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Tissue engineering in urology

A patient's own cells are the raw material for the cultivation of transplant tissue. Urologists at the University Hospital of Tübingen (UKT) want to use them to treat urethral defects.

Diseases of the urogenital tract cannot always be treated satisfactorily with medicines or surgical interventions. A narrowing or malformation of the urethra, a torn urethra or a failure of the urethral sphincter due to age are all indications leading the Tübingen physicians in a different direction. In the hospital's own Laboratory for Tissue Engineeringi, they are developing and optimising procedures for cultivating autologousi transplant tissue. They hope that this will lead to sustainable healing success.

Prof. Dr. Arnulf Stenzl (Photo: private)

Prof. Dr. Arnulf Stenzl (Photo: private)

Dr. Karl-Dietrich Sievert (Photo: private)

Dr. Karl-Dietrich Sievert (Photo: private)


The cells for laboratory cultivation do not always come from the same tissue where the transplant will occur. For therapy on the urethral narrowing, for example, transplant tissue cultivated from cells in the rinsing fluid of the patient’s urine is used. The advantage is obvious: this does not require the removal of cells from the patient's body.

The Tübingen team led by the medical director of the Hospital of Urology, Dr. Arnulf Stenzl, is also working on producing replacement urethras, with urothelial cells forming the raw material.

Urethra reconstruction without support material

Initially, biocompatible and biodegradable support materials were used to reconstruct urethras both in Tübingen as well as in other laboratories. Urothelial cells were sown and cultivated on the matrices so that a single-layered implant could grow. Although this method works in principle, the result is not good enough for the Tübingen urologists. "Even if we are relatively close to an organ, we still have the problem that a single-layered urothelium like this leads to scar formation. Among other things, this is due to direct contact with urine; we know from clinical experience that this promotes scar formation," explained Dr. Karl-Dietrich Sievert, managing head physician at the Hospital of Urology.

Sievert and his colleagues have therefore decided to go for multi-layered urothelia. The research on it is in full swing and the results are extremely promising. By modifying the cell culture medium, the Tübingen team has succeeded in cultivating a multi-layered replacement tissue from a single-layered urothelial cell culture, which can be used as a graft without a support matrix. "In fact we obtain a kind of urothelium fleece, a three- to seven-layered, expanded epitheliumi, which we can apply directly," said Sievert who is counting on the fact that the procedure can be clinically tested in approximately one and a half to two years. At the moment, in-vivo assays are being conducted using a pig as the animal model.

Regenerating muscle function with stem and progenitor cells

A current, still purely scientific, project of the group around Stenzl is looking into the use of autologous mesenchymal stem cells. The researchers hope to use these to be able to repair a dysfunction of the urethral sphincter. If the sphincter no longer works correctly due to age, it can lead to incontinence with all the associated physical and psychological problems.

To regenerate muscle function, stem cells must first be made to differentiate into cells of the striated musculature. Progenitor cells are already being used experimentally for myoblasts (muscle generation cells), which are injected directly into the sphincter. Here the Tübingen group takes various approaches. Cell populations are used that either produce their own growth factors or growth factors are brought in from outside. The goal is to preserve well integrating muscle cells that can be used to repair urethral sphincter function.

In vitro cultivated urothelial replacement tissue (Figure: Maurer S. et al., 2005)

In vitro cultivated urothelial replacement tissue (Figure: Maurer S. et al., 2005)

The biggest hurdle with all these regenerative medicine projects is the need to work according to GMP conditions. As Stenzl explains, "The constraints imposed by the authorities are enormous and we are happy to have a partner in TETEC, a firm based in Reutlingen, that has the corresponding laboratories and experts." Among other things, animal-free cell and tissue cultures are being worked on jointly.

In cell biology, foetal calf serum has generally been used as culture medium. For Stenzl and his team, however, that is out of question. "To be allowed to use cultures for therapy in humans, we must work with animal-free products and therefore find substitutes. We are concentrating right now on the development of synthetic media. The TETEC team already has a lot of experience with serum-free cultures for cultivating chondroblasts and is supporting us in this endeavour." The researchers could theoretically also use patient blood as a medium, but the cells grown in this way are not optimum and there would quickly be a problem of quantity as 100 milliliters needs to be taken from the patient several times over.

New sources for stem cells

Monolayer of urothelial cells prior (on the left) and a few days after (on the right) the onset of stratification (Figure: Maurer S. et al., 2005)

Monolayer of urothelial cells prior (on the left) and a few days after (on the right) the onset of stratification (Figure: Maurer S. et al., 2005)

Cooperation also looms large in-house: Stenzl recently tapped a new source for stem cells together with four other partners at the UKT. The group is isolating stem cells from testicular biopsiesand wants to characterise, cultivate and differentiate them within the scope of the joint project. "We foresee great potential in these cells and are approaching the possibilities of embryonic stem cells without being confronted by all the ethical issues," said Stenzl. Sievert added, "The possible applications go far beyond the urothelium. We are examining any differentiationi and can imagine that in the long term the corresponding cells will be used in infertility treatment and in oncological therapies."

leh - 20.10.2006
© BIOPRO Baden-Württemberg GmbH, first published at www.bio-pro.de<, the Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

Further information:

University Hospital of Tübingen
Clinic for Urology

Prof. Dr. Arnulf Stenzl
(Medical Director)
PD Dr. Karl-Dietrich Sievert
(Assistant Medical Director)
Hoppe-Seyler-Str. 3
72076 Tübingen

Phone: +49 (0)7071 29-86613
Fax: +49 (0)7071 29-5092
urologie [at] med [dot] uni-tuebingen [dot] de
www.uro-tuebingen.de<