1 Applications of metals for bone regeneration 2

The regeneration of bone tissue is a main purpose of most therapies in dental medicine. 19 For bone regeneration, calcium phosphate (CaP)-based substitute materials based on natural (allo20 and xenografts) and synthetic origins (alloplastic materials) are applied for guiding the regeneration 21 processes. The optimal bone substitute has to act as a substrate for bone ingrowth into a defect, 22 while it should be resorbed even in the time frame needed for complete regeneration up to the 23 condition of restitution ad integrum. In this context, the modes of action of CaP-based substitute 24 materials have been frequently investigated and it has been shown that such materials strongly 25 influence regenerative processes such as osteoblast growth or differentiation and also on osteoclastic 26 resorption due to different physicochemical properties of the materials. However, the material 27 characteristics needed for the required ratio between the formation of new bone tissue and material 28 degradation has not been found until now. The addition of different substances such as collagen or 29 growth factors and also of different cell types have already been tested but did not allow for 30 sufficient or prompt application. Moreover, metals or metal ions are differently used as basis or as 31 supplement for different materials in the field of bone regeneration. Moreover, it has already been 32 shown that different metal ions are integral components of bone tissue playing functional roles in 33 the physiological cellular environment as well as in the course of bone healing. The present review 34 focuses on frequently used metals as integral parts of materials designated for bone regeneration 35 with the aim to give an overview of currently existing knowledge about the effects of metals in the 36 field of bone regeneration. 37