REVIEW PAPER

A review of the antibacterial effects of silver nanomaterialsand potential implications for human healthand the environment

Catalina Marambio-Jones • Eric M. V. Hoek

Received: 29 July 2009 / Accepted: 6 March 2010 / Published online: 23 March 2010

� Springer Science+Business Media B.V. 2010

Abstract Here, we present a review of the antibac-

terial effects of silver nanomaterials, including pro-

posed antibacterial mechanisms and possible toxicity

to higher organisms. For purpose of this review, silver

nanomaterials include silver nanoparticles, stabilized

silver salts, silver–dendrimer, polymer and metal oxide

composites, and silver-impregnated zeolite and acti-

vated carbon materials. While there is some evidence

that silver nanoparticles can directly damage bacteria

cell membranes, silver nanomaterials appear to exert

bacteriocidal activity predominantly through release of

silver ions followed (individually or in combination)

by increased membrane permeability, loss of the

proton motive force, inducing de-energization of the

cells and efflux of phosphate, leakage of cellular

content, and disruption DNA replication. Eukaryotic

cells could be similarly impacted by most of these

mechanisms and, indeed, a small but growing body of

literature supports this concern. Most antimicrobial

studies are performed in simple aquatic media or cell

culture media without proper characterization of silver

nanomaterial stability (aggregation, dissolution, and

re-precipitation). Silver nanoparticle stability is gov-

erned by particle size, shape, and capping agents as

well as solution pH, ionic strength, specific ions and

ligands, and organic macromolecules—all of which

influence silver nanoparticle stability and bioavailabil-

ity. Although none of the studies reviewed definitively

proved any immediate impacts to human health or the

environment by a silver nanomaterial containing

product, the entirety of the science reviewed suggests

some caution and further research are warranted given

the already widespread and rapidly growing use of

silver nanomaterials.

Keywords Silver � Nanoparticle �Antimicrobial � Antibacterial � Nanotechnology �Nanotoxicology � Safety � EHS

Introduction

The broad-spectrum antimicrobial properties of silver

encourage its use in biomedical applications, water

and air purification, food production, cosmetics,

clothing, and numerous household products. With

the rapid development of nanotechnology, applica-

tions have been extended further and now silver is the

engineered nanomaterial most commonly used in

consumer products (Rejeski 2009). Clothing, respi-

rators, household water filters, contraconceptives,

antibacterial sprays, cosmetics, detergent, dietary

supplements, cutting boards, sox, shoes, cell phones,

laptop keyboards, and children’s toys are among the

C. Marambio-Jones � E. M. V. Hoek (&)

Department of Civil and Environmental Engineering,

California NanoSystems Institute, University

of California, Los Angeles, 5732G Boelter Hall,

PO Box 951593, Los Angeles, CA 90095-1593, USA

e-mail: emvhoek@ucla.edu

123

J Nanopart Res (2010) 12:1531–1551

DOI 10.1007/s11051-010-9900-y

retail products that purportedly exploit the antimi-

crobial properties of silver nanomaterials.

Different forms of silver nanomaterials already in

such products include: metallic silver nanoparticles

(Arora et al. 2008; Chi et al. 2009; Choi et al. 2008;

Hwang et al. 2008; Kim et al. 2007, 2008a, b; Kvitek

et al. 2008; Lok et al. 2006; Raffi et al. 2008; Schrand

et al. 2008; Sondi and Salopek-Sondi 2004; Vertelov

et al. 2008), silver chloride particles (Choi et al.

2008), silver-impregnated zeolite powders and acti-

vated carbon materials (Cowan et al. 2003; Inoue

et al. 2002; Yoon et al. 2008a, b), dendrimer–silver

complexes and composites (Balogh et al. 2001;

Lesniak et al. 2005; Zhang et al. 2008), polymer-

silver nanoparticle composites (Bajpai et al. 2007;

Damm and Munstedt 2008; Damm et al. 2008; Hlidek

et al. 2008; Jin et al. 2007; Kim et al. 2009a, b;

Kvitek et al. 2008; Naidu et al. 2008; Nita 2008;

Sambhy and Sen 2008; Sanpui et al. 2008; Xu et al.

2006), silver-titanium dioxide composite nanopow-

ders (Yeo and Kang 2008), and silver nanoparticles

coated onto polymers like polyurethane (Jain and

Pradeep 2005). While all of these forms of silver

exert antimicrobial activity to some extent through

release of silver ions, silver nanoparticles might

exhibit additional antimicrobial capabilities not

exerted by bulk or ionic silver (Chen and Schluesener

2008).

Already, silver nanoparticles have been shown to

be effective biocides against: (a) bacteria such as

Escherichia coli, Staphylococcus aureus, Staphylo-

coccus epidermis, Leuconostoc mesenteroides, Bacil-

lus subtilis, Klebsiella mobilis, and Klebsiella

pneumonia among others (Benn and Westerhoff

2008; Chen and Chiang 2008; Falletta et al. 2008;

Hernandez-Sierra et al. 2008; Ingle et al. 2008; Jung

et al. 2009; Kim 2007; Kim et al. 2007, 2009a, b;

Kvitek et al. 2008; Raffi et al. 2008; Ruparelia et al.

2008; Smetana et al. 2008; Sondi and Salopek-Sondi

2004; Vertelov et al. 2008; Yang et al. 2009; Yoon

et al. 2008a, b); (b) fungi such as Aspergillus niger,

Candida albicans, Saccharomyces cerevisia, Tricho-

phyton mentagrophytes, and Penicillium citrinum

(Kim et al. 2007, 2008a, b, 2009a, b; Roe et al.

2008; Vertelov et al. 2008; Zhang et al. 2008); and (c)

virii such as Hepatitis B, HIV-1, syncytial virus

(Elechiguerra et al. 2005; Lu et al. 2008; Sun et al.

2008; Zodrow et al. 2009). Hybrid silver nanocom-

posites with dendrimers and polymers have been

shown effective for S. aureus, Pseudomonas aeru-

ginosa, E. coli, B. subtilis, and K. mobilis (Balogh

et al. 2001; Zhang et al. 2008). Furthermore, silver

loaded in nanoporous materials such as silver-

exchanged zeolites exhibit antibacterial effects for

Pseudomonas putida, E. coli, B. subtilis, S. aureus,

and P. aeruginosa (Cowan et al. 2003; Inoue et al.

2002; Lind et al. 2009; McDonnell et al. 2005).

Despite the vast number of papers touting the

beneficial antimicrobial effects of silver nanomateri-

als, a relatively modest number of studies have

attempted to elucidate the mechanisms by which

silver nanomaterials exert this antimicrobial activity.

As a result, the mechanisms are not widely under-

stood or agreed upon. For bacteria, commonly

proposed mechanisms in the literature begin with

the release of silver ions (Hwang et al. 2008; Smetana

et al. 2008) followed by generation of reactive

oxygen species (ROS) (Hwang et al. 2008; Kim

et al. 2007) and cell membrane damage (Choi et al.

2008; Raffi et al. 2008; Smetana et al. 2008; Sondi

and Salopek-Sondi 2004), but there are many

contradictory findings reported.

The more widespread our use of silver nanoma-

terials becomes the more widespread will become the

potential for human and ecosystem exposure. Silver

nanoparticles may be released to the environment

from discharges at the point of production, from

erosion of engineered materials in household prod-

ucts (e.g., antibacterial coatings and silver-impreg-

nated water filters), and from washing or disposal of

silver-containing products (Benn and Westerhoff

2008). Silver released to both natural and engineered

systems will likely impact the lowest trophic levels

first, i.e., bacteria. However, little is known about

trophic transfer of silver and impacts to higher

organisms. Indeed, silver nanoparticles have already

been proven toxic to both aerobic and anaerobic

bacteria isolated from wastewater treatment plants

(Choi and Hu 2008), which we speculate could lead

to severe disruption of this critical environmental

infrastructure if the load of silver into wastewater

treatment plants increases significantly.

Given the vast number of products leveraging the

benefits of silver, it seems prudent to assess the

potential human and ecosystem hazards associated

with its increased utilization. The main routes of

human exposure would be the respiratory system,

gastrointestinal system, and skin, which are interfaces

1532 J Nanopart Res (2010) 12:1531–1551

123

between the internal systems of the human body and

the external environment (Chen and Schluesener

2008). For example, silver nanomaterials may enter

through the respiratory tract due to inhalation of dust

or fumes containing silver nanomaterials at the point

of manufacture, it may be ingested from water,

children’s toys, or food containers treated with silver,

or it may penetrate the skin via silver-containing

textiles and cosmetics. Additionally, other potential

entryways could include the female genital tract (due

to incorporation of silver nanoparticles into numerous

female hygienic products), via systemic administra-

tion as it is used for some imaging and therapeutic

purposes (Chen and Schluesener 2008; Schrand et al.

2008; West and Halas 2003), or by incorporation into

medical implants, catheters, and wound dressings

(Furno et al. 2004; Galiano et al. 2008; Maneerung

et al. 2008; Roe et al. 2008).

In addition to broad-spectrum antimicrobial

effects, silver nanoparticles have produced toxic

effects in higher cell lines like zebra fish, clams,

rats, and humans (Arora et al. 2008, 2009; Asharani

et al. 2008; Braydich-Stolle et al. 2005; Hsin et al.

2008; Hussain et al. 2005; Kim et al. 2008a, b; Sung

et al. 2008; Yeo and Kang 2008; Yeo and Yoon

2009). Evidence in rodents shows that after entering

into the body silver nanoparticles can accumulate

and, in some cases, damage tissues such as the liver,

lungs, and olfactory bulbs, or penetrate the blood–

brain barrier (Arora et al. 2009; Braydich-Stolle et al.

2005; Hussain et al. 2005; Sung et al. 2008). A study

in human cells concluded that silver can be genotoxic

(Asharani et al. 2009). Additionally, a release of ionic

silver led to the sterility of Macoma balthica clams in

the San Francisco Bay during the 1980s (Brown et al.

2003). If silver nanomaterials exhibit similar or

stronger reactivity, the impacts of this isolated event

in San Francisco may foreshadow potential ecosys-

tem impacts of silver nanomaterials.

The various forms of silver nanomaterials are

among the most promising antimicrobial agents being

developed from nanotechnology, but the preliminary

evidence of effects on higher organisms alerts us to

remain cautious of its widespread utilization. This

cautiousness demands additional research to deter-

mine how to safely design, use, and dispose products

containing silver nanomaterials without creating new

risks to humans or the environment. Consequently,

the goal of this article is to provide a critical review

of the state-of-knowledge about silver nanomaterial

antibacterial effects with insights toward better

understanding potential implications for human

health and the environment.

Typical forms of silver nanomaterials

Herein, the term ‘‘silver nanomaterials’’ refers to any

silver-containing materials with enhanced activity

due to their nanoscale features. In some cases,

commercial products containing metallic silver nano-

particles in the range of 5–50 nm or ionic silver are

given the name ‘nanosilver’ (Panyala et al. 2008).

Silver nanoparticles are nanoscale clusters of metallic

silver atoms, Ag0, engineered for some practical

purpose—most typically antimicrobial and sterile

applications.

The most common method of producing silver

nanoparticles is chemical reduction of a silver salt

dissolved in water with a reducing compound such as

NaBH4, citrate, glucose, hydrazine, and ascorbate

(Gulrajani et al. 2008; Martinez-Castanon et al. 2009;

Panacek et al. 2006; Pillai and Kamat 2004). Strong

reductants lead to small monodisperse particles,

while generating larger sizes can be difficult to

control. Weaker reductants produce slower reduction

reactions, but the nanoparticles obtained tend to be

more polydisperse in size. In order to generate silver

nanoparticles with controlled sizes, a two-step

method is usually utilized. In this method, nuclei

particles are prepared using a strong reducing agent

and they are enlarged by a weak reducing agent

(Schneider et al. 1994; Shirtcliffe et al. 1999). Since

reducing agents for silver nanoparticle synthesis are

often considered toxic or hazardous, the use of green

synthesis methods is becoming a priority (Panacek

et al. 2006). A recent review of green synthesis

methods for silver nanoparticles discussed the use of

polysaccharides, polyphenols, Tollens agent, irradia-

tion, biological reduction, and polyoxometalate

(Sharma et al. 2009).

Polysaccharides and polyphenols are typically

used as capping agents during silver nanoparticle

synthesis, but they may also contribute to reduction

of silver ions through as yet poorly understood

mechanisms. For polysaccharides, the reduction of

silver may be linked to the oxidation of aldehyde

groups to carboxylic acid groups (Manzi and van

J Nanopart Res (2010) 12:1531–1551 1533

123

Halbeek 1999). Typical polysaccharides used are

glucose, starch, and heparin (Batabyal et al. 2007;

Huang and Yang 2004; Manno et al. 2008; Singh

et al. 2009; Venediktov and Padokhin 2008). In the

Tollens method, a silver ammoniacal solution is

reduced by an aldehyde forming silver nanoparticles.

This method can be altered (i.e., ‘‘modified Tollens

method’’) by reducing Ag? using saccharides in the

presence of ammonia resulting in films with nano-

particles sizes ranging from 50 to 200 nm and silver

hydrosols ranging from 20 to 50 nm (Panacek et al.

2006; Saito et al. 2003; Yu and Yam 2004). Silver

nanoparticles can also be synthesized by irradiating

silver salts solutions containing reducing and capping

agents. Different sources of irradiation have been

used such as laser, microwave, ionization radiation,

and radiolysis (Abid et al. 2002; Ha et al. 2006; Li

et al. 2006; Long et al. 2007; Mahapatra et al. 2007;

Pillai and Kamat 2004; Sharma et al. 2007, 2008;

Yanagihara et al. 2001; Yin et al. 2004; Zeng et al.

2007).

Biological methods involve the production of

silver nanoparticles utilizing extracts from bio-organ-

isms as reductant, capping agents or both (Li et al.

2007; Sanghi and Verma 2009). Such extracts can

include proteins, amino acids, polysaccharides, and

vitamins (Eby et al. 2009; Sharma et al. 2009). Plant

extracts such as apiin (a glucoside compound) and

leaf extract from magnolia, Persimmon, geranium,

and Pine leaf have also been used as reducing agents

of Ag? to produce silver nanoparticles (Kasthuri

et al. 2009; Shankar et al. 2003; Song and Kim 2009).

Additionally, silver nanoparticles can be synthesized

by several microorganisms such as the bacterial

strains Bacillus licheniformis, K. pneumonia, and

fungi strains such as Verticillium and Fusarium

oxysporum, Aspergillus flavus (Ahmad et al. 2003;

Kalishwaralal et al. 2008; Mokhtari et al. 2009;

Mukherjee et al. 2001; Senapati et al. 2004; Vig-

neshwaran et al. 2007). It is not clear if these

microbes are impacted (favorably or unfavorably) by

exposure to engineered forms of nano-scaled silver,

but their seemingly favorable interactions with silver

suggest resistance may be fairly widespread.

Another procedure utilized to synthesize silver

nanoparticles is the solvated metal atom dispersion

(SMAD) method (Stoeva et al. 2002). In this method,

a metal is co-vaporized with a solvent onto a liquid

nitrogen cooled surface, as liquid nitrogen is removed

the metal atoms and solvent warms causing the

aggregation of metal atoms. SMAD can be performed

in conjunction with digestive ripening, in this way the

nanoparticles resulting from SMAD method are

further refined by heating them in inert atmosphere

in the presence of selected ligands that encourage the

particles to reach a narrow size range. As a result,

monodisperse spherical particles are obtained (Sme-

tana et al. 2005, 2008).

The use of silver ions as antimicrobial agents is

limited by the solubility of silver ions in biological

and environmental media containing Cl-, because

AgCl has a very low solubility and rapidly precip-

itates out of solution. In some cases, silver salts are

stabilized with hyperbranched polymers or dendri-

mers that act as nanoreactors, wherein silver ions

are initially complexed with a specific moiety in the

polymeric structure and then reduced to form silver

nanoparticles within the polymeric matrix (Fig. 1)

(Lesniak et al. 2005; Zhang et al. 2008). Dendri-

mer–silver complexes prevent silver ions from

precipitating and keep silver dispersed in the media

long enough to be delivered where it is desired

(Balogh et al. 2001; Lesniak et al. 2005; Zhang

et al. 2008). Silver ions can also be stabilized in

zeolite channels (Fig. 2) or deposited in activated

carbon fibers (Inoue et al. 2002; Ogden et al. 1999;

Pal et al. 2009).

Composites of silver coatings over titanium diox-

ide nanoparticles are used in products such as baby

bottles and blood-clotting agents to produce antibac-

terial activity (Yeo and Kang 2008). Other hybrid

silver nanomaterials may include silver nanoparticles

coated onto polyurethane and silver–magnetite com-

posite nanoparticles (Fe3O4@Ag); both of these

hybrids are utilized for water disinfection (Gong

et al. 2007; Jain and Pradeep 2005). One of the

challenges of using silver (or any) nanoparticles for

water treatment is recovering the particles after the

treatment process. Silver–magnetite nanoparticles

offer the potential advantage of being removed by a

magnet, avoiding release to the environment, and

making possible direct reuse without additional

separation processes. For example, in related

research, magnetite particles proved effective for

removal of arsenic from water (Mayo et al. 2007;

Yavuz et al. 2006). However, for silver materials, an

additional concern is controlling the release of metal

ions into the final produce water.

1534 J Nanopart Res (2010) 12:1531–1551

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Evidence of silver toxicity in microbes

and higher organisms

Here, toxicity refers to any deleterious effects on an

organism upon exposure to silver. Obviously, if the

practical intent is to disinfect or sterilize a specific

type of organism, then toxicity may be interpreted

as a positive outcome (e.g., antibacterial, antiviral,

etc.). However, if the same material exerts unin-

tended or undesired impacts to other organisms, then

such toxicity may be interpreted as a potential

hazard.

Evidence of toxicity to bacteria

Table 1 presents a concise summary of silver nano-

material antibacterial studies. Kim et al. reported that

13.4-nm silver nanoparticles prepared by reduction of

silver nitrate with sodium borohydride show mini-

mum inhibitory concentration (MIC) against E. coli

below 6.6 nM and above 33 nM for S. aureus (Kim

et al. 2007). In another study, 16-nm silver nanopar-

ticles generated by gas condensation were able to

completely inhibit colony forming units (CFU)

ability of E. coli at 60 lg/mL (Raffi et al. 2008).

Fig. 1 General formation

scheme of PAMAM

dendrimer complexes and

nanocomposites. PAMAM

structural subunits:

core = ethylenediamine,

branching site = –N\,

chains connecting the

branching sites =

–CH2CH2CONHCH2CH2–.

Terminal groups on the

surface are marked as

–CH2CH2–CO–Z. Silver

ions (represented by M?)

can be pre-organize and

subsequently contained in

the form of solubilized and

stabilize, high-surface area

silver domains. Redrawn

based on (Balogh et al.

2001)

Fig. 2 Silver ions

stabilized in zeolite

channels and ionic

exchange of silver ions with

other cations in the media.

Left picture shows zeolite

type A and right pictureshows zeolite type X.

Adapted from (Auerbach

2003)

J Nanopart Res (2010) 12:1531–1551 1535

123

Commercially available silver nanopowders at a

concentration of 300 lg/mL and SMAD-produced

silver nanoparticles at a concentration of 30 lg/mL

were able to reduce (after 10 min contact time)

colony forming units of E. coli and S. aureus from

2 9 104 CFU/mL to 0 and\20, respectively (Smetana

et al. 2008).

Additionally, MICs ranging from 13.5 to 1.69 lg/mL

were reported for bacterial strains such as S. aureus

CCM 3953, Enterococcus faecalis CCM 4224, E. coli

CCM 3954, and P. aeruginosa CCM 3955, and for

strains isolated from human clinical material like

P. aeruginosa, methicillin-susceptible S. epidermidis,

methicillin-resistant S. epidermidis, methicillin-resistant

S. aureus, vancomycin-resistant Enterococcus

faecium, and K. pneumonia when exposed to

26-nm silver nanoparticles prepared by the reduc-

tion of [Ag(NH3)2]? with D-maltose (Kvitek et al.

2008).

Silver nanoparticles also produced 76% reduction

of B. subtilis CFU after applying silver nanoparticles

with a size distribution from 14 to 710 nm in an

aerosol form (Yoon et al. 2008a, b). Likewise, silver

nanoparticles are effective against E. coli, S. aureus,

and L. mesenteroides. Also, 10-nm Myramistin�

stabilized silver nanoparticles inhibit growth of

E. coli and S. aureus at 2.5 lg/mL and L. mesen-

teroides at 5 lg/mL (Vertelov et al. 2008).

Table 1 Bactericidal activity of nano-scaled silver and silver loaded in zeolite

Silver form Size data Bacterial strain Key aspects References

Silver nanoparticles/

nano-sized silver

powders

13.4 nmb E. coli, S. aureus Minimal inhibition concentration against

E. coli was lower than 6.6 nM and

higher than 33 nM for S. aureus

(Kim et al. 2007)

16 nm E. coli Complete inhibition of CFU ability at

60 lg/mL

(Raffi et al. 2008)

1 lm E. coli, S. aureus CFU reduced by 4 to 5 log units (Smetana et al.

2008)

26 nm Standard strains and

strains isolated

from clinical

material

Minimal inhibition concentration from

1.69 to 13.5 lg/mL

(Kvitek et al. 2008)

10 nma E. coli, S. aureus Growth inhibition achieved at 5 lg/mL (Vertelov et al.

2008)L. mesenteroides Growth inhibition achieved at 2.5 lg/mL

Silver nanoparticles

applied as aerosol

14.1–710 nmc B. subtilis 76% CFU reduction by applying silver

nanoparticles aerosol on B. subtilisaerosol

(Yoon et al. 2008a,

b)

Silver nanoparticles

stabilized in

hyperbranched

polymers

1.4–7.1 nmb E. coli, S. aureus,

B. subtilis,

K. mobilis

Microbial activity increases as silver

content in polymer decreases since

decrease in silver nanoparticle size

(Zhang et al. 2008)

Silver–dendrimer

complexes and

nanocomposites

S. aureus,

P. aeruginosa,

E. coli

Antimicrobial activity was comparable or

higher to those of silver nitrate

solutions. The activity and solubility did

not decrease even in presence of sulfate

or chloride ions

(Balogh et al. 2001)

Silver zeolite E. coli CFU reduced by 7 log units in 5 min (Inoue et al. 2002)

Zeolite containing

silver and zinc

E. coli Minimal bactericidal concentration of

78 lg/mL

(as Ag?) for bacteria grown is Luria-

Bertani broth

(Cowan et al. 2003)

E. coli, S. aureus,

P. aeruginosaMinimal bactericidal concentration of

39 lg/mL

(as Ag?) for bacteria grown is Tryptic

Soy broth

Note: Size measured by a dynamic light scattering, b TEM images, and c scanning mobility particle sizer

1536 J Nanopart Res (2010) 12:1531–1551

123

Dendrimer–silver nanocomposites have also been

proven effective antibacterials. For example,

poly(amidoamine) dendrimer–silver composites have

been used against S. aureus, P. aeruginosa, E. coli,

B. subtilis, and K. mobilis (Balogh et al. 2001; Zhang

et al. 2008). Additionally, silver ions loaded in zeolites

elicit antibacterial properties. Two recent studies

demonstrated 7 log reduction in CFUs for E. coli,

from an initial concentration of 107 CFU/cm3, after

5 min of contact time with 333.3 lg/mL of Ag-loaded

zeolite (Inoue et al. 2002), and MICs of 78 lgAg?/mL

for E. coli and 39 lgAg?/mL for S. aureus and

P. aeruginosa, plus some bactericidal activity against

Listeria monocytogenes (Cowan et al. 2003).

Evidence of toxicity to other microorganisms

Silver nanoparticles also inactivate fungi, virii, and

algae (Table 2). For example, silver nanoparticles of

sizes ranging from 1.4 to 7.1 nm and stabilized in

Table 2 Summary of silver nanoparticles toxicity to other microorganisms

Strain Silver nanoparticles Size (nm) Key aspects Reference

Fungi

A. niger Myramistin� stabilized

silver nanoparticles

10a MIC were found to be 5 mg/L (Vertelov et al. 2008)

Silver nanoparticles

stabilized in hyper

branched polymers

1.4–7.1b Formation of inhibition zones

around silver nanoparticles

inoculated spots in agar plates

(Zhang et al. 2008)

S. cerevisiae Myramistin� stabilized

silver nanoparticles

10a MIC were found to be 5 mg/L (Vertelov et al. 2008)

T. mentagrophytes Silver nanoparticles 3b IC80 between 1 and 4 mg/L (Kim et al. 2008a, b)

C. Albanicas Silver nanoparticles 3b Silver nanoparticles inhibited

micelial formation, which is

responsible for pathogenicity

(Kim et al. 2008a, b)

Silver nanoparticles 3b Antifungal activity may be exerted

by cell membrane structure

disruption and inhibition of

normal budding process

(Kim et al. 2009a, b)

Silver nanoparticles

coated on plastic

catheters

3–18b Catheter coated with silver

nanoparticles inhibited growth

and biofilm formation.

(Roe et al. 2008)

Yeast (isolated

from bovine

mastitis)

Silver nanoparticles 13.4b MIC estimated between 6.6 nM

and 13.2 nM

(Kim et al. 2007)

P. citrinum Silver nanoparticles

stabilized in hyper

branched polymers

1.4–7.1b Formation of inhibition zones

around silver nanoparticles

inoculated spots in agar plates

(Zhang et al. 2008)

Viruses

Hepatitis B virus Silver nanoparticles 10b Inhibition of virus replication (Lu et al. 2008)

HIV-1 Silver nanoparticles 16.19 ± 8.68b Only 1–10 nm nanoparticles

attached to virus restraining virus

from attaching to host cells.

(Elechiguerra et al. 2005)

Syncitial virus Silver nanoparticles 44% inhibition of Syncitial virus

infection

(Sun et al. 2008)

Algae

C. reinhardtii Silver nanoparticles 10–200a EC50 for the photosynthetic yield

was found in 0.35 mg/L of total

silver content after 1 h of

exposure

(Navarro et al. 2008)

Note: Size measured by a dynamic light scattering and b TEM images

J Nanopart Res (2010) 12:1531–1551 1537

123

hyperbranched polymers, and silver nanoparticles

stabilized with Myramistin� (size 10 nm) inhibited

the growth of A. niger (Tomsic et al. 2009; Vertelov

et al. 2008; Zhang et al. 2008); the same Myramistin�

stabilized particles were found toxic toward S. cere-

visiae showing a MIC of 5 mg/L. Further, 3-nm silver

nanoparticles showed IC80 values from 1 to 4 lg/mL

against T. mentagrophytes and 2 to 4 lg/mL for

C. albanicans (Kim et al. 2008a, b); while in other study,

it was reported that the antifungal activity of silver

nanoparticles against C. albanicans could be exerted

by cell membrane structure disruption leading to

reproduction inhibition (Kim et al. 2009a, b). Addi-

tionally, silver nanoparticles (sizes ranging from 3 to

18 nm) coated in catheters were able to inhibit growth

of C. albicans. Although, in this case, no analysis of

the antifungal molecular mechanism was done, the

authors speculate that silver ions (Ag?) released from

the matrix were the antifungal agents (Kim et al.

2008a, b, 2009a, b; Roe et al. 2008). Furthermore,

silver nanoparticles suppress yeast growth and show

MIC between 6.6 and 13.2 nM (Kim et al. 2007).

Silver nanoparticles of sizes from 1.4 to 7.1 nm and

stabilized in hyperbranched polymers (HPAMAM-

N(CH3)2/AgNPs composite) inhibit P. citrinum

growth (Zhang et al. 2008). Although information

about toxicity for algae is limited, silver nanoparticles

reduced the photosynthetic yield of Chlamydomonas

reinhardtii; in this case, the observed toxicity was

attributed to Ag? ions (Navarro et al. 2008).

Evidence of virus inactivation is also reported in

literature. For example, silver nanoparticles of 10 nm

are able to inhibit hepatitis B virus replication (Lu

et al. 2008). Additionally, PVP-coated silver nano-

particles in the range 1–10 nm attach to HIV-1 virus,

inhibiting the virus from attaching to host cells

(Elechiguerra et al. 2005). In other study, PVP-coated

silver nanoparticles reduced respiratory syncytial

virus infection by 44% (Sun et al. 2008). Polysulfone

ultrafiltration membranes impregnated with silver

nanoparticles of sizes ranging from 1 to 70 nm

showed enhanced virus removal, thus improving

water disinfection via low pressure membrane filtra-

tion (Zodrow et al. 2009).

Evidence of toxicity for mammalian cells

Significant evidence has been reported in relation to

the toxicity of silver nanoparticles to higher organ-

isms. It has been shown toxic to fish such as zebrafish

(Asharani et al. 2008; Yeo and Kang 2008; Yeo and

Yoon 2009), Diptera species such as Drosophila

melanogaster, known asfruit fly (Ahamed et al. 2010)

and different mammalian cell lines of mice (Brayd-

ich-Stolle et al. 2005; Hussain et al. 2005), rats (Kim

et al. 2008a, b; Sung et al. 2008), and also humans

(Asharani et al. 2009; Braydich-Stolle et al. 2005;

Hsin et al. 2008; Hussain et al. 2005). This review

presents only a few, brief examples of silver nano-

material toxicity for mammalian cells (Table 3).

More detailed, focused reviews on this topic are

available elsewhere (Chen and Schluesener 2008;

Panyala et al. 2008).

Table 3 Evidence of nano-scaled silver toxicity for mammalian cells

Target cell/organism Key aspects Reference

Rat lung cells Reduction in lung function and inflammatory lesions (Sung et al. 2008)

Sprague-Dawley rats Silver nanoparticles accumulation in olfactory bulb

and subsequent translocation to the brain

(Kim et al. 2008a, b)

Mouse stem cells Cell leakage and reduction of mitochondrial function (Braydich-Stolle et al. 2005)

Rat liver cells Cell leakage and reduction of mitochondrial function (Hussain et al. 2005)

Human fibrosarcoma

and human skin/carcinoma

Oxidative stress. Low doses produced apoptosis

and higher dose necrosis

(Arora et al. 2008)

Mouse fibroblast 50 lg/mL induced apoptosis to 43.4% of cells (Arora et al. 2009)

Human colon cancer 100 lg/mL produced necrosis to 40.2% of cells

Human glioblastoma Silver nanoparticles were found cytotoxic,

genotoxic and antiproliferative

(Asharani et al. 2009)

Human fibroblast Silver nanoparticles were found cytotoxic,

genotoxic and antiproliferative

(Asharani et al. 2009)

1538 J Nanopart Res (2010) 12:1531–1551

123

Evidence of silver nanoparticle toxicity for mam-

malian cells was presented in the in vivo studies

performed by Sung et al. (2008) and Kim et al.

(2008a, b). In the former, a 90-day inhalation study in

rats showed that silver nanoparticles reduce lung

function and produce inflammatory lesions in the

lungs. In the later, silver nanoparticles accumulated

in the olfactory bulbs of Sprague-Dawley rats and

also accumulated in the brain.

Evidence from in vitro studies is also available in the

literature. For example, silver nanoparticles have been

shown to reduce mitochondrial function and to

increase membrane leakage of mouse spermatogonial

stem cell and rat liver cells (Braydich-Stolle et al. 2005;

Hussain et al. 2005). Studies performed on human

fibrosarcoma and human skin/carcinoma cells with

silver nanoparticles used in a topical antimicrobial

agent concluded that in the presence of the nanopar-

ticles the cellular levels of glutathione are reduced,

indicating oxidative stress, that results in cellular

damage and lipid peroxidation (Arora et al. 2008).

However, in the study performed by Arora et al. the

dose required to induce apoptosis (0.78–1.56 lg/mL)

was much smaller than that required to produce

necrosis (12.5 lg/mL) in both cell types. Therefore,

the authors concluded that, after the required in vivo

studies, it would be possible to define a safe range for

the application of silver nanoparticles as a topical

antimicrobial agent. Similar differences of the required

concentration to cause apoptosis or necrosis were

found in a second study by the same authors in mouse

fibroblasts and liver cells (Arora et al. 2009). In this

second article, it was suggested that although silver

nanoparticles may enter into the cells, the cellular

antioxidant mechanisms would limit oxidative stress.

Mechanistic studies of silver nanoparticle toxicity

in mammalian cells have considered mouse fibroblast

and human colon cancer cells (Hsin et al. 2008). In

this study, silver nanoparticle doses of 50 lg/mL

induced apoptosis to 43.4% of fibroblast cells, while

100 lg/mL produced necrosis to 40.2% of the cancer

cells. The authors concluded that the apoptotic

mechanisms in fibrosblast cells are a mitochondrial

mediated pathway including the generation of ROS in

the cell, which activate the apoptosis regulators JNK

and p53 proteins inducing protein Bax to migrate to

the surface of the mitochondria. That subsequently

induces cytochrome C release from mitochondria and

cleavage of PARP. Additionally, in a study done by

Asharani, a possible mechanism of toxicity to human

cells was proposed (Asharani et al. 2009). Silver

nanoparticles would affect the mitochondrial respira-

tory chain, causing ROS generation and affecting the

production of ATP, which subsequently leads to DNA

damage. In this study, the authors also concluded that

‘‘even and small dose of Ag-NP (silver nanoparticles)

has the potential to cause toxicity’’ and that silver

nanoparticles are cytotoxic, genotoxic, and antipro-

liferative, being as toxic for human glioblastoma as

for normal human fibroblasts cells.

Mechanisms of silver’s antibacterial properties

Although the mechanisms behind the activity of

nano-scaled silver on bacteria are not yet fully

elucidated, the three most common mechanisms of

toxicity proposed to date are: (1) uptake of free silver

ions followed by disruption of ATP production and

DNA replication, (2) silver nanoparticle and silver

ion generation of ROS, and (3) silver nanoparticle

direct damage to cell membranes. The various

observed and hypothesized interactions between

silver nanomaterials and bacteria cells are conceptu-

ally illustrated in Fig. 3.

Fig. 3 Diagram summarizing nano-scaled silver interaction

with bacterial cells. Nano-scaled silver may (1) release silver

ions and generate ROS; (2) interact with membrane proteins

affecting their correct function; (3) accumulate in the cell

membrane affecting membrane permeability; and (4) enter into

the cell where it can generate ROS, release silver ions, and

affect DNA. Generated ROS may also affect DNA, cell

membrane, and membrane proteins, and silver ion release will

likely affect DNA and membrane proteins. Similar pictures

have been published in (Damm et al. 2008; Neal 2008)

J Nanopart Res (2010) 12:1531–1551 1539

123

Free silver ion uptake

Silver nanoparticles have been reported to dissolve

generating silver ions and it is thought that in vivo this

release would be product of reactions of silver nano-

particles with H2O2 (Asharani et al. 2009). Asharani has

proposed the following reaction as a possible mecha-

nism for silver nanoparticle oxidative dissolution.

2AgþH2O2 þ 2Hþ ! 2Agþ þ 2H2O E0 ¼ 0:17 V:

Asharani suggests that in eukaryotic cells this

reaction could occur in the mitochondria, where

exists an important concentration of H?. Similarly,

we hypothesized that a similar mechanism could

occur in the bacterial cell membrane where proton

motive force takes place.

Another possible mechanism for the oxidative

dissolution of silver nanoparticles has been reported

by Choi et al., in this case silver is oxidized in the

presence of oxygen. Choi et al. speculated that the

observed changed of color of their silver nanoparti-

cles suspensions, over a week period, would be

attributed to this mechanism.

4Agþ O2 þ 2H2O$ 4Agþ þ 4OH�:

The amount of free silver ion measured in this case

was approximately 2.2% of the total silver content in

the silver nanoparticle suspension (Choi et al. 2008).

In other article, a 0.1% content of the total silver in

partially oxidized silver nanoparticles suspensions

was attributed to silver ions (Lok et al. 2007).

Ionic silver has known antibacterial properties;

thus, it is expected that eluted ions from silver

nanoparticles are responsible for at least a part of

their antibacterial properties. At sub-micromolar

concentrations, Ag? interacts with enzymes of the

respiratory chain reaction such as NADH dehydro-

genase resulting in the uncoupling of respiration from

ATP synthesis. Silver ions also bind with transport

proteins leading to proton leakage, inducing collapse

of the proton motive force (Dibrov et al. 2002; Holt

and Bard 2005; Lok et al. 2006). Silver inhibits the

uptake of phosphate and causes the efflux of intra-

cellular phosphate (Schreurs and Rosenberg 1982).

The interaction with respiratory and transport pro-

teins is due to the high affinity of Ag? with thiol

groups present in the cysteine residues of those

proteins (Holt and Bard 2005; Liau et al. 1997;

Petering 1976). Additionally, it has been reported that

Ag? increases DNA mutation frequencies during

polymerase chain reactions (Yang et al. 2009).

Bacterial cells exposed to milli-molar Ag? doses

suffer morphological changes such as cytoplasm shrink-

age and detachment of cell wall membrane, DNA

condensation and localization in an electron-light region

in the center of the cell, and cell membrane degradation

allowing leakage of intracellular contents (Feng et al.

2000; Jung et al. 2008). Physiological changes occur

together with the morphological changes. Bacterial cells

enter an active, but non-culturable state in which

physiological levels can be measured but bacteria are

not able to growth and replicate.

Several studies have linked the toxicity of silver

nanoparticles to the release of silver ions. For example,

Smetana et al. observed that silver ions eroded from

high-surface area silver powders prepared by SMAD

method interacted and destroyed bacterial cells (Sme-

tana et al. 2008). In the same study, a second

preparation of silver nanoparticles using water-soluble

ligands was used to obtain silver nanoparticles with

higher surface area to improve their antibacterial

efficacy. However, the second preparation of silver

nanoparticles showed lower toxicity toward bacterial

cells than uncoated powders, suggesting the ligands

prevented silver ion erosion; thus, diminishing the

resulting toxicity. Another possible reason for this

result is that the surface coatings prevented adhesion

of silver nanoparticles to the bacterial cell surface, but

the authors did not explore this option.

Hwang et al. observed that Ag? induced the same

effect in bioluminescence bacteria sensitive to mem-

brane protein damage and slightly less effect in a strain

sensitive to superoxides compared to silver nanopar-

ticles (Hwang et al. 2008). The authors suggested that

silver nanoparticles produce silver ions that move

inside the cell producing ROS through redox reactions

with oxygen. In other research, bacterial activity of

activated carbon fiber supported silver was attributed

to the synergistic action of silver ions, superoxides,

and hydrogen peroxide (Le Pape et al. 2004).

Generation of reactive oxygen species

Reactive oxygen species (ROS) are natural byprod-

ucts of the metabolism of respiring organisms. While

1540 J Nanopart Res (2010) 12:1531–1551

123

small levels can be controlled by the antioxidant

defenses of the cells such glutathione/glutathione

disulfide (GSH/GSSG) ratio, excess ROS production

may produce oxidative stress (Nel et al. 2006). The

additional generation of free radicals can attack

membrane lipids and lead to a breakdown of mem-

brane and mitochondrial function or cause DNA

damage (Mendis et al. 2005).

Metals can act as catalysts and generate ROS in

the presence of dissolved oxygen (Stohs and Bagchi

1995). In this context, silver nanoparticles may

catalyze reactions with oxygen leading to excess free

radical production. Studies done in eukaryotic cells

suggest that silver nanoparticles inhibit the antioxi-

dant defense by interacting directly with GSH,

binding GSH reductase or other GSH maintenance

enzymes (Carlson et al. 2008). This could decrease

the GSH/GSSG ratio and, subsequently, increase

ROS in the cell. Silver ions eluted from nano-scaled

silver or chemisorbed on its surface may also be

responsible for the generation of ROS by serving as

electron acceptor. In bacterial cells, silver ions would

likely induce the generation of ROS by impairing the

respiratory chain enzymes through direct interactions

with thiol groups in these enzymes or the superoxide-

radical scavenging enzymes such as superoxide

dismutases (Park et al. 2009). ROS generation from

silver nanoparticles and silver ions may also be

induced photocatalytically; however, no correlations

have been reported between bacterial toxicity and

photocatalytic ROS concentration (Choi and Hu

2008).

Evidence of toxicity related to ROS generated

from silver nanoparticles and silver ions, released

from or chemisorbed on its surface, has been shown

previously. Kim et al. determined the existence of

free radicals from silver nanoparticles by means of

spin resonance measurements (Kim et al. 2007). They

observed that silver nanoparticles and silver nitrate

toxicity was abolished in the presence of an antiox-

idant, these results leaded them to suggest that the

antimicrobial mechanisms of silver nanoparticles

against S. aureus and E. coli was related to the

formation of free radicals from the surface of silver

nanoparticles and subsequent free radical induced

membrane damage.

Bactericidal activity of silver ions loaded in

nanoporous materials such as zeolites has also been

related to the generation of ROS. Using ROS

scavengers, it was determined that superoxide anions,

hydrogen peroxide, hydroxyl radicals, and singlet

oxygen contributed to the antibacterial activity

against E. coli (Inoue et al. 2002). In another article,

the bactericidal activity of activated carbon fiber

supported silver occurred only in the presence of

oxygen and could not be explained by the silver ions

eluted from the fiber (Yoon et al. 2008a, b). These

observations together with a study of gene expression

related to oxidative stress lead the authors to suggest

that the strong bactericidal activity of this materials

resulted from the combined effects of silver ions,

superoxides ions, and hydrogen peroxide (Le Pape

et al. 2004).

A study of the toxicity effects of different silver

forms on nitrifying bacteria showed that not only

Ag? and AgCl, but also silver nanoparticles are able

to induce intracellular ROS generation. Moreover, the

bacterial inhibition of each of these silver species

correlates with their individual generation of intra-

cellular ROS concentration. However, at the same

level of intracellular ROS concentration, silver

nanoparticles appeared more toxic than the other

species indicating that other factors besides the

generation of intracellular ROS played a role in the

overall toxicity (Choi et al. 2008). In other research, a

panel of recombinant bioluminescent bacteria was

used to test different pathways of silver nanoparticles

toxicity such as oxidative stress, DNA damage and

protein or membrane damage in bacterial strains. The

addition of silver nanoparticles to growing bacterial

cultures leaded to the production of superoxide

radicals, but not of hydroxyl radicals. The authors

conclude that toxicity occurs via membrane protein

damage and oxidative stress, but not DNA damage

(Hwang et al. 2008).

Direct cell membrane damage

Silver nanoparticles interact with the bacterial mem-

brane and are able to penetrate inside the cell.

Transmission electron microscopy data show that

silver nanoparticles adhere to and penetrate into

E. coli cells and also are able to induce the formation

of pits in the cell membrane (Choi et al. 2008; Raffi

et al. 2008; Sondi and Salopek-Sondi 2004). Silver

nanoparticles have been observed within E. coli cells

albeit at sizes much smaller than the original particles;

moreover, silver nanoparticles with oxidized surfaces

J Nanopart Res (2010) 12:1531–1551 1541

123

induce the formation of ‘‘huge holes’’ in E. coli

surfaces after the interaction and large portions of the

cellular content seemed to be ‘‘eaten away’’ (Smetana

et al. 2008).

Silver nanoparticle accumulation on the cell mem-

brane and uptake within the cell has also been reported

for other bacteria such as V. cholera, P. aeruginosa,

and S. typhus. In these cases, only nanoparticles

smaller than 10 nm attached to bacteria cell mem-

branes or where observed inside the bacteria (Morones

et al. 2005). However, in other research silver

nanoparticles with sizes up to 80 nm were transported

through the inner and outer membrane of P. aerugin-

osa (Xu et al. 2004). Silver nanoparticle composites

and silver nanoparticles stabilized with surfactants are

also thought to interact with cell membranes. Myram-

istin� capped silver nanoparticles showed notable

antibacterial activity against gram-positive and

-negative bacteria, it was speculated that Myramistin�

anchors to the cell wall and weakens it allowing

penetration of silver nanoparticles inside the cells

(Vertelov et al. 2008). Composites of HPAMAM-

N(CH3)2 silver nanoparticle are thought to catch

bacteria by ionic interactions between the cationic

polymer and the negative cell membrane, followed by

release the silver nanoparticles (Zhang et al. 2008).

The detailed mechanism by which silver nanopar-

ticles interact with cytoplasmic membranes and are

able to penetrate inside cells is not fully determined.

One hypothesis is that the interaction between

nanoparticles and bacterial cells are due to electro-

static attraction between negatively charged cell

membranes and positively charged nanoparticles

(Raffi et al. 2008). However, this mechanism does

not likely explain the adhesion and uptake of

negatively charged silver nanoparticles. It has been

also proposed that the preferential sites of interaction

for silver nanoparticles and membrane cells might be

sulfur containing proteins—in a similar way as silver

interacts with thiol groups of respiratory chain

proteins and transport proteins, interfering with their

proper function (Morones et al. 2005). This seems

more likely than electrostatic attraction because

evidence of protein membrane damage on bacteria

after silver nanoparticle exposure has been demon-

strated with bioluminescence bacteria (Hwang et al.

2008).

Another proposed mechanism of E. coli membrane

damage by silver nanoparticles relates to metal

depletion, i.e., the formation of irregular-shaped pits

in the outer membrane and change in membrane

permeability by the progressive release of LPS

molecules and membrane proteins (Amro et al.

2000; Sondi and Salopek-Sondi 2004). This may be

fairly general for gram-negative bacteria. It has been

reported that extrusion pump systems such as Mex-

AB-OprM system of P. aeruginosa could also play an

important role in controlling the accumulation of

silver nanoparticles in living cells (Xu et al. 2004).

The same pump systems are responsible for the silver

resistance of several bacteria (see ‘‘Mechanisms of

silver resistance’’ section).

Despite the mechanism of interaction involved, it is

evident that silver nanoparticles attached to bacterial

cell membranes increase permeability and disturb

respiration. Proteomic data show the accumulation of

envelope protein precursors in E. coli cells after

exposure to silver nanoparticles (Lok et al. 2006).

Energy from ATP and proton motive force is required

in order to newly synthesize envelope proteins to be

translocated to the membrane, therefore cytoplasmic

accumulation of protein precursors suggests dissipa-

tion of proton motive force and depletion of intracel-

lular levels of ATP. In a similar way, silver ions have

also been linked to the collapse of proton motive force

and destabilization of the cell membrane, but the

concentrations at which this occur are much higher

than the ones of silver nanoparticles (micromolar vs.

nanomolar) (Dibrov et al. 2002; Lok et al. 2006).

Mechanisms of silver resistance

Bacterial strains resistant to specific toxicants are

naturally selected in environments where these agents

are present (Gupta and Silver 1998). In this way, the

widespread use of silver, whether in nano or bulk

form, could lead to selection of bacterial communities

exhibiting silver resistance. Since most commercial

uses of silver and silver nanoparticles relate to

fighting infection, widespread silver resistance is a

growing concern. In fact, it has been suggested that it

already occurs extensively, but it not recognized due

to a lack of testing for silver resistance (Silver et al.

2006). For example, 10% of the enteric bacteria

tested randomly in a hospital in Chicago, IL, showed

genes for Ag? resistance (Silver 2003).

Silver resistance in bacteria (and other heavy

metals) is often encoded by plasmids genes, as for

1542 J Nanopart Res (2010) 12:1531–1551

123

example the Salmonella plasmid pMG101, within the

IncHI incompatibility group, as well as in other five

plasmids in the same group (Gupta et al. 2001).

Although resistance is mainly encoded by plasmids,

bacterial chromosomes have also been reported to

encode Ag? resistance genes (sil) in strains such as

E. coli K-12 and O157:H7 (Gupta et al. 2001; Silver

et al. 2006). The plasmid pMG101 has been studied in

detail (Gupta et al. 1999; Silver 2003; Silver et al.

2006), this plasmid has nine genes, whose products

have been identified to be proteins responsible for

heavy metal resistance. Here, the resistance is

achieved by two efflux systems SilCBA and SilP

acting in combination with two periplasmic binding

proteins SilE and SilF. The complex SilCBA is

constituted by three proteins SilC in the outer mem-

brane, SilA in the inner membrane and SilB that links

SilA and SilC. This complex acts as an antiporter that

transports Ag? out of the cell by pumping a proton

inside. In turn, SilC is a P-type ATPase that transports

Ag? from the cytoplasm to the perisplasm. These two

efflux pumps work jointly with proteins SilE and SilF,

which bind to Ag?. SilF is thought to act as a

‘‘chaperone’’ by taking one Ag? ion from its release

site in SilP to its uptake site in SilCBA while SilE

binds 5 Ag? ions to 10 histidines preventing silver ions

entrance to the cytoplasm (Gupta et al. 1999).

Limited evidence has been reported of the resis-

tance shown by silver-resistant strains to silver

nanoparticles. However, in one study, it was reported

that albumin-stabilized oxidized silver nanoparticles

were unable to inhibit growth of 116 AgNO3R and

J53 (pMG101) silver-resistant strains even when

apply at a concentration of up to 80 nM (Lok et al.

2007). Therefore, it seems that silver resistance may

also be of concern for the efficacy of silver nanopar-

ticles use as antibacterial agent.

Bacterial resistance and sensitivity to silver is

affected by environmental conditions such as the

presence of halides in the media due to mainly the

variation of silver bioavailability experienced at

different concentrations of Cl- and other halides

such as Br- and I- (Gupta et al. 1998). For moderate

Cl- concentration, silver is precipitated as AgCl,

which decreases silver bioavailability and increases

bacterial silver resistance, as observed for E. coli J53

(pMG101). Nevertheless, silver bioavailability rises

when ionic complexes such as AgCl2-, AgCl3

2- are

formed as product of a higher halide concentration.

This increase in bioavailability increases sensitivity

of the silver-resistant and silver-sensitive bacteria.

Similar, behavior is also observed for silver in the

presence of other halides (Gupta et al. 1998).

Further insights about potential toxicity to higher

organisms

Silver nanomaterials exhibit outstanding antibacterial

properties that give rise to many potentially beneficial

applications. However, misuses of silver nanoparti-

cles as a bactericide may also result in unintended

exposure to higher organisms, including humans.

This is of concern because silver nanoparticles appear

to have toxic effects in higher organisms (‘‘Evidence

of silver toxicity in microbes and higher organisms’’

section). While eukaryotic and prokaryotic cells are

different in many ways, understanding the funda-

mental mechanisms governing silver nanoparticle

toxicity in bacterial cells may shed light on the

potential effects of silver nanoparticles on important

organelles such as mitochondria.

Mitochondria are believed to have evolved from

bacteria (i.e., the ‘‘serial primary endosymbiosis

theory’’) and they share several characteristics

(Kutschera 2009). For example, the inner membrane

of a mitochondrion and the prokaryotic cell mem-

brane are structurally very similar. Respiration occurs

in bacterial cells similarly as in the mitochondria of

eukaryotes, including electron transport, ATP syn-

thesis, and proton motive force. Likewise mitochon-

drial DNA, the bacterial DNA are analogous, and the

division of the mitochondria is similar to fission of

prokaryotes (Slonczewski and Foster 2009). Based on

these similarities, it is hypothesized that silver

nanoparticles may affect mitochondria in higher

organisms via similar mechanisms as in bacterial

cells—assuming they can be internalized by the cell.

Factors affecting the toxicity of silver

nanomaterials

Several factors have been reported to influence silver

nanoparticle toxicity like particle size, shape, crys-

tallinity, surface chemistry, capping agents, as well,

as for environmental factors such as pH, ionic

strength, and the presence of ligands, divalent

cations, and macromolecules (Carlson et al. 2008;

J Nanopart Res (2010) 12:1531–1551 1543

123

Choi and Hu 2008; Kvitek et al. 2008; Lok et al.

2007; Morones et al. 2005; Pal et al. 2007; Smetana

et al. 2008). Many publications have shown size-

dependent toxicities of silver nanoparticles (Carlson

et al. 2008; Choi and Hu 2008; Martinez-Castanon

et al. 2008; Morones et al. 2005). As particle size

decreases, the specific surface area increases leaving

a higher number of atoms exposed on the surface

available for redox, photochemical, and biochemical

reactions in addition to physicochemical interactions

with cells.

As discussed previously, one of the key mecha-

nisms for silver nanomaterials to exert biocidal

activity is through the release of silver ions. As the

rate of ion release, in general, is proportional to

particle surface area, nanoparticles can release ions

more rapidly than larger particles and macroscopic

materials. In effect, chemisorbed silver ions would be

the cause of the antibacterial activity observed by

Lok et al., who reported that only partially oxidized

silver nanoparticles exhibit antibacterial activities,

while zero valent silver nanoparticles do not (Lok

et al. 2007). This surface area effect also influences

RO generation. For example, at the same silver

concentration, silver nanoparticles of 15 nm gener-

ated higher levels of ROS in macrophages than 30

and 50 nm particles (Carlson et al. 2008).

High atom densities at h111i facets increased the

toxicity of silver nanoparticles to several bacterial

strains; the increased toxicity was the result of the

higher reactivity presented by the h111i facets

(Morones et al. 2005). Silver nanoparticle shape

may also be a factor. Truncated triangular nanoplates

exert stronger antibacterial activity than spherical-

and rod-shaped silver nanoparticles because they

contain more h111i facets; thus, they would be more

reactive (Pal et al. 2007). Hence, the antibacterial

properties of silver nanoparticles are related to both

size (i.e., reactive surface area) and crystallinity (i.e.,

surface reactivity).

Stability of silver nanoparticles also influences

toxicity since the formation of aggregates tends to

decrease biocidal activity (Kvitek et al. 2008; Shriv-

astava et al. 2007; Teeguarden et al. 2007). Different

surfactants and polymers (e.g., sodium dodecyl

sulfate, polyoxyethylene-sorbitan monooleate, poly-

vinylpyrrolidone, Na?-carrying poly(glutamic acid),

hydroxyl functionalized ionic liquids and hydroxyl

functionalized cationic surfactants) have been used to

stabilize silver nanoparticle dispersions and enhance

biocidal activity (Dorjnamjin et al. 2008; Kvitek et al.

2008; Yu 2007). However, some ligand-capped silver

nanoparticles—although highly stable and monodis-

perse in suspension—were less bioactive because the

capping agent hindered release of silver ions (Sme-

tana et al. 2008).

Environmental conditions such as pH, ionic

strength, presence of complexing agents, and natural

organic matter, also affect the toxicity of silver

nanoparticles. High salt concentrations and pH values

close to the isoelectric point promote nanoparticle

aggregation by screening electrical double layer

repulsion (Nel et al. 2009). However, water chemistry

also governs silver dissolution and/or re-precipitation

through various possible redox and precipitation

reactions (Lok et al. 2007). Dissolved Ag? ions are

sparingly soluble in the presence of various ligands

such as chloride (pK = 9.75), sulfate (pK = 4.9),

sulfide (pK = 49), hydroxide (pK = 7.8) and dis-

solved organic carbon (pK [ 7.5) (Choi et al. 2008;

Gao et al. 2009). The released Ag? can also form Ag0

-containing clusters through light or chemical reduc-

tion (Morones et al. 2005). Therefore, nanomaterials in

aqueous suspensions must be considered in a contin-

uous state of flux where the apparent speciation is

controlled by the aquatic media pH, redox potential,

ionic composition, and exposure to light.

Previously, cysteine ligands and chloride were

used to scavenge or precipitate eluted silver ions from

silver nanoparticles; thus, diminishing their toxicity

(Navarro et al. 2008). Sulfide ligands have also been

used to reduce the inhibition of silver nanoparticles to

nitrifying bacteria (Choi et al. 2009). More recently,

it was reported that halide ions act as precipitating

agents and profoundly affect the ‘‘bioavailability’’ of

Ag? in unexpected ways (Silver 2003). For example,

at low chloride concentrations, soluble Ag? binds to

cell membranes impacting respiration and producing

other toxics effects (Gupta et al. 1998). As chloride

concentration increases, silver becomes less bioavail-

able because the solubility of AgCl is very low.

However, further increase in halide concentration

results in the formation of water-soluble anionic

complexes in the form of AgCl2- and AgCl32-.

These anionic complexes are more bioavailable and

increase silver toxicity to both silver-sensitive and

silver-resistant bacteria. Other halides such as Br-

and I- have similar effects, but the concentrations at

1544 J Nanopart Res (2010) 12:1531–1551

123

which ionic complexes form depends on their

respective solubility limits.

Finally, aerobic versus anaerobic conditions are

important when assessing the antibacterial properties

of silver loaded in zeolite or activated carbon fibers

(Inoue et al. 2002; Le Pape et al. 2002; 2004).

Dissolved oxygen is important in these cases because

ROS contributes significantly to bactericidal activity.

Dissolved organic carbon (DOC) seems also to

influence the toxicity of silver nanoparticles, specif-

ically, toxicity may decrease for aquatic invertebrates

as the concentration DOC increases (Gao et al. 2009).

A concise summary of the factors discussed above is

presented in Table 4. Since water chemistry dramat-

ically impacts the toxicity for virtually all forms of

silver nanomaterials, it may be difficult to predict

environmental impacts using laboratory data produced

in relatively simple aquatic media or media that is not

very representative of natural aquatic chemistries. This

presents a major hurdle to science-based policy

development for environmental protection.

Summary and future research

In summary, silver nanomaterials exhibit broad-

spectrum biocidal activity toward bacteria, fungi,

viruses, and algae. This motivates its use in a large

number of biomedical and environmental applica-

tions as well as a growing list of consumer products.

However, if the amount of nano-scaled silver entering

sewers becomes higher than the tolerable levels for

microbial communities in wastewater treatment

plants, critical environmental infrastructure might

be impacted. Further, there is mounting evidence that

silver nanoparticles exhibit an array of cytotoxic and

genotoxic effects in higher organisms. This raises

concern about possible impacts to higher organisms

including humans.

The antibacterial mechanisms of silver nanomate-

rials are not fully elucidated, but the prevailing

paradigm suggests various combinations of: (1) silver

ion release followed by cellular uptake and a cascade

of intracellular reactions, (2) extracellular and intra-

cellular generations of ROS, and (3) direct interac-

tions between nano-scaled silver and cell membranes.

At sub-micromolar concentrations, silver ions are

internalized and react with thiol groups of cellular

proteins, which lead to uncoupling of ATP synthesis

from respiration, loss of proton motive force, and

interference with the phosphate efflux system. At

milli-molar levels, silver nanoparticles induce detach-

ment of the cell wall membrane from the cytoplasm,

possible release of intracellular content, DNA con-

densation and loss of replication ability. ROS

produce oxidative stress resulting in membrane lipid

and DNA damage. Finally, silver nanoparticles

increase cell membrane permeability and, subse-

quently, penetrate inside cells to induce any one or

the entire cascade of effects just described.

Table 4 Factors affecting nano-scaled silver toxicity

Factor Tendency Possible explanation

Particle size Smaller particles sizes tend to enhance

antibacterial properties

As size decrease, there is lager number of atoms on

the surface available to interact with bacteria or to

release a higher amount of silver ions

Particle stability Higher stability produces a higher

antibacterial properties

Non-stable nanoparticles will tend to form

aggregates thus surface area will be reduced and

the density of atoms available on the surface will

be lower (Kvitek et al. 2008; Shrivastava et al.

2007; Teeguarden et al. 2007)

Particle shape Particles with shapes containing more\111[facets like triangular particles tend to have

strongest antibacterial properties

\111[ facets would contain larger atom densities

thus more atoms available for interaction

(Morones et al. 2005)

Water chemistry Depending in a case to case base Since water chemistry affects particle suspension/

solubility, particle size distribution, as well as,

bacterial ability to face environmental stresses,

water chemistry will affect the interaction between

nano-scaled silver and bacteria thus influencing the

resulting toxicity

J Nanopart Res (2010) 12:1531–1551 1545

123

Silver nanoparticle toxicity is influenced by intrin-

sic nanoparticle features like size, shape, chemistry,

crystallinity, and capping agents, but also by the

aquatic chemistry through such factors as solution

pH, redox state, ionic strength, and ionic composi-

tion. Most of the toxicity data presented in the

literature are obtained in relatively simple media like

distilled water or cell culture media, which do not

reflect the aquatic environment inside living organ-

isms or the natural environment. Hence, the surface

chemistry, reactivity, and state of dispersion achieved

in the laboratory may not be relevant for assessing

behavior in real systems. In natural waters, the wide

variation of pH, ionic strength, ionic composition,

and natural organic matter will induce widely varying

aggregation states of silver nanoparticles; thus,

resulting in widely varying antimicrobial activities

and toxicities. In addition, most toxicity data are

obtained by dispersing silver nanomaterials in or on

nutrient rich growth media; however, oligotrophic

conditions prevail in most natural environmental

systems. Microorganisms in these conditions may be

more or less vulnerable to silver than predicted by

laboratory studies.

Although significant progress has been made to

elucidate the mechanisms of silver nanomaterial

toxicity, further research is required to fully under-

stand the processes involved and to safely exploit the

tremendous antimicrobial properties of silver without

jeopardizing human health, critical infrastructure, and

the environment. Future in vivo, in vitro, and

environmental studies should consider more system-

atically the various effects of aquatic chemistry on

nano-scaled silver fate, transport, and toxicity.

Acknowledgments Financial support for this research was

provided by the University of California Toxic Substances

Research and Training Program: Lead Campus Program in

Nanotoxicology.

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