Who knows: Maybe we can do without implants in the future? Researchers at the TU Berlin are currently working on the development of third generation teeth. The team led by Dr. Roland Lauster, Professor of Medical Biotechnology, has successfully demonstrated in all in vitro tests that teeth are able to grow back using the body’s own material. Sometimes this happens – not just in sharks and crocodiles – but spontaneously on its own:

“Although there are occasional reports that people also grow back teeth for the third time or even entire sets of teeth, why this happens in some people and not in others is still largely unknown”…

…, Dr. Roland Lauster, Professor of Medical Biotechnology at the TU Berlin, outlines the phenomenon. Following the in vitro successes of recent years, the Berlin scientist’s research project is now set to enter the preclinical phase.

Because one thing is clear: if a tooth is lost, it should not just be replaced for cosmetic reasons. A tooth cavity may cause a number of health problems – from a lack of masticatory function to craniomandibular dysfunction (CMD), i.e. tension in the head and neck area.

Information on growth is available

Dr. Jennifer Rosowski ©TU Berlin/PR/Tobias Rosenberg

“Basically, science assumes that the human jaw also contains all the information necessary for the growth of new teeth over the course of a lifetime”…

…, says Dr. Jennifer Rosowski, research assistant to Roland Lauster, who has dedicated her doctoral thesis to the topic of regenerative teeth. The question is what triggers this process.

It is important to realize that hair, teeth or even nails develop as a result of so-called ‘mesenchymal condensation’. In the case of tooth growth, certain precursor cells accumulate in the jaw beneath the outer skin layer. These cells condense and form a kind of tooth nucleus. As a result of this condensation, they begin to interact with the surrounding cell layers in the jaw via specific impulses.

“Within the tooth bud that is formed in this way, various cell types are differentiated: the enamel organ, the tooth papilla and the dental ridge. These tissues gradually develop into a “complete tooth”…

…, describes Dr. Rosowski. The information as to which tooth should be formed – incisor or molar – comes from the surrounding jaw tissue.

Cultivation of pulpa cells

The researchers at TU Berlin now want to extract the natural third set of teeth from the inside of an extracted tooth. This means that their plan is to cultivate and process so-called dental pulpa cells in such a way that they form an active tooth nucleus. And when this dental nucleus is implanted in a patient, the idea is that it begins to communicate with the surrounding tissue. In doing so, it should send out a whole series of impulses that initiate tooth formation. We asked:

Dr. Roskowski: How long does this process take?

“After the cells have been removed, these 3-4 weeks are increased in the laboratory until the required amount of cells is produced, subsequently they are cultivated three-dimensionally for 24 hours and then implanted. The inserted tooth nucleus is very small (approx. 0.5 cm in diameter) and is able to be inserted with minimal invasiveness. We estimate that the growth takes about the same time as that of the first tooth, i.e. about ten to twelve months,” explains Dr. Rosowski.

Could something else grow out of this cell? In other words, isn’t there still the risk of proliferation?

Dr. Rosowski: “The information about the type of tooth, position and size is regulated by the gradients of signal molecules located in the jaw tissue. We assume that the tooth nucleus, implanted in the tooth cavity, adapts to the microenvironment and forms the required tooth. The tooth pulpa cells from the patient are derived from the progenitor cells of tooth development and it is known that all cells have a so-called cellular memory….

…It is therefore unlikely that the pulp cells produce a different cell type. As long as the cells are not subjected to severe manipulation – for example genetic modification – no proliferation is to be expected, since the regulation of cell number and cell size by the surrounding tissue is also carried out via impulses.”

That is reassuring.

Patient’s own material instead of stem cells

By the way, research on regenerative teeth has been going on for quite some time. And so other work groups have already provided proof using animal models that a nucleus implanted in the jaw can actually grow back into a complete tooth.

However, Roland Lauster and his team see their own method as offering a decisive competitive advantage: “All competing research groups use embryonic stem cells.

“This actually prohibits the actual use of the procedure, as the use of stem cells is highly controversial ethically in most countries and is not permitted by law,” explains Jennifer Rosowski.

“In comparison, we would only use cell material from the patient’s own teeth. In this way, we avoid all ethical and legal concerns and have the decisive advantage that, in the case of a real application, it is the patient’s own body tissue: The new tooth would therefore not trigger a rejection reaction.”

The teeth required for the research were provided in the form of wisdom teeth that had been surgically removed by oral surgery at the Charité Universitätsmedizin Berlin. The Berlin scientists have developed a special cultivation method that enables the adult cells contained therein to re-differentiate into a kind of embryonic state and then be aggregated into a tooth nucleus. The tooth pulpa cells are separated, cleaned and then cultivated in microtitre plates whose surfaces are coated with a hydrogel. The hydrogel prevents the cells from adhering to the walls of the microplates. They float freely in the medium, but are actually programmed by nature in such a way that they seek a three-dimensional structure. As a result, they condense independently, without external pressure, into a kind of cell ball. This process takes 24 hours and the resulting cell ball is about 200 to 500 micrometers in size.

Patented process

“We were the only group worldwide who were able to demonstrate that this independent mesenchymal condensation into a cell ball triggers the production of specific impulses and the production of various genes. These impulses are required in order to interact with the surrounding jaw tissue”…

…, Jennifer Rosowski explains the method, which has since been patented worldwide. In order to prove this so-called inductiveness (general validity), the scientists have co-cultivated the tooth nuclei together with cells from the gums. During embryonic tooth development, these two cell types interact and thereby trigger tooth formation. The scientist was able to definitively prove this interaction.

The team is currently working on a preclinical pilot study to determine the efficacy of the drug, which is planned to take approximately 24 months including preparation and follow-up time. So far, basic research on the topic – Dr. Rosowski’s doctoral thesis – has been financed from the department’s budget. But the researchers are hoping for further support:

“We applied for funding from the BMBF for the pilot study, but the approval is still pending – the decision will be announced around Sept. 2019,” said Dr. Rosowski describing the next steps, “if the study is successful, there are a number of conceivable ways to exploit the funding: From setting up a start-up to cooperating with investors”.

But before this can happen, extensive clinical trials must first be approved for use as a medical product. If everything goes well, we can expect the product to be ready for the market in 3-5 years.

 

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