*3.1. Bone Regeneration*

## 3.1.1. Growth Factors and Peptides

Several FDA approved growth factors as BMP-2 have been used in clinics for bone and cartilage regeneration. In a mesoporous bioactive glass (MBG) covered silicate 1393 bioactive glass scaffolds candidate for bone repairing application, BMP-2 release was higher than that of DNA and dexamethasone. MBG successfully physically absorbed and released the active molecule without upsetting its pharmacological activity [68]. Fish hydrogel-based mesoporous strontium-doped calcium silicate scaffolds were proved to be efficient BMP-2 carriers for in vitro human Wharton jelly mesenchymal stem cell differentiation [69]. Customized 3D-printed osteoinductive implants were realized integrating porous silicon BMP-2 carriers within a 3D-printed PCL patient-specific implant [70]. FDM 3D MesoCS scaffolds combined with PCL were presented as odontoinductive biomaterial with efficient BMP-2 delivery capability [71]. In vitro tested BMP-2 pre-loaded mesoporous calcium silicate/PCL scaffolds, even if not suitable for clinical applications, exhibited high biocompatibility and sustained drug delivery pattern compared to the ones directly immersed with BMP-2 after the FDM fabrication [45].

As some authors reported some relevant side-effect related to the use of BMP-2 [72], 3D dipyridamole-coated hydroxyapatite (HA)/beta-tri-calcium phosphate (β-TCP) scaffolds were successfully used to promote bone regeneration in critical bone defects as well as BMP-2 [73].

Since vascularization is a key step of the osteogenesis process, 3DP dimethyloxallyl glycine loaded MBGs and poly(3-hydroxybutyrate-*co*-3-hydroxyhexanoate) polymers scaffolds and results showed that dimethyloxallyl glycine was effectively released improving angiogenesis and osteregeneration in the bone faults [74]. Vascular endothelial growth factor (VEGF), was well encapsulated in chitosan/dextran sulfate microparticles and mixed into a calcium phosphate paste for the 3D plotting of growth factor loaded calcium-phosphate-based scaffolds applicable for bone tissue engineering [75].

Materials for tissue regeneration can be functionalized with engineered peptides able to regulate bone healing and regeneration. In vitro tests with naringin and calcitonin gene-related peptide-loaded 3DP MBG/sodium alginate/gelatin scaffolds showed that their high porosity assure efficient sustained drug delivery [76]. Peptide osteostatin and Zn2<sup>+</sup> ions loaded meso-macroporous 3D scaffolds based on MBGs, exhibited a synergistic effect improving human mesenchymal stem cell growth, promoting their osteogenic differentiation [77]. SLS 3DP poly(3-hydroxybutyrate) scaffolds, when post-printing loaded with osteogenic growth peptide, exhibited the ability to support cell growth and tissue restoration [78].
