## 5 Adjunctive Materials to Synthetic Bone Graft Substitutes (Growth Factors)
### Bone Morphogenetic Proteins ( BMPs)  
In 1965, [PERSON] described bone formation after the implantation of demineralized bone matrix in soft tissues of rabbits [101] and discovered bone morphogenetic proteins to be important elements in this complex process. Since then, BMPs have become a major subject of orthopedic research, and at the same time, have been intensively used clinically in different forms of human recombinant BMPs [102].  
BMPs are members of the TGF-beta superfamily, a class of molecules deeply associated with the complex signaling pathways of osteoblastic differentiation and osteogenesis. Today, more than twenty BMPs have been identified. They have osteoinductive activity and promote cartilage formation and angiogenesis [103]. BMP-2, -4, -6, -7, -9 and -14 have significant osteogenic properties [104]. BMP-2 is especially associated with osteoblastic differentiation from mesenchymal stem cells and has the capacity to promote local neo  
Figure 11: Experimental composite materials for bone substitutes type collagen–hydroxyapatite (first line) and collagen–hydroxyapatite–magnesium (second line): left row (up and bottom) macroscopic view, middle row (up and bottom) scanning electron microscopy image, right row (up and bottom) transmission electron microscopy image [99].  
vascularization. BMP-7 has potent osteoinductive properties and the potential to promote angiogenesis, similar to BMP-2 [8]. Recent studies show that BMP-6 may be superior to BMP-2 and BMP-7 in promoting osteoblast differentiation in vitro and inducing bone formation in vivo, and, secondarily, it is involved in iron metabolism regulation [105].  
One of the main characteristics of this class of substances is their solubility. This makes both transport and fixation to the desired bone level very difficult. The concentration of the BMPs decreases due to dilution, which leads to a significant decrease in their local healing effects. On the other hand, heterotrophic ossifications may occur after diffusion in the surrounding soft tissues, with significant associated morbidity. One of the major research directions is the development of transporting and fixing vehicles of BMPs capable of ensuring a maximum concentration at the desired bone site and a prolonged time of releasing [106]. The main categories of carriers are as follows: natural polymers (collagen, hyaluronic acid, gelatin, fibrin), synthetic polymers (polylactic acid, polyglycolic acid, polyethylene glycol, poly-E-caprolactone), inorganic materials (calcium phosphate or calcium sulphate ceramics, bioglass) and combinations between these groups (composites containing either natural or synthetic polymers with ceramics) [107].  
The main advantage of natural polymers is their biocompatibility; on the other hand, their animal origin brings an important immunogenicity and disease transmission potential, which are clear disadvantages for clinical use.  
Synthetic polymers are moldable into porous three-dimensional scaffolds, such as blocks or chips, without any immune potential [108]. These structured carriers have the ability to replace certain bone defects while the attached BMPs facilitate osteoconduction at this level.  
Non-structured carriers are used especially on the surface of various implants, favoring their fixation to the surrounding host bone.