmidt@regmed.uni-tuebingen.de
E-mail: lothar.just@regmed.uni-tuebingen.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/innovative-3d-bioreactors-for-higher-cell-and-tissue-quality