Silver in dermatology - From ancient use to modern innovations

Silver as an antimicrobial agent

The antimicrobial action of silver is directly proportional to the rate and the amount of silver being released, with the nature of the silver antimicrobial used being a pertinent factor in determining its efficacy.^[4] The antimicrobial actions of silver are illustrated in Figure 2. A recent study has found synergistic activity of metal-metalloid-based antimicrobials (silver nitrate and potassium tellurite) with the advantage of combined bacteriostatic, bactericidal, and anti-biofilm activity.^[5]

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Figure 2:

Antimicrobial actions of silver. AgNPs: Silver nanoparticles, DNA: Deoxyribonucleic acid, RNA: Ribonucleic acid.

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Role of silver in specific infectious diseases

Uses of silver nitrate in viral infections

Silver nitrate is an effective caustic agent used to achieve hemostasis. Silver nitrate acts by causing coagulation of proteins, leading to tissue necrosis and eschar formation, eventually leading to thrombus formation and hemostasis.^[11]The caustic property of silver nitrate has been used for various applications in dermatology, such as in warts and molluscum contagiosum.^[11]

Warts

The self-limiting superficial penetration potential of silver nitrate makes it ideal for the treatment of warts, especially in patients with an increased risk of reduced tissue healing capacity. Silver nitrate (10%) is effective in the treatment of verruca vulgaris, causing 63.33% complete regression of lesions without significant side effects.^[12] Verruca vulgaris treated with silver nitrate pencils has shown 43% complete resolution and 26% partial resolution.^[13] The silver duct tape occlusion method has also been found to be effective in the management of plantar warts by creating a macerating and keratolytic environment, leading to stimulation of the immune response.^[14] Silver nitrate application causes localized tissue irritation and immune reactions by the host against the virus, causing both biochemical and physical destruction.^[15] Silver nitrate application to the periungual region causes gray-black staining and rarely gangrenous necrosis.^[16]

Pox virus infections (Molluscum contagiosum [MC] and Monkeypox infections)

MC lesions responded well to 40% silver nitrate application, with 70% of lesions resolving in one application with a maximum of three applications needed for 97.7% resolution. Following application, the lesions become brown-black immediately, surrounded by an erythematous halo. Applying lignocaine jelly before the procedure prevents the erythematous flare, pruritus, and burning sensation.^[17] A black crust forms before the MC lesion drops between days 10 and 14.^[18] Silver nitrate paste has been tried successfully with 70% efficacy for MC to avoid unnecessary irritation caused by dripping of solution formulation onto the normal skin.^[17]

In a study by Rogers et al., polysaccharide-coated AgNPs of size 10 nm and silver nitrate decreased monkeypox virus plaque formation by 60-79% and 29-40%, respectively.^[19]

Herpes simplex virus (HSV) infection

A study by Pan et al., showed that AgNPs inhibited HSV-1 by reducing plaque formation, viral progeny production, and genomic load. AgNPs also interfere with HSV-1 messenger RNA expression and protein synthesis, alter the shape of viral particles, affect the virus’s entry, release, and cell-to-cell spread, and enhance the efficacy of acyclovir.^[20] AgNPs in a concentration of 100 μg/mL have also been shown to inhibit HSV-2 replication in vitro completely.^[21]

Human immunodeficiency virus (HIV)

AgNPs have demonstrated anti-HIV-1 activity by preventing CD4-dependent virion binding and fusion with a half-maximal inhibitory concentration between 0.44 and 0.91 mg/mL.^[22] Silver ions, by themselves, exert lower efficiency in inhibiting HIV-1 infection in vitro than AgNPs. This is evident from a study that showed that the therapeutic index of silver salts such as silver nitrate and SSD in HIV-1 inhibition was 12 times lower than AgNPs.^[22] It is also observed that the mutations in antiretroviral HIV strains conferring resistance were not found to affect the efficacy of AgNPs.^[22] However, the efficacy of AgNPs in HIV needs further confirmation with human studies since the majority of data are based on in vitro studies.^[22]

Silver and antifungal effect

AgNPs produced by the bioreduction of aqueous Ag⁺ ions by the leaf extract of Solanum trilobatum plant leaf have been found to have a higher inhibitory effect on Pityrosporum ovale. This effect has been proposed to enhance the efficacy of anti-dandruff shampoos. S. trilobatum-based AgNPs have also shown antifungal activity against Candida albicans and Candida parapsilosis.^[23] Silver-zinc zeolite nanoparticles coated soft denture liners are beneficial in the prevention of oral candidiasis.^[24] AgNPs have demonstrated anti-fungal activity against Microsporum canis, Trichophyton mentagrophytes, and Microsporum gypseum by creating pores in cell walls and plasma membranes and also against invasive mycosis like mucormycosis.^[25,26] Recently, antifungal creams such as luliconazole and ketoconazole have been combined with AgNPs to combat superficial mycoses.^[27,28] The various mechanisms by which AgNPs exhibit their antifungal effect are illustrated in Figure 3.^[29]

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Figure 3:

Mechanism of antifungal action of silver nanoparticles. AgNPs: Silver nanoparticles, ROS: Reactive oxygen species, ATPase: Adenosine triphosphatase, K⁺: Potassium ion, H⁺: Hydrogen ion, C oxidase: Cytochrome C oxidase, TCA: Tricarboxylic acid.

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Silver in parasitic infections

AgNP impairs the glycoprotein present on the surface of the parasite and can inhibit the proliferation of promastigotes, as demonstrated by Allahverdiyev et al., in Leishmania tropica. It was further studied that in the presence of increased ultraviolet light, AgNP further hampers amastigote endurance in the host cell.^[30] Inhibitory action against Leishmania amazonensis has also been studied.^[31]

Silver in burns and wound healing

Silver compounds have been exploited for their noteworthy role in the management of burns. The gold standard silver agent in the management of burns is SSD.^[34] Silver nitrate (0.5%) is considered the standard and popular silver salt solution for burn wound therapy. On the contrary, the reduction of nitrate to nitrite can lead to oxidative cell damage, impairing re-epithelialization.^[34]

The benefits of silver in wound healing can be attributed to various reasons, such as broad-spectrum antimicrobial activity, reduction in the activity of matrix metalloproteinase, combating biofilm formation, and its anti-inflammatory properties.^[35,36] An ideal silver dressing maintains a sustained, therapeutic silver ion concentration (>30 ppm) while not causing local or systemic toxicity (≤60 ppm). The role of silver in wound healing is illustrated in Figure 4.

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Figure 4:

Role of silver in wound healing.

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The various forms of silver dressings used in wound care include SSD, silver-coated nylon, silver-coated polyethylene, silver-coated foam, silver-coated silicone, silver-coated cellulose hydrofiber, and silver-coated polyurethane (PU) sponge.^[35] Silver-coated PU negative pressure wound therapy (NPWT) combines the benefit of NPWT and delivers an optimal concentration of silver that is below the toxic threshold to fibroblasts and keratinocytes.^[35] The advantages of silver-containing dressings include less frequent change of dressing, reduced pain levels, and accelerated wound healing in contaminated wounds. Silver has no beneficial role in non-infected clean wounds as it can delay epithelialization.^[35]

Dynamic reversible hydrogels have demonstrated a significant application in wound dressing. The use of SSD as a catalyst for the construction of hyaluronic acid-based hydrogels has enabled hydrogels to possess concurrent dynamics, stability, and antimicrobial properties.^[37] Silver in dressings can be either in ionic form or metallic form (extremely small crystals or nanocrystals). The metallic silver needs to react with substances in the wound bed to form soluble salts such as silver nitrate, silver chloride, or silver oxide, releasing free silver ions.^[36]

AgNP-loaded collagen chitosan dressing exerted significant biological effects on wound healing by regulation of growth and inflammatory factors (vascular endothelial growth factor [VEGF], basic fibroblast growth factor, transforming growth factor-beta 1, interleukin [IL]-1 beta, and epidermal growth factor-like domain 7).^[38]

Silver in graft procedures

NPWT combined with AgNP sheets has shown better results in patients undergoing graft procedures in terms of better graft integration and decreased levels of systemic inflammatory markers.^[39]

Silver as an astringent

Silver nitrate is used as an astringent in concentrations of 0.1-0.5% by drawing water out of the cells, causing dryness of exudative lesions. Hence, it is used in the management of leg ulcers and burns. Higher concentrations of silver nitrate are found to induce pain.^[40]

Silver in hyperhidrosis and bromhidrosis

PU sheets, modified using hydrophilic polymers and coated with SSD, are used as cushion insoles in patients with plantar hyperhidrosis. Perspiration leads to the swelling of hydrophilic polymers on the PU surface, causing SSD release, which has bactericidal properties. Hence, silver prevents bad odor in bromhidrosis and bacterial infections in plantar hyperhidrosis.^[41] In a randomized controlled trial by Celleno et al., an antiperspirant product based on silver citrate, aluminum hydrochloride, and agaricine showed beneficial antiperspirant and anti-bacterial activity with the added advantage of not staining the clothes.^[42]

Silver as a hemostatic agent

Silver nitrate is an inexpensive, readily available topical hemostatic agent effective in concentrations of 10% applied with light pressure over the bleeding site after application.^[43] Interaction of silver ions with proteins causes denaturation and precipitation of proteins and obstruction of small vessels. Silver nitrate application causes the formation of a thin eschar which prevents the formation of deep tissue necrosis.^[44] Side effects of topical silver nitrate application include a burning sensation and temporary black discoloration.^[44] However, application over large areas can cause permanent black discoloration due to silver particle impregnation. Inadvertent application of silver nitrate in large amounts can be neutralized by saline application.^[43]

Silver in papulosquamous disorders

Silver in autoimmune bullous disorders

Topical nano colloidal silver is effective in the management of hard-to-heal ulcers of pemphigus vulgaris with a significant positive effect on the ulcer area and exudate.^[48] Physiotulle silver dressings containing silver used in erosions of pemphigus vulgaris resulted in a significant reduction of pain score, reduced length of hospital stay, and reduced frequency of change of dressings.^[49]

Silver in onychocryptosis

High-strength silver nitrate is beneficial in the management of hypergranulation tissue, complicating ingrown toenails in concentrations of 40%, 75%, and 90% through applicator sticks.^[50]

Silver in umbilical granuloma

Umbilical granuloma, which presents with a pinkish to skin-colored granulomatous tissue, is the most documented umbilical abnormality in neonates. Careful application of silver nitrate 20% has been used once weekly over the lesion till resolution while protecting the surrounding area with petroleum jelly. Considering high rates of caustic burns and post-inflammatory pigmentation, other treatment modalities, such as the usage of common salt, electrocautery, cryotherapy, and topical steroids, are preferred.^[51]

Silver in acne vulgaris

Acne vulgaris, due to its chronic and relapsing nature, demands long-term antibiotic use, resulting in antibiotic resistance demanding the use of alternative treatment options. With the use of AgNP gel on the rising trend, the combination of AgNP gel and 2.5% benzoyl peroxide is effective in both moderate inflammatory and non-inflammatory acne lesions.^[52] A combination of AgNPs and extracts of Azadirachta indica (neem) leaves and Curcuma caesia rhizome has demonstrated good antibacterial activity against Propionibacterium acnes with a sustained drug release.^[53,54]

Silver socks in epidermolysis bullosa

Silver-fibered cotton socks and silver vinyl insole material can be used for foot care in epidermolysis bullosa which has the advantages of reducing friction and heat, conducting heat away from the skin, and additional antibacterial action.^[55]

Silver in cosmeceuticals

With the growing trend in the use of skincare and cosmetic products, consumers prefer safer products with long-term efficacy. This has led to the use of the term “cosmeceutical,” implying the overlap of cosmetics and pharmaceuticals. The cosmeceutical industry has integrated nanotechnology in the form of AgNPs in various products such as moisturizers, sunscreens, lipsticks, face cleansers, whitening creams, deodorants, toothpaste, and anti-aging products.^[56] The combination of silver and gold nanoparticles to produce yellow-red pigment has been utilized in the production of various cosmetic products such as lipsticks, foundations, powders, and eyebrow pencils.^[54]

Preference for silver as a nanoparticle in cosmeceuticals is attributed to its antimicrobial and anti-inflammatory properties.^[56] The anti-inflammatory effects are due to disruption of the VEGF pathway, decrease in TNF-alpha and IL-6, inhibitory effect on nuclear factor-kB signaling, and inhibition of prostaglandin and cyclooxygenase synthesis.^[56] Silver zeolite has been used as a deodorant in the axilla due to its strong and long-lasting bactericidal ability.^[57] The uses of silver in dermatology, venereology, and leprosy have been summarized in Table 1.

Use of silver-coated instruments in dermatology

The antimicrobial properties of silver have been highly valued in varied medical applications through the silver coating of instruments. Ready-to-use medical instruments with instant antimicrobial effects have been devised, which activate bioactive silver coating upon package opening.^[1] Invasive surgical tools, including medical needles, are coated with AgNPs with a particle diameter of 0.1-300 nm and silver concentration of 0.01-20% to prevent infection and provide pain relief. It was found that a silver concentration of <0.01% shows negligible antimicrobial effect, and more than 20% reduces the needle strength.^[1]

Silver stains

Silver staining involves utilizing silver to selectively modify the appearance of a specific target in the microscopy of histological sections. The uses of silver stains in dermatology are mentioned in Table 2.^[58-60]

Silver in Raman spectroscopy

Raman spectroscopy has been used recently to diagnose skin diseases, especially skin tumors such as basal cell carcinoma and melanoma, based on autofluorescence. AgNPs with unique optical properties of strong absorption and scattering of light have made them useful in surface-enhanced Raman spectroscopy.^[8]

Argyria

The term “argyria” derived from the Greek word argyros, meaning silver, was coined by Fuchs in 1840. It is an uncommon benign condition characterized by chronic exposure and the deposition of silver in the tissue.^[61,62] Argyria can be localized or generalized based on the mode and quantity of silver absorbed.^[62] The commonly characterized forms of localized argyrias are (i) cutaneous, (ii) oral cavity, and (iii) ocular. A few unusual localized argyrias are penis, vagina, urinary tract, nasal mucosa, and trachea.^[61,62]

Generalized argyrias occur due to systemic absorption of silver that gets widely deposited in the skin, nails, eyes, and mucous membranes.^[61] As alternative medicine gains popularity, the availability of silver-containing solutions increases, consequently raising the incidence of argyria. This trend is particularly noticeable in Asia, where there is a growing number of case reports documenting instances of argyria.^[63] Exceeding the daily oral exposure of 5 μg/kg/day of silver exposes the patients to risks of skin discoloration.^[64]

Apart from cutaneous deposition of silver, systemic side effects such as renal toxicity, leukopenia, and cytotoxicity have also been reported, especially through SSD dressings in burns involving >40% of body surface area.^[34]

Localized argyrias occur due to the impregnation of silver confined to the site of direct contact, especially in professions such as silversmithing and industries involving photography, soldering, batteries, and mirrors. Dental procedures, including those involving amalgam tattooing, as well as the use of silver jewelry such as earrings and nasal piercings, have also been linked to localized argyria.^[65] The presence of the Tyndall effect causes the brown colloidal silver particles located in the dermis to give off a bluish-gray appearance when observed through the skin.^[66] The differential diagnoses of argyria are mentioned in Table 3.

Histologically, yellow-brown colored collagen bundles resembling pseudo-ochronosis have been described occasionally.^[61] Management options include sunscreens, 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, 755 nm alexandrite laser, and low-fluence Q-switched Nd:YAG laser and avoidance of offending silver-containing agents.^[63,67]

Silver as an allergen

Most of the cases of allergic contact dermatitis (ACD) to silver seem to be related to occupation, such as jewelers, photographers, and silver miners.^[68] ACD has been reported to be silver sulfadiazine, silver nitrate, or silver fulminate.^[69] The side effects of topical silver preparations include stinging, pain, redness, chemical burns, and post-inflammatory pigmentation.^[70] The widespread erythema with irritant contact dermatitis is seen especially in atopic individuals and in clustered lesions over the intertriginous areas.^[17]