Why do joint implants sometimes loosen so that sufferers have to undergo surgery again? And can a genetic bone disease possibly be cured with gene therapy? Researchers at Charité are investigating these questions using miniature bones on a chip. What is special about this is that the bone is grown from human bone cells and provides more meaningful results in this area than animal experiments.
Since 2016, researchers at Charité have been working on a miniature bone on a chip. Now the system is so stable that it can be used for various investigations and research into new therapies. Nina Stelzer from the Julius Wolff Institute and the Berlin Institute of Health (BIH) at Charité played a key role in this.
Now, the doctoral student in biotechnology and her colleagues are trying to use the model to develop a gene therapy for the bone disease osteopetrosis - a disease in which the cells that break down bone are dysfunctional due to a gene defect and which can be fatal if left untreated. In parallel, she is conducting research with induced pluripotent stem cells, for example, to study the effects of gene mutations on bone.
Meanwhile, her colleague Melanie Ort is investigating the phenomenon of aseptic osteolysis, i.e. why hip or knee prostheses become loose in some patients, necessitating revision surgery. Metal debris is suspected of upsetting the balance between bone-degrading and bone-building cells, triggering local inflammation and also having effects on the overall immune system. "The model offers a wide range of possibilities for very different research questions," says Nina Stelzer, "and is a fine example of how research can be done not only 'from bench to bedside,' but also the other way around, from bedside to lab."
Made from human bone cells
It is human bone that is being grown on a two-organ chip here at Campus Virchow Klinikum. In a chamber on the chip are bone cells taken from biopsies of patients who have undergone surgery: Osteoclasts, cells that break down bone, their counterparts osteoblasts and mesenchymal stromal cells, and immune cells. The researchers, in collaboration with the Core Unit for Cell Harvesting (BCRT-CH), previously isolated the cells step by step from the bone marrow (osteoclasts were differentiated from monocytes) – and placed them on a cylindrical cancellous bone about one centimeter high. This small bone comes from a tissue bank and serves as a scaffold for the bone cells. To enable the cells to grow and perform their function, they are continuously supplied with a nutrient medium from a second chamber of the chip via a compressed air connection. This contains everything the cells need to survive - similar to a real blood circulation system.
In about five to eight weeks, the dynamic 3D culture organizes itself independently and, considering the basic functions, comes "close" to the original, according to Stelzer: "The bone cells really form a homeostasis. That is, the bone-degrading cells break down bone and the bone-building cells build bone. So it's all in balance."
The model's proximity to the clinic is an unbeatable advantage. That's because the miniature bones reflect the heterogeneity of patients in terms of age, gender, pre-existing conditions and other individual characteristics. "None of us is the same, and the immune system is as individual as a fingerprint," says Melanie Ort. "We can map this diversity much better on the chip than in animal studies, since animals are not comparable to humans in many respects. In this respect, our model is much more meaningful than a mouse, for example."
Immune reactions can be measured
Even though the human immune system is much more complex than here on the chip - it is sufficient for the experiments. On the model with its dynamic cultivation, the researchers can observe very well how human cells behave and react to certain stimuli. Typical breakdown or degradation products can be measured, as can toxicity products or an immune response. If, for example, the population of immune cells shifts and there are suddenly a lot of T cells, this is an alarm signal. In Melanie Ort's project, for example, such an immune reaction can mean metal intolerance.
Immune reactions also play a major role in Nina Stelzer's "gene therapy project". In this approach, the researchers want to introduce a healthy gene into the precursor cells of the bone-degrading cells and then return the genetically corrected cells to the patients. The gene that triggers osteopetrosis is replaced in the laboratory, so to speak. At least, that's the idea. "Before such a complicated therapy can be used in the clinic, it must of course first be tested for risks. And that's what's happening right now," explains Nina Stelzer. That will probably take a few more years.
Patients who are to receive a new joint implant could benefit much sooner. According to Stelzer, the idea of the model being used for personalized prediction of potential metal intolerance is "within reach." Patients with a nickel allergy, for example, could be considered. A biopsy would be enough to grow an individual miniature bone on which prosthetic metals such as titanium, cobalt or chromium could then be tested.
Thanks to the miniature bones on the chip, the research projects get by without a single animal test. So this is a genuine replacement.
(Text: Beatrice Hamberger)
Research group: Cell Biology
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