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Cells and biomaterials for the treatment of intervertebral disc defects

A new therapeutic method uses a patient’s own cartilage cells for the regeneration of intervertebral discs. The NMI Natural and Medical Sciences Institute in Reutlingen and its partners are scientific partners in the first clinical application of the new method. The key aim of the researchers from Reutlingen is the validation of the safety, efficiency and efficacy of the new method in order to prepare for approval for broad application in patients.

Histological cuts through intervertebral discs help researchers to analyse the state of tissue. Collagenous tissue is stained green; proteoglycans, which are key components of the cartilage matrix, are stained red. © NMI Reutlingen

The new therapy involves the use of cartilage cells that have been removed from a patient’s intervertebral disc. In order to reach these cells, doctors would normally perform a biopsy. Although this procedure is minimally invasive, it still involves certain risks, and is therefore not performed for the sole purpose of obtaining cells. The situation is different when a herniated disc causes such major problems that it needs to be surgically removed. The removed tissue may then be used to isolate individual cells in the laboratory. For cell therapy, these cells are then propagated in large numbers under controlled conditions. After a few weeks, several hundred thousand cells have become several million cells that can be injected in the patient’s intervertebral disc where they form extracellular material in line with their genetic nature. Ideally, the form and consistency of the intervertebral disc improves to a degree that it is again able to fulfil its function as ‘crumple zone’ between two vertebrates. 

The cells need to be propagated in the laboratory because they display a somewhat autistic behaviour. Prof. Dr. Jürgen Mollenhauer is the head of R&D at Reutlingen-based TETEC AG, which works closely with the Reutlingen-based NMI in the development of new cell therapies. Mollenhauer explains: “The cartilage cells of the intervertebral disc do not communicate with their environment, which is why they do not realise that they need to proliferate. Although it was possible to induce the generation of cell clusters in experimental cell models, the cells are not redistributed enough for the entire tissue area to benefit.”

Quality checks accompany the production of cell therapeutics

During the mass proliferation of the cells in the laboratory, the cells must of course not lose their properties and qualities. So ways need to be found to prevent this from happening. A team of researchers headed up by Dr. Karin Benz at the NMI Reutlingen is developing new test systems to continuously monitor cell quality. The researchers’ work is part of a BMBF-funded cooperative project that aims to assess and guarantee the safety, efficiency and efficacy of the new method – from the time when the cells are placed in culture and up to five years after they have been injected into the intervertebral disc of selected patients. In addition to the NMI and TETEC AG, the project also involves hospitals in Germany and Austria where the new method is being applied in patients for the first time. TETEC AG also produces the hydrogel that is used as carrier substance for anchoring the cells during and after injection. It consists of two liquid components that are combined in a two-chamber injector as the components are injected into the intervertebral disc and form a gel which fixes the cells in the damaged disc.

The NMI is specifically focussed on the development of biomarkers and assays with which cell quality can be reliably tested. What would be ideal is a marker that works both in cell culture supernatants and in blood and urine samples. “Direct tests can only be carried out until such time as the cells are transplanted into the patient. We do this by analysing the cell culture supernatants. Afterwards, direct testing is replaced by indirect monitoring for which we use blood and urine samples, amongst other things. In addition, we also carry out classical clinical examinations to assess mobility, activity and general condition of the patient. And these examinations are supplemented by magnetic resonance imaging (MRI),” Benz explains. The data are continuously correlated with previous tests using markers from the cell culture supernatant. The researchers hope that these comprehensive tests will create a data base that is comprehensive enough to be able to apply for approval of the therapy in Europe.

Test development benefits from innovative biotech methods

The therapeutic cells are injected into the intervertebral disc using a specifically developed two-chamber application system. The gel forms only when the cross-linking agent of one chamber comes into contact with the cell suspension of the other chamber as the two liquids are injected into the intervertebral disc. © TETEC AG

Proteins that are produced by the cells themselves are best suited as markers. The NMI team has planned the search for suitable compounds with military precision and did not want to miss any opportunity. Therefore, Tübingen-based CeGaT GmbH was commissioned to carry out transcriptome analyses that involved the screening of the entire transcriptome, i.e. the entire set of RNA molecules in one go, for suitable proteins. “We not only looked for known molecules, but we actually detected new markers. Thanks to enormous progress in the development of novel DNA sequencing technologies, transcriptome analyses have become an important as well as relatively cheap tool for finding marker proteins,” Benz said. The researchers now have quite a few candidates that seem to be suitable markers, including inflammation mediators such as interleukins. “We are also investigating the use of several degradation and assembly markers, for example metalloproteases that degrade extracellular matrix proteins,” said Benz. 

The test systems used are based on proven methods that are adapted and optimised by the NMI team. The tests need to be rapid enough to make them suitable as product control immediately prior to transplantation. This would allow a team of doctors to react and alter the number of injected cells if required. “Before we send the cells to doctors, we have a time frame of around 24 hours to assess the property and quality of the cells. This is perfectly sufficient for identifying proteins with ELISA tests and similar assays, for example,” Benz says. In the long term, Benz not only wants to focus on the testing of the quality of cell therapy products, but also wants to develop prognostic markers to predict whether a patient’s cells are suitable for treatment. With such tests, the NMI team would be making an important contribution to individualised patient treatment.

Further information:

NMI Reutlingen
Dr. Karin Benz
Markwiesenstraße 55
72770 Reutlingen
Tel.: +49 (0)7121 51530-827
E-mail: benz(at)nmi.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/cells-and-biomaterials-for-the-treatment-of-intervertebral-disc-defects