Antibacterial Activity of Silver and Its Application in Dentistry, Cardiology and Dermatology

The application of silver preparations as a microbicide to stop dentin caries is becoming more common. In vitro experiments demonstrated the microbicidal effectiveness of silver diamine fluoride (SDF) on cariogenic microbes in a human dentin model. Besides, silver nanoparticles have also been recognized in in vitro studies to have a microbicidal impact against growth, adhesion, and biofilm development ofin human dentin models. SDF has an intense antimicrobial effect on dental plaque. It reduces the metabolism of carbohydrates in dental plaque and stimulates a different balance of plaque flora [ 41 42 ].

The antimicrobial features of silver nanoparticles have also been studied in detail in dental medicine. Based on the results of the research, there is a growing interest in AgNPs [ 40 ]. The oral cavity is an active ecosystem that is regularly colonized by diverse pathogenic microorganisms, so dental materials and implants have an increased risk of infection [ 13 ]. In vitro examinations show the unique antimicrobial silver nanoparticles’ action when bound to dental materials such as nanocomposites, acrylic resins, composite resins, adhesives, intracanal drugs and implant coatings [ 40 ]. They are also used to make membranes for guided tissue regeneration in periodontal treatment [ 6 ]. Smaller silver nanoparticles have increased antibacterial activity against oral anaerobic pathogenic bacteria [ 6 ]. It is important to note that AgNPs, thanks to their antitumor properties, have shown positive results in the treatment of oral cancer [ 40 ].

Silver has been used in dentistry for over a century and is a crucial component in dental amalgam fillings [ 4 ]. It is used in reconstructive dentistry, as well as in implantology and the production of dentures. Biofilms on the surface of a dental implant can cause inflammatory lesions on the peri-implant mucosa, consequently increasing the risk of implant failure [ 13 ]. The main goal of using silver nanoparticles is to prevent infection during and after dental surgery, i.e., thanks to their antibacterial activity, microbial colonization through embedded biomaterials are reduced [ 4 39 ].

Studies on animals revealed that inhaled AgNPs are disseminated to all body organs [ 63 76 ]. In the rats, AgNPs increased heart rate and reduced dilation of the artery [ 71 77 ]. Dependent on the dose, AgNPs can induce vasodilation or vasoconstriction in separated rat aortic rings [ 71 78 ]. In rats, AgNPs could pass the blood–brain barrier inducing necrosis and neuronal degeneration [ 36 79 ]. AgNPs affect the beginning of fish embryos development. It causes chromosomal aberrations and DNA damage, and prevent the generation of zebrafish. Those data show that AgNPs might have possible teratogenic consequences in human [ 36 80 ]. In some endothelial cells, AgNPs activates apoptosis through increased caspase three activity [ 54 ].

The toxicity of AgNPs is not only connected with the release of silver from the nanomaterials [ 62 ]. Both oxidative stress and production of reactive oxygen species (ROS) have central role in AgNPs toxicity [ 46 68 ]. AgNPs damage cellular components and lead to DNA damage, and damage to the cell membrane [ 36 69 ], which are the hallmarks of early apoptosis. AgNPs increase the ROS production, which is responsible for myocardial damage [ 63 67 ], and simultaneously reduces the production of nitric oxide [ 67 ]. Silver nanoparticles promoted oxidative stress and DNA destruction in human endothelial cells. Those data suggest that the AgNPs were toxic to endothelial precursors that participate in angiogenesis [ 70 71 ]. ROS could harm the heart muscle and lead to inflammation and oxidative stress in rats [ 63 73 ].

The effect of AgNPs depend on their size, dose, and exposure time [ 54 ]. Data on AgNPs’ effects are debatable because they described potential toxicity and possible advantages [ 54 ]. Some studies showed that AgNPs have antiplatelet properties [ 47 60 ]. AgNPs stimulates the generation of vascular endothelial growth factor (VEGF), which is connected with the production of new blood vessels or angiogenesis [ 13 54 ]. Another potential of AgNPs is the induction of endothelial vasodilatation and therefore improved blood flow in the heart [ 13 54 ]. So it could be used as a potential antihypertensive agent [ 54 ]. The nanocomposite with AgNPs and multilayer films containing AgNPs have antibacterial, mechanical, and hemodynamic properties in cardiovascular implant coating [ 5 61 ].

Silver ions, generally in the form of a silver salt, show much higher toxicity than any size of AgNPs [ 14 ]. In the cardiovascular system, Ag ionic form, such as silver chloride and silver nitrate, caused cardiac changes in rats such as left ventricular hypertrophy [ 54 ], causing hypersensitivity and inhibiting regular fibroblast function and causing paravalvular outflow in patients [ 5 55 ]. AgNPs are secure and harmless in biomedical implants, as opposed to silver ions. [ 5 ]. Although AgNPs are also partially soluble and release Ag ions [ 56 ]. Moreover, cationic coatings (positive charge) for AgNPs cause higher toxicity than anionic and neutral coatings [ 14 ]. AgNPs could be detected in the cardiovascular system after inhalation, dermal exposure, oral exposure, or direct injection. Inhaled AgNPs, which penetrate in circulation, are associated with cardiovascular functions such as cardiac rhythm disorders and coagulation [ 35 58 ].

Biomaterials play an important role in cardiology. Thus, a coronary artery stent significantly enhanced the treatment of heart attack by providing mechanical support to narrowed vessels [ 47 ]. Silver in cardiology was first used in a silicone heart valve coated with silver to dodge bacterial infection and decrease inflammation response [ 5 48 ]. Clinical trials showed that a heart valve coated with silver causes side effects. Silver induces hypersensitivity, represses regular fibroblast activity, and causes paravalvular outflow [ 34 48 ]. New nanocomposites with AgNPs and carbon for stents and heart valves have anti-thrombogenic and antibacterial characteristics [ 34 50 ]. The use of cardiac pacemakers, whose surfaces have been treated with AgNPs, dodges the application of antibiotic-loaded pouches. This approach decreases the risk of infection in the first few months after surgery and increases the likelihood of a positive outcome for patients [ 51 ]. The study of de Mel et al. showed that polymeric materials for cardiovascular implants with integrated AgNPs have antibacterial and anti-thrombogenic properties [ 52 ]. The potential application of AgNPs in cardiology is to use them as a vehicle to deliver drugs at a specific site in the organism [ 46 53 ].

5.3. Application of Silver Nanoparticles in Dermatology

0) becomes ionized (Ag+) and highly active against bacteria. Because only the ionized form of silver has desired antiseptic properties, contact with wound fluid is necessary if the source is metallic silver [

Thanks to its antimicrobial properties, silver has well-established use in dermatology. It is an active antimicrobial agent with broad-spectrum activity, so it is used to prevent and treat infections in acute wounds (such as traumatic, surgical, and burn injuries) and chronic wounds (such as diabetic foot ulcers, pressure ulcers, venous leg ulcers) [ 81 ]. When in contact with wound fluid, metallic silver salt (Ag) becomes ionized (Ag) and highly active against bacteria. Because only the ionized form of silver has desired antiseptic properties, contact with wound fluid is necessary if the source is metallic silver [ 82 ]. Silver has been incorporated into various dressing products in addition to creams, gels, and barrier protectants, which differ in their solubility and the rate at which silver ions are released into the wound bed. Nanocrystalline silver dressings were launched commercially as antimicrobial dressings in 1998 [ 83 ]. They are designed for sustained silver release, releasing antibacterial silver levels for 3–7 days, resulting in less frequent re-application of silver preparations or dressings [ 84 ]. Another benefit of silver use in modern wound management is the availability of various products for different wound situations (e.g., gauzes, hydrocolloids, hydrogels, alginates, foams). Wound characteristics which determine the choice of suitable dressing are: depth, amount of exudate, bleeding, pain. Providing a moist wound environment is an essential principle of wound healing. In addition, silver dressings appear to decrease matrix metalloproteinases that are upregulated in non-healing, chronic wounds [ 85 ]. They may also promote cellular proliferation and re-epithelialization by inducing the production of metallothionein by epidermal cells. Metallothionein increases zinc- and copper-dependent enzymes required for cellular proliferation and matrix remodeling [ 82 ].

Because of numbered qualities, the use of silver dressings can reduce the treatment time and thus lead to cost savings compared to the treatment of silver-free dressings. However, published reviews found different results regarding their effectiveness. Silver-containing dressings improve the likelihood of healing venous leg ulcers, as confirmed by the 2018 Cochrane review [ 86 ]. On the other hand, many studies found no significantly higher healing rates [ 87 88 ]. Considering all that and their relatively high price, in modern wound management, the use of silver dressings is supported only if there are symptoms of wound infection.

Topical silver preparation, silver sulfadiazine (SSD) as a 1% cream, applied once to twice a day, is usually used in partial-thickness and full-thickness burns [ 81 ]. It was discovered in the 1960s. Based on systematic reviews from 2014, 2017, and 2018, it was presumed that more advanced methods, with and without silver, lead to more improved wound healing and infection-prevention than silver sulfadiazine [ 89 90 ]. Therefore, SSD is no longer so often recommended as it used to be. There is also a risk of toxicity to host cells (fibroblasts and keratinocytes) [ 81 ]. Silver sulfadiazine 1% cream is sulfa-drug, a group of synthetic antibiotics containing the sulfonamide molecular structures. Allergic reactions to sulfa drugs are among the most common drug allergies, so they should be prescribed with caution. Other uncommon adverse effects of silver sulfadiazine are hemolysis in patients with glucose-6-dehydrogenase (G6PD) deficiency, hyperosmolality, methemoglobinemia, and leukopenia (neutropenia) in children [ 91 ]. These conditions are reversible once the cream is discontinued. Silver sulfadiazine has a low toxicity profile, but the application to large burn sites or prolonged use in bullous disorders should be avoided [ 92 ]. Argyria is a blue-purple-gray discoloration of the skin produced by silver deposition and can be localized or generalized. Argyria is not treatable or reversible. There are also a few reported cases of argyria secondary to silver dressings [ 93 ]. Topical incorporation of silver into the skin depends on the vehicle used, concentration, particle size and shape, substance type (depending if the source of silver is salt or nanoparticle). Smaller nanometer particles are better able to penetrate the skin than larger particles [ 94 ].

3). It is used for its caustic actions, in solid form or solutions, more durable than 5%. In clinical practice, it is often used to treat small recalcitrant ulcerations or to diminish excess granulation tissue, also called hypergranulation, which can negatively influence wound healing [

molluscum contagiosum

, which are common viral infections, especially among children [

molluscum contagiosum

were prescribed 40% silver nitrate paste with an excellent cure rate [

Another silver preparation that has widespread use in dermatology is silver nitrate (AgNO). It is used for its caustic actions, in solid form or solutions, more durable than 5%. In clinical practice, it is often used to treat small recalcitrant ulcerations or to diminish excess granulation tissue, also called hypergranulation, which can negatively influence wound healing [ 81 95 ]. Silver nitrate is also used effectively to treat warts and, which are common viral infections, especially among children [ 96 ]. In one study, 389 sequential patients withwere prescribed 40% silver nitrate paste with an excellent cure rate [ 97 ]. Silver nitrate is also used to stop bleeding in small superficial wounds after curettage or shaving lesions in dermatological surgery. Although it is used because of its astringent and caustic features, caution is needed because the depth of injury can be increased [ 96 ].

Propionibacterium acnes

bacterium is believed to have a crucial function in the pathophysiology [

Silver also has anti-inflammatory effects and may have angiogenic properties. Its action on the cytokine system mediates the anti-inflammatory properties of silver [ 83 ]. Acne is a chronic inflammatory condition of the pilosebaceous units, and the Gram-positivebacterium is believed to have a crucial function in the pathophysiology [ 98 ]. Because of the combination of anti-inflammatory and antimicrobial activity, it was assumed that topical silver preparations would benefit acne vulgaris. A small number of studies were conducted to test this hypothesis [ 99 ]. Soaps with nanosilver are broadly applied in the medication of acne. In conclusion, silver preparations are often used “off-label” in this indication due to the low possibility of developing bacterial resistance, the absence of irritation, and the preservation of the skin barrier.

Staphylococcus aureus

, compared to about 5% of the unaffected individuals [

S. aureus

, so it is presumed to enhance AD’s clinical signs and symptoms. In a few studies, the use of silver-coated textiles in patients with AD was analyzed. Most of them demonstrated that approximately seven days of wearing such textiles could significantly diminish

S. aureus

density and improve AD symptoms compared with wearing cotton [

Atopic dermatitis (AD) is the most widespread chronic inflammatory skin disease marked by pruritus and relapsing course [ 100 101 ]. It is also known as eczema and atopic eczema. More than 90% of patients with atopic dermatitis have skin colonized with, compared to about 5% of the unaffected individuals [ 102 ]. Silver has an excellent antibacterial effect on, so it is presumed to enhance AD’s clinical signs and symptoms. In a few studies, the use of silver-coated textiles in patients with AD was analyzed. Most of them demonstrated that approximately seven days of wearing such textiles could significantly diminishdensity and improve AD symptoms compared with wearing cotton [ 103 ]. On the other side, it has its disadvantages. Washing of silver-infused textiles is one of them. The amount of silver lost from textiles can range from 100% loss after four washes to less than 1%. Additionally, there is a possibility that textile silver ends up in the water supply, reducing the number of beneficial bacteria used to treat it [ 104 ].

Trichophyton violaceum

, but not against

Microsporum canis

or

Microsporum gypseum

[

M. canis

was more resistant to silver nanoparticles [

Trichophyton mentagrophytes

and

Candida albicans

[

Because of the increasing resistance of fungal strains, including dermatophyte strains, there is an urgent need for novel antifungals. So, the antifungal activity of AgNPs has been tested. In one study, it was effective against, but not againstor 105 ]. Mousavi et al. also found thatwas more resistant to silver nanoparticles [ 106 ]. Atef et al. reported the growing inhibition of the silver nanoparticles onand 107 ]. Some researchers also compared the antifungal activity of AgNPs with the current antifungals. Mousavi et al. found that griseofulvin had higher anti-dermatophyte activity than silver nanoparticles [ 106 ]. Others showed that silver nanoparticles had superior efficiency compared with fluconazole and less antifungal efficiency than griseofulvin. However, they also showed that the antifungal outcomes of fluconazole and griseofulvin were enhanced in the presence of the silver nanoparticles [ 108 ]. In conclusion, the antifungal activity of AgNPs is yet to be confirmed with more similar studies.