## 4 Discussion
### Scaffolds
PLGA was investigated as a single scaffold biomaterial for several reasons: it posesses excellent biocompatibility, non-toxic metabolites that can be safely eliminated from the metabolic cycle, and excellent processability; the degradation time of PLGA can be controlled to be consistent with bone regeneration; PLGA has suitable mechanical strength to adequately support the defect area at the early stage; grafts can be loaded with a variety of bioactive factors, such as SCs, growth factors, and drugs, to promote the regeneration of bone defects [118; 119; 120]. Inflammation is one of the main reasons for bone graft resorption. Synthetic porous polymers can be loaded with anti-inflammatory medicines (such as ibuprofen) and growth factors to reduce inflammatory reactions and enhance bone regeneration [121]. In the present review, we found that the application of synthetic polymer scaffolds, alone or in combination with bioactive molecules and/or mesenchymal SCs, resulted in improved bone regeneration. The bioceramic scaffolds have high compressive strength, excellent biocompatibility and stability, bioactivity, and osteogenic properties. The mechanical strength of ceramics is superior to polymers, but is still inferior to natural bones, especially in terms of tensile and torsional strength [9]. Disadvantages include low tensile strength and toughness, fabrication hitches, brittleness, and slow resorption rate. Hydroxyapatite (HAP) (Ca\({}_{10}\)(PO\({}_{4}\))\({}_{6}\)(OH)\({}_{2}\)) is the main mineral component of bone tissue and, as a scaffold, it is a bioactive ceramic material of high biocompatibility because it forms direct chemical connections with bone tissue. It has excellent bioactive, and bioresorbable properties and can be synthesized in various forms, such as ceramic plates, blocks, granules, and powder for various bone tissue applications [122; 123]. In the bone tissue, HAP is deposited around and within the collagen fibers in the form of thin slabs and sticks (length 20-40 nm, width 15 nm, and thickness of 1.5-3 nm) in regular spaces [122; 123]. Synthetic HAP is similar to a natural mineral apatite in bones and is widely used for bone repairs. Its structural composition is the same as natural bone, with a nominal stoichiometric Ca/P atomic ratio of 1:67 [122; 123]. Still, mechanical properties are very low compared to natural bone [41; 42]. Due to brittleness and fragility, HAP is commonly mainly used in the form of composite scaffolds with polymer materials [124; 125]. Numerous studies have shown, that after applying a HAP scaffold, the rapid activation and binding of osteoblasts to the scaffold surface occurred due to the rapid deposition of the biological carbonate HAP, which is the primary substrate for binding of the osteoprogenitor cells [126]. The osteoprogenitor cells are known to better bond to rough surfaces than smooth surfaces. For this purpose, in addition to good biological characteristics, the topography of the HAP scaffold has an impact on cell adhesion, proliferation, and differentiation [127]. Cells on rough surface show phenotypes that are similar to osteoblasts and release pro-osteoblastic mediators such as prostaglandandins and LTGF-\(\beta\). In vitro research showed that osteoprogenitor cells do not differ in terms of the surface of synthetic and biological HAP [127; 128]. Combining the advantages of two or more different scaffold materials into a composite scaffold has been a matter of research in many previous trials [129; 130]. Composite scaffolds of bioceramics with synthetic polymers have been used in the majority of studies, either as a single regenerative therapy or as a carrier of bioactive molecules or SCs. Thesescaffolds mimic the natural bone matrix, a combination of organic/inorganic composites. Composite scaffolds combine the excellent biological activity of HAP and mechanical properties and 3D architecture of synthetic polymers. The HAP/PLGA scaffold was extensively studied for bone regeneration. [PERSON] et al.