## 6 Future of Bone Substitute Materials from Advanced Biomaterials Research Perspective
Figure 12: The multidisciplinary approach to the research of advanced biocomposites for bone replacement/reconstruction from the perspective of personalized medicine. One of the most attractive application fields envisages the prevention of traumatic brain injuries resulting from a car crash [119]. Finite element analysis of the skull implant is used to predict mechanical behavior of the skull BS made of HA/TiO\({}_{2}\) under various static and dynamic loading conditions. Using ANSYS software (2015-2016) and LS-DYNA software, promising results were obtained after FEM simulation of a frontal car crash considering a medium class sedan driving at 50 km/h speed (EURO NCAP standard condition) in the worse conditions: the \"pilot\" (dummy virtual model Hybrid III) does not wear the safety belt and the air-bag system is OFF. The bioccomposite BS presented good mechanical results after this frontal impact (Figure 13). The FEM analysis was applied in order to identify the optimal chemical composition of the biocomposites that meet the minimum impact resistance conditions according to the conditions described above. Thus, biocomposites with a ceramic matrix made of submicronic particles of hydroxyapatite were identified as appropriate compared to biocomposites with a matrix of HA, but with particles of micrometric size [89]. At the same time, FEM contributed to the identification of the optimal manufacturing parameters of nanostructured biocomposites through powder metallurgy technology [120]. Composite grafts combine scaffolding properties with biological elements to stimulate cell proliferation and differentiation and eventually osteogenesis. Autograft is considered ideal for grafting procedures, providing osteoinductive growth factors, osteogenic cells and an osteoconductive scaffold. Synthetic graft substitutes offer structural support but lack osteoinductive or osteogenic properties. Calcium sulfate has an osteoconductive crystalline structure which resorbs rapidly (1-3 months), creating porosity in capillaries, and perivascular mesenchymal tissue can grow [121]. Figure 13: FEM simulation of (**a**) one sedan frontal impact with (**b**) the “pilot” having an alloplastic bone graft in frontal-cranial position; (**c**) von-Mises stress map for the skull and (**d**) von-Mises stress map for the graft (Courtesy of Prof. [PERSON], University of Craiova, Faculty of Mechanics). \(\beta\)-tri-calcium phosphate (\(\beta\)-TCP) is considered as the \"gold standard\" for synthetic bone grafts, with properties similar to the inorganic phase of bone. Like other bone substitutes, \(\beta\)-TCP's main property is osteeconduction. Its resorption is slower than the resorption of calcium sulfate, being made in 13-20 weeks after implantation and then completely replaced by remodeled bone. Due to this property, most of the time, it is used to fill large, contained defects in association with bone marrow aspirate [122]. Using this method, the healing rates vary from 90% to 100% [123]. Biphasic calcium phosphates (HA and \(\beta\)-TCP ceramics) can be used in association with autologous, expanded, bone marrow-derived mesenchymal stromal cells at a dose up to 200 million cells. The efficiency and safety of their use has been set by ORTHO--1, a European, multicentric, human clinical trial. The results were promising, with HA and \(\beta\)-TCP ceramics, in a ratio of 20/80 in weight, being the most efficient support for autologous cells, compared to the equivalent macro and microstructure of different calcium phosphate bioceramics. The radiological success rate (in at least three views) was 74%, and the combined clinical criteria success rate was 85% [124]. Another direction is bioactive factors releasing. Bone scaffolds may deliver bioactive molecules or cells to accelerate healing and tissue regeneration. Administration of growth factors and other bioactive molecules to promote bone formation and repair has achieved promising results.