## 4 Discussion
### Bioactive Molecules  
Bioactive molecules and the cell therapies incorporated in the scaffolds significantly improved bone regeneration in comparison to the scaffold alone in the majority of studies. Scaffolds with BMPs significantly promoted bone regeneration in a dose-dependent manner [22; 24; 31; 46; 51; 56; 57; 83; 84]. BMPs activate MSCs differentiation during bone formation through the activation of the Smad-dependent signaling pathway or the MAPK pathway [10]. The protracted slow release of BMP-2 using microspheres resulted in a better bone quality compared to the early deleterious effect of the supraphysiological dose of BMP [2]. The timing of the application of BMP-2 is important, especially for critical-sized defects, due to the initial burst release of rhBMP-2 and the insufficient number of SCs from the boundary of the bone defect in such cases [137]. [PERSON] et al. [79] found the application of BMP-2 to the mandibular defect one week after surgery, compared with admixing with a hyaluronic acid scaffold before the operation, resulted in significant increases in the mineral density, total volume, and trabecular volume of bone. [PERSON] et al. [92] found that the combined use of VEGF + BMP-2 with the PLLA/PEG scaffold for rabbit mandibular defect resulted in increased osteoblastic activity and neovascularization when compared with the use of BMP-2 or VEGF alone. Similarly, the combined use of FGF + BMP-2 with PLGA/PCL/nHA scaffold for rabbit mandibular defect resulted in significantly promoted proliferation and osteogenic differentiation of BMSCs and osteogenesis than when BMP-2 and FGF were used alone [25]. In a study on sub-human primates of different ages, the host recipient tissue had the same capacity to respond to BMP-2 induction regardless of the subject's age [55]. In addition, previous studies have shown good bone regeneration of scaffolds with BMP-7 or BMP-6 factors [50; 63; 109]. [PERSON] et al. [83] found that the combined use of VEGF + BMP-6 with the PLGA scaffold for rat mandibular defects resulted in significantly enhanced bone repair through the enhancement of angiogenesis and the differentiation of endogenously recruited MSCs into the bone repair site. Despite the encouraging results of BMPs for bone regeneration in the maxillofacial area for the bridging and ingrowth of bone, the results of biomechanical testing were not uniform. The mechanical tests performed in previous papers showed that the regeneration in the mandibular critical-size defects reconstructed with BMP-7 and BMP-2 showed a wide range of mechanical properties due to the varied proportions of woven and lamellar bone formation that were histologically shown, as well as possible variations in the concentration of BMPs within the grafts [73; 74; 75]. A study with porous nHAP/collagen/PLGA scaffolds with incorporated insulin-loaded microspheres showed a higher bone restoration capacity than the defects that were filled with nHAC scaffolds [33]. This finding may be important in the bone regeneration of patients diagnosed with diabetes. Several studies investigated the use of concentrated growth factor (CGF), a third-generation platelet concentrate extracted from blood, featuring a wide range of sources, low cost, absorbability, lack of immunogenicity, and bone inducibility [101; 102]. [PERSON] et al. [102] investigated the HAP/collagen scaffold in combination with CGF to repair mandibular rabbit defects. The results showed a higher rate of new bone formation, better bone quality, higher osteocalcin and BMP-2 expression, and higher compressive strength and elastic modulus of the nHAC/CGF cohort. Due to the positive influence of BMPs on mandibular bone regeneration in in vivo studies, several case reports and case series reported the human application of BMPs [138; 139; 140; 141; 142; 143; 144; 145; 146]. [PERSON] et al. [138] successfully used a BMP bioimplant for the primary reconstruction of a 6 cm mandibular critical-size defect after the segmental resection of ameloblastoma. [PERSON] et al.