Nanoscale Particle Therapies for Wounds and Ulcers

Roberta Cortivo; Vincenzo Vindigni; Laura Iacobellis; Giovanni Abatangelo; Paolo Pinton; Barbara Zavan

Disclosures

Nanomedicine. 2010;5(4):641-656. 

In This Article

Silver-based Nanoparticles

Although antibiotics are of great importance, their overuse and the failure of healthcare facilities to apply basic infection control policies and procedures have contributed to the high mortality and morbidity of burn wound patients due to infections caused by multidrug-resistant nosocomial pathogens (e.g., Pseudomonas aeruginosa, methicillin-resistant staphylococci, vancomycin-resistant enterococci).[36–39] Thus, antimicrobial therapy that controls colonization and proliferation of microbial pathogens, including multidrug-resistant organisms, is the most important aspect of skin wound care.[40] The recent introduction of antimicrobial agents containing silver has revolutionized burn wound care.[41] Interestingly, for thousands of years, silver and silver ions have been used for their bactericidal properties,[42–44] which include:

  • Multilevel antibacterial effects that considerably reduce the chances of developing resistance, since this effect of silver is thought to be due to blockage of respiratory enzyme pathways and alteration of microbial DNA and the cell wall;[45]

  • Effectiveness against multidrug-resistant organisms;[46,47]

  • Low systemic toxicity.[48,49]

Nanotechnology has provided the means of producing pure silver nanoparticles (SNPs), markedly increasing the rate of silver ion release. Jain et al. synthesized silver (Ag+) nanoparticles by a proprietary process that involves photoassisted reduction of Ag+ to metallic nanoparticles and their biostabilization.[49,50] The gel formulation containing SNPs in the size range of 7 to 20 nm has been tested to identify the minimum inhibitory concentration and minimum bactericidal concentration against standard reference cultures, as well as multidrug-resistant organisms. SNPs have been shown to destroy Gram-negative bacteria more effectively than Gram-positive bacteria. They also exhibit good antifungal activity, synergism when associated with commonly used antibiotics such as ceftazidime, additive effects when associated with streptomycin, kanamicin, ampiclox, polymyxyn B, as well as antagonistic effects with chloramphenicol.

Surprisingly, SNPs also exhibited good anti-inflammatory properties. These results were confirmed by Tian et al. in an in vivo model that demonstrated promotion of wound healing by silver through reduction of cytokine-modulated inflammation.[51] Silver-induced neutrophil apoptosis and decreased matrix metalloproteinase (MMP) activity may also have contributed to overall dampening of the inflammatory response and, as a consequence, an accelerated rate of wound healing. Moreover, the authors showed that in wounds treated with SNPs, the high levels of TGF-β normally present in keloids and hypertrophic scars were lower and associated with higher IFN-γ levels compared with nontreated wounds in the period before wound closure. As IFN-γ has been demonstrated to be a potent antagonist of fibrinogenesis through its ability to inhibit fibroblast proliferation and matrix production, its control of TGF-β production may play a role.[51]

Since cytokines play an important role in wound healing, the authors investigated the expression patterns of IL-6, TGF-β1, IL-10, VEGF and IFN-γ with quantitative real-time PCR. Levels of IL-6 mRNA in the wound areas treated with SNPs were maintained at statistically significantly lower levels throughout the healing process, while mRNA levels of TGF-β1 were higher in the initial period of healing in the site treated with SNPs. The same trend was observed for IL-10, VEGF and IFN-γ mRNA. Moreover, in this study, better cosmetic results were observed in animals treated with SNPs. In terms of wound healing, enhanced expression of TGF-β1 mRNA was found in both keloids and hypertrophic scars.

Cumulative evidence has suggested that TGF-β1 plays an important role in tissue fibrosis and postinjury scarring. The authors demonstrated that lower levels of TGF-β coincided temporally with increased levels of IFN-γ before wound closure in the SNP-treated group. Since IFN-γ has been demonstrated to be a potent antagonist of fibrogenesis through its ability to inhibit fibroblast proliferation and matrix production, its control of TGF-β production may play a role in the positive effects of silver on wound healing. Regarding angiogenesis, it is well known that VEGF promotes healing.[52] Tian et al. detected much higher levels of VEGF mRNA in keratinocytes present at the wound edge and in those that migrated to cover the wound surface. Besides a scarce expression in mononuclear cells, VEGF was not expressed in other cell types in the wound, indicating that keratinocytes are a major source of VEGF in the wound. As this factor is highly specific for endothelial cells, it is likely to have a paracrine function in the sprouting of capillaries on the wound edge and in granulation tissue. It appears from these findings that silver treatment not only acts as an antibacterial, but also directly acts on dampening the process of inflammation, thus promoting scarless wound healing.[51]

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