*3.5. Nanobiomaterials for Coating*

Micro/nanoscale tissue engineering scaffolds play a vital role on the organization of natural extracellular matrix [530]. Nanostructured 3D scaffolds enhance cell functioning, migration, differentiation, proliferation, and extracellular matrix formation [531].

Nanobiomaterials used for coatings include silica (SiO2), titania (TiO2), zirconia (ZrO2), alumina (Al2O3), zinc oxide (ZnO), CNT, graphene, and various combined oxides [532]. Simple calcium phosphate coating method on metals, glasses, inorganic ceramics and organic polymers (such as PLGA, PS, PP, and silicone), collagens, and silk fibers can improve biocompatibility or enhance the bioreactivity for orthopedic applications [494,533]. TiO2 and Al2O3 can be used as biologically active coating agents, supporting cell adhesion, growth, osteogenic differentiation, bone matrix production, and mineralization [534]. Nanostructured TiO2 has a positive effect on the performance of bone cells. TiO2 is available in the form of nanocrystals [535], nanofibers [536], nanoparticles [537], also immobilized on nanotubes [538]. TiO2 nanotube coating on any substrate enhances hydroxyapatite formation in SBF [539]. Nano silica coating on Ti-6Al-4V alloys generates apatite and supports adhesion and attachment of human osteoblast-like Saos-2 cells [540]. Nitinol coated stainless steel has shown enhanced biocompatibility but Ni ions produce an allergic response and toxicity [541]. Zirconia coated pure and yttrium-stabilized nanostructure promote deposition of apatite from SBF, which supports cell adhesion and growth [542]. Zinc oxide doped with alumina or functionalized with the silane coupling agent KH550 supports the proliferation of fibroblasts [543].

Carbon nanotubes have been used with various synthetic and natural polymers or minerals for the improvement of mechanical properties [544]. CNT and other nano-carbon forms stimulate cell adhesion and growth of osteogenic cells. Graphene-based films and composites used for biomaterial coatings can be obtained from pure or oxidized graphene. These graphene-based films improve the osteogenic differentiation manifested by collagen I and osteocalcin, high calcium phosphate deposition, and high alkaline phosphatase activity [545,546]. Due to the antimicrobial impression of graphene, graphene oxide (GO), and their derivatives, these materials can be used for implant coating [547]. Graphene oxide (GO) coating on the collagen scaffold induces morphological changes depending on GO concentration [548]. The application of GO improved physical properties like compressive strength as well as adsorption of Ca and proteins without changing porosity [549]. Graphene oxide-silk fibroin (GO-SF) composite used as an alternative to coating with collagen, showed improved biomechanical properties and proved could work in cellular environments [550].

HA can accelerate new bone formation by coating on titanium and tantalum scaffolds. It was demonstrated that after 6 weeks of implantation with titanium and tantalum scaffolds coated is possible to reach fully dense bone formation [551]. Calcium-phosphate-coated Fe foam showed better differentiation and proliferation rate of human mesenchymal stem cells than uncoated Fe foam [552]. Polymer-coated mesoporous silica nanoparticles are effective, cell-specific targeted chemotherapeutic agent delivery method [553]. In rat calvarial defects, HA-coated PLGA scaffolds alone promote bone regeneration and increased exposure to HA nanoparticles on the scaffold surface has been documented to result in accelerated bone deposition by local progenitors [554].
