The silver lining: Towards the responsible and limited usage of silver

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DOI: 10.1111/jam.13525
Cite this publication
Abstract
Silver has attracted a lot of attention as a powerful, broad spectrum and natural antimicrobial agent since the ancient times because of its non-toxic nature to the human body at low concentrations. It has been used in treatment of various infections and ulcers, storage of water, and prevention of bacterial growth on the surfaces and within materials. However there are numerous medical and health benefits of colloidal or nano silver apart from its microbicidal ability which as yet have not been fully embraced by the medical community. These include antiplatelet activity, antioxidant effect, anticancer activity, wound healing and bone regeneration, enhancement of immunity, and increase in antibiotic efficiency. Additionally silver also provides protection against alcohol toxicity, upper respiratory tract infections and stomach ailments. Although nanosilver has been proposed for various topical applications, its usage by ingestion and inhalation remains controversial due to the lack of detailed and precise toxicity information. These beneficial properties of silver can be utilised 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. This article is protected by copyright. All rights reserved.
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
ingestion, inhalation, low concentration,
medical applications, nanosilver.
Correspondence
Meenal Kowshik, Department of Biological
Sciences, Birla Institute of Technology &
Science Pilani K K Birla Goa Campus, NH
17/B, Zuarinagar, Goa 403726, India.
E-mails: meenal@goa.bits-pilani.ac.in;
meenalkowshik@gmail.com
2017/0016: received 9 January 2017, revised
1 June 2017 and accepted 19 June 2017
doi:10.1111/jam.13525
Summary
Silver has attracted a lot of attention as a powerful, broad spectrum and natural
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
infections and ulcers, storage of water and prevention of bacterial growth on the
surfaces and within materials. However, there are numerous medical and health
benefits of colloidal or nanosilver apart from its microbicidal ability which as yet
has not been fully embraced by the medical community. These include
antiplatelet activity, antioxidant effect, anticancer activity, wound healing and
bone regeneration, enhancement of immunity, and increase in antibiotic
efficiency. Additionally silver also provides protection against alcohol toxicity,
upper respiratory tract infections and stomach ailments. Although nanosilver has
been proposed for various topical applications, its usage by ingestion and
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.
Introduction
Natural colloidal silver was used as a strong and broad-
spectrum antibiotic, since the late 1800s with no harmful
side effects observed, for well over 100 years. There have
been anecdotal references of ancient Greeks using silver
plates, silver cups and silver utensils which conferred
antimicrobial properties and prevented them from infec-
tious illness. Besides, silver has a long history of medical
usage and was mostly used empirically even before the
understanding that microbes were the agents of infection
(Alexander 2009). Silver preparations were used by Hip-
pocrates the ‘Father of Medicine’, to treat ulcers and pro-
mote healing of wounds (Hippocrates (400 B.C.E.)).
In recent years, nanosilver has received a lot of atten-
tion in academic and scientific community due to its
potential antimicrobial applications and hence is widely
studied for its release and effects (Nowack et al. 2011).
Presently, nanosilver-incorporated products have been
used in a diverse range of applications such as food
preservation and packaging, implants and other medical
devices, clothing and textiles, water purification and dis-
infection, cosmetics and personal care products, etc.
Although silver is successfully used for topical and surface
applications in various fields, its usage is limited in cases
of medical applications which require oral ingestion or
inhalation. The primary concern associated with such
applications is the risk of accumulation of silver in the
body leading to heavy metal toxicity.
Silver can have numerous health benefits to the human
body when used within a limit and be potentially harmful
when used in excess. It is also desirable to supplement the
diet with adequate amounts of antioxidants like selenium,
vitamin E and amino acids like N-acetyl cysteine to safe-
guard from any potential harmful effects of heavy metals
like silver. Hence, occasional short term usage of limited
and minimal amounts of silver is preferred over the use of
excessive amounts of silver over long periods of time, espe-
cially in case of oral administration or inhalation. In this
context, the following review seeks to unravel the potential
medical and health applications of silver which have still
not been completely explored and used.
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1068
Journal of Applied Microbiology ISSN 1364-5072
Antimicrobial activity
Silver ions and silver-based compounds possess strong
biocidal effects on micro-organisms including bacteria,
fungi, yeasts and viruses. Silver can exist in different
forms such as elemental/metallic, ionic, nanosilver (1
100 nm) and colloidal (11000 nm) (Kulinowski 2008).
The latter three forms are preferred over the metallic
form due to their smaller size and higher surface area
which facilitates higher antimicrobial efficiency.
Antibacterial activity of nanosilver (Fig. 1) has been
demonstrated against a wide range of Gram-positive and
Gram-negative bacteria (Wijnhoven et al. 2009; Duncan
2011). The bactericidal activity of silver has been reported
to reside in its ionic form, and micromolar doses (1
10 lmol l
1
) of silver ions are sufficient to kill bacteria
in water (Liu et al. 1994). The reported minimum inhibi-
tory concentration and minimum bactericidal concentra-
tion of AgNPs in the size range of 720 nm against
standard reference cultures are in the range of 078625
and 125lgml
1
respectively (Jain et al. 2009). Nanosil-
ver is also effective against strains of organisms that are
resistant to potent chemical antimicrobials including
multidrug-resistant bacteria like methicillin-resistant Sta-
phylococus aureus (MRSA), methicillin-resistant Staphylo-
cocus epidermidis, vancomycin-resistant Enterococcus,
extended spectrum b-lactamase producing Klebsiella,
multidrug-resistant Pseudomonas aeruginosa, ampicillin-
resistant Escherichia coli O157:H7 and erythromycin-resis-
tant Streptococcus pyogenes (Yu 2007; Duncan 2011; Lara
et al. 2011).
Silver has also been demonstrated to decimate most of
the well-known bacterial pathogens that cause serious
secondary infections during a viral infection such as
Streptococcus pneumonia,Corynebacterium diphtheria,
Neisseria gonorrhoeae,Klebsiella pneumonia,Haemophilus
influenza,Bordetella pertussis,Mycobacterium and Pneu-
mococci. These bacteria can cause complications including
pneumonia, bronchitis, conjunctivitis, sinusitis, otits
media and other chronic illness such as asthma (Gordon
and Holtorf 2006).
Antifungal activity of silver nanoparticles (AgNPs) of
various sizes has been demonstrated against Candida albi-
cans and Candida glabrata which are common causes of
oral thrush and dental stomatitis. Infections like these are
particularly difficult to treat because the fungal micro-
organisms involved form protective biofilms that prevent
prescription antifungal drugs from functioning. These
AgNP suspensions exhibited fungicidal activity against
the tested strains at very low concentrations in the range
of 0433lgml
1
. Hence, AgNPs appear to be a new
potential strategy to combat these infections. As the
AgNPs
Penetrate inside bacteria
e
Ag+
Release of
Ag+ ions to enhance
bactericidal activity
Generation
of ROS
Destroy membrane
proteins
Membrane damage
and cell death Inhibit bacterial
DNA replication Inactivate
bacterial
proteins
Destroy
bacterial
cell wall
Inhibit electron
transport
e
S–S–S P–P–P
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
K. Naik and M. Kowshik The silver lining
nanoparticles are relatively stable in liquid medium, their
use as mouthwash solution is proposed (Monteiro et al.
2012).
Electrically generated silver ions at <2lgml
1
concen-
tration were shown to exhibit more efficient fungicidal
properties than silver compounds such as silver sulfadi-
azine and silver nitrate. The growth of all fungal organ-
isms was inhibited by silver concentration between 05
and 47lgml
1
, and the fungicidal concentration of sil-
ver was as low as 19lgml
1
(Berger et al. 1976a).
AgNPs exhibited considerable antifungal activity against
C. albicans and Trichophyton mentagrophytes, the cause of
fungal infections of the hair, skin and nails. The antimi-
crobial activity of silver was found to be comparable to
Amphotericin B, one of the most powerful prescription
antifungal drugs and superior to the well-known antifun-
gal drug fluconazole (Kim et al. 2008a).
Silver nanoparticles could also be used as an effective
treatment for fungal infections of the eyes. Fungal kerati-
tis is emerging as a major cause of vision loss in develop-
ing nations largely due to the unavailability of effective
antifungal agents. AgNPs were reported to exhibit potent
in vitro antifungal activity against over 216 different
strains of ocular fungal pathogens such as Fusarium sp.,
Aspergillus sp. and Alternaria alternate isolated from
patients with fungal keratitis (Xu et al. 2013).
Antiviral activity of natural mineral silver in a variety
of forms including colloidal silver has been demonstrated
through nearly three decades of medical research (Fig. 2).
It has been reported that silver can stop different types of
viruses from replicating by merely binding to them.
Recent research demonstrates that silver is so powerfully
effective against viruses that it even stops the deadly HIV
virus from infecting human cells. The vital requirement
in order to exhibit such powerful antiviral activity is the
size of the silver particles. Nanoparticles of size ranging
from 1 to 100 nm are efficient as smaller size leads to
more interaction and inhibition of viruses (Galdiero et al.
2011; Khandelwal et al. 2014). Silver nanoparticles
undergo a size-dependent interaction with HIV-1 virus
and nanoparticles in the size range of 110 nm were able
to attach to the virus. The interaction is via preferential
binding of AgNPs to the gp120 glycoprotein knobs which
bear the exposed sulphur residues and inhibit the virus
from binding to host cells in vitro (Elechiguerra et al.
2005).
Colloidal silver was found to show remarkable efficacy
against the smallpox virus. Collargol and Protargol were
the two medicinal preparations of colloidal silver used in
the study. The reduction in concentration of viral parti-
cles was about 11 000 and 700 times for collargol and
protargol respectively (Bogdanchikova et al. 1992). Her-
pes simplex virus types I and II was reported to be
inactivated by silver nitrate at concentrations of
30 lmol l
1
or less (Shimizu et al. 1976). AgNPs of
approximately 10 nm were demonstrated to inhibit mon-
keypox virus in vitro, supporting their potential use as an
antiviral therapeutic agent (Rogers et al. 2008). AgNPs of
approximately 1050 nm in diameter were demonstrated
to interact with viral DNA of hepatitis B virus and pre-
vent replication in vitro. In this case the antiviral mecha-
nism was attributed to the direct interaction between the
nanoparticles and HBV double-stranded DNA or viral
particles (Lu et al. 2008).
The collective authoritative medical literature reports
silver to be virucidal against over 24 viruses. Additionally,
it has been proposed that 200 plus viral strains known to
cause upper respiratory tract infections, including most
flu viruses, will also most likely succumb to the powerful
antiviral qualities of very small particles of oligodynamic
silver (Gordon and Holtorf 2006).
Mode of antimicrobial action of silver
The actual mechanism of toxicity of nanosilver is pro-
posed to be the sum of various mechanisms and hence
termed as multimodal action. Silver is known to react
with nucleophilic amino acid residues in proteins, and
attach to sulfydryl, amino, imidazole, phosphate and car-
boxyl groups. It causes bacterial cell wall damage and dis-
ruption of cytoplasmic membrane leading to leaching of
metabolites, interferes with DNA synthesis, denatures
proteins and enzymes (dehydrogenases), binds to ribo-
somes and inhibits protein synthesis, interferes with elec-
tron transport system and is involved in the production
of reactive oxygen species (ROS) (Hatchett and White
1996; Feng et al. 2000). The primary mode of silver toxi-
city is its potential to release silver ions. Irrespective of
the form of the silver used, a major characteristic that
will affect the microbicidal effect of the silver is the con-
centration of silver ions released. The nano form with its
large surface area to volume ratio has high potential for
release of silver ions (Sotiriou and Pratsinis 2010). All
forms of silver including silver compounds and silver
salts have potential to release silver ions. Even the bioci-
dal effect of elemental silver is due to formation of silver
ions at low concentration on its surface.
Nanostructured silver targets the bacterial cell wall and
cell membrane which is a protective barrier and serves
several functions (Sondi and Salopek-Sondi 2004).
Nanoparticles <10 nm in diameter can bind to bacterial
cell wall and cause its perforation leading to rapid
increase in cell permeability and ultimately cell death. In
E. coli, nanosilver with average particle size of 12 nm is
reported to result in formation of irregular shaped pits in
the bacterial cell membrane. Silver ions can also cause the
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1070
The silver lining K. Naik and M. Kowshik
cell membrane to detach from the cell wall nevertheless,
the mechanism of this process has still been unknown
(Feng et al. 2000). Moreover, nanosilver binds with
membrane proteins and sulphur-containing proteins
through electrostatic interaction (Holt and Bard 2005;
Wong and Liu 2010), and inhibits their function or dam-
ages their structure by generating free radicals (Choi and
Hu 2008).
Silver can attack the respiratory chain in bacteria and
lead to cell death (Sondi and Salopek-Sondi 2004). Respi-
ration is the critical point in bacterial cell metabolism
and is the mechanism of obtaining energy to perform all
the energy-demanding life processes. Energy generation
relies on the respiratory enzyme complexes associated
with the respiratory chain, and silver ions disrupt the
function of these enzymes by binding to the functional
groups of amino acids and inhibiting the efficient elec-
tron transport via the respiratory chain. This ultimately
results in the complete breakdown of electron transport
and blockage of phosphorylation of ADP to ATP. NADH
dehydrogenase complex is reported to be a potential tar-
get for silver ion activity (Holt and Bard 2005). Forma-
tion of proton-depleted regions around AgNPs was
observed due to the micro-galvanic effect which could
further lead to disruption of electrochemical gradient
(Cao et al. 2011).
Virus replication cycle Antiviral mechanism
Silver nanoparticles
Interactions with
viral surface
Glycoproteins
Virus
cannot
bind
host cells
Virus adsorption
Virus
penetration
Host cell
Nucleus
Uncoating
Virus
replication
Block
virus
replication
Assembly
Progeny
virions
No progeny
virions
Figure 2 Antiviral 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 1071
K. Naik and M. Kowshik The silver lining
The creation of free radicals and induction of oxidative
stress also contributes towards toxicity of AgNPs/ions
(Kim et al. 2007; Cao and Liu 2010; Wong and Liu
2010). Production of ROS is dependent to some extent
on the catalytic activity of nanoscale silver. ROS genera-
tion is initiated mainly as an outcome of the respiratory
enzymes and respiratory chain dysfunction (Choi and Hu
2008). ROS are generated within or outside of the cell, as
a consequence of cell damage/disruption (Liu et al.
2010). Studies using nitrifying bacteria have revealed that
the increase in intracellular ROS levels was correlated
with the rate of bacterial growth inhibition (Choi and Hu
2008). Sustained release of silver ions by AgNPs inside
the bacterial cells in an environment with lower pH may
create free radicals and induce oxidative stress, thus fur-
ther enhancing the bactericidal activity (Morones et al.
2005; Song et al. 2006).
Genetic material being one of the important target
sites, nanostructured silver was also reported to cause
damage to the DNA (Feng et al. 2000; Kim et al. 2010).
DNA loses its replication ability once the bacteria are
treated with nanosilver. This is due to the capacity of sil-
ver ions to bind to the phosphorane residues of DNA
molecules (Hatchett and White 1996; Morones et al.
2005). This interaction may prevent cell division and may
ultimately lead to cell death. Furthermore, silver ions are
also reported to affect gene expression. In E. coli, it has
been shown that nanosilver denatures the 30S ribosomal
subunit by preventing the expression of S2 protein, a
component of the ribosomal subunit. Additionally, the
expression of genes encoding other proteins and enzymes
involved in energy reactions in ATP synthesis was also
inhibited (Gogoi et al. 2006).
Release of silver ions is also reported to cause inactiva-
tion of proteins. Silver ions can interact with sulphur-
containing proteins and thiol groups of vital enzymes in
bacterial cell and result in their impaired function or
inactivation (Hatchett and White 1996; Cao and Liu
2010). Silver exhibits catalytic activity by binding to the
functional groups of amino acids and forming SS
bonds between the adjacent SH groups in proteins. The
formation of additional SSbonds may induce molec-
ular changes and lead to protein and enzyme inactivation
(Wzorek and Konopka 2007). AgNPs are also reported to
modulate the phosphotyrosine profile of putative bacte-
rial peptides that could affect cellular signalling and
therefore inhibit the growth (Shrivastava et al. 2007).
Antifungal activity of nanosilver against C. albicans was
attributed to disruption of cell membrane structure and
integrity resulting in inhibition of normal budding pro-
cess (Kim et al. 2009). Trehalose is known to play a pro-
tective role in yeast by preventing the inactivation or
denaturation of proteins and biological membranes,
caused by a variety of stress conditions, including desic-
cation, dehydration, heat, cold, oxidation and toxic
agents (Alvarez-Peral et al. 2002; Elbein et al. 2003).
Nanosilver-treated cells were shown to accumulate more
intracellular as well as extracellular glucose and trehalose
as compared to the untreated cells. This increase in the
sugar amount was attributed to several intracellular com-
ponents released during membrane disruption by nanosil-
ver (Lee et al. 2010b). It was also hypothesized that silver
ion primarily affects the function of membrane-bound
enzymes such as those in the respiratory chain resulting
in loss of cellular integrity and osmosis (Mendes et al.
2014). Potential damage to the cell wall and transmem-
brane proteins and up-regulation of cell wall-strengthen-
ing genes in surviving cells was recently reported in the
yeast Saccharomyces cerevisiae (Niazi et al. 2011). Addi-
tionally, when C. albicans and S. cerevisiae cells were
exposed to AgNPs, significant changes to the membrane
structure were observed. Pit formation was detected on
the cell surfaces which finally resulted in the formation of
pores and cell death (Nasrollahi et al. 2011). Silver ion is
reported to form complexes with the bases contained in
DNA and is also a potent inhibitor of fungal DNases
(Saraniya Devi and Valentin Bhimba 2014).
Antibiofilm activity
In the natural world, more than 99% of all bacteria exist
as biofilms (Costerton et al. 1987). Biofilms are the pro-
tective structures created by the colonies of pathogens in
order to evade the effects of antibiotic drugs. They are
protected by an extracellular matrix held together by pro-
teins and polysaccharides commonly referred to as extra-
cellular polymeric substance. This affects the efficiency of
the strongest of antibiotics and biofilms can be as much
as a thousand times more resistant than planktonic cells.
The growth of biofilms is a major problem within the
healthcare and food industries. Biofilms can form on
many medical implants such as catheters, artificial hips
and contact lenses. According to the National Institute of
Health more than 60% of all infections are caused by
biofilms. These include, but are not limited to endocardi-
tis, cystic fibrosis, otitis media, chronic prostatitis, uri-
nary tract infections, dental plaque infections, gingivitis,
periodontitis, chronic sinusitis, burn wound infections
and bone infections (Kim 2001).
Many recent studies have demonstrated conclusively
that antimicrobial silver can penetrate through the bacte-
rial biofilms to completely destroy them and can even
prevent microbes from developing biofilms. As compared
to the antibiotics, silver is proposed to be less affected by
the micro-environmental variations found in biofilms due
to its multimodal mechanism of action (Bjarnsholt et al.
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1072
The silver lining K. Naik and M. Kowshik
2007). Antibiofilm activity of nanosilver has been sum-
marized in Table 1.
Antibiofilm activity of nanosilver in combination with
other compounds has also been assessed and a higher
efficacy in blocking the biofilm formation is observed due
to the synergistic effect. Combination of curcumin
nanoparticles and AgNPs inhibited biofilm formation
more effectively as compared to when used alone (Loo
et al. 2016). Antibiofilm activity of biocompatible chi-
tosan stabilized AgNPs (CS-AgNPs) was evaluated against
clinical isolate of E. coli under in vitro conditions. It was
reported that 81% biofilm inhibition was brought about
by 100 lgml
1
of free AgNPs while complete inhibition
(100%) was successfully achieved using CS-AgNPs com-
posite at 75 lgml
1
(Namasivayam and Roy 2013).
Enhanced biofilm inhibition in polymer-stabilized
nanoparticles is due to the inhibition of exopolysaccha-
ride synthesis limiting the formation of biofilm (Kalish-
waralal et al. 2010) and the diffusion of CS-AgNPs
through the channels present in the biofilms followed by
the sustained release of antimicrobial metal nanoparticles
(Jena et al. 2012). This enhanced activity of stabilized
nanoparticles is also attributed to the stabilizing agent
which prevents the aggregation of particles into larger
forms that can significantly decrease their activity (Mar-
kowska et al. 2013). Synergistic effect of biogenic AgNPs
has also been studied with plant products and antibiotics
on the biofilms of clinical isolates of Staph. aureus and
Candida tropicalis, and has been extended to applications
such as coating on catheters for antibiofilm activity
against Staph. aureus (Namasivayam et al. 2011, 2012).
Antibiofilm activity of several other AgNPs composites
such as starch-stabilized AgNPs (Mohanty et al. 2012),
AgNP-incorporated PU (polyurethane), PCLm (polycap-
rolactam), PC (polycarbonate) and PMMA (polymethyl-
methaacrylate) nanocomposites (Sawant et al. 2013),
citrate-capped AgNPs of various sizes (Park et al. 2013;
Habash et al. 2014), AgCl incorporated TiO
2
(Naik and
Kowshik 2014a), AgNPs stabilized by polyvinylpyrroli-
done (Bryaskova et al. 2011), b-cyclodextrin-stabilized
AgNPs (Jaiswal et al. 2015), AgNPs stabilized by hydrol-
ysed casein peptides (Radzig et al. 2013), and other
AgNPs (Fabrega et al. 2009; Gurunathan et al. 2014) have
been recently reported.
In addition to the above-mentioned preliminary stud-
ies of the antibiofilm activity of AgNPs, some nanosilver
coated or incorporated medical devices are already at the
stage of clinical trials. The most prominent examples are
surgical masks (Li et al. 2006), catheters (Stevens et al.
2011), drains (Lackner et al. 2008) and wound dressings
(Knetsch and Koole 2011; Velazquez-Velazquez et al.
2015). Dental composites containing AgNPs have been
fabricated and are reported to act against biofilms of oral
bacteria such as Streptococcus mutans. These new
nanocomposites significantly reduced the metabolic activ-
ity and lactic acid production of Strep. mutans biofilms
as compared to the two commercial composites (Cheng
et al. 2012). Likewise, bone cements modified with
AgNPs significantly reduced biofilm formation on the
surface of the cement (Slane et al. 2015). The above data
validates that AgNPs can effectively and rapidly destroy
biofilms produced by a variety of microbes at clinically
Table 1 Antibiofilm activity of nanosilver
Material Micro-organisms tested
Antibiofilm
concentration References
AgNP-coated surfaces Methicillin-resistant Staphylococcus aureus (MRSA),
methicillin-resistant Staphylococcus epidermidis (MRSE)
50 lgml
1
Ansari et al. (2015)
AgNPs Multidrug-resistant strains of Pseudomonas aeruginosa 20 lgml
1
Palanisamy et al. (2014)
Biologically synthesized AgNPs Escherichia coli 0564 lgml
1
Barapatre et al. (2016)
Pseudomonas aeruginosa
Staphylococcus aureus
Silver ions Staphylococcus epidermidis 50 ppb Chaw et al. (2005)
AgNPs Pseudomonas aeruginosa 50100 nmol l
1
Kalishwaralal et al. (2010)
Staphylococcus epidermidis
Nanometer scale silver coatings Proteus mirabilis Not determined Sahal et al. (2015)
Candida glabrata
Candida tropicalis
AgNPs Pseudomonas aeruginosa 100 mg ml
1
Martinez-Gutierrez et al. (2013)
AgNPs Staphylococcus aureus 15 lgml
1
Goswami et al. (2015)
Escherichia coli
Biogenic AgNPs coated catheter Staphylococcus aureus 100 lgml
1
Namasivayam et al. (2013)
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology 1073
K. Naik and M. Kowshik The silver lining
achievable concentrations, making silver a potential anti-
biofilm drug.
Antiquorum sensing activity
Quorum sensing (QS) is a cell-to-cell-based communica-
tion mechanism which functions by means of production
and reception of diffusible signal molecules also called as
autoinducers by bacteria, to regulate the expression of cer-
tain phenotypes that are dependent on population density.
This phenomenon is used by bacteria to understand
changes in their environment and consequently apply
specific strategies that allow adaptation to environmental
stress in space and time. Compounds that inhibit or inter-
fere with QS have become significant as novel class of next
generation antimicrobial and antibiofilm agents. Develop-
ment of resistance to anti-QS compounds is minimal as
these agents only target virulence mechanisms and do not
impede growth, whereas the conventional antibiotics pre-
vent the bacterial cell division or kill the bacterial cells and
increase the selective pressure towards antibiotic resistance.
QS signalling molecules serve as a switch to pathogenic
state in most of the bacteria and are important for the
establishment of infection. This co-operative behaviour of
pathogenic organisms aids in the development of biofilm
(Whitehead et al. 2001; Wagh Nee Jagtap et al. 2013).
Although the molecular interplay between QS and biofilm
formation remains ambiguous, it is now clear that QS is
involved in the maturation and differentiation of biofilms
(Favre-Bont
eet al. 2003). A simple screening protocol of
anti-QS compounds, based on the decrease in production
of violet colour pigment by Chromobacterium violaceum
has been developed and widely used (McLean et al. 2004).
Recently, AgNPs have been reported to exhibit potent
anti-QS activity (Fig. 3). Silver nanowires exhibit anti-QS
activity in the concentration range of 054mgml
1
.
There was a reduction of about 60% in violacein synthe-
sis at 05mgml
1
, whereas a concentration of
4mgml
1
resulted in 80% reduction, compared to
100% violacein synthesis in the control (Wagh Nee Jagtap
et al. 2013). In an anti-QS study of AgCl-TiO
2
nanoparti-
cles (ATNPs), a significant drop in violacein production
was observed at 100, 200 and 300 lgml
1
of ATNPs
(effective silver concentration of 117, 234 and
352 lgml
1
respectively) using NB as the growth med-
ium. The anti-QS concentration of ATNPs decreased to
25 lgml
1
of ATNPs (effective silver concentration of
029 lgml
1
) in modified Tris minimal media. The sil-
ver present in ATNPs inhibited QS by interfering with
the AHL activity (Naik and Kowshik 2014b).
Possible mechanism for anti-QS activity by mycofabri-
cated AgNPs has been reported in P. aeruginosa model
recently. AgNPs inhibit the LasIR-RhlIR-mediated AHLs
production in P. aeruginosa after cellular internalization.
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
biofilms (Singh et al. 2015). Similarly, few other studies
have reported the anti-QS activity of biologically synthe-
sized AgNPs (Arunkumar et al. 2014; Singh et al. 2015;
Anju and Sarada 2016).
Silver-based composites
Several studies are currently developing nanocomposites
containing silver that present higher efficiency due to
their composite nature. In order to utilize the benefits of
nanosilver without any harmful effects, the main focus is
to reduce the total silver dose and improve its biocom-
patibility. Moreover, subsequent release of free nanoparti-
cles in the environment can cause unforeseeable effects
on the ecosystem and human health (Esteban-Tejeda
et al. 2010). To overcome such difficulties, it is proposed
that AgNPs be embedded or incorporated in various
matrices such as polymers, zeolites, ceramics, glasses, etc.
In this regard many silver-based nanocomposites have
been synthesized wherein AgNPs are uniformly dispersed
in a suitable matrix in order to avoid agglomeration
problems, facilitate slow and sustained release of silver
into the media and reduce their toxic effects. The antimi-
crobial activity of silver-based nanocomposites has been
summarized in Table 2.
Upper respiratory tract infections
Colloidal or nano silver owing to its strong and broad-
spectrum antimicrobial properties could possibly have the
potential to heal a variety of upper respiratory tract infec-
tions in an effective way. Some of these infections include
pneumonia, bronchitis, cystic fibrosis, chronic obstructive
pulmonary disease, sinus, asthma, allergies and other lung
diseases. The treatment consists of atomizing silver using
a nebulizer or nasal spray. Although this treatment
appears to be very promising, its full-fledged use is lim-
ited until the long-term safety of inhaling minute silver
particles into lungs is exhibited by clinical studies.
A 28-day inhalation toxicity study of AgNPs in rats did
not exhibit any significant changes in the haematology
and blood biochemical values for both male and female
rats, and no distinct histopathology findings were
observed, indicating that exposure to silver did not have
any significant health effects (Ji et al. 2007). However a
90-day animal study resulted in lung function changes
due to prolonged AgNP inhalation exposure (Sung et al.
2008). Another AgNP inhalation toxicity study for
90 days indicated that lungs and liver were the major
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1074
The silver lining K. Naik and M. Kowshik
target tissues for prolonged AgNP accumulation. How-
ever, a higher dose with prolonged exposure was needed
to induce any toxic responses (Sung et al. 2009).
Inhalation exposure studies of colloidal silver have not
been conducted on human subjects until now. Recent
human oral exposure study demonstrated that a 14-day
oral dosing of a commercial colloidal silver product did
not produce any observable clinically important toxic
effect. No morphological changes were detected in the
lungs, heart or abdominal organs. No significant changes
were noted in pulmonary ROS or pro-inflammatory cyto-
kine generation. Further study of silver-based nanomate-
rials over longer human exposures is necessary to
determine the risks (Munger et al. 2014).
As colloidal silver has been shown to alleviate inflam-
matory symptoms in cystic fibrosis patients (Baral et al.
2008), it could be developed into successful treatment
for chronic lung infections associated with cystic fibrosis.
Currently there is no evidence to support the use of sil-
ver products in the above-mentioned upper respiratory
Nanosilver
Exported to
extra-cellular
space
Autoinducer
transcription
complex
Autoinducer
synthase
Cognate receptor
No production
of signal
molecules
Autoinducer
synthase
Cognate receptor
Transcription
of QS
regulated
genes
Signal molecules
QS signalling Anti-QS activity
No
expression of QS
regulated genes
Figure 3 Antiquorum sensing mechanism of action of nanosilver. [Colour figure can be viewed at wileyonlinelibrary.com]
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology 1075
K. Naik and M. Kowshik The silver lining
tract infections but their potential benefits might be
worthy of further exploration. Nanosilver could also
have potential applications in the treatment of tubercu-
losis, a serious infectious airborne bacterial disease
caused by the bacterium Mycobacterium tuberculosis. The
antibiotic-resistant tuberculosis pathogens were rapidly
killed when tested against nanosilver capped with bovine
serum albumin (Seth et al. 2011). AgNPs were found to
inhibit M. tuberculosis by inducing metabolic distur-
bances in the cytoplasm of these cells at a concentration
of 10 ppm (Song et al. 2006). Silver can be used in res-
piratory devices like ventilators, inhalers and continuous
positive airway pressure machines to prevent the growth
of micro-organisms in the water reservoir and breathing
apparatus. This acts as a disinfectant and helps keep the
devices clean of microbial build up and biofouling. Sil-
ver when used in these apparatus also helps keep the
lungs infection free and prevents the chronic upper res-
piratory tract infections associated with usage of such
devices.
Antibacterial zombies effect
In order to prevent bacterial recolonization and prolifera-
tion it is highly desirable for an antimicrobial agent to
have long-term effectiveness (Brady et al. 2003; Ferrara
et al. 2011). One of the most effective methods to pro-
long antimicrobial activity is incorporation of antimicro-
bial agents in sustained release delivery systems that
enable their continuous use (Gao et al. 2011; Agarwal
et al. 2012).
In a recent study, it has been discovered that when P.
aeruginosa cells are killed by silver, the dead bacteria act
as sponge-like repositories which attract and absorb tiny
silver particles from its surroundings, and then leach that
silver out killing other nearby cells in a chain reaction
that continues until all the bacterial cells are killed. The
researchers termed this process as the ‘zombies’ effect.
This phenomenon consisted of two important character-
istics. Firstly, the metallic species were not deactivated by
the killing mechanism and therefore could carry on their
Table 2 Antimicrobial activity of silver-based nanocomposites
Material Micro-organisms tested Inhibitory concentration Reference
Silver bromide nanoparticle/polymer
composite
Bacillus cereus 50 lgml
1
Sambhy et al. (2006)
Escherichia coli 50 lgml
1
PAEMA-co-Ag cotton fabric Escherichia coli 965% Liu et al. (2014)
Poly (2-aminoethyl methacrylate) (PAEMA) Staphylococcus aureus 995%
Silver nanoparticle (Ag NP)-loaded
chitosan composites
Escherichia coli DH5a0515 mmol l
1
Yang et al. (2016)
AgNPs/alginate Escherichia coli 3mgl
1
Van Phu et al. (2014)
Silver-Titania (Ag0Np/TiO
2
Np) Staphylococcus aureus ATCC 25923 2082 lgml
1
Gavriliu et al. (2009)
Escherichia coli ATCC 25922 1588 lgml
1
Enterobacter cloacae ATCC 13047 (G-) 1588 lgml
1
Acinetobacter (G-) baumannii ATCC 17978 2082 lgml
1
Candida albicans ATCC 10231 1588 lgml
1
Pseudomonas aeruginosa ATCC 27853 1588 lgml
1
Ag/(C, S)-TiO
2
nanoparticles Escherichia coli ATCC C3000 25 mg ml
1
Hamal et al. (2010)
B. subtilis spores ATCC 6633 25 mg ml
1
TiO
2
@C/Ag core-shell composite Escherichia coli ATCC 25922 10 lgml
1
Tan et al. (2009)
Staphylococcus aureus ATCC 6538 20 lgml
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-TiO
2
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 lgml
1
Jadalannagari et al. (2014)
Staphylococcus aureus 300 lgml
1
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1076
The silver lining K. Naik and M. Kowshik
biocidal effect repeatedly and secondly the dead bacteria
served as an efficient sustained release reservoir for releas-
ing the lethal metallic cations for further action against
other live bacteria (Wakshlak et al. 2015).
Gastrointestinal diseases
Colloidal oxide of silver was tested on human subjects
for the treatment of peptic ulcer in a clinical study.
Tablets containing colloidal silver oxide were given for
oral ingestion to 88 patients with peptic ulcers over a
period of 9 days. All cases except one were reported to
be healed within 6 weeks (Rendin et al. 1958). Thereafter
no studies have been conducted to test the efficacy of sil-
ver for treatment of ulcers. When antimicrobial suscepti-
bility of different antibiotic groups and silver solution
was tested against organisms causing food poisoning such
as Salmonella typhi and E. coli, it was observed that col-
loidal silver exhibited superior antimicrobial activity com-
pared to other antibiotics (Feng et al. 2000; Assar and
Hamuoda 2010). In a study designed to investigate the
effects of nanosilver on the production of cytokines, it
was observed that the cytokine production was signifi-
cantly inhibited by nanosilver. These experimental data
suggested that anti-inflammatory benefits of nanosilver
could be used to treat immunologic and inflammatory
diseases such as Crohn’s disease (Shin et al. 2007).
AgNP-impregnated Lactobacillus fermentum have been
found to be effective against rotavirus and norovirus
which cause food poisoning and winter vomiting out-
breaks. As AgNPs used in this study are extremely small
with large surface area, it enables them to clump around
the virus increasing the inhibitory effect. There are con-
cerns about using such small silver particles in humans as
they could pass into other parts of the body and cause
harm. Hence attaching these AgNPs to the surface of the
bacterium enables fixing of the silver onto a larger entity
that cannot pass into other parts of the body. Although
the bacteria eventually die as a result of the silver, they
remain intact and the dead cells carrying the silver parti-
cles can then be added to solutions and used. It has been
proposed that the same technique could be applied to
combat other viruses such as influenza and those causing
common cold. These bacteria could also be incorporated
into nasal sprays, water filters and hand washes for
achieving antiviral activity (Verstraete 2010).
Synergistic effect of silver and antibiotics
Recently, AgNPs have been reported to be suitable candi-
dates for use in combinations with traditional antibiotics
in order to increase their antimicrobial efficiency.
Improved effectiveness against pathogens was observed
when AgNPs were used in combination with 26 different
antibiotics such as ampicillin, kanamycin, erythromycin,
chloramphenicol, penicillin G, amoxicillin, erythromycin,
clindamycin and vancomycin. The antibiotic molecules
contain many active hydroxyl and amino groups which
react with AgNPs by the process of chelation. Hence, the
synergistic effect may be attributed to the binding reac-
tion of antibiotic and AgNPs (Klippstein et al. 2010;
Naqvi et al. 2013). No cytotoxic effect of AgNPs on
mammalian cells was observed at concentrations with
effective antibacterial activity. Furthermore, restoration of
the susceptibility of a drug-resistant E. coli strain to
ampicillin was observed when ampicillin was combined
with AgNPs (Shahverdi et al. 2007; Fayaz et al. 2010;
Pan
a
cek et al. 2016).
Silver-Water Dispersion was demonstrated to work
synergistically with antibiotic drugs and produce an addi-
tive effect when used in combination with them. This sil-
ver solution has been shown to be effective against MRSA
and many multiple drug-resistant (MDR) strains (E. coli,
P. aeruginosa). According to the study, antibiotics may
cause symptoms in patients to temporarily disappear and
yet leave behind a host of resistant organisms. These
resistant organisms can reappear at a later stage straining
the immune system. Therefore, it is proposed that the
combination of silver solution and antibiotics will pro-
vide more complete clearing of the pathological organism
from the body (De Souza et al. 2006).
When antibiotics are boosted with a small amount of
silver these drugs can kill 101000 times more bacteria.
This is because silver increases the membrane permeabil-
ity which allows more antibiotics to enter the bacterial
cells. This mechanism may overpower the resistance
mechanisms that rely on shuttling the drug back out
which results in making the bacteria sensitive to the
antibiotic. This disruption in the cell membrane is also
reported to increase the effectiveness of vancomycin, a
large molecule antibiotic, on Gram-negative bacteria
which have a protective outer coating (Morones-Ramirez
et al. 2013). Furthermore, the drug interaction study
showed no antagonism indicating that concomitant use
of colloidal silver with these antibiotics does not affect
the absorption or therapeutic efficacy of either agent.
Hence, use of colloidal silver in combination with antibi-
otics can be an effective strategy due to its low toxicity
and high therapeutic activity against pathogenic micro-
organisms (Iroha et al. 2007).
Blood platelet disorders
Anticoagulant therapies are associated with serious bleed-
ing complications as exact dosing can be a challenge.
Excessive amounts of an anticoagulant can cause blood
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology 1077
K. Naik and M. Kowshik The silver lining
loss, whereas too little of an anticoagulant may clog
patient’s arteries. Researchers have tested the effectiveness
of nanosilver particles as an anticoagulant and demon-
strated that nanosilver has an innate antiplatelet property.
It effectively prevents integrin-mediated platelet
responses, both in vivo and in vitro, in a concentration-
dependent manner. Experiments with laboratory mice
showed that nanosilver particles effectively controlled
clumping of platelets irrespective of the disease that
caused it. In ultra-structural studies it was observed that
nanosilver accumulated within platelet granules and
reduced interplatelet proximity. Surprisingly when nano-
gold was tested, it showed no antiplatelet activity (Shri-
vastava et al. 2009). In another study, nanosilver
prevented platelet adhesion without conferring any lytic
effect on them and effectively prevented integrin-
mediated platelet responses in a concentration-dependent
manner (Bandyopadhyay et al. 2012). Antiplatelet activity
has also been demonstrated by Gluconobacter roseus-
mediated biologically synthesized AgNPs (Krishnaraj and
Berchmans 2013). However, further detailed studies are
warranted before silver can be proposed as a potential
antiplatelet agent.
Antioxidant effect of silver
Antioxidants are substances that when present at low
concentrations, significantly prevent or delay a pro-oxi-
dant initiated oxidation of the substrate (Prior and Cao
1999). A pro-oxidant is a toxic substance that can cause
oxidative damage to lipids, proteins and nucleic acids
resulting in various pathological diseases. Examples of
pro-oxidants include reactive oxygen and nitrogen species
(ROS and RNS) which are products of normal aerobic
metabolic processes (G
ulc
ßin 2012). It has been reported
that an increased intake of dietary antioxidants could
protect against chronic diseases such as cancers, cardio-
vascular and cerebrovascular diseases (Ramasamy et al.
2013).
CC1(4) solvent, a kidney and liver toxin was used to
damage the livers of mice after which the mice were trea-
ted with AgNPs. It was observed that the silver cured the
mice of majority of the liver damage caused by the toxin.
Silver was effective in revival of all biological parameters
to near normal in all intoxicated groups indicating the
curing effects of AgNPs at low dosages on CC1(4)-
induced liver injury. This hepatocurative effect of dam-
aged mice livers was attributed to the strong antioxidant
effect of silver (Suriyakalaa et al. 2013).
A mouse model of allergic airway disease was used to
evaluate the effect of AgNP inhalation on airway hyper-
responsiveness and inflammation and to investigate the
related molecular mechanisms. The results indicated that
AgNPs may attenuate antigen-induced airway inflamma-
tion and hyper-responsiveness. One of the molecular
bases in the murine model of asthma could be antioxi-
dant effect of AgNPs. These findings may provide a
potential molecular mechanism of AgNPs in preventing
or treating asthma (Park et al. 2010).
Wound healing and bone regeneration
It was way back in 1970s that electrically generated silver
ions were used for the first time to treat severe cases of
antibiotic-resistant osteomyelitis, a bone infection that
causes large wounds in the flesh. In this study, silver ions
were directly generated into open infected wounds
through the use of a small, battery operated colloidal sil-
ver generator operating at 09 volts. It was observed that
the silver effectively killed the disease causing micro-
organisms and also triggered regrowth of human tissue
and bone at the site of the infection. Electrically gener-
ated silver ions not only killed the pathogens and healed
the infection but also stimulated tissue and bone
regrowth (Becker 2000).
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
into the required embryonic stem cells. Silver ions were
generated directly into the human body by passing a tiny
electrical microcurrent through surgically implanted silver
rods or silver mesh. These silver ions could stimulate
wound healing and tissue regeneration by killing infec-
tions and triggering a process called cellular dedifferentia-
tion (Becker 2002). The process of silver-assisted wound
healing by means of cellular dedifferentiation is explained
as follows (Fig. 4). When silver ions come in contact with
the wound bed, they combine with proteins, peptides and
other chemical species normally present in the tissues.
After all the available sites are saturated with binding of
silver ions, the antibacterial action of silver begins at
about 2030 min following the exposure of bacteria to
the ions. The next reaction is an association between the
silver ions and sensitive cells present in the wound such
as mature fibroblast and epithelial cells, resulting in ded-
ifferentiation of these cells into embryonic cell types cap-
able of redifferentiation into other cell types. Production
of dedifferentiated fibroblasts requires a continuous sup-
ply of excess silver ions for at least 4872 h following sat-
uration of the active chemical sites in the previous
reaction. If sufficient silver ions are made available, a
third reaction begins to take place. This constitutes a
specific physical association of at least some of the silver
ions with the collagen fibres present in the wound to
produce a unique structure called as silver-collagen com-
plex having the specific properties required to induce
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1078
The silver lining K. Naik and M. Kowshik
activation of the dedifferentiated fibroblast cells previ-
ously produced. After this, an adequate blastema is
formed in the tissue which supports regeneration and
wound repair by the process of redifferentiation of blas-
tema into the required cell types (Becker et al. 1998).
Electrically generated silver ions were reported to kill
numerous forms of infectious micro-organisms. For
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 10100 times superior to silver sul-
fadiazine in case of both Gram-positive and Gram-nega-
tive pathogens in terms of achieving the minimal lethal
dose (Berger et al. 1976b).
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-
ies on anticancer property of silver are based on cytotoxic
effect of silver. The anticancer properties of colloidal sil-
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.
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-
ing cancer cells without harming normal cells.
It has long been suspected that infectious agents are
associated with solid tumour cancers like Kaposi ‘s sar-
coma as well as nontumour-based cancers such as leukae-
mia and many other types of cancers like
adenocarcinoma, lymphoma and breast cancer. Many
mechanisms of carcinogenesis by infectious micro-organ-
isms have been proposed such as induction of chronic
inflammation, production of mutagenic compounds by
bacterial metabolism, transformation of cells by inserting
active oncogenes into the host genome, inhibiting tumour
suppressors or stimulating mitosis and infectious agents
like human immunodeficiency virus leading to induction
Dermis Epidermis
Step 1: Antimicrobial effect
Step 1: Binding of silver ions to fibroblasts, etc.
Step 3: De-differentiation and formation of
silver-collagen complex
Silverions Chronic
wound
Bacterial colonization
and Biofilm formation
Excess supply of silver ions
More silver ions
Step 4: Re-differentiation and wound repair
Key
Neutrophil
Macrophage
Fibroblast
Collagen
Endothelial
cell
Balstemal
cell
Figure 4 Silver-assisted regeneration and repair of wound. [Colour
figure can be viewed at wileyonlinelibrary.com]
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology 1079
K. Naik and M. Kowshik The silver lining
of immunosuppression with consequently reduced
immunosurveillance (Parsonnet 1995; Kuper et al. 2000).
Hence, nanosilver may have the potential to play a dual
role by either destroying the infectious aetiological agent
of the cancer and/or the cancer cells.
Increase in immunity
In addition to its antimicrobial effect, colloidal silver is
also known to be a powerful immune system booster.
Trace amounts of silver are present in the bodies of all
humans and animals, however, it is not an essential ele-
ment. A correlation between low silver levels in body and
disease has been observed wherein individuals with low
silver levels in their hair analysis were frequently found to
be sick with innumerable colds, flu, fevers and various
other sicknesses. It was proposed that silver deficiency
could be the key to the improper function of the immune
system (Becker and Selden1985).
Increasing evidence of AgNPs and their possible
immunomodulatory effects have been reported (Edwards-
Jones 2009). It has been demonstrated that silver ions
greatly enhance the ability of immune cells to digest
infectious agents. This is facilitated by increasing the
digestive aids of these immune cells, like superoxide and
hydrogen peroxide more commonly known as ROS
(Thurman and Gerba 1989; Jansson and Harms-Ringdahl
1993; Feng et al. 2000).
Silver ions are reported to activate mast cells which are
a crucial component of the immune system and play an
important role in allergic reactions, wound healing and
defence against pathogens. Silver activates mast cells by
bypassing the early signalling events required for the
induction of calcium influx. These activated mast cells
then destroy microbial cells before they can colonize the
key areas of body (Suzuki et al. 2002). Furthermore, sil-
ver also plays a vital role in stimulating the lymphatic
system. It is a crucial part of the immune system as it fil-
ters out toxins from the circulatory system in the body.
Silver nanoparticles have the ability to reduce cytokine
expression and thus reduce excessive inflammation that
slows down the process of healing. Cytokines are sig-
nalling molecules in the body that direct the immune sys-
tem to send white blood cells and other infection fighting
agents to the site of infection. This causes mild inflam-
mation which is a normal part of healing. However, in
case of chronic infection or serious wound trauma, the
pro-inflammatory effects of cytokine expression can result
in excessive unwanted inflammation which in turn
impedes the healing process. In such cases, antimicrobial
silver has a modulating effect on cytokine expression,
resulting in both reduced inflammation and increased
Silver nanoparticles
Membrane
cleavage CANCER
CELL
Mitochondria
Caspase 3 Apoptosis
DNA
fragmentation
Nucleus
Cell
blebbin
g
Figure 5 Caspase-mediated cancer cell
apoptosis by silver nanoparticles. [Colour
figure can be viewed at
wileyonlinelibrary.com]
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology1080
The silver lining K. Naik and M. Kowshik
healing. Antimicrobial silver also promotes wound heal-
ing by reducing microbial burden.
When wound healing properties of AgNPs were inves-
tigated in an animal model, rapid healing and improved
cosmetic appearance was observed in a dose-dependent
manner. Moreover, the study confirmed that AgNPs
exerted positive effects such as antimicrobial activity,
reduction in wound inflammation and modulation of
fibrogenic cytokines (Tian et al. 2007). It has been
implied that AgNPs could one day play a key medical
role in decreasing inflammation in chronic infections,
wounds and other inflammatory medical conditions
(Shin et al. 2007; Klippstein et al. 2010).
Toxicology of silver and silver-based
nanoparticles
High degree of commercialization of nanosilver-related
applications has led to a rapid increase in widespread use
of numerous consumer products containing nanosilver.
Hence, thorough investigations on safe design, use and
disposal without creating new risk to humans or the
environment is warranted (Tran et al. 2013). The toxic
effects of nanosilver are dependent on the size, concentra-
tion and time of exposure. A comprehensive review of
the possible risks of nanosilver to mammalian cells
in vitro has been discussed in detail by Tran et al. In the
present review, the authors have summarized the impact
of nanosilver on human health and animals based on sev-
eral in vivo toxicity studies.
Silver is reported to exhibit low toxicity in the human
body, and minimal risk is expected due to clinical expo-
sure by inhalation, ingestion, dermal application or
through the urological or haematogenous route. How-
ever, long-term occupational exposure of silver or
chronic ingestion or inhalation of silver preparations can
lead to deposition of silver particles in the skin and eyes
termed as Argyraemia. These conditions are not life-
threatening but cosmetically undesirable. When silver is
absorbed into the human body, it enters the systemic cir-
culation as a protein complex which is then eliminated
by the liver and kidneys. Silver metabolism is modulated
by induction and binding to metallothioneins. This com-
plex mitigates the cellular toxicity of silver and con-
tributes to tissue repair (Lansdown 2006).
In vivo porcine skin exposure studies conducted to
assess the inflammatory and penetrating potential of
AgNPs into porcine skin have shown that the toxicity is
influenced by the residual contaminants in the AgNPs
solution, and that the AgNPs themselves might not be
responsible for an increase in cell mortality. Hence, com-
plete characterization of not only the nanoparticles but
also the vehicle is suggested in order to distinguish
between AgNPs and contaminant toxicity (Samberg et al.
2010). Studies on the effects of AgNPs on gene expression
in mouse brain suggest that AgNPs may produce neuro-
toxicity by generating free radical-induced oxidative stress
and by altering gene expression, producing apoptosis and
neurotoxicity at high concentrations; 1001000 mg kg
1
body weight (Rahman et al. 2009). In another study,
mice exposed to 191 910
7
particles per cm
3
for
6hd
1
, 5 d week
1
using the nose-only exposure system
for 2 weeks exhibited modulation in the expression of
several genes associated with motor neuron disorders,
neurodegenerative disease and immune cell function,
indicating potential neurotoxicity and immunotoxicity
(Lee et al. 2010a). Oral toxicity of AgNPs assessed over a
period of 28 days in SpragueDawley rats has shown that
doses above 300 mg resulted in slight liver damage as
indicated by dose-dependent changes in the alkaline
phosphatase and cholesterol levels. A dose-dependent
accumulation of silver in all the tissues examined (bone
marrow, kidneys, etc.) was also noted, however, there was
no indication of genetic toxicity in male and female rat
bone marrow (Kim et al. 2008b). In vivo studies on lung
toxicity as a result of inhalation of subacute doses of
AgNPs (33mgm
3
,4hd
1
for 10 days) in mice
showed minimal pulmonary inflammation or cytotoxicity
which was in contrast to published in vitro studies (Ste-
bounova et al. 2011).
Conclusion
Historically silver has been used as a major therapeutic
agent in medicine especially in infectious diseases includ-
ing surgical infections (Alexander 2009). However, there
have been apprehensions associated with the usage of
nanosilver through this long and diverse history of its
applications. A continuous debate on the benefits and
drawbacks of the use of silver-incorporated products in
healthcare and medicine has prevailed ever since. The
physician Paracelsus who founded the discipline of toxi-
cology quoted back in 1529 that ‘Poison is in everything,
and no thing is without poison. The dosage makes it
either a poison or a remedy.’ Silver can be highly benefi-
cial to the human body when used within limits and
potentially harmful when used in excess. It is reported to
have an advantageous risk: benefit ratio. Further studies
on nanosilver with increasing time of exposure and dose
and with additional organ systems are recommended. In
order to use the potential medical benefits of silver,
in vivo human clinical studies and trials are required.
Conflict of Interest
The authors declare no conflict of interest.
Journal of Applied Microbiology 123, 1068--1087 ©2017 The Society for Applied Microbiology 1081
K. Naik and M. Kowshik The silver lining
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K. Naik and M. Kowshik The silver lining
  • ... μg/mL). 16,17 However, small silver particles (D < 6 nm) afford advantages of enhanced stability and renal clearance with rapid and efficient urinary excretion. 18−21 A promising approach to enhance the antimicrobial activity of the cluster is to conjugate its ligands to a penicillin nucleus. ...
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  • ... The MD showed antimicrobial and antibiofilm activities versus S. aureus and E. faecalis, but a lower efficacy against E. coli. The antimicrobial activity is definitely due to the silver-based component (TIAB), because the antibacterial activity exerted by silver ions as well as by TiO 2 nanoparticles has long been known [13,23]. TIAB can be used as an effective topic therapeutic agent in the treatment of chronic periodontitis along with supportive periodontal therapy and after ocular surgery. ...
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  • ... Silver nanoparticle (AgNPs) is one nanomaterial that has been widely used an attractive due its strong antimicrobial effect against fungi, yeast and bacteria as multidrug-resistant such as P. aeruginosa, at concentrations as low as 0.1% (w/w). AgNP can be synthetized in different shapes and size that range from 1-100 nm [1,[7][8][9][10]. Hydrogels are tridimensional polymeric structure and biocompatibility. ...
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  • ... The toxicity of nanosilver to these organisms has raised concerns that release of nanosilver to the environment may disrupt the operation of STPs as well as natural processes in the ecosystem that support plant life. According to Naik and Kowshik [13] the Ag + range concentration of 1 to 10 µmol/l and AgNPs size 7 to 20 nm of range 0.78 to 6.25 and 12.5 µg/ml was required to cause kill or damage bacteria in water. ...
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    Silver nanoparticle (Ag NP)-loaded chitosan composites have numerous biomedical applications; however, fabricating uniform composite microparticles remains challenging. This paper presents a novel microfluidic approach for single-step and in situ synthesis of Ag NP-loaded chitosan microparticles. This proposed approach enables obtaining uniform and monodisperse Ag NP-loaded chitosan microparticles measuring several hundred micrometers. In addition, the diameter of the composites can be tuned by adjusting the flow on the microfluidic chip. The composite particles containing Ag NPs were characterized using UV–vis spectra and scanning electron microscopy-energy dispersive X-ray spectrometry data. The characteristic peaks of Ag NPs in the UV–vis spectra and the element mapping or pattern revealed the formation of nanosized silver particles. The results of antibacterial tests indicated that both chitosan and composite particles showed antibacterial ability, and Ag NPs could enhance the inhibition rate and exhibited dose-dependent antibacterial ability. Because of the properties of Ag NPs and chitosan, the synthesized composite microparticles can be used in several future potential applications, such as bactericidal agents for water disinfection, antipathogens, and surface plasma resonance enhancers.
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    In modern era, viral infections constitute one of the main health problems. Chemically synthesized antiviral drugs have adverse side effects which are associated with other health complications. The emergence of new infectious diseases and increase in frequency of drug resistant viruses demand the most effective and novel therapeutic agents, one of which are nanoparticles. Nanoparticles excel as therapeutic agents due to their unique physiochemical properties and a universally applicable physical mode of action. Their large surface area to volume ratio offers them an edge as an antiviral agent. The review focuses on the mechanism of action of silver nanoparticles and their novel therapeutic applications against some viruses bearing potentially fatal consequences.