nanosilver a smart antimicrobial agent

www.wjpr.net Vol 7, Issue 01, 2018.

328

Badhwar et al. World Journal of Pharmaceutical Research

NANOSILVER – A SMART ANTIMICROBIAL AGENT

Harvinder Popli and Reena Badhwar*

Department of Pharmaceutics, Delhi Pharmaceutical Sciences & Research University, New

Delhi-17, India.

ABSTRACT

Nanotechnology is considered of paramount importance in the health

care segment. Nanotechnology drug delivery has demonstrated

enormous patients‘ benefits. Silver has been in use since centauries in

different forms such as metallic silver, silver nitrate, silver

sulfadiazine for treatment of various diseases. After converting silver

metal into their nanosize significantly changes the chemical, physical

and therapeutic properties. Silver nanoparticles gaining importance

due to its broad spectrum and targeting action. This review is to study

Nanosilver and its potential / application as a smart antimicrobial

agent for various disease / indication.

KEYWORDS: Nanotechnology, Nanosilver, Broad spectrum antimicrobial agent.

Fig: 1 Contents of the article.

World Journal of Pharmaceutical Research

SJIF Impact Factor 7.523

Volume 7, Issue 01, 328-347. Review Article ISSN 2277–7105

Article Received on

02 Nov. 2017,

Revised on 23 Nov. 2017,

Accepted on 13 Dec. 2017

DOI: 10.20959/wjpr20181-10296

*Corresponding Author

Reena Badhwar

Department of

Pharmaceutics, Delhi

Pharmaceutical Sciences &

Research University, New

Delhi-17, India.


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1. INTRODUCTION

In the present scenario, Nano scale materials have emerged up as new antimicrobial agents

owing to their high surface area to volume ratio and the unique chemical and physical

properties.[1-2]

Silver nanoparticles (NPs), or Nanosilver (NS), are clusters of silver atoms that

range in diameter from 1 to 100 nm and are attracting interest as antibacterial and

antimicrobial agents for applications in medicine. NS is a promising field of research and has

been highly commercialized.[3]

―Silver nanoparticles are emerging as one of the fastest

growing product categories in the nanotechnology industry‖, according to a market study

report. The ultimate goal for wound healing is a swift revitalization with minimal scarring

and maximal function.

2. Chronology of Silver

For centuries, along with gold, copper and other precious metal, silver has been widely used

for the treatment of burns and chronic wounds. Hippocrates, father of modern medicine,

believed that silver powder had beneficial healing, antibacterial properties and listed as a

treatment for ulcers.[4-5]

in the history of 2500-year the utilization of silver for water

purification and disease control has been established and there has been no evidence of

carcinogenic activity.[6]

In 1700, silver nitrate was utilized for the treatment of venereal

diseases, fistulae from salivary glands, and bone and perennial abscesses.[7-8]

Halsted was one

of the first American surgeons who advocated the use of silver foil for wound dressings, and

silver sutures in surgical incisions to prevent infections.[9]

In the 1840s James Marion Sims used the silver metal sutures to treat and cure women who

had vesico-vaginal fistulas. Over 120 years ago, in 1889, M. C. Lea synthesized citrate

impregnated silver colloid[10]

and observed the average diameter of these particles between 7

and 9 nm while, Moudry in 1953 observed gelatin stabilized silver nanoparticles diameter in

the range of 2-20 nm.[11]

Whereas, Manes, synthesized silver nanoparticles impregnated with

carbon with diameter below 25nm.[12]

In the earliest of 20th century, the commercial sale of

medicinal nanoscale silver colloids, known under different trade names such as Collargol,

Argyrol, and Protargol, invented and they came in use over last 50 years ago[13-14]

, revealed

that electric colloidal silver became the stronghold of antimicrobial therapy in the first part of

the 20th Century until the introduction of antibiotics in the early 1940s. Nanosilver-

impregnated with neurosurgical catheters have been made-up to reduce catheter-associated


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infections. In vitro studies revealed prolonged silver ion release that lasted for at least 6 days,

in addition to greatly decreased growth of S. aureus.[15]

3. Different forms of silver

Nanocrystalline silver: Nanocrystalline silver wound dressings have been commercially

available for over a decade (e.g. Acticoat™) and are in current clinical use for the treatment

of various wounds, including burns.[16-17-18]

Nanocrystalline silver have better efficacy against

various types of microorganism such as Escherichia coli, Pseudomonas aeruginosa,

Streptococcus faecalis and Staphylococcus aureus.[19]

Various comparison studies of

nanocrystalline silver V/s already available silver product were performed and found that

nanocrystalline silver have enhanced antibacterial efficacy than other silver formulations such

as silver sulfadiazine antibiotics, silver salt, colloidal silvers and wound dressing contains

bacterial cellulose.[20]

Silver zeolite

Silver zeolite (SZ) show good antibacterial activities against gram positive bacteria(S.mutans,

S.sanguis etc.) and gram negative bacteria (pseudomonas gingivitis). (SZ) are considered as

an appropriate material for dental treatment.[21]

In Japan, ceramics are manufactured coated

with silver zeolite to pertain antimicrobial property to their products. These ceramics are used

for food preservation, disinfection of medical products and decontamination of materials such

as medical supply and kitchen ware.[22]

Silver-zeolite has previously been useful to balloon

catheters to control urinary tract infections.[23]

Metallic silver: After gold and copper metallic silver was the third metal known to be utilized

in Ancients time.[24]

Metallic silver preparations are applied to many commercial products

such as shampoo, soap, detergent, and shoes.[25]

Metallic silver in a moist environment will

react and results in the formation and release of silver ions. These ions are highly potent as

antimicrobial agent.[26]

Silver sulfadiazine

Silver sulfadiazine (AgSD) is a broad-spectrum antibiotic combination of silver and

sulfadiazine. The main use of silver sulfadiazine is to avoid infections, prevents wound

colonization even in the presence of antibiotic-resistant bacteria.[27]

Since decades it has been

used as standard topical therapy for patients with partial-thickness burns and venous stasis

ulcers.[28]

But there are some serious side effects related with SSD treatment consist of


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sensitivity, hemolytic anemia, hyperbilirubinemia, anaphylaxis, toxic epidermal necrolysis,

Stevens-Johnson syndrome and bacterial resistance.[29]

Silver salt: For a long time silver salt (silver nitrate) have been used as an eye drop for a

newborn neonatal eyes infection.[30]

Silver nitrate cauterization is also used against the

pyogenic grauloma of hands.[31]

But there is a limitation of silver ions that there is continuous

release of adequate concentration of Ag ion from the metal form. This limitation can be

overcome by nanosilvers.[32]

4. Antimicrobial mechanism of silver

The mechanism of action (antimicrobial effects) of silver is entirely unknown, it has been

projected that silver and silver ions (such as silver nitrate, silver acetate etc.) penetrate

bacterial cell walls and membranes by way of interaction with sulfur-containing proteins or

thiol groups[33]

, after penetrating the cell, AgNO3 damages bacterial DNA and respiratory

enzymes, leading to loss of the cell‘s replicating abilities and ultimately cell death.[34-35]

Mahendra Rai et al, 2009; explained that the antimicrobial action of silver is directly

dependent on nanoparticles size and shape because silver nanoparticles (AgNPs) containing

small size and large surface area are more able to penetrate bacterial cell walls and

membranes, and as a result, the antimicrobial effect will be better.[36-37]

Wen-Ru Li, et al;

2010; explained the antibacterial activity and effective mechanism of silver nanoparticles

(SNPs) on Escherichia coli. Due to smaller size and large surface area (SNPs) may break the

barrier of outer membrane of cells and can increase the permeability to cells, peptidoglycan

and periplasm, which may destroy respiratory chain, dehydrogenates the membrane which

leads towards cell death.[38]

Holt KB et al, 2005; found that silver ions (Ag+) inhibited the

respiration of E. coli by influencing change of oxygen dissolved in culture resolution.[39]

Kim

et al; 2008; narrated that Ag+ interacted with thiol (–SH) group of cysteine by replacing the

hydrogen atom to form –S–Ag, accordingly hindering the enzymatic function of affected

protein to inhibit growth of E. coli.[40]

Benjamin Le Ouay et al, 2015; explained that the silver-containing compounds or species

interact with the bacterial cell which leads to the cellular death.[41]

Scherer‘s and Rosenberg et

al, 1982; silver ions may inhibits (i) phosphate process (uptake and exchange) in Escherichia

coli and can (ii) causes efflux of accumulated phosphate as well as of mannitol, succinate,

glutamine and proline.[42]

Danilcauk, M, Lund, et al, 2006; performed electron spin resonance

spectroscopy studies of silver nanoparticles with bacteria and resulted that there is formation

http://www.sciencedirect.com/science/article/pii/S1748013215000493


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of free radicals by the silver nanoparticles while in contact with the bacteria, and these free

radicals have the capacity to damage the cell membrane and make it porous which ultimately

lead to cell death.

Fig 2: Mechanism of action of silver and silver ions.

5. Toxicity of silver

[43] Danielle McShan et al, 2014; explained the main mechanisms of toxicity of silver is that it

causes oxidative stress through the generation of reactive oxygen species and causes damage

to cellular components including DNA damage, activation of antioxidant enzymes, depletion

of antioxidant molecules (e.g., glutathione), binding and disabling of proteins, and damage to

the cell membrane.[44]

Rasmus Foldbjerg et al, 2009; Investigated the toxicity of silver

nanoparticles (Ag NPs) in vitro. The comparison study was investigated between, poly vinyl

pyrolidone (PVP)-coated Ag NPs (69nm±3 nm) and Ag+ in a human monocytic cell line

(THP-1). The characterization of silver nanoparticles was conducted in both stock suspension

and cell media with or without serum and antibiotics. Dynamic light scattering and zeta

potential measurements methods were also utilized for the characterization of these

nanoparticles. The presence of apoptosis could be confirmed by the TUNEL method. By

using the flowcytometric annexin V/propidium iodide (PI) assay, both Ag NPs and Ag+ were


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shown to induce apoptosis and necrosis in THP-1 cells depending on dose and exposure time.

A number of studies have implicated the production of reactive oxygen species (ROS) in

cytotoxicity mediated by nanoparticles. To assess the levels of intracellular ROS during

exposure to Ag NPs and Ag+ the fluorogenic probe, 2_, 7_-dichlorofluorescein was used.

After conducting and assessing various studies the result found that a drastic increase in ROS

levels could be detected after 6–24 hr suggesting that oxidative stress is an important

mediator of cytotoxicity caused by Ag NPs and Ag+.[45]

Leaper, et al, 2006; observed the

toxicity of silver in the form of argyria, only when there is a large open wound and large

amount of silver ions are used for dressing. There are no regular reports of silver allergy.[46]

Braydich-Stolle et al. 2005, reported the toxicity of silver nanoparticles on C18-4 cell, a cell

line with spermatogonial stem cell characteristics. From the study, it was concluded that the

cytotoxicity of silver nanoparticles to the mitochondrial activity increased with the increase in

the concentration of silver nanoparticles.[47]

Lu et al, 2008; suggested that nanosilvers uptake

by human skin and cause keratinocytes is dependent on the size and shape of the

nanoparticles and incubation time.[48]

Rani A, Sethu et al; 2012, proposed that nanosilvers not

only bind to cytosolic proteins leads to corona, but also convey genes involved in DNA

damage. Increased ataxia telangiectasia mutated (ATM) and ATM-related levels in fibroblast

cells specify double DNA strand rupture.[49]

Braydich-Strolle et al; 2010 studied mouse stem

cells and resulted that smaller nanosilvers particles are more likely to fabricate reactive

oxygen species (ROS) and cause apoptosis.[50]

Reidy B, Haase A, et al; 2013, explained that

interaction of nanosilvers with proteins is believed to be an important mechanism of toxicity

for nanosilvers.[51]

Trickler et al; 2010, suggested that the cytotoxicity of

polyvinylpyrrolidone (PVP)-coated nanosilvers in rat brain cells is size- and shape-

dependent, leading to pro-inflammatory effects.

Characterization of silver nanoparticles (Ag Nps)

The physicochemical properties of silver nanoparticles define behavior, bio-distribution,

safety, and efficacy of synthesized particles. Following techniques are frequently used for its

characterization.[52]


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Fig 3: Characterization of silver nanoparticles.

Zeta potential analyzer

This is a technique with help of which can determine the particles stability and surface charge

of nanoparticles in solution (colloids, emulsion and suspension).[53]

The advantages of this

technique is that it improve formulation stability and shelf life and reduce formulation time

and cost.

UV- Visible Spectroscopy

This technique is primary characterization of synthesized silver nanoparticles.[54]

It is used to

analysis the synthesis and stability of AgNPs. The absorption of AgNPs depends upon the

many factors such as dielectric medium, particles size and chemical surroundings.[55]

[56]

X-ray diffractometry (XRD)

This is the 2nd characterization of silver nanoparticles, which is helpful to provide important

information including molecular structure, crystalline nature and particle sizes of the silver

nanoparticles. X-ray diffraction technique is very useful for the analysis of qualitative and

quantitative identification of the materials.[57]

XRD also has long been used to characterize

and identify bulk and nanomaterials, pharmaceutical and forensic sciences materials.


335


Dynamic light scattering (DLS)

This technique helps to probe the sizes and size distribution from submicron to nanosize (2-

500 nm) particles of silver[58-59]

, which are not observed by XRD technique. DLS technique is

a very straightforward technique which depends upon the interaction of particles and light.[60]

The main advantages of this technique are that it is nondestructive, simple, cheap, and rapid

and can be used for any solvent of interest. The disadvantage of this technique is that it

requires dust free sample before use.[61]

[62]

Scanning electron microscopy (SEM)

This technique is performed over DLS because it can provide proper sizes, size distribution

as well as morphology and shape of the silver nanoparticles.[63]

It is helpful to probe

important information regarding degree of aggregation and purity but it is not able to

determine the internal structure of silver nanoparticles.

[64]

Transition electron microscopy (TEM)

This method is used to provide morphologic, compositional and crystallographic information

of silver nanoparticles.[65]

(TEM) is better than (SEM) because it can provide improved, high

resolution images, particles size and shape and size distribution of silver nanoparticles.

Hence, if we performed TEM then there is no need of SEM technique for testing. The

disadvantages of (TEM) are that required thin sample section, high vacuum, and the critical

part of TEM is that sample preparation is time consuming.[66]

[67-68] Fourier transforms infrared spectroscopy (FTIR)

FTIR is able to give reproducibility accuracy. It is used to study the nanoscale materials such

as silver nanoparticles, carbon nanotubes, and gold nanoparticles confirmation of functional

molecules. It is also useful to find out whether biomolecules are involved in the synthesis of

nanoparticles.[69-132]

[70]

Atomic force microscopy (AFM)

With the help of this technique, not only examine the shape, size and morphology of the

samples but also can observe the aggregation and dispersion, which are necessary

characterization of the silver nanoparticles. The purpose of performing this technique is that

this information cannot be obtained by upper discussed techniques. (AFM) is very convenient

techniques because it does not damage many types of native surfaces. The main advantage of

(AFM) is that it can measure up to the sub-nanometer scale in aqueous medium.[71]


336


7. Comparative evaluation of silver nanoparticles in various indications

[72] Yuesheng Huang et al, 2007 evaluated the clinical efficacy and safety of Acticoat with

Nanocrystalline silver Vs silver sulfadiazine cream. These two preparations were evaluated

for external use on management of the residual wounds post burn. Acticoat was used as the

treated group for those who have redness, swelling, and excessive secretion (‗‗heavy‘‘

exudates) in the wound and the dressings were changed once every 3 days. Silver

sulfadiazine (SD-Ag) was used as control group which was treated under the usual clinical

routine. After studies the result was found that Acticoat with Nanocrystalline silver promotes

the healing process earlier than silver sulfadiazine. No adverse reaction of Acticoat was found

during the study.

[73]

Maneerung et al; 2007, suggested a novel technique for preparation of wound dressing

using bacterial cellulose and the antibacterial effect of silver nanoparticles impregnated on

the wound dressing. The silver nanoparticles impregnated with bacterial cellulose

demonstrated efficient antimicrobial activity against E. coli and S. aureus.

[74]

Joseph J Castellano et al; 2007, Compared antimicrobial activities of eight commercially

available silver-containing dressings, Acticoat_ 7, Acticoat_ Moisture Control, Acticoat_

Absorbent, Silvercel _ TM, Aquacel_ Ag, Contreet_ F, Urgotol_ SSD and Actisorb against

commercially available topical antimicrobial creams, a non treatment control, and a topical

silver-containing antimicrobial gel, Silvasorb. Zone of inhibition and quantitative testing was

performed by standard methods using Escherichia coli, Pseudomonas aeruginosa,

Streptococcus faecalis and Staphylococcus aureus. This test result found that all silver

dressings and topical antimicrobials displayed antimicrobial activity. Silver-containing

dressings with the highest concentrations of silver exhibited the strongest bacterial inhibitive

properties. Topical antimicrobial creams, including silver sulfadiazine, Sulfamylon and

gentamicin sulfate, and the topical antimicrobial gel Silvasorb exhibited better bacterial

inhibition and bactericidal properties, essentially eliminating all bacterial growth at 24 hours.

[75] Moti Harats et al; 2016, Compared the antimicrobial effectiveness of the AQUACEL Ag

BURN glove to silver sulfadiazine (SSD; standard care). Eight hands trials were tested,

dressed with an AQUACEL Ag BURN glove and eight were dressed with SSD. After

assessing all trials and studies the author concluded that the utilization of a hydro fiber silver

impregnated glove for partial thickness hand burns, has clinical consequence in the outpatient

setting reducing the need for hospitalization, and the amount of dressing changes required.


337


[76] Abhishek Adhya et al 2015 compared the effectiveness of topical silver sulfadiazine

(SSD) Vs nanocrystalline silver (AgNPs) hydrogel in burn wounds management against 2°

burn injury. The study time interval was taken one year. Silver sulfadiazine was applied and

tested on 54 patients and silver nanocrystals were tested on 52 patients, after various studies it

was concluded that AgNPs can be an effective and superior alternative to SSD for burn

wounds, predominantly 2° deep dermal burns.

[77]

Hilde Beele et al; 2010, compared antimicrobial-efficacy of an ionic silver

alginate/carboxymethylcellulose (SA/CMC) dressing Vs non silver calcium alginate fiber

(AF) dressing, on chronic venous leg and pressure ulcers. The study trials were performed on

36 patients for 4 weeks. In conclusion, the SACMC dressing showed a greater ability to

prevent wounds progressing to infection when compared with the AF control dressing. In

addition, the results of this study also showed an improvement in wound healing for SACMC

when compared with a non silver dressing.

[78]

Oliver Brandt et al 2012 compared the percutaneous absorption and the antimicrobial

potency of silver sulfadiazine (SSD) with a new composition, nanoscalic silver (NS Ag).

Antimicrobial activity of NS Ag utilized as a 0.1% formulation was comparable not only with

0.1% SSD against different bacterial strains including methicillin-resistant Staphylococcus

aureus, but also against different yeast and dermatophyte species. The antimicrobial studies

against Methicillin-resistant Staphylococcus aureus (MRSA), E. coli, and P. aeruginosa were

performed by tryptic soy broth (TSB) methods and S. pyogenes was grown in Todd-Hewitt

broth. After assessing above given test and studies it was resulted that topical application of

NS Ag resulted in significantly lower percutaneous absorption and internal organ deposition

compared to silver sulfadiazine.

[79]

André R. Fajardo et al; 2013, formed Silver sulfadiazine (AgSD) loaded

chitosan/chondroitin sulfate (CHI/CS) films which are used to be applied as a potential

wound dressing material. These films were used to evaluate antimicrobial activity against

Pseudomonas aeruginosa and Staphylococcus aureus. After various studies and

characterization the result found to be that the CHI/CS/AgSD films are good candidates to be

tested as a wound dressing material.

[80]

Kiran Jadhav et al; 2016, synthesized silver nanoparticles (AgNPs) by simple treatment of

silver nitrate with aqueous extract of Ammonia baccifera and prepared silver based nanogel.


338


The comparison tests were performed between formulated gel (0.03%w/w) and marked

formulation Silverex™ionic (silver nitrate gel 0.2%w/w). Formulated AgNPs gel consisting

of 95% lesser concentration of silver compared to marketed formulation. After

characterization and various comparison studies the result was found that bactericidal

efficacy of formulated gel (0.03%w/w) and marked formulation Silverex™ionic (silver

nitrate gel 0.2%w/w) showed equal zone of inhibition against all bacteria. Hence, the

formulated AgNPs gel could serve as a better alternative with least toxicity towards the

treatment.

[81]

Ping Gong et al; 2007, prepared bifunctional Fe3O4@Ag nanoparticles antibacterial

properties. These nanoparticles were prepared by reducing silver nitrate on the surface of

Fe3O4 nanoparticles using the water-in-oil micro emulsion method. The antibacterial activity

was performed against Escherichia coli (gram-negative bacteria), Staphylococcus epidermidis

(gram-positive bacteria) and Bacillus subtilis (spore bacteria).After performing various

studies characterizations the result was found that Fe3O4@Ag nanoparticles presented good

antibacterial performance against above given bacteria.

[82]

Sirikamon Saengmee et al; 2013, evaluated the antimicrobial activities of silver inorganic

materials, including silver Zeolite (AgZ), silver Zirconium Phosphate silicate(AgZrPSi) and

silver zirconium Phosphate (AgZrP) against oral microorganism. The antimicrobial activities

of this powder were evaluated by means of minimum inhibitory concentration (MIC) value

and minimal Lethal Concentration (MLC).The (MIL) and (MLC) were determined using

modified membrane methods. Morphology and structure of these silver materials were

confirmed by scanning electron microscopy (SEM) and X-rays diffraction methods. The

antimicrobial activities of these (AgZ), (AgZrP),(AgZrPSi) were tested against

Staphylococcus mutant, Staphylococcus aureus, Candida albicans using the disk diffusing

methods. After whole studies the author concluded that these all forms of silver material can

inhibit the microbial growth of all upper given test organisms presently available for

infections in burns.

[83]

Jaya Jain, et al; 2009‘ formulated antimicrobial gel containing silver nanoparticles (SNPs)

in the size range of 7-20 nm. This antimicrobial gel was formulated using proprietary

biostabilization process. The antibacterial activity of gel such as Minimum Inhibitory

Concentration (MIC), Minimum Bactericidal Concentration (MBC), Time Kill Study, Post

Agent Effect (PAE) and Fractional Inhibitory Concentration Index (FICi) were determined by


339


double dilution technique. The antibacterial activity was tested against pseudomonas

aeruginosa, Aspergillus Niger, Staphylococcus epidermidis and multidrug-resistant

(MDR).This antimicrobial gel was comparable with commercially available drug silver

sulfadiazine even though at a 30-fold less silver concentration. The interaction of SNPs with

commonly used antibiotics was investigated, effects were synergistic (ceftazidime), additive

(streptomycin, kanamycin, ampiclox, polymyxin B). Toxicity of silver nanoparticles was also

investigated. After investigation of above given studies the author concluded that silver

nanoparticles could provide a safer alternative to conventional antimicrobial agents in the

form of a topical antimicrobial formulation.

8. Use of silver and nanosilvers particles

Prophylactic antibacterial effect of silver:

Silver is used in bone cement.

Silver ions are used as wound dressing in

different types of wound healing.

Silver nanoparticles are used in textiles

fields like socks and fabrics.

Silver nanoparticles are used in

cerebrospinal fluid as a coating material.

First of all crede used silver nitrate in the

form of eye drop to prevent gonococci eye

infection.

Silver sulfadiazine cream is used in the

treatment of burns.

Silver nitrate is used in the problem of

cauterization.[84]

Silver alloy is used in surgical, medical and

microsurgical instrument.[86]

Salvo

Silver nanoparticles are used in the surgical

masks. (Consisting of a mixture of silver

nitrate and titanium dioxide).[85]

Colloidal silver is used in asthma, allergies

and inflammation.[87]


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9. CONCLUSION

Nanosilver is available in many different forms. The mechanism of nanosilvers is not yet

understood fully. Silver nanoparticles are available in different dosages forms for various

diseases like different types of wounds (Acute wounds, chronic wounds, 1st, 2

nd, 3

rd and 4

th

degrees burns). Now nanosilvers are considered gold standard for effective delivery due to its

excellent wound healing properties. There are some issues of stability and various kind of

delivery which are still unresolved.

10. ACKNOWLEDGEMENT

One of the author miss Reena Badhwar kindly acknowledges to Delhi Pharmaceutical

Sciences & Research University, New Delhi-17, India for providing financial assistance in

the form of senior research fellowship for her doctoral study. No writing assistance was

utilized in the production of this manuscript.

11. Conflict of Interest

The author declared no conflict of interest.

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