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Theranostics 2020, Vol. 10, Issue 20 and oxygen via inhibiting angiogenesis. It has been demonstrated that AgNPs can inhibit VEGF-induced angiogenesis by inactivating PI3K/AKT pathway [271]. Besides, AgNPs can block VEGF-induced Akt phosphorylation, this may influence the proliferation and migration of cells [272]. Another study has proved that AgNPs can disrupt the HIF-1 signaling pathway, thus lead to inhibition of angiogenesis [161]. Other Medical Applications The special physicochemical properties of AgNPs make the nanoparticles and composites having considerable application prospects in the biomedical field. Besides the antimicrobial and anticancer applications mentioned above, AgNPs exhibit good properties in promoting wound repair and bone healing, as well as inhibition of inflammation. AgNPs can also be used as an additive in dental materials and adjuvant in vaccines. Wound Repair The wound healing is closely related to the prognosis of surgical treatment. The rapid development of nanotechnology in recent years has provided a new therapeutic strategy for healing wounds, but the specific mechanisms of AgNPs on wound healing still need more exploration. Jun Tian et al. [288] found that AgNPs could increase wound healing rate with less hypertrophic scarring in the thermal injury model. Compared with the healing time of deep partial-thickness wounds treated with silver sulfadiazine, the AgNPs treated group could heal in a shorter period and a superior cosmetic appearance was observed, including nearly normal hair growth and less hypertrophic scarring. In the healing process, lower level of TGF-β and increased level of interferon-γ were detected at the same time in AgNPs treated group, while the former was related to keloids and hypertrophic scars, and the later was involved in the inhibition of fibroblast proliferation. In addition, higher level of VEGF mRNA detected in keratinocytes at the edge of the wound suggested that AgNPs might promote wound healing by inducing angiogenesis. These results indicated that AgNPs could participate in wound healing by regulating various cytokines and achieve cosmetic effects. Other mechanisms of AgNPs in wound repair are being explored. AgNPs can remain in the cytoplasm of fibroblasts in skin biopsies, and promote the reconstruction of dermis and epidermis [289]. Some studies prove that AgNPs can induce the proliferation and migration of keratinocytes, decrease the amounts of collagen and hydroxyproline, and promote the differentiation of fibroblasts into myofibroblasts, which may help wound early adhesion, contraction 9014 and closure [290]. Besides, AgNPs can promote wound healing by regulating the production of cytokines or proteins, such as inflammatory cytokines, VEGF and MMPs [163, 291]. The above studies of AgNPs on wound repair broaden our understanding of the activity of AgNPs in cellular events. The role of AgNPs in wound repair is positive for clinical wound care and postoperative results. Bone Healing Bone is an active tissue with regenerative and restorative capabilities. The self-repairing capability of bone is usually compromised when bacterial infection occurs in bone defects. Bone grafts are commonly implanted to replace or restore large defects that usually resulted from severe trauma, tumor resection or genetic malformation. Orthopedic infections are usually related to bone destruction and implant loose [292]. AgNPs can be used as doping materials for synthetic bone scaffolds. AgNPs-implanted crystallized hydroxyapatite (HA) or titanium scaffolds display strong antibacterial ability against both Gram-positive and Gram-negative bacterial strains [162]. AgNPs can promote fracture healing as an osteoconductive biomaterial. For example, AgNPs can naturally stimulate the osteogenic differentiation and matrix mineralization of MC3T3-1 cells [293]. In a mouse model, AgNPs has been proved to stimulate proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro, and promote the healing process of bone fracture [294]. Dental Applications Plaque biofilm formation is one of the causes of dental diseases. AgNPs have been incorporated into some dental biomaterials for reducing biofilm formation due to its antibacterial activity. Polymethyl methacrylate (PMMA), also known as acrylic resins, and composite resins are applied for the fabrication of dentures, but potential harmful organisms are likely to adhere to the rough surface of dentures [155]. AgNPs incorporated in PMMA can improve the antibacterial effect of dental material. It is proved that PMMA-AgNPs showed great anti-bacterial effect by continuous releasing of Ag+ even in 28 days. It is highlighted that increased loading of AgNPs in PMMA also improved the mechanical properties [155]. While Acosta-Torres et al. demonstrated PMM- AgNPs could efficiently decrease the adherence of Candida albicans and exhibit no obvious genotoxicity or cytotoxicity. Comparison study of the anti-bacterial and anti-biofilm efficacies of AgNPs capped with carboxymethyl cellulose and sodium alginate, respectively, showed that carboxymethyl cellulose- http://www.thno.orgPDF Image | Silver nanoparticles Synthesis medical applications safety
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