# Nanomaterials in Bone Regeneration
## 4 Nanoparticles
### Silver Nanoparticles  
Due to its antibacterial properties, silver and its compounds have been used for a variety of medical purposes for more than a thousand years. The importance of silver is growing, especially at a time when growing bacterial resistance is a major global problem. Today, silver is used not only as an antiseptic agent but also for its anticancer properties or as a vaccine adjuvant, antidiabetic agent, and biosensor [102]. The particles with controlled size and shape can be synthesized by physical (mechanical and vapor-based processes) or chemical (reducing silver ions to silver atoms) methods. Silver ions reduction can also be achieved by biological methods using enzymes, alkaloids, phenolic compounds, and terpenoids from extracts of microorganisms and plants [103].  
Size and shape determine various actions of nanoparticles, including cellular uptake, targeting to cells, in vivo distribution, and protein corona formation. Nanoparticles administered by intravenous injection travel along blood circulation into target organs with abundant vasculatures. It is suitable to design nanoparticles that can effectively reach target tissues. The size of nanoparticles also affects cellular uptake and biological action in target cells. Too small nanoparticles are extensively excreted by kidneys from target tissues [104].  
Particle shape also has an important impact on the performance of nanoparticles as a carrier of therapeutic agents through changes in ligand targeting, cellular uptake, transport, and degradation [105].  
Silver nanoparticles (Ag-NPs) can effectively kill a variety of pathogens at very low concentrations, e.g., Gram-positive and Gram-negative bacterial strains (_Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus_), fungi (_Candida albicans, Aspergillus niger_), and viruses (HBV, HIV). The antimicrobial mechanisms of Ag-NPs include destructing bacterial cell walls, producing reactive oxygen species (ROS), and damaging DNA structures. Bacterial resistance to silver is rare. It is currently tested that Ag-NPs act against tumor cells in vitro and in vivo [106]. Recently, [PERSON] et al. introduced a new type of silver particles smaller than Ag-NPs, so-called silver Angstrom (1 A = 0.1 nm) particles (Ag-APs), which exhibit stronger anticancer activities and lower toxicity compared with Ag-NPs [107].  
In bone engineering, Ag-NPs are used for fabricating antibacterial nanocomposite-based scaffolds and implants to replace large defects. They promote bone regeneration and wound healing by effectively suppressing bacterial infection and inflammation. Studies in vitro show that Ag-NPs can naturally stimulate proliferation and osteogenic differentiation of MSCs and mineralization of ECM [108]. It was found that Ag-NPs at 2.5 and 5 \(\upmu\)g/mL stimulate osteodifferentiation more efficiently than at 10 \(\upmu\)g/mL [109].  
In some dental applications, Ag-NPs are used as antiplaque agents. An example is the production of dental prostheses from acrylic resins, on the rough surface of which microorganisms adhere. Ag-NPs incorporated in acrylic resins improve the antibacterial effect of this dental material and decrease the adherence of _Candida albicans_[110].  
However, Ag-NPs contained in various medicinal products such as dressings, creams, solutions, and scaffolds come into contact with the skin by inhalation, ingestion, or injection into the body. They are transported via blood circulation to various organs and may be cytotoxic, limiting their applications. They are stored mainly in the dermis, spleen, liver, kidneys, and lungs, and a smaller amount in teeth and bones. Ag-NPs may cause dermal, ocular, respiratory, hepatobiliary, and reproductive toxicity. This limits their applications [111].