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The cardiac surgeons "dream" transplants that grow with their carrier

Prof. Dr. Gerhard Ziemer (Photo: private)

Prof. Dr. Gerhard Ziemer (Photo: private)

Children that have had blood vessel and cardiac valve transplants need to have to undergo further follow-on operations because current transplants are unable to grow along with the children. There is therefore a great deal of expectation resting on tissue engineering; regenerative physicians and cardiac surgeons at the University Hospital in Tübingen hope to develop replacement tissue that is capable of growing along with transplant patients.

The surgical correction of congenital cardiac defects is Prof. Dr. Gerhard Ziemer’s speciality. Prof. Dr. Gerhard Ziemer is the Medical Director of the Department of Thoracic, Cardiac and Vascular Surgery at the University Hospital in Tübingen. Children with cardiac defects require new cardiac valves or new blood vessel connections between the heart and the circulatory system. The heart surgeon has an outstanding international reputation and a great deal of experience in transplanting cardiac valves and blood vessels. Unfortunately, Ziemer and his colleagues are often short of human transplants (homografts).

Although the patient’s own replacement tissue that is able to grow along with the patient can be used, its use is nevertheless limited. "In 1989, we were the first to operate on a newborn baby and transplant an aortic valve using the baby’s own pulmonary valve. The patient is now 17 years old and an enthusiastic drummer. Since the regenerative ability of autologousi transplants strongly depends on the load and stress exerted on the graft, this kind of replacement is not always possible," said Ziemer. In addition, the pulmonary valve needs to be repeatedly replaced over the years. Since cardiac valves in the pulmonary position are exposed to less stress than other cardiac valves, it is also possible to use venous valves from cattle.

Cardiac valve prostheses can be produced from bovine pericardial tissue. The tissue is treated with the quantity of glutaraldehyde necessary to retain the structure of the prosthesis and to prevent it from being rejected.

"Glutaraldehyde interlinks the collagen in the tissue so that the patient’s body will not recognise it as foreign. However, xenotransplants do not grow new tissue. Even if fibroblasts happen to accumulate, this only leads to malformations," said Ziemer.

The shortcomings of the replacement materials are the reason why the researchers are looking for alternatives. Tissue engineering offers excellent prospects, both immediately and in the long term. "Children need grafts that grow along with them and that have a stable matrix that can be overgrown by the patient’s own tissue. The grafts must not calcify nor must they pose any mechanical problems," said Ziemer, summarising the particular demands of children’s surgery.

"Fishing for stem cells"

Dr. Hans-Peter Wendel (Photo: private)

Dr. Hans-Peter Wendel (Photo: private)

More than ten scientists and doctoral students are investigating the development of possible substitutes in the hospital’s own research laboratory headed up by Dr. Hans-Peter Wendel. "The first step on the road to transplants that grow along with the patient are self-colonising transplants," said Wendel, who has already achieved excellent results in this field.

Wendel’s team uses commercially available vascular prostheses that are modified so that endothelial cells start to colonise them after transplantation. "The vascular prostheses are equipped with capture molecules that are able to specifically recognise and bind endothelial stem cells contained in the circulating blood," said Wendel. Based on these stem cells, an endothelial layer that coats the entire prosthesis will develop and it will take over all the functions of natural endotheliumi. The research is so promising that the project is now funded in the BMBF’s BioProfile programme.

The clinicians are supported by the company Jotec GmbH, based in Hechingen. Wendel is working on the development of a special version of this method for cardiac valves. He hopes to be able to recolonise acellularised xenotransplants with the patient’s own endothelial cells – this is a way of virtually reanimating the cells. Wendel eventually hopes to be able to develop a transplant that grows as the patient grows. Self-colonising vascular prostheses have an excellent chance of being ready for clinical application within the next two to three years.

Model system for vascular prostheses

Researchers at the University of Tübingen have developed outstanding skills in the field of vascular grafts and coatings. "We have become a centre of reference in Europe. Industrial companies contact us to have their new biochemical coatings tested in our laboratories," said Ziemer. Wendel and his team have a variety of test models that can be used to test the compatibility of the vascular prostheses, which must affect the clotting process at the same time as not leading to inflammations. The researchers are not only investigating vascular implants but are also working on medical devices such as oxygenators of heart-lung machines that are used for the extracorporeal enrichment of blood with oxygen.

Intelligent repair material

tem cells after their injection into the myocard (Picture: Prof. Ziemer, University of Tübingen)

tem cells after their injection into the myocard (Picture: Prof. Ziemer, University of Tübingen)

Regenerative therapies also have great future potential in the treatment of cardiac infarction. Some hospitals are using stem cells that are injected into the infarcted area in order to stimulate the regeneration of heart tissue. However, Wendel identifies several problems associated with this type of treatment. "Although the results seem very promising, we still do not know enough about the potential consequences. In addition, we need to learn a lot more about such types of therapies," said Wendel. Ziemer and Wendel are pursuing a different path and place their hopes on peri-operative methods.

Thrombocyte attached to an implant (Photo: Prof. Ziemer, University of Tübingen)

Thrombocyte attached to an implant (Photo: Prof. Ziemer, University of Tübingen)

In peri-operative methods, certain stem cells are isolated from the blood that is removed during the operation. Highly specific capture molecules, such as those used for self-cultivating vascular prostheses, are used to isolate the stem cells. The selected stem cells are re-injected into the "patient" during the same operation. This method works very well in the animal model. "Even if we only inject the stem cells into a coronary artery, we still observe that the cells will dock to the heart tissue," said Wendel. If the researchers are able to confirm these results and transfer them to humans, then they will have reached an important milestone in developing new treatment methods. However, several years of research will be necessary before it is possible to apply the method in clinical applications.

Wendel even dares to look far into the future. He hopes that in about eight to ten years’ time he will be able to develop constructs, pharmacological substances for example, that will be able to induce certain stem cells in the body to attach to a specific type of tissue. It is important that these constructs are able to recognise two specific targets, the stem cell and the target tissue. A lot more research will be necessary and we won’t be doing any pure in vitroi research in this field in the near future," said Wendel who is nevertheless optimistic that such concepts will some day expand the therapies available.

leh - 20.08.06
© 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
Hospital of Thoracic, Cardiac and Vascular Surgery

Prof. Dr. Dr. h.c. Gerhard Ziemer
Medical Director)
Phone: +49 (0)7071 29-86638
gdziemer [at] med [dot] uni-tuebingen [dot] de

Dr. Hans Peter Wendel
(Head of research laboratory)
Phone: +49 (0)7071 29-86605
hp [dot] wendel [at] uni-tuebingen [dot] de

Hoppe-Seyler-Straße 3
72076 Tübingen
Fax: +49 (0)7071 29-4047