Vascularization and osteogenesis in bone physiological processes influenced by bioactive molecules and scaffolds

In bone tissue engineering, bioactive molecules which modulate bone growth and biocompatible biomaterials, which often provide biomimetic properties, are combined with progenitor or stem cells involved in bone physiological processes. This tissue replacement approach provides a new therapeutic strategy for bone repair and regeneration especially for larger bone defects which often occur after trauma or bone tumor resection for instance. In this context, the aim of this thesis is to investigate the detailed biological functions of new bioactive molecules. Further the thesis is focused on hydrogels used for instance as delivery systems of such bioactive factors or cells, aiming to develop the basis for new clinical applications in bone pre-vascularization and regeneration. First, this thesis assesses the impact of fucoidan extracts, a group of marine origin bioactive molecules, on the formation of vascular structures in co-culture models relevant for bone repair and in osteosarcoma. Human mesenchymal stem cells (MSCs) which can differentiate to the bone forming osteoblastic cells, respectively the osteosarcoma cell line MG63 and outgrowth endothelial cells (OECs) which possess a high potential of angiogenesis, were used to create co-culture models relevant for bone regeneration or osteosarcoma. Here the aim was to study the angiogenic and osteogenic regulatory effects of fucoidan in the co-cultures as functional units. In both types of co-culture models, crude fucoidan extracts significantly reduced angiogenesis which was associated with a decrease of angiogenic factors on the protein level, thus suggesting an impairing effect of this type of fucoidan on angiogenesis in co-cultures via binding and reducing the levels of free angiogenic factors VEGF and SDF-1 in the system. In the next part of this thesis, the physiological molecule vitamin D3 (calcitriol) was studied in terms of its potential to modulate the inflammatory or immunological response in a bone regeneration respectively infection co-culture model stimulated with LPS. Bone infections after the application of implant materials for instance are associated with severe clinical consequences. Vitamin D3 revealed a beneficial effect on angiogenic activity in co-cultures, as well as a positive effect on osteogenic activity. Here, especially the mineralization in the late osteogenic process was enhanced. However, although no significant impact on the inflammatory response was observed, Vitamin D3 induced an increase in the gene expression of the antimicrobial peptide LL-37 in MSC, thus indicating a potential beneficial influence on the immune defense in the bone in case of infection to be further refined. Last, the thesis examines bio-functionalized hydrogels for bone regeneration and tissue engineering. In this part, hydrogels consisting of mineralized silk fibroin fibers and UV-inducible gel-components induced excellent MSCs adherence along the bio-functionalized silk fiber component and a significant upregulation of VEGF expression level, thereby indicating a high potential of this injectable composite biomaterial for bone regeneration and vascularization. Overall, bioactive compounds and bio-functional scaffolds investigated in this thesis showed the ability to modulate angiogenesis on the cellular and molecular level, to trigger the immune defense or to serve as injectable bone materials guiding the performance of osteogenic cells via their biomimetic properties. Nevertheless, further research will be necessary to employ these approaches in a clinical setting for bone repair and regeneration.


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