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Cartilage and joints - laboratory replacements

It is becoming increasingly common for localized cartilage defects to be cured with transplants cultivated from the patient’s own cartilage cells. Past successes are accelerating the development of regenerative therapies in orthopaedics.

Every year in Germany, some 400 to 600 autologousi chondrocytei transplantations (ACT) are performed – some of these in the Orthopaedic Clinic at the University Hospital in Tübingen (UKT). Small cartilage samples are taken from the patient, the cartilage cells (chondrocytes) are isolated and cultivated on a biocompatible matrix as new cartilage tissue. Using this cartilage tissue, localized defects, resulting, for example, from traumatic injuries or osteochondrolysis (Osteochondrosis dissecans) can be repaired. The defective cartilage area is removed and replaced by a graft of the same size and shape.

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Cartilage damage to the medial area of the knee joint with osteochondrolysis (left), covering of the defect with a matrix-coupled autologous chondrocyte transplant (chondrocyte transplantation, right) (Photos: UKT)

Proving the regenerative strength of such grafts is a scientific question that researchers at the Orthopaedic Clinic are pursuing under the leadership of medical director Dr. Nikolaus Wülker. Dr. Wilhelm Aicher leads the cell biology research lab for orthopaedics and examines cartilage cells and their progenitor cells. "What interests us above all is how we can produce chondrocytes, which regenerate cartilage from progenitor cells, that can withstand the biomechanical and metabolic peculiarities of the joint," said Aicher. Research into the biomechanical characteristics is extraordinarily important since the graft is subjected to enormous mechanical strain at the site over years and decades.

ACT will be further optimised

The interaction of the cultivated tissue with the support material is being intensely investigated. A special field of Aicher’s group is the isolation and characterisation of signalling and messenger substances from the cell cultures. The scientists are particularly interested in these substances for their importance in anchoring the cells to the matrix. Different matrix materials are tested for their suitability for ACT. "Most polymers are not suited to our purposes because the cells cannot adhere to them. Currently, the most promising are esterified hyaluronic acid and collagen," said Aicher.

Aicher is keen to share his knowledge on ACT with colleagues such as Dr. Kuno Weise of the Casualty Hospital (BG Unfallklinik) Tübingen at advanced training seminars at the Aeskulap Academy in Tuttlingen. Weise is an internationally recognised expert in ACT and co-operates closely with the UKT on both clinical and research levels. In the context of ACT research and development, the NMI Reutlingen and TETEC AG (Reutlingen) are also important partners. They have special laboratories where the chondrocytes can be cultivated according to the quality and safety standards necessary for materials used in treating patients.

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Cut through a collagen fleece before colonisation with chondrocytes

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Cut through a two-layered collagen carrier colonised with chondrocytes, prepared for ACT: left, in the open-porous area, the chondrocytes can be seen as small dark points. On the right the collagen membrane can be seen, which acts as mechanical stabilisation. (Photos: Orthopaedic Clinic, Tübingen)

Biological materials should improve prostheses

Despite rising ACT interventions, prosthetics will remain an important topic for orthopaedists for a long time to come; about 300,000 artificial joints are inserted each year in Germany alone. Regenerative approaches also play a role in this. The Tübingen team wants to improve the body’s acceptance of prostheses with the aid of biological coatings. This is an interesting alternative, particularly for prostheses with porous surfaces that the bone grows into and that are not anchored with bone cement. This affects hip prostheses, for example. "So far, the main area of improvement has been in the surface structures of the prostheses; for example, the pore diameter has been optimised to make it possible for the bone to grow into the microporous surface within days or weeks," explained Wülker, who hopes that the growing in of the prostheses will improve, i.e., speed up, by coating the prostheses with specific proteins.

Since prostheses are usually driven into the bone with a hammer, such a coating must have a high level of tolerance - a genuine challenge for the scientists. The correct amount of protein for the coating must also be determined. Aicher and his team have just begun working on these questions - a three-year research grant has been applied for from the Federal Ministry of Economics and Technology. The researchers are also receiving support from young biotech companies and prosthesis manufacturers participating in this project as industrial partners.

Cultivation of replacement tissue for degenerated intervertebral discs and meniscus

A further regenerative medicine project involves therapy for intervertebral disc degeneration. In a large, state-funded BioProfile project, researchers at the University Hospital and the NMI in Reutlingen want to cultivate intervertebral cartilage cells and test their potential as a therapeutic substitute. This work is not just about cell and tissue biology. "One problem is applying the cultivated cells to the ring of the intervertebral disc. We want to find support material for the cells that can be injected as a liquid and which ideally will solidify to seal the injection site," said Aicher. He is pursuing different approaches aimed at achieving this. One approach is focussing on two-component systems that function similarly to glues. Each component in itself is liquid or viscous. If the components are mixed together, however, the mixture solidifies. This project is in the starting phase of pre-clinical development and is being funded by the BMBF.

Parallel to this, regenerative therapy deals with meniscus damage. "Time and again there are tears in the meniscus that cannot be treated. The long-term consequence of this is arthrosisi," said Wülker explaining the motivation for the study of new treatment possibilities. The basic idea is to cultivate meniscus cells that are colonised on a half-moon shaped support material, which is then sewn onto the knee joint.

Another challenge arising from this project is the mechanical load capacity of the graft. It must withstand pressure and tensile loads, and the surface facing the cartilage must be protected from wear and tear caused by friction. Different biological materials come into play here, such as fleeces, sponges, nets and membranes which are all tested by Aicher and his team. The whole thing is complicated still further by the fact that on the side of the graft facing the periosteum, blood vessels must be able to enter in order to supply the meniscus tissue with nutrients. "We are trying to colonise the cells in such a way that they generate the factors that promote the ingrowing of vessels. Meanwhile, we have a strategy to activate the cells," said Aicher, appearing optimistic. This study is currently being funded by the German organisation Arthrosehilfe, and the researchers are also planning to make these issues part of a BMBF project.

leh - 17.10.2006
© 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
Orthopaedic Clinic

Prof. Dr. Nikolaus Wülker
Medical Director
Prof. Dr. Wilhelm Aicher
Laboratory of Cell Biological Research
Hoppe-Seyler-Straße 3
72076 Tübingen

Tel.: 07071 29-86046
Fax: 07071 29-4091
orthopaedie [at] med [dot] uni-tuebingen [dot] de
www.medizin.uni-tuebingen.de/ortho<