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Bone substitutes from the laboratory for use in oral and maxillofacial surgery

Dr. Dorothea Alexander is the head of the bone tissue culture laboratory. (Photo: private)

Dr. Dorothea Alexander is the head of the bone tissue culture laboratory. (Photo: private)

"Geriatric jaws" will soon be a thing of the past thanks to modern regenerative medicine. Doctors and scientists at the University of Tübingen are working hard to develop functional bone tissue that can also be used for the treatment of larger wounds.

Tissues such as bone and cartilage are used by oraland maxillofacial surgeons every day. The majority of problems involve the jaw. Malformed or underdeveloped jaw-bones, serious injuries or tumours that lead to the destruction of bones are the most common jaw problems the oral and maxillofacial surgeons have to deal with. In addition, there are atrophies, i.e., the wasting away of the jaw, which are often caused by loss of teeth. All these cases would benefit greatly from the possibility of using laboratory-cultivated functional bone tissue.

An adequate replacement might prevent the further degenerationof the jaw-bone. "We now know that bone function depends on the metabolism. Force transmissions stimulate the metabolism, which in turn prevents the degeneration of bone," said Prof. Dr. Dr. Siegmar Reinert, Medical Director of the Centre of Dentistry, Oral Medicine and Maxillofacial Surgery at the University Hospital in Tübingen (UKT) explaining that mechanical strain prevents the degeneration of bones."

Nowadays, relatively small bone defects can easily be treated with cultivated bone tissue. Three years ago, a technique was established at the University Hospital in Tübingen that allowed the replacement of small parts of the jaw-bone with tissue that was cultivated in the laboratory. "The filling of defects occurring in partially-atrophied jaws was the first use for which cultivated tissue was commercially available. We have been very pleased with this type of grafts," said Reinert.

Tissue-engineered grafts can only be used for small bone defects

Reinert’s team uses a cell-/matrix product produced by a company called BioTissue, the cells of which are produced from the patient’s own cells. The original cells are removed from the periosteum of the patient’s jaws. The cultured cells, in combination with biocompatible carrier material (scaffold), are then grafted onto the patient’s jaw.

The great advantage of this new method is that it does not require the removal of bone cells from other parts of the body for transplantation into the degenerated jaw section. Usually, bone is removed from the iliac crest or from the chin. There is always an element of risk associated with such interventions – usually not through the loss of material but rather as a consequence of the intervention itself.

However, there are some disadvantages associated with the regenerative method. The grafts cannot be strained mechanically to an extent that would be necessary to treat severe atrophies. The jaw-bone of some patients is no thicker than about two millimetres. In such patients, it is not possible to graft the jaw with an amount of cultivated replacement tissue so that it is thick enough to anchor tooth implants.

Replacement tissue needs blood vessels

The problem being that blood vessels need to run through the entire tissue graft. However, it is still impossible to reliably supply cultivated bone tissue with blood vessels. Therefore in larger bone grafts, only the outer cell layers are supplied with essential nutrients; the central layers usually do not receive the nutrients they need. Therefore, the transplantation of large bone grafts is currently not a viable option as the tissue graft will gradually be absorbed by the body.

Reinert’s team are working on the more effective vascularisation of larger pieces of replacement tissue. The researchers are experimenting with growth factors: "It is one of our major aims to increase the size of material that can be transplanted. In the long-term, we hope to be able to transplant entire jaw sections," said Reinert, suggesting that this will require specifically shaped grafts. Jaw augmentations made from cultivated tissue must be given the appropriate shape through scaffolds. "We are looking for moulds that can be vascularised," said the hospital director.

The right interaction is absolutely necessary

Dr. Dorothea Alexander, who is the head of the bone tissue culture laboratory in Reinert’s clinic, is looking for a suitable absorbable scaffold material. "We are testing numerous carrier materials for their influence on the proliferationand differentiationi of periosteum cells into bone tissue. A stable but flexible 3D structure would be best," said Alexander. The scaffolds must be able to resist the mechanical strain in the jaw area. The team is currently testing three types of materials, including collagen, polylactide and calcium phosphate.

Calcium phosphate scaffolds

Calcium phosphate scaffolds

Reinert’s team is also looking at the shape, hardness and pore size that would guarantee a stable structure. "As far as surgery is concerned, many types of materials can be used; however, we need a force-bearing material for anchoring the implant into the bone," said Reinert. Titanium is the material of choice for this purpose; it is biocompatible and the bone easily grows up to the titanium surface.

Assessing the stem cell potential of periosteum cells

Alexander is also working on improving the conditions for cell and tissue culture. To achieve this, she is analysing periosteum cells and their potential to differentiate. "Periosteum cells are similar to mesenchymal stem cells. However, some details about the cells are still unknown," said the biologist. It is Alexander’s major aim to find out which genes or gene products play a key role in the chronological order of the steps involved in the differentiation process. In future, particular focus will be put on important growth and differentiation factors. "The more we know about the osteogenic differentiation process of periosteum cells, the more we will be able to use this knowledge for the production of suitable bone implants," said Alexander.

She also wants to find out why the periosteum cells of some patients won’t differentiate into bone cells in vitroi. "In some cultures, calcification does not occur even after 20 days," said Alexander, who hopes to gain a better understanding of this problem by comparing the expressioni profiles of the genes involved in the differentiation from periosteum to bone cells at different points in time. "Some of the genes involved in the calcification process are already known; however, many further investigations are necessary," said Alexander.

At the moment, Alexander is concentrating on the effect of different BMPs (bone morphogenetic proteins) on the differentiation of periosteum cells. She assumes that, although these proteins play a central role, there are still many other factors that affect the differentiation process in some way or other.

leh - 18.12.06
© 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 Tübingen
Centre of Dentistry, Oral Medicine and Maxillofacial Surgery

Prof. Dr. Dr. Siegmar Reinert (Medical Director)
siegmar [dot] reinert [at] med [dot] uni-tuebingen [dot] de
Dr. Dorothea Alexander (Head of laboratory)
dorothea [dot] alexander [at] med [dot] uni-tuebingen [dot] de
Osiandersstr. 2-8
72076 Tübingen

Phone: +49 (0)7071 29-86174
Fax: +49 (0)7071 29-3481