Applied Microbiology - 2017 - Naik - The Silver Lining Towards The Responsible and Limited Usage of Silver

Journal of Applied Microbiology ISSN 1364-5072
REVIEW ARTICLE
The silver lining: towards the responsible and limited usage

of silver
K. Naik and M. Kowshik
Department of Biological Sciences, BITS Pilani K K Birla Goa Campus, Zuarinagar, Goa, India
Keywords Summary
ingestion, inhalation, low concentration, Silver has attracted a lot of attention as a powerful, broad spectrum and natural
medical applications, nanosilver.
antimicrobial agent since the ancient times because of its nontoxic nature to the
human body at low concentrations. It has been used in treatment of various
Correspondence
Meenal Kowshik, Department of Biological infections and ulcers, storage of water and prevention of bacterial growth on the
Sciences, Birla Institute of Technology & surfaces and within materials. However, there are numerous medical and health
Science Pilani K K Birla Goa Campus, NH – benefits of colloidal or nanosilver apart from its microbicidal ability which as yet
17/B, Zuarinagar, Goa 403726, India. has not been fully embraced by the medical community. These include
E-mails: meenal@goa.bits-pilani.ac.in; antiplatelet activity, antioxidant effect, anticancer activity, wound healing and
meenalkowshik@gmail.com
bone regeneration, enhancement of immunity, and increase in antibiotic
efficiency. Additionally silver also provides protection against alcohol toxicity,
2017/0016: received 9 January 2017, revised
1 June 2017 and accepted 19 June 2017 upper respiratory tract infections and stomach ailments. Although nanosilver has
been proposed for various topical applications, its usage by ingestion and
doi:10.1111/jam.13525 inhalation remains controversial due to the lack of detailed and precise toxicity
information. These beneficial properties of silver can be utilized by using silver at
very low concentrations which are not harmful to the human body and
environment. The following review discusses the diverse medical applications of
silver and further recommends human clinical studies for its in vivo usage.
devices, clothing and textiles, water purification and dis-

Introduction
infection, cosmetics and personal care products, etc.
Natural colloidal silver was used as a strong and broad- Although silver is successfully used for topical and surface
spectrum antibiotic, since the late 1800s with no harmful applications in various fields, its usage is limited in cases
side effects observed, for well over 100 years. There have of medical applications which require oral ingestion or
been anecdotal references of ancient Greeks using silver inhalation. The primary concern associated with such
plates, silver cups and silver utensils which conferred applications is the risk of accumulation of silver in the
antimicrobial properties and prevented them from infec- body leading to heavy metal toxicity.
tious illness. Besides, silver has a long history of medical Silver can have numerous health benefits to the human
usage and was mostly used empirically even before the body when used within a limit and be potentially harmful
understanding that microbes were the agents of infection when used in excess. It is also desirable to supplement the
(Alexander 2009). Silver preparations were used by Hip- diet with adequate amounts of antioxidants like selenium,
pocrates the ‘Father of Medicine’, to treat ulcers and pro- vitamin E and amino acids like N-acetyl cysteine to safe-
mote healing of wounds (Hippocrates (400 B.C.E.)). guard from any potential harmful effects of heavy metals
In recent years, nanosilver has received a lot of atten- like silver. Hence, occasional short term usage of limited
tion in academic and scientific community due to its and minimal amounts of silver is preferred over the use of
potential antimicrobial applications and hence is widely excessive amounts of silver over long periods of time, espe-
studied for its release and effects (Nowack et al. 2011). cially in case of oral administration or inhalation. In this
Presently, nanosilver-incorporated products have been context, the following review seeks to unravel the potential
used in a diverse range of applications such as food medical and health applications of silver which have still
preservation and packaging, implants and other medical not been completely explored and used.
1068 Journal of Applied Microbiology 123, 1068--1087 © 2017 The Society for Applied Microbiology
13652672, 2017, 5, Downloaded from https://ami-journals.onlinelibrary.wiley.com/doi/10.1111/jam.13525 by Cochrane Netherlands, Wiley Online Library on [01/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
K. Naik and M. Kowshik The silver lining
extended spectrum b-lactamase producing Klebsiella,

Antimicrobial activity
multidrug-resistant Pseudomonas aeruginosa, ampicillin-
Silver ions and silver-based compounds possess strong resistant Escherichia coli O157:H7 and erythromycin-resis-
biocidal effects on micro-organisms including bacteria, tant Streptococcus pyogenes (Yu 2007; Duncan 2011; Lara
fungi, yeasts and viruses. Silver can exist in different et al. 2011).
forms such as elemental/metallic, ionic, nanosilver (1– Silver has also been demonstrated to decimate most of
100 nm) and colloidal (1–1000 nm) (Kulinowski 2008). the well-known bacterial pathogens that cause serious
The latter three forms are preferred over the metallic secondary infections during a viral infection such as
form due to their smaller size and higher surface area Streptococcus pneumonia, Corynebacterium diphtheria,
which facilitates higher antimicrobial efficiency. Neisseria gonorrhoeae, Klebsiella pneumonia, Haemophilus
Antibacterial activity of nanosilver (Fig. 1) has been influenza, Bordetella pertussis, Mycobacterium and Pneu-
demonstrated against a wide range of Gram-positive and mococci. These bacteria can cause complications including
Gram-negative bacteria (Wijnhoven et al. 2009; Duncan pneumonia, bronchitis, conjunctivitis, sinusitis, otits
2011). The bactericidal activity of silver has been reported media and other chronic illness such as asthma (Gordon
to reside in its ionic form, and micromolar doses (1– and Holtorf 2006).
10 lmol l 1) of silver ions are sufficient to kill bacteria Antifungal activity of silver nanoparticles (AgNPs) of
in water (Liu et al. 1994). The reported minimum inhibi- various sizes has been demonstrated against Candida albi-
tory concentration and minimum bactericidal concentra- cans and Candida glabrata which are common causes of
tion of AgNPs in the size range of 7 20 nm against oral thrush and dental stomatitis. Infections like these are
standard reference cultures are in the range of 078 625 particularly difficult to treat because the fungal micro-
and 125 lg ml 1 respectively (Jain et al. 2009). Nanosil- organisms involved form protective biofilms that prevent
ver is also effective against strains of organisms that are prescription antifungal drugs from functioning. These
resistant to potent chemical antimicrobials including AgNP suspensions exhibited fungicidal activity against
multidrug-resistant bacteria like methicillin-resistant Sta- the tested strains at very low concentrations in the range
phylococus aureus (MRSA), methicillin-resistant Staphylo- of 04–33 lg ml 1. Hence, AgNPs appear to be a new
cocus epidermidis, vancomycin-resistant Enterococcus, potential strategy to combat these infections. As the
AgNPs
Penetrate inside bacteria
Release of
Ag+ ions to enhance
bactericidal activity
Ag+
Generation
Destroy membrane of ROS e–
proteins
P–P–P
Inhibit electron
transport
e–
S–S–S
Destroy
bacterial
Membrane damage cell wall
and cell death Inhibit bacterial
DNA replication Inactivate
bacterial
proteins
Figure 1 Antibacterial mechanism of action of silver nanoparticles. [Colour figure can be viewed at wileyonlinelibrary.com]
Journal of Applied Microbiology 123, 1068--1087 © 2017 The Society for Applied Microbiology 1069
The silver lining K. Naik and M. Kowshik
nanoparticles are relatively stable in liquid medium, their inactivated by silver nitrate at concentrations of
use as mouthwash solution is proposed (Monteiro et al. 30 lmol l 1 or less (Shimizu et al. 1976). AgNPs of
2012). approximately 10 nm were demonstrated to inhibit mon-
Electrically generated silver ions at <2 lg ml 1 concen- keypox virus in vitro, supporting their potential use as an
tration were shown to exhibit more efficient fungicidal antiviral therapeutic agent (Rogers et al. 2008). AgNPs of
properties than silver compounds such as silver sulfadi- approximately 10–50 nm in diameter were demonstrated
azine and silver nitrate. The growth of all fungal organ- to interact with viral DNA of hepatitis B virus and pre-
isms was inhibited by silver concentration between 05 vent replication in vitro. In this case the antiviral mecha-
and 47 lg ml 1, and the fungicidal concentration of sil- nism was attributed to the direct interaction between the
ver was as low as 19 lg ml 1 (Berger et al. 1976a). nanoparticles and HBV double-stranded DNA or viral
AgNPs exhibited considerable antifungal activity against particles (Lu et al. 2008).
C. albicans and Trichophyton mentagrophytes, the cause of The collective authoritative medical literature reports
fungal infections of the hair, skin and nails. The antimi- silver to be virucidal against over 24 viruses. Additionally,
crobial activity of silver was found to be comparable to it has been proposed that 200 plus viral strains known to
Amphotericin B, one of the most powerful prescription cause upper respiratory tract infections, including most
antifungal drugs and superior to the well-known antifun- flu viruses, will also most likely succumb to the powerful
gal drug fluconazole (Kim et al. 2008a). antiviral qualities of very small particles of oligodynamic
Silver nanoparticles could also be used as an effective silver (Gordon and Holtorf 2006).
treatment for fungal infections of the eyes. Fungal kerati-
tis is emerging as a major cause of vision loss in develop-
Mode of antimicrobial action of silver
ing nations largely due to the unavailability of effective
antifungal agents. AgNPs were reported to exhibit potent The actual mechanism of toxicity of nanosilver is pro-
in vitro antifungal activity against over 216 different posed to be the sum of various mechanisms and hence
strains of ocular fungal pathogens such as Fusarium sp., termed as multimodal action. Silver is known to react
Aspergillus sp. and Alternaria alternate isolated from with nucleophilic amino acid residues in proteins, and
patients with fungal keratitis (Xu et al. 2013). attach to sulfydryl, amino, imidazole, phosphate and car-
Antiviral activity of natural mineral silver in a variety boxyl groups. It causes bacterial cell wall damage and dis-
of forms including colloidal silver has been demonstrated ruption of cytoplasmic membrane leading to leaching of
through nearly three decades of medical research (Fig. 2). metabolites, interferes with DNA synthesis, denatures
It has been reported that silver can stop different types of proteins and enzymes (dehydrogenases), binds to ribo-
viruses from replicating by merely binding to them. somes and inhibits protein synthesis, interferes with elec-
Recent research demonstrates that silver is so powerfully tron transport system and is involved in the production
effective against viruses that it even stops the deadly HIV of reactive oxygen species (ROS) (Hatchett and White
virus from infecting human cells. The vital requirement 1996; Feng et al. 2000). The primary mode of silver toxi-
in order to exhibit such powerful antiviral activity is the city is its potential to release silver ions. Irrespective of
size of the silver particles. Nanoparticles of size ranging the form of the silver used, a major characteristic that
from 1 to 100 nm are efficient as smaller size leads to will affect the microbicidal effect of the silver is the con-
more interaction and inhibition of viruses (Galdiero et al. centration of silver ions released. The nano form with its
2011; Khandelwal et al. 2014). Silver nanoparticles large surface area to volume ratio has high potential for
undergo a size-dependent interaction with HIV-1 virus release of silver ions (Sotiriou and Pratsinis 2010). All
and nanoparticles in the size range of 1–10 nm were able forms of silver including silver compounds and silver
to attach to the virus. The interaction is via preferential salts have potential to release silver ions. Even the bioci-
binding of AgNPs to the gp120 glycoprotein knobs which dal effect of elemental silver is due to formation of silver
bear the exposed sulphur residues and inhibit the virus ions at low concentration on its surface.
from binding to host cells in vitro (Elechiguerra et al. Nanostructured silver targets the bacterial cell wall and
2005). cell membrane which is a protective barrier and serves
Colloidal silver was found to show remarkable efficacy several functions (Sondi and Salopek-Sondi 2004).
against the smallpox virus. Collargol and Protargol were Nanoparticles <10 nm in diameter can bind to bacterial
the two medicinal preparations of colloidal silver used in cell wall and cause its perforation leading to rapid
the study. The reduction in concentration of viral parti- increase in cell permeability and ultimately cell death. In
cles was about 11 000 and 700 times for collargol and E. coli, nanosilver with average particle size of 12 nm is
protargol respectively (Bogdanchikova et al. 1992). Her- reported to result in formation of irregular shaped pits in
pes simplex virus types I and II was reported to be the bacterial cell membrane. Silver ions can also cause the
Virus replication cycle Antiviral mechanism
Silver nanoparticles
Virus Interactions with

Virus adsorption cannot viral surface
bind Glycoproteins
host cells
Host cell
Virus
penetration
Nucleus
Uncoating
Block
Virus virus
replication replication
Assembly
Progeny No progeny
Figure 2 Antiviral mechanism of action of virions virions
silver nanoparticles. [Colour figure can be
viewed at wileyonlinelibrary.com]
cell membrane to detach from the cell wall nevertheless, relies on the respiratory enzyme complexes associated
the mechanism of this process has still been unknown with the respiratory chain, and silver ions disrupt the
(Feng et al. 2000). Moreover, nanosilver binds with function of these enzymes by binding to the functional
membrane proteins and sulphur-containing proteins groups of amino acids and inhibiting the efficient elec-
through electrostatic interaction (Holt and Bard 2005; tron transport via the respiratory chain. This ultimately
Wong and Liu 2010), and inhibits their function or dam- results in the complete breakdown of electron transport
ages their structure by generating free radicals (Choi and and blockage of phosphorylation of ADP to ATP. NADH
Hu 2008). dehydrogenase complex is reported to be a potential tar-
Silver can attack the respiratory chain in bacteria and get for silver ion activity (Holt and Bard 2005). Forma-
lead to cell death (Sondi and Salopek-Sondi 2004). Respi- tion of proton-depleted regions around AgNPs was
ration is the critical point in bacterial cell metabolism observed due to the micro-galvanic effect which could
and is the mechanism of obtaining energy to perform all further lead to disruption of electrochemical gradient
the energy-demanding life processes. Energy generation (Cao et al. 2011).
The creation of free radicals and induction of oxidative caused by a variety of stress conditions, including desic-
stress also contributes towards toxicity of AgNPs/ions cation, dehydration, heat, cold, oxidation and toxic
(Kim et al. 2007; Cao and Liu 2010; Wong and Liu agents (Alvarez-Peral et al. 2002; Elbein et al. 2003).
2010). Production of ROS is dependent to some extent Nanosilver-treated cells were shown to accumulate more
on the catalytic activity of nanoscale silver. ROS genera- intracellular as well as extracellular glucose and trehalose
tion is initiated mainly as an outcome of the respiratory as compared to the untreated cells. This increase in the
enzymes and respiratory chain dysfunction (Choi and Hu sugar amount was attributed to several intracellular com-
2008). ROS are generated within or outside of the cell, as ponents released during membrane disruption by nanosil-
a consequence of cell damage/disruption (Liu et al. ver (Lee et al. 2010b). It was also hypothesized that silver
2010). Studies using nitrifying bacteria have revealed that ion primarily affects the function of membrane-bound
the increase in intracellular ROS levels was correlated enzymes such as those in the respiratory chain resulting
with the rate of bacterial growth inhibition (Choi and Hu in loss of cellular integrity and osmosis (Mendes et al.
2008). Sustained release of silver ions by AgNPs inside 2014). Potential damage to the cell wall and transmem-
the bacterial cells in an environment with lower pH may brane proteins and up-regulation of cell wall-strengthen-
create free radicals and induce oxidative stress, thus fur- ing genes in surviving cells was recently reported in the
ther enhancing the bactericidal activity (Morones et al. yeast Saccharomyces cerevisiae (Niazi et al. 2011). Addi-
2005; Song et al. 2006). tionally, when C. albicans and S. cerevisiae cells were
Genetic material being one of the important target exposed to AgNPs, significant changes to the membrane
sites, nanostructured silver was also reported to cause structure were observed. Pit formation was detected on
damage to the DNA (Feng et al. 2000; Kim et al. 2010). the cell surfaces which finally resulted in the formation of
DNA loses its replication ability once the bacteria are pores and cell death (Nasrollahi et al. 2011). Silver ion is
treated with nanosilver. This is due to the capacity of sil- reported to form complexes with the bases contained in
ver ions to bind to the phosphorane residues of DNA DNA and is also a potent inhibitor of fungal DNases
molecules (Hatchett and White 1996; Morones et al. (Saraniya Devi and Valentin Bhimba 2014).
2005). This interaction may prevent cell division and may
ultimately lead to cell death. Furthermore, silver ions are
Antibiofilm activity
also reported to affect gene expression. In E. coli, it has
been shown that nanosilver denatures the 30S ribosomal In the natural world, more than 99% of all bacteria exist
subunit by preventing the expression of S2 protein, a as biofilms (Costerton et al. 1987). Biofilms are the pro-
component of the ribosomal subunit. Additionally, the tective structures created by the colonies of pathogens in
expression of genes encoding other proteins and enzymes order to evade the effects of antibiotic drugs. They are
involved in energy reactions in ATP synthesis was also protected by an extracellular matrix held together by pro-
inhibited (Gogoi et al. 2006). teins and polysaccharides commonly referred to as extra-
Release of silver ions is also reported to cause inactiva- cellular polymeric substance. This affects the efficiency of
tion of proteins. Silver ions can interact with sulphur- the strongest of antibiotics and biofilms can be as much
containing proteins and thiol groups of vital enzymes in as a thousand times more resistant than planktonic cells.
bacterial cell and result in their impaired function or The growth of biofilms is a major problem within the
inactivation (Hatchett and White 1996; Cao and Liu healthcare and food industries. Biofilms can form on
2010). Silver exhibits catalytic activity by binding to the many medical implants such as catheters, artificial hips
functional groups of amino acids and forming –S–S– and contact lenses. According to the National Institute of
bonds between the adjacent –SH groups in proteins. The Health more than 60% of all infections are caused by
formation of additional –S–S– bonds may induce molec- biofilms. These include, but are not limited to endocardi-
ular changes and lead to protein and enzyme inactivation tis, cystic fibrosis, otitis media, chronic prostatitis, uri-
(Wzorek and Konopka 2007). AgNPs are also reported to nary tract infections, dental plaque infections, gingivitis,
modulate the phosphotyrosine profile of putative bacte- periodontitis, chronic sinusitis, burn wound infections
rial peptides that could affect cellular signalling and and bone infections (Kim 2001).
therefore inhibit the growth (Shrivastava et al. 2007). Many recent studies have demonstrated conclusively
Antifungal activity of nanosilver against C. albicans was that antimicrobial silver can penetrate through the bacte-
attributed to disruption of cell membrane structure and rial biofilms to completely destroy them and can even
integrity resulting in inhibition of normal budding pro- prevent microbes from developing biofilms. As compared
cess (Kim et al. 2009). Trehalose is known to play a pro- to the antibiotics, silver is proposed to be less affected by
tective role in yeast by preventing the inactivation or the micro-environmental variations found in biofilms due
denaturation of proteins and biological membranes, to its multimodal mechanism of action (Bjarnsholt et al.
2007). Antibiofilm activity of nanosilver has been sum- Antibiofilm activity of several other AgNPs composites
marized in Table 1. such as starch-stabilized AgNPs (Mohanty et al. 2012),
Antibiofilm activity of nanosilver in combination with AgNP-incorporated PU (polyurethane), PCLm (polycap-
other compounds has also been assessed and a higher rolactam), PC (polycarbonate) and PMMA (polymethyl-
efficacy in blocking the biofilm formation is observed due methaacrylate) nanocomposites (Sawant et al. 2013),
to the synergistic effect. Combination of curcumin citrate-capped AgNPs of various sizes (Park et al. 2013;
nanoparticles and AgNPs inhibited biofilm formation Habash et al. 2014), AgCl incorporated TiO2 (Naik and
more effectively as compared to when used alone (Loo Kowshik 2014a), AgNPs stabilized by polyvinylpyrroli-
et al. 2016). Antibiofilm activity of biocompatible chi- done (Bryaskova et al. 2011), b-cyclodextrin-stabilized
tosan stabilized AgNPs (CS-AgNPs) was evaluated against AgNPs (Jaiswal et al. 2015), AgNPs stabilized by hydrol-
clinical isolate of E. coli under in vitro conditions. It was ysed casein peptides (Radzig et al. 2013), and other
reported that 81% biofilm inhibition was brought about AgNPs (Fabrega et al. 2009; Gurunathan et al. 2014) have
by 100 lg ml 1of free AgNPs while complete inhibition been recently reported.
(100%) was successfully achieved using CS-AgNPs com- In addition to the above-mentioned preliminary stud-
posite at 75 lg ml 1 (Namasivayam and Roy 2013). ies of the antibiofilm activity of AgNPs, some nanosilver
Enhanced biofilm inhibition in polymer-stabilized coated or incorporated medical devices are already at the
nanoparticles is due to the inhibition of exopolysaccha- stage of clinical trials. The most prominent examples are
ride synthesis limiting the formation of biofilm (Kalish- surgical masks (Li et al. 2006), catheters (Stevens et al.
waralal et al. 2010) and the diffusion of CS-AgNPs 2011), drains (Lackner et al. 2008) and wound dressings
through the channels present in the biofilms followed by (Knetsch and Koole 2011; Velazquez-Velazquez et al.
the sustained release of antimicrobial metal nanoparticles 2015). Dental composites containing AgNPs have been
(Jena et al. 2012). This enhanced activity of stabilized fabricated and are reported to act against biofilms of oral
nanoparticles is also attributed to the stabilizing agent bacteria such as Streptococcus mutans. These new
which prevents the aggregation of particles into larger nanocomposites significantly reduced the metabolic activ-
forms that can significantly decrease their activity (Mar- ity and lactic acid production of Strep. mutans biofilms
kowska et al. 2013). Synergistic effect of biogenic AgNPs as compared to the two commercial composites (Cheng
has also been studied with plant products and antibiotics et al. 2012). Likewise, bone cements modified with
on the biofilms of clinical isolates of Staph. aureus and AgNPs significantly reduced biofilm formation on the
Candida tropicalis, and has been extended to applications surface of the cement (Slane et al. 2015). The above data
such as coating on catheters for antibiofilm activity validates that AgNPs can effectively and rapidly destroy
against Staph. aureus (Namasivayam et al. 2011, 2012). biofilms produced by a variety of microbes at clinically
Table 1 Antibiofilm activity of nanosilver
Antibiofilm
Material Micro-organisms tested concentration References
AgNP-coated surfaces Methicillin-resistant Staphylococcus aureus (MRSA), 50 lg ml 1

Ansari et al. (2015)
methicillin-resistant Staphylococcus epidermidis (MRSE)
AgNPs Multidrug-resistant strains of Pseudomonas aeruginosa 20 lg ml 1 Palanisamy et al. (2014)
Biologically synthesized AgNPs Escherichia coli 05–64 lg ml 1
Barapatre et al. (2016)
Pseudomonas aeruginosa
Staphylococcus aureus
Silver ions Staphylococcus epidermidis 50 ppb Chaw et al. (2005)
1
AgNPs Pseudomonas aeruginosa 50–100 nmol l Kalishwaralal et al. (2010)
Staphylococcus epidermidis
Nanometer scale silver coatings Proteus mirabilis Not determined Sahal et al. (2015)
Candida glabrata
Candida tropicalis
1
AgNPs Pseudomonas aeruginosa 100 mg ml Martinez-Gutierrez et al. (2013)
AgNPs Staphylococcus aureus 15 lg ml 1 Goswami et al. (2015)
Escherichia coli
Biogenic AgNPs coated catheter Staphylococcus aureus 100 lg ml 1
Namasivayam et al. (2013)
achievable concentrations, making silver a potential anti- production in P. aeruginosa after cellular internalization.
biofilm drug. In the absence of AHLs, the receptors LuxI and LuxR
cannot bind to the DNA, thereby inhibiting the expres-
sion of targeted genes which encode virulence factors and
Antiquorum sensing activity
biofilms (Singh et al. 2015). Similarly, few other studies
Quorum sensing (QS) is a cell-to-cell-based communica- have reported the anti-QS activity of biologically synthe-
tion mechanism which functions by means of production sized AgNPs (Arunkumar et al. 2014; Singh et al. 2015;
and reception of diffusible signal molecules also called as Anju and Sarada 2016).
autoinducers by bacteria, to regulate the expression of cer-
tain phenotypes that are dependent on population density.
Silver-based composites
This phenomenon is used by bacteria to understand
changes in their environment and consequently apply Several studies are currently developing nanocomposites
specific strategies that allow adaptation to environmental containing silver that present higher efficiency due to
stress in space and time. Compounds that inhibit or inter- their composite nature. In order to utilize the benefits of
fere with QS have become significant as novel class of next nanosilver without any harmful effects, the main focus is
generation antimicrobial and antibiofilm agents. Develop- to reduce the total silver dose and improve its biocom-
ment of resistance to anti-QS compounds is minimal as patibility. Moreover, subsequent release of free nanoparti-
these agents only target virulence mechanisms and do not cles in the environment can cause unforeseeable effects
impede growth, whereas the conventional antibiotics pre- on the ecosystem and human health (Esteban-Tejeda
vent the bacterial cell division or kill the bacterial cells and et al. 2010). To overcome such difficulties, it is proposed
increase the selective pressure towards antibiotic resistance. that AgNPs be embedded or incorporated in various
QS signalling molecules serve as a switch to pathogenic matrices such as polymers, zeolites, ceramics, glasses, etc.
state in most of the bacteria and are important for the In this regard many silver-based nanocomposites have
establishment of infection. This co-operative behaviour of been synthesized wherein AgNPs are uniformly dispersed
pathogenic organisms aids in the development of biofilm in a suitable matrix in order to avoid agglomeration
(Whitehead et al. 2001; Wagh Nee Jagtap et al. 2013). problems, facilitate slow and sustained release of silver
Although the molecular interplay between QS and biofilm into the media and reduce their toxic effects. The antimi-
formation remains ambiguous, it is now clear that QS is crobial activity of silver-based nanocomposites has been
involved in the maturation and differentiation of biofilms summarized in Table 2.
(Favre-Bonte et al. 2003). A simple screening protocol of
anti-QS compounds, based on the decrease in production
Upper respiratory tract infections
of violet colour pigment by Chromobacterium violaceum
has been developed and widely used (McLean et al. 2004). Colloidal or nano silver owing to its strong and broad-
Recently, AgNPs have been reported to exhibit potent spectrum antimicrobial properties could possibly have the
anti-QS activity (Fig. 3). Silver nanowires exhibit anti-QS potential to heal a variety of upper respiratory tract infec-
activity in the concentration range of 05–4 mg ml 1. tions in an effective way. Some of these infections include
There was a reduction of about 60% in violacein synthe- pneumonia, bronchitis, cystic fibrosis, chronic obstructive
sis at 05 mg ml 1, whereas a concentration of pulmonary disease, sinus, asthma, allergies and other lung
4 mg ml 1 resulted in 80% reduction, compared to diseases. The treatment consists of atomizing silver using
100% violacein synthesis in the control (Wagh Nee Jagtap a nebulizer or nasal spray. Although this treatment
et al. 2013). In an anti-QS study of AgCl-TiO2 nanoparti- appears to be very promising, its full-fledged use is lim-
cles (ATNPs), a significant drop in violacein production ited until the long-term safety of inhaling minute silver
was observed at 100, 200 and 300 lg ml 1 of ATNPs particles into lungs is exhibited by clinical studies.
(effective silver concentration of 117, 234 and A 28-day inhalation toxicity study of AgNPs in rats did
352 lg ml 1 respectively) using NB as the growth med- not exhibit any significant changes in the haematology
ium. The anti-QS concentration of ATNPs decreased to and blood biochemical values for both male and female
25 lg ml 1 of ATNPs (effective silver concentration of rats, and no distinct histopathology findings were
029 lg ml 1) in modified Tris minimal media. The sil- observed, indicating that exposure to silver did not have
ver present in ATNPs inhibited QS by interfering with any significant health effects (Ji et al. 2007). However a
the AHL activity (Naik and Kowshik 2014b). 90-day animal study resulted in lung function changes
Possible mechanism for anti-QS activity by mycofabri- due to prolonged AgNP inhalation exposure (Sung et al.
cated AgNPs has been reported in P. aeruginosa model 2008). Another AgNP inhalation toxicity study for
recently. AgNPs inhibit the LasIR-RhlIR-mediated AHLs 90 days indicated that lungs and liver were the major
Nanosilver
Autoinducer
Exported to
transcription
extra-cellular
complex
space
Autoinducer Cognate receptor Autoinducer Cognate receptor

synthase synthase
No production
of signal
molecules
Signal molecules
Transcription
of QS No
regulated expression of QS
genes regulated genes
QS signalling Anti-QS activity
Figure 3 Antiquorum sensing mechanism of action of nanosilver. [Colour figure can be viewed at wileyonlinelibrary.com]
target tissues for prolonged AgNP accumulation. How- were noted in pulmonary ROS or pro-inflammatory cyto-
ever, a higher dose with prolonged exposure was needed kine generation. Further study of silver-based nanomate-
to induce any toxic responses (Sung et al. 2009). rials over longer human exposures is necessary to
Inhalation exposure studies of colloidal silver have not determine the risks (Munger et al. 2014).
been conducted on human subjects until now. Recent As colloidal silver has been shown to alleviate inflam-
human oral exposure study demonstrated that a 14-day matory symptoms in cystic fibrosis patients (Baral et al.
oral dosing of a commercial colloidal silver product did 2008), it could be developed into successful treatment
not produce any observable clinically important toxic for chronic lung infections associated with cystic fibrosis.
effect. No morphological changes were detected in the Currently there is no evidence to support the use of sil-
lungs, heart or abdominal organs. No significant changes ver products in the above-mentioned upper respiratory
Table 2 Antimicrobial activity of silver-based nanocomposites
Material Micro-organisms tested Inhibitory concentration Reference
Silver bromide nanoparticle/polymer Bacillus cereus 50 lg ml 1 Sambhy et al. (2006)

composite Escherichia coli 50 lg ml 1
PAEMA-co-Ag cotton fabric Escherichia coli 965% Liu et al. (2014)
Poly (2-aminoethyl methacrylate) (PAEMA) Staphylococcus aureus 995%
1
Silver nanoparticle (Ag NP)-loaded Escherichia coli DH5a 05–15 mmol l Yang et al. (2016)
chitosan composites
AgNPs/alginate Escherichia coli 3 mg l 1 Van Phu et al. (2014)
Silver-Titania (Ag0Np/TiO2Np) Staphylococcus aureus ATCC 25923 2082 lg ml 1 Gavriliu et al. (2009)
Escherichia coli ATCC 25922 1588 lg ml 1
Enterobacter cloacae ATCC 13047 (G-) 1588 lg ml 1
Acinetobacter (G-) baumannii ATCC 17978 2082 lg ml 1
Candida albicans ATCC 10231 1588 lg ml 1
Pseudomonas aeruginosa ATCC 27853 1588 lg ml 1
Ag/(C, S)-TiO2 nanoparticles Escherichia coli ATCC C3000 25 mg ml 1 Hamal et al. (2010)
B. subtilis spores ATCC 6633 25 mg ml 1
TiO2@C/Ag core-shell composite Escherichia coli ATCC 25922 10 lg ml 1 Tan et al. (2009)
Staphylococcus aureus ATCC 6538 20 lg ml 1
Nanohybrids of silver and clay Staphylococcus aureus c. 300 lmol l 1
silver Su et al. (2009)
Streptococcus pyogenes
Pseudomonas aeruginosa
Escherichia coli
Salmonella typhimurium (G-)
Acinotobacter baumannii
AgCl-TiO2 Escherichia coli 2345 117 ppb Naik et al. (2013)
Bacillus subtilis 2545 117 ppb
Pseudomonas aeruginosa 741 585 ppb
Staphylococcus aureus 737 234 ppb
Candida albicans 3958 117 ppb
5% Ag-Hap Escherichia coli 160 lg ml 1
Jadalannagari et al. (2014)
Staphylococcus aureus 300 lg ml 1
tract infections but their potential benefits might be

Antibacterial zombies effect
worthy of further exploration. Nanosilver could also
have potential applications in the treatment of tubercu- In order to prevent bacterial recolonization and prolifera-
losis, a serious infectious airborne bacterial disease tion it is highly desirable for an antimicrobial agent to
caused by the bacterium Mycobacterium tuberculosis. The have long-term effectiveness (Brady et al. 2003; Ferrara
antibiotic-resistant tuberculosis pathogens were rapidly et al. 2011). One of the most effective methods to pro-
killed when tested against nanosilver capped with bovine long antimicrobial activity is incorporation of antimicro-
serum albumin (Seth et al. 2011). AgNPs were found to bial agents in sustained release delivery systems that
inhibit M. tuberculosis by inducing metabolic distur- enable their continuous use (Gao et al. 2011; Agarwal
bances in the cytoplasm of these cells at a concentration et al. 2012).
of 10 ppm (Song et al. 2006). Silver can be used in res- In a recent study, it has been discovered that when P.
piratory devices like ventilators, inhalers and continuous aeruginosa cells are killed by silver, the dead bacteria act
positive airway pressure machines to prevent the growth as sponge-like repositories which attract and absorb tiny
of micro-organisms in the water reservoir and breathing silver particles from its surroundings, and then leach that
apparatus. This acts as a disinfectant and helps keep the silver out killing other nearby cells in a chain reaction
devices clean of microbial build up and biofouling. Sil- that continues until all the bacterial cells are killed. The
ver when used in these apparatus also helps keep the researchers termed this process as the ‘zombies’ effect.
lungs infection free and prevents the chronic upper res- This phenomenon consisted of two important character-
piratory tract infections associated with usage of such istics. Firstly, the metallic species were not deactivated by
devices. the killing mechanism and therefore could carry on their
biocidal effect repeatedly and secondly the dead bacteria when AgNPs were used in combination with 26 different
served as an efficient sustained release reservoir for releas- antibiotics such as ampicillin, kanamycin, erythromycin,
ing the lethal metallic cations for further action against chloramphenicol, penicillin G, amoxicillin, erythromycin,
other live bacteria (Wakshlak et al. 2015). clindamycin and vancomycin. The antibiotic molecules
contain many active hydroxyl and amino groups which
react with AgNPs by the process of chelation. Hence, the
Gastrointestinal diseases
synergistic effect may be attributed to the binding reac-
Colloidal oxide of silver was tested on human subjects tion of antibiotic and AgNPs (Klippstein et al. 2010;
for the treatment of peptic ulcer in a clinical study. Naqvi et al. 2013). No cytotoxic effect of AgNPs on
Tablets containing colloidal silver oxide were given for mammalian cells was observed at concentrations with
oral ingestion to 88 patients with peptic ulcers over a effective antibacterial activity. Furthermore, restoration of
period of 9 days. All cases except one were reported to the susceptibility of a drug-resistant E. coli strain to
be healed within 6 weeks (Rendin et al. 1958). Thereafter ampicillin was observed when ampicillin was combined
no studies have been conducted to test the efficacy of sil- with AgNPs (Shahverdi et al. 2007; Fayaz et al. 2010;
ver for treatment of ulcers. When antimicrobial suscepti- Panacek et al. 2016).
bility of different antibiotic groups and silver solution Silver-Water Dispersion was demonstrated to work
was tested against organisms causing food poisoning such synergistically with antibiotic drugs and produce an addi-
as Salmonella typhi and E. coli, it was observed that col- tive effect when used in combination with them. This sil-
loidal silver exhibited superior antimicrobial activity com- ver solution has been shown to be effective against MRSA
pared to other antibiotics (Feng et al. 2000; Assar and and many multiple drug-resistant (MDR) strains (E. coli,
Hamuoda 2010). In a study designed to investigate the P. aeruginosa). According to the study, antibiotics may
effects of nanosilver on the production of cytokines, it cause symptoms in patients to temporarily disappear and
was observed that the cytokine production was signifi- yet leave behind a host of resistant organisms. These
cantly inhibited by nanosilver. These experimental data resistant organisms can reappear at a later stage straining
suggested that anti-inflammatory benefits of nanosilver the immune system. Therefore, it is proposed that the
could be used to treat immunologic and inflammatory combination of silver solution and antibiotics will pro-
diseases such as Crohn’s disease (Shin et al. 2007). vide more complete clearing of the pathological organism
AgNP-impregnated Lactobacillus fermentum have been from the body (De Souza et al. 2006).
found to be effective against rotavirus and norovirus When antibiotics are boosted with a small amount of
which cause food poisoning and winter vomiting out- silver these drugs can kill 10–1000 times more bacteria.
breaks. As AgNPs used in this study are extremely small This is because silver increases the membrane permeabil-
with large surface area, it enables them to clump around ity which allows more antibiotics to enter the bacterial
the virus increasing the inhibitory effect. There are con- cells. This mechanism may overpower the resistance
cerns about using such small silver particles in humans as mechanisms that rely on shuttling the drug back out
they could pass into other parts of the body and cause which results in making the bacteria sensitive to the
harm. Hence attaching these AgNPs to the surface of the antibiotic. This disruption in the cell membrane is also
bacterium enables fixing of the silver onto a larger entity reported to increase the effectiveness of vancomycin, a
that cannot pass into other parts of the body. Although large molecule antibiotic, on Gram-negative bacteria
the bacteria eventually die as a result of the silver, they which have a protective outer coating (Morones-Ramirez
remain intact and the dead cells carrying the silver parti- et al. 2013). Furthermore, the drug interaction study
cles can then be added to solutions and used. It has been showed no antagonism indicating that concomitant use
proposed that the same technique could be applied to of colloidal silver with these antibiotics does not affect
combat other viruses such as influenza and those causing the absorption or therapeutic efficacy of either agent.
common cold. These bacteria could also be incorporated Hence, use of colloidal silver in combination with antibi-
into nasal sprays, water filters and hand washes for otics can be an effective strategy due to its low toxicity
achieving antiviral activity (Verstraete 2010). and high therapeutic activity against pathogenic micro-
organisms (Iroha et al. 2007).
Synergistic effect of silver and antibiotics
Blood platelet disorders
Recently, AgNPs have been reported to be suitable candi-
dates for use in combinations with traditional antibiotics Anticoagulant therapies are associated with serious bleed-
in order to increase their antimicrobial efficiency. ing complications as exact dosing can be a challenge.
Improved effectiveness against pathogens was observed Excessive amounts of an anticoagulant can cause blood
loss, whereas too little of an anticoagulant may clog AgNPs may attenuate antigen-induced airway inflamma-
patient’s arteries. Researchers have tested the effectiveness tion and hyper-responsiveness. One of the molecular
of nanosilver particles as an anticoagulant and demon- bases in the murine model of asthma could be antioxi-
strated that nanosilver has an innate antiplatelet property. dant effect of AgNPs. These findings may provide a
It effectively prevents integrin-mediated platelet potential molecular mechanism of AgNPs in preventing
responses, both in vivo and in vitro, in a concentration- or treating asthma (Park et al. 2010).
dependent manner. Experiments with laboratory mice
showed that nanosilver particles effectively controlled
Wound healing and bone regeneration
clumping of platelets irrespective of the disease that
caused it. In ultra-structural studies it was observed that It was way back in 1970s that electrically generated silver
nanosilver accumulated within platelet granules and ions were used for the first time to treat severe cases of
reduced interplatelet proximity. Surprisingly when nano- antibiotic-resistant osteomyelitis, a bone infection that
gold was tested, it showed no antiplatelet activity (Shri- causes large wounds in the flesh. In this study, silver ions
vastava et al. 2009). In another study, nanosilver were directly generated into open infected wounds
prevented platelet adhesion without conferring any lytic through the use of a small, battery operated colloidal sil-
effect on them and effectively prevented integrin- ver generator operating at 09 volts. It was observed that
mediated platelet responses in a concentration-dependent the silver effectively killed the disease causing micro-
manner (Bandyopadhyay et al. 2012). Antiplatelet activity organisms and also triggered regrowth of human tissue
has also been demonstrated by Gluconobacter roseus- and bone at the site of the infection. Electrically gener-
mediated biologically synthesized AgNPs (Krishnaraj and ated silver ions not only killed the pathogens and healed
Berchmans 2013). However, further detailed studies are the infection but also stimulated tissue and bone
warranted before silver can be proposed as a potential regrowth (Becker 2000).
antiplatelet agent. In a later study by the authors, local tissue regenera-
tion in humans was induced using patient’s own cells at
the desired site which could be caused to de-differentiate
Antioxidant effect of silver
into the required embryonic stem cells. Silver ions were
Antioxidants are substances that when present at low generated directly into the human body by passing a tiny
concentrations, significantly prevent or delay a pro-oxi- electrical microcurrent through surgically implanted silver
dant initiated oxidation of the substrate (Prior and Cao rods or silver mesh. These silver ions could stimulate
1999). A pro-oxidant is a toxic substance that can cause wound healing and tissue regeneration by killing infec-
oxidative damage to lipids, proteins and nucleic acids tions and triggering a process called cellular dedifferentia-
resulting in various pathological diseases. Examples of tion (Becker 2002). The process of silver-assisted wound
pro-oxidants include reactive oxygen and nitrogen species healing by means of cellular dedifferentiation is explained
(ROS and RNS) which are products of normal aerobic as follows (Fig. 4). When silver ions come in contact with
metabolic processes (G€ ulcßin 2012). It has been reported the wound bed, they combine with proteins, peptides and
that an increased intake of dietary antioxidants could other chemical species normally present in the tissues.
protect against chronic diseases such as cancers, cardio- After all the available sites are saturated with binding of
vascular and cerebrovascular diseases (Ramasamy et al. silver ions, the antibacterial action of silver begins at
2013). about 20–30 min following the exposure of bacteria to
CC1(4) solvent, a kidney and liver toxin was used to the ions. The next reaction is an association between the
damage the livers of mice after which the mice were trea- silver ions and sensitive cells present in the wound such
ted with AgNPs. It was observed that the silver cured the as mature fibroblast and epithelial cells, resulting in ded-
mice of majority of the liver damage caused by the toxin. ifferentiation of these cells into embryonic cell types cap-
Silver was effective in revival of all biological parameters able of redifferentiation into other cell types. Production
to near normal in all intoxicated groups indicating the of dedifferentiated fibroblasts requires a continuous sup-
curing effects of AgNPs at low dosages on CC1(4)- ply of excess silver ions for at least 48–72 h following sat-
induced liver injury. This hepatocurative effect of dam- uration of the active chemical sites in the previous
aged mice livers was attributed to the strong antioxidant reaction. If sufficient silver ions are made available, a
effect of silver (Suriyakalaa et al. 2013). third reaction begins to take place. This constitutes a
A mouse model of allergic airway disease was used to specific physical association of at least some of the silver
evaluate the effect of AgNP inhalation on airway hyper- ions with the collagen fibres present in the wound to
responsiveness and inflammation and to investigate the produce a unique structure called as silver-collagen com-
related molecular mechanisms. The results indicated that plex having the specific properties required to induce
Step 1: Antimicrobial effect

Bacterial colonization
Electrically generated silver ions were reported to kill
Silverions Chronic and Biofilm formation numerous forms of infectious micro-organisms. For
wound
Epidermis
example, Providencia stuartii, a burn wound isolate which

was resistant to all antibiotics except amikacin, was sus-
ceptible to electrically generated silver with a minimum
bactericidal concentration of 073 g ml 1. Oligodynamic
Ag+ was found to be 10–100 times superior to silver sul-
Dermis
fadiazine in case of both Gram-positive and Gram-nega-

tive pathogens in terms of achieving the minimal lethal
dose (Berger et al. 1976b).
Step 1: Binding of silver ions to fibroblasts, etc.
Excess supply of silver ions Anticancer activity
The idea that silver could be effective against cancer has
been around since a long time. In 1970s, Dr. Becker pro-
posed that silver can revert cancerous cells back to
healthy cells when electrochemical treatment was used to
generate silver ions directly into a cancer cell culture
(Becker and Selden 1985). However, there are no further
studies confirming such a mechanism. More recent stud-
Step 3: De-differentiation and formation of
ies on anticancer property of silver are based on cytotoxic
silver-collagen complex effect of silver. The anticancer properties of colloidal sil-
More silver ions ver and AgNPs stabilized by chitosan were tested against
human breast cancer cells (MCF-7) and liver cancer cells
(HepG2) for development of anticancer drugs. It was
observed that both the forms of silver caused the breast
and liver cancer cells to self-destruct in a dose-dependent
manner. The experimental results indicated that there
was an immediate induction of cellular damage in terms
of loss of cell membrane integrity, oxidative stress and
apoptosis postsilver treatment (Franco-Molina et al.
Step 4: Re-differentiation and wound repair 2010; Prema and Thangapandiyan 2015). When biologi-
cally synthesized AgNPs were tested on tumour-bearing
mice and Dalton’s lymphoma ascites cell lines, they acti-
vated the caspase 3 enzyme leading to induction of apop-
tosis (Fig. 5) which was further confirmed by subsequent
nuclear fragmentation (Sriram et al. 2010). Additionally,
silver ions can displace the K+-dependent glucose trans-
port mechanism which is the exclusive means by which
cancerous cells obtain nutrition, thereby selectively starv-
Key ing cancer cells without harming normal cells.
Neutrophil Endothelial Fibroblast It has long been suspected that infectious agents are
cell associated with solid tumour cancers like Kaposi ‘s sar-
Macrophage Balstemal Collagen coma as well as nontumour-based cancers such as leukae-
cell
mia and many other types of cancers like
Figure 4 Silver-assisted regeneration and repair of wound. [Colour adenocarcinoma, lymphoma and breast cancer. Many
figure can be viewed at wileyonlinelibrary.com] mechanisms of carcinogenesis by infectious micro-organ-
isms have been proposed such as induction of chronic
activation of the dedifferentiated fibroblast cells previ- inflammation, production of mutagenic compounds by
ously produced. After this, an adequate blastema is bacterial metabolism, transformation of cells by inserting
formed in the tissue which supports regeneration and active oncogenes into the host genome, inhibiting tumour
wound repair by the process of redifferentiation of blas- suppressors or stimulating mitosis and infectious agents
tema into the required cell types (Becker et al. 1998). like human immunodeficiency virus leading to induction
Silver nanoparticles
Membrane
cleavage CANCER
CELL
Mitochondria
DNA
fragmentation
Nucleus
Caspase 3 Apoptosis
Figure 5 Caspase-mediated cancer cell

apoptosis by silver nanoparticles. [Colour
Cell figure can be viewed at
blebbing wileyonlinelibrary.com]
of immunosuppression with consequently reduced (Thurman and Gerba 1989; Jansson and Harms-Ringdahl
immunosurveillance (Parsonnet 1995; Kuper et al. 2000). 1993; Feng et al. 2000).
Hence, nanosilver may have the potential to play a dual Silver ions are reported to activate mast cells which are
role by either destroying the infectious aetiological agent a crucial component of the immune system and play an
of the cancer and/or the cancer cells. important role in allergic reactions, wound healing and
defence against pathogens. Silver activates mast cells by
bypassing the early signalling events required for the
Increase in immunity
induction of calcium influx. These activated mast cells
In addition to its antimicrobial effect, colloidal silver is then destroy microbial cells before they can colonize the
also known to be a powerful immune system booster. key areas of body (Suzuki et al. 2002). Furthermore, sil-
Trace amounts of silver are present in the bodies of all ver also plays a vital role in stimulating the lymphatic
humans and animals, however, it is not an essential ele- system. It is a crucial part of the immune system as it fil-
ment. A correlation between low silver levels in body and ters out toxins from the circulatory system in the body.
disease has been observed wherein individuals with low Silver nanoparticles have the ability to reduce cytokine
silver levels in their hair analysis were frequently found to expression and thus reduce excessive inflammation that
be sick with innumerable colds, flu, fevers and various slows down the process of healing. Cytokines are sig-
other sicknesses. It was proposed that silver deficiency nalling molecules in the body that direct the immune sys-
could be the key to the improper function of the immune tem to send white blood cells and other infection fighting
system (Becker and Selden1985). agents to the site of infection. This causes mild inflam-
Increasing evidence of AgNPs and their possible mation which is a normal part of healing. However, in
immunomodulatory effects have been reported (Edwards- case of chronic infection or serious wound trauma, the
Jones 2009). It has been demonstrated that silver ions pro-inflammatory effects of cytokine expression can result
greatly enhance the ability of immune cells to digest in excessive unwanted inflammation which in turn
infectious agents. This is facilitated by increasing the impedes the healing process. In such cases, antimicrobial
digestive aids of these immune cells, like superoxide and silver has a modulating effect on cytokine expression,
hydrogen peroxide more commonly known as ROS resulting in both reduced inflammation and increased
healing. Antimicrobial silver also promotes wound heal- between AgNPs and contaminant toxicity (Samberg et al.
ing by reducing microbial burden. 2010). Studies on the effects of AgNPs on gene expression
When wound healing properties of AgNPs were inves- in mouse brain suggest that AgNPs may produce neuro-
tigated in an animal model, rapid healing and improved toxicity by generating free radical-induced oxidative stress
cosmetic appearance was observed in a dose-dependent and by altering gene expression, producing apoptosis and
manner. Moreover, the study confirmed that AgNPs neurotoxicity at high concentrations; 100–1000 mg kg 1
exerted positive effects such as antimicrobial activity, body weight (Rahman et al. 2009). In another study,
reduction in wound inflammation and modulation of mice exposed to 191 9 107 particles per cm3 for
fibrogenic cytokines (Tian et al. 2007). It has been 6 h d 1, 5 d week 1 using the nose-only exposure system
implied that AgNPs could one day play a key medical for 2 weeks exhibited modulation in the expression of
role in decreasing inflammation in chronic infections, several genes associated with motor neuron disorders,
wounds and other inflammatory medical conditions neurodegenerative disease and immune cell function,
(Shin et al. 2007; Klippstein et al. 2010). indicating potential neurotoxicity and immunotoxicity
(Lee et al. 2010a). Oral toxicity of AgNPs assessed over a
period of 28 days in Sprague–Dawley rats has shown that
Toxicology of silver and silver-based
doses above 300 mg resulted in slight liver damage as
nanoparticles
indicated by dose-dependent changes in the alkaline
High degree of commercialization of nanosilver-related phosphatase and cholesterol levels. A dose-dependent
applications has led to a rapid increase in widespread use accumulation of silver in all the tissues examined (bone
of numerous consumer products containing nanosilver. marrow, kidneys, etc.) was also noted, however, there was
Hence, thorough investigations on safe design, use and no indication of genetic toxicity in male and female rat
disposal without creating new risk to humans or the bone marrow (Kim et al. 2008b). In vivo studies on lung
environment is warranted (Tran et al. 2013). The toxic toxicity as a result of inhalation of subacute doses of
effects of nanosilver are dependent on the size, concentra- AgNPs (33 mg m 3, 4 h d 1 for 10 days) in mice
tion and time of exposure. A comprehensive review of showed minimal pulmonary inflammation or cytotoxicity
the possible risks of nanosilver to mammalian cells which was in contrast to published in vitro studies (Ste-
in vitro has been discussed in detail by Tran et al. In the bounova et al. 2011).
present review, the authors have summarized the impact
of nanosilver on human health and animals based on sev-
Conclusion
eral in vivo toxicity studies.
Silver is reported to exhibit low toxicity in the human Historically silver has been used as a major therapeutic
body, and minimal risk is expected due to clinical expo- agent in medicine especially in infectious diseases includ-
sure by inhalation, ingestion, dermal application or ing surgical infections (Alexander 2009). However, there
through the urological or haematogenous route. How- have been apprehensions associated with the usage of
ever, long-term occupational exposure of silver or nanosilver through this long and diverse history of its
chronic ingestion or inhalation of silver preparations can applications. A continuous debate on the benefits and
lead to deposition of silver particles in the skin and eyes drawbacks of the use of silver-incorporated products in
termed as Argyraemia. These conditions are not life- healthcare and medicine has prevailed ever since. The
threatening but cosmetically undesirable. When silver is physician Paracelsus who founded the discipline of toxi-
absorbed into the human body, it enters the systemic cir- cology quoted back in 1529 that ‘Poison is in everything,
culation as a protein complex which is then eliminated and no thing is without poison. The dosage makes it
by the liver and kidneys. Silver metabolism is modulated either a poison or a remedy.’ Silver can be highly benefi-
by induction and binding to metallothioneins. This com- cial to the human body when used within limits and
plex mitigates the cellular toxicity of silver and con- potentially harmful when used in excess. It is reported to
tributes to tissue repair (Lansdown 2006). have an advantageous risk: benefit ratio. Further studies
In vivo porcine skin exposure studies conducted to on nanosilver with increasing time of exposure and dose
assess the inflammatory and penetrating potential of and with additional organ systems are recommended. In
AgNPs into porcine skin have shown that the toxicity is order to use the potential medical benefits of silver,
influenced by the residual contaminants in the AgNPs in vivo human clinical studies and trials are required.
solution, and that the AgNPs themselves might not be
responsible for an increase in cell mortality. Hence, com-
Conflict of Interest
plete characterization of not only the nanoparticles but
also the vehicle is suggested in order to distinguish The authors declare no conflict of interest.
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Journal of Applied Microbiology ISSN 1364-5072

The silver lining: towards the responsible and limited usage

devices, clothing and textiles, water purification and dis-

extended spectrum b-lactamase producing Klebsiella,

Virus replication cycle Antiviral mechanism

Virus Interactions with

Table 1 Antibiofilm activity of nanosilver

AgNP-coated surfaces Methicillin-resistant Staphylococcus aureus (MRSA), 50 lg ml 1

Autoinducer Cognate receptor Autoinducer Cognate receptor

QS signalling Anti-QS activity

Table 2 Antimicrobial activity of silver-based nanocomposites

Material Micro-organisms tested Inhibitory concentration Reference

Silver bromide nanoparticle/polymer Bacillus cereus 50 lg ml 1 Sambhy et al. (2006)

tract infections but their potential benefits might be

Step 1: Antimicrobial effect

example, Providencia stuartii, a burn wound isolate which

fadiazine in case of both Gram-positive and Gram-nega-

Figure 5 Caspase-mediated cancer cell

References effects on bacterial and mammalian cells. Antimicrob

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