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Stimulation of the angiogenic potential of the haematoma via application of mechanically regulated MMPs
Grit Kasper, Dr.-Ing.; Carsten Perka, Prof. Dr. med.; Juliane Tiedemann, M.S.; Aline Groothuis, M.S
Several studies have shown that angiogenesis is one of the crucial processes determining bone healing outcome and might be the mechanism by which most of the known risk factors act. Angiogenesis occurs in the early phase of bone healing, a phase which is also characterized by susceptibility to mechanical boundary conditions, the release of a variety of growth factors, proteases and the recruitment of mesenchymal stem cells (MSCs). Matrix metalloproteinases (MMPs) seem to be essential for the coordination of these processes by their involvement in 1.) matrix remodelling and 2.) release of latent growth factors in their optimal proportion.
In a study that supports this view we recently demonstrated that specific MMPs are expressed in the hematoma and are over-expressed in MSCs in response to mechanical loading. We also showed the dependence of angiogenesis stimulation by MSCs on mechanical loading conditions was shown. Therefore, we hypothesize that mechanical stimulation of the hematoma regulates the expression of MMPs, which are upstream of different pro-angiogenic pathways. Thus, we intend to analyze protein expression levels of MMPs in mechanically stimulated hematoma in vitro in a bioreactor. The differentially expressed MMPs identified in this way will be tested in vitro for their impact on the pro-angiogenic potential of the hematoma.
Subsequently, an approach for a potential in vivo testing and application of these identified pro-angiogenic MMPs will be developed, enabling the optimal concentration and combination of different MMPs to be determined. Furthermore, different delivery methods will be tested for their suitability, taking into account cost and their pro-angiogenic effect. These approaches will include 1.) delivery of recombinant protein, 2.) application of MSCs over-expressing MMPs and 3.) nanoparticles loaded with expression plasmids for MMP. Our long-term aim is to test the optimized MMP application techniques in a sheep model to determine their impact on angiogenesis and bone regeneration outcome.