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Deferoxamine (DFO/Desferal®) to accelerate bone healing and treat fracture healing disorders (PROOF-DESFERAL)

03/2021-02/2024

Funding programme / funding institution: Bundesministerium für Bildung und Forschung

Grant number: PROOF-DESFERAL

Project homepage: -

Project description:

Fracture healing combines temporal and spatial fine-tuned and tightly regulated regenerative processes which lead to a complete restoration of the broken bone without formation of fibrous scar. However, 10 % of patients with fractures suffer from fracture healing disorders such as delayed healing or non-unions leading to immobility, pain and a loss in life quality and to an economic burden for the society. Patients with fracture healing disorders require often several further revision surgeries to close the gap. Usually, regeneration processes during fracture healing are completed within 4 months. If healing takes longer, it is termed ‘delayed’. If bridging of the fracture gap does not take place after 9 months, it is termed ‘non-union’, a state which is further classified as hypertrophic non-union, pseudarthrosis (joint-like structure) and atrophic non-union according to bridging and callus formation. Although there are treatment strategies available including recombinant human (rh) BMP-2 and rhBMP-7 for local delivery into the fracture gap, effectiveness and observations of several adverse effects strongly restricted their clinical use.

In the proposed study, we aim at paving the path for using the HIF-stabilizer Deferoxamine (DFO) for a new application to prevent fracture healing disorders as a cost-effective and low-risk alternative to recombinant growth factors such as BMP-2. We consider the FDA approved DFO and commercially available as Desferal® (Novartis), listed on World Health Organization's List of Essential Medicines, suitable for rapid clinical translation to improve fracture healing and the treatment of bone healing disorders. In the next step, we strive for clinical translation.

The BfR is participating in this study as one of two laboratories that will test varying concentrations of DFO regarding their influence on mesenchymal stromal cells (precursor cells for bone forming osteoblasts). The other in vitro laboratory will be situated at the Charité Universitätsmedizin Berlin. Both laboratories will work with the same protocols, cell culture reagents and cells. Furthermore, both laboratories will recieve blinded samples of DFO in diferent concentrations. The data from both laboratories will then be send to a third project partner for evaluation. This is meant to investigate how good the comparability of in vitro studies from different laboratories actually is and if such study design has clear advantages. In addition, the data from the in vitro experiment is meant to be compared with data from animal experiments to evaluate how precise a carfully conducted in vitro study can predict the outcome of in vivo approaches. These research questions have direct relevance for the work of Department 9 (Experimental Toxicology and ZEBET) in the field of the 3R (Reduce, Replace, Refine), since this study is meant to show that the number of animal experiments can be reduced by an improved study design and the use of reliable in vitro data.

Project partners:

  • Charité - Universitätsmedizin Berlin

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