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Bone graft substitute materials are becoming more common as alternative therapy strategies when bone defects in patients need to be treated. The interaction between bone cells and biomaterials occur at the surface of the materials. A great deal is known about the importance of surface topography and physic-chemical properties of biomaterials. It is also known that cells require proteins in order to interact with biomaterials. Less is known about how material properties and proteins interact forming the biological interface that cells will be exposed to, and that might determine if new bone is formed or not in the patient. The overall aim of the present thesis was to systematically investigate bone graft substitute material surface reactions and the interface in order to better understand how biomaterials may promote bone formation. Bio-Oss (BO) is a commonly used bone graft substitute material in reconstruction of periodontal and dentoalveolar bone defects. BO is mainly considered to be “osteoconductive”, but we could show that it does interact with a biological fluid (α-MEM cell culture medium) through dissolution/precipitation reactions. A significant reduction of calcium and phosphate levels in the medium was obtained even with low concentrations of BO. A release of silicon from the material was also demonstrated. An osteogenic response was seen in close contact to the BO particles when cultured with different types of pre-osteoblastic cells (Paper I). X-Ray Photoelectron Spectroscopy (XPS) with fast-frozen sample technique was used to further characterize the surface of BO, Frios Algipore (AP) and 45S5 Bioglass (BG). These three bone graft substitute materials are used as “model systems”, because they have all demonstrated newly formed bone on the surface after implantation in patients. From the XPS analysis it can be concluded that AP and BG acquired a positively charged surface while BO gained a negatively charged surface. Only AP and BG adsorb organic components (amino acids) from the medium (Paper II). Next we investigated initial surface reactions and the formation of a biological interface in the presence of proteins (serum) for the three biomaterials. The major findings were that in the presence of proteins BO underwent a surface charge reversal, all three biomaterials adsorbed proteins on the surface and all three biomaterials altered the chemical composition of the cell culture medium (Paper III-IV). Silicon (Si), which was released from BO as well as from BG, is interesting in relation to bone health. Positive effects of BG Si dissolution products on osteoblasts have been reported earlier. In the present study inhibitory interactions of Si on the RANK/RANKL/OPG signaling pathway as well as with gap junction intercellular communication in vitro are reported. These new findings implicate that Si could potentially be beneficial for patients with imbalance in bone remodeling (osteoporosis) and treatments of bone defects (Paper V). In conclusion, biomaterials of different origins interact with a solution resembling the extracellular tissue fluid. The dissolution-precipitation reactions are influenced by the material concentration used and should be taken into consideration when designing experiments and when biomaterials are used clinically. The presence of proteins will influence surface reactions, the formation of the biological interface and have implications on cellular responses. Possible dissolution products from the biomaterials should be investigated.  Si, a dissolution product, is shown to have an inhibitory effect on osteoclastogenesis and bone resorption in vitro. Potential clinical value of Si in treatment of patients with bone defects should be further investigated.