Next Article in Journal
Antibiotic Activity of Actinobacteria from the Digestive Tract of Millipede Nedyopus dawydoffiae (Diplopoda)
Next Article in Special Issue
Silver Nanoparticle Conjugation-Enhanced Antibacterial Efficacy of Clinically Approved Drugs Cephradine and Vildagliptin
Previous Article in Journal
Explorative Study on Isolation and Characterization of a Microviridae G4 Bacteriophage, EMCL318, against Multi-Drug-resistant Escherichia coli 15-318
Previous Article in Special Issue
Microbiome Analysis of Biofilms of Silver Nanoparticle-Dispersed Silane-Based Coated Carbon Steel Using a Next-Generation Sequencing Technique
Open AccessReview

Antimicrobial Silver in Medicinal and Consumer Applications: A Patent Review of the Past Decade (2007–2017)

1
School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia
2
ARC Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, QLD 4072, Australia
3
Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
*
Author to whom correspondence should be addressed.
Antibiotics 2018, 7(4), 93; https://doi.org/10.3390/antibiotics7040093
Received: 20 August 2018 / Revised: 8 October 2018 / Accepted: 16 October 2018 / Published: 26 October 2018
(This article belongs to the Special Issue Silver-Based Antimicrobials)

Abstract

The use of silver to control infections was common in ancient civilizations. In recent years, this material has resurfaced as a therapeutic option due to the increasing prevalence of bacterial resistance to antimicrobials. This renewed interest has prompted researchers to investigate how the antimicrobial properties of silver might be enhanced, thus broadening the possibilities for antimicrobial applications. This review presents a compilation of patented products utilizing any forms of silver for its bactericidal actions in the decade 2007–2017. It analyses the trends in patent applications related to different forms of silver and their use for antimicrobial purposes. Based on the retrospective view of registered patents, statements of prognosis are also presented with a view to heightening awareness of potential industrial and health care applications.
Keywords: antibiotic resistance; antimicrobial activity; medicinal silver; patents; silver; silver nanoparticles; synergism antibiotic resistance; antimicrobial activity; medicinal silver; patents; silver; silver nanoparticles; synergism

1. Introduction

Silver is a soft and shiny transition metal which is known to have the highest reflectivity of all metals [1]. Among its many useful properties, silver it recognized to have antimicrobial activity. Silver is known to be biologically active when it is dispersed into its monoatomic ionic state (Ag+), when it is soluble in aqueous environments [2]. This is the same form which appears in ionic silver compounds such as silver nitrate and silver sulfadiazine, which have been frequently used to treat wounds [3]. Another form of silver is its native nanocrystalline form (Ag0). The metallic (Ag0) and ionic forms can also appear loosely associated with other elements such as oxygen or other metals and can form covalent bonds or coordination complexes [3].
To date, there are three known mechanisms by which silver acts on microbes. Firstly, silver cations can form pores and puncture the bacterial cell wall by reacting with the peptidoglycan component [4]. Secondly, silver ions can enter into the bacterial cell, both inhibiting cellular respiration and disrupting metabolic pathways resulting in generation of reactive oxygen species [5]. Lastly, once in the cell silver can also disrupt DNA and its replication cycle [6] (Figure 1). A recently published review includes more details about the bactericidal mechanisms of silver, along with methods of silver nanoparticle preparation [7]. Throughout history, silver has consistently been used to restrict the spread of human disease by incorporation into articles used in daily life. The earliest recorded use of silver for therapeutic purposes dates back to the Han Dynasty in China circa. 1500 B.C.E [8]. Silver vessels and plates were frequently used during the Phoenician, Macedonian, and Persian empires [9]. Families of the higher socioeconomic classes during the middle-ages were so acquainted with the usage of silver that they developed bluish skin discolorations known as argyria, an affliction which may have led to the term ‘blue blood’ to describe members of the aristocracy [10]. Modern medicine utilizes medical grade forms of silver, such as silver nitrate, silver sulfadiazine, and colloidal silver [11].
The discovery of antibiotics in the early 20th century led to a cessation in the development of silver as an antimicrobial agent. However, the development of increasing levels of bacterial resistance to most antibiotics in recent years has led to reexamination of the potential of this ancient remedy [7,12] including studies with patients using colloidal silver and antibiotics [13]. This review aims to demonstrate the wide and ever-expanding applications of silver in medicine, health care, and other daily life activities, with a focus on the patents registered during the past decade. A similar patent review was published in Expert Opinion on Therapeutic Patents in 2005 [14], covering patents compiled from 2001–2004. The current review extends to the years 2007–2017. An analysis of the growth of patents describing antimicrobial silver applications is presented throughout this review, along with commentary of selected examples demonstrating some of the more interesting applications. Our analysis has separated these discussions of the use of silver into four general categories: Medical applications, personal care products, domestic household products, and agricultural/industrial applications.

2. Discussion

2.1. Antimicrobial Silver for Clinical and Medical Usage

This section presents a selection of some of the most interesting and unique patented products which utilize silver for their bactericidal action in the medical field, including therapies based on silver’s antimicrobial properties. The product numbers referred to in this section correspond to those listed in Table 1.
Surface coatings incorporating silver are a common application. One new approach is a method for producing ready packed medical apparatus which sterilizes itself upon the opening of the package, by creating a vapor that activates a silver-containing hydrophilic surface coating (Product No. 1). The antimicrobial properties of silver have been highly valued in medical application where implanted devices are coated with silver nanoparticles for the antimicrobial effects, but manufacturers need to be aware that this application is claimed in a patent application (Product No. 2) with a very broad claim 1: “An article that is implantable in an animal, the article comprising a microparticulate silver-containing antimicrobial layer stably adhered upon at least one surface of the article.” However, the application does not appear to have progressed towards granting. Invasive surgical tools such as medical grade needles (Product No. 3) can also be coated with silver nanoparticles as described in its related patent (Product No. 4). Medical devices that are directly introduced into the human body that contain silver include vascular catheters (Product No. 5), bone implants (Product No. 6), and biliary duct brackets (Product No. 7). Another topical application of antimicrobial silver has incorporated it into coatings applied to the interior surface of a building's exterior wall (Products No. 8a and 8b).
Another general use is for topical treatments. Numerous topical gels with different formulations of silver have been patented. Silver was first used to treat burn wounds in the form of 0.5% silver nitrate solution and silver sulfadiazine cream in 1960 [35]. However, this was impractical as the dressings required rehydration every couple of hours. To overcome this limitation silver nanoparticle-based gels and silver salt-based gels have been developed (Products No. 9a, 9b and 10), with all approaches still considered novel.
Silver based wound dressings have greatly improved in efficacy compared to standard dressings, and more complex dressings have been developed. New knowledge in burn wound management led to the discovery of a method to immobilize silver nanoparticles on a gel-support matrix which is attached to a wound dressing (Product No. 11). A recently commercialized wound dressing allows a prolonged use of the dressing for up to 7 days or until saturation, without reapplication (Figure 2). It is made possible through its design, which slowly releases silver ions upon contact with wound exudates. Its highly absorbent padding is also coated with a layer of silicone which is aimed to reduce pain during removal and reapplication of the dressing. (Product No. 12). The use of silver with wound dressings is known to reduce scarring and such formulations are widely used (Product No.13). Silver-based wound dressings are available under brand names with different compositions, such as Mepilex® Ag, Acticoat™, Aquacel®, Flaminal®, Allevyn® Ag, and Biatain® Ag, SILVERCEL™. Other products containing a silver component, not specifically developed for wound healing, have been patented for treatment of bacterial infection (Products No. 14a and 14b).
Silver has also been applied across the dental field. Silver has been the key component in dental amalgam fillings for more than one hundred years. However, its antimicrobial properties were not patented. Silver is used in the prevention of infection during and after dental surgery (Product No. 15). Dental support fixtures made out of silver and denture materials, and other body restoration objects, having silver nanoparticles as additives can reduce bacterial infections, especially during first few months of installation (Products No. 16 and 17).

2.2. Antimicrobial Silver in Personal Care Products

This section presents grooming products and devices which utilize silver for its sanitizing effects, summarized in Table 2. Hygiene and grooming products such as shavers (Product No. 18), toothbrushes (Product No. 19) and sanitary pads (Product No. 20) are frequently employed under adverse conditions where they encounter the bacteria microbiome, but are relied upon to be sanitary. One example of such usage is by the German public company “Beiersdorf AG” which has products incorporating silver for its added antimicrobial properties. They have applied silver over a wide range of products from shower gels and deodorants to first aid bandages (Figure 3).
Since using silver to treat skin infections is common, researchers in dermatology frequently resort to silver for treating conditions related to bacterial colonization, such as body odors (Product No. 21), acne outbreaks (Product No. 22), eczema and rash (Product No. 23).
A range of other personal health products have also added silver to improve their hygienic capacities, including contact lenses (Product No. 24), antimicrobial fabric garments (Products No. 25a, 25b and 25c), breast pump assemblies (Product No. 26), and hair dye (Product No. 27).
Most cosmetic products come in the form of cream, aqueous lotions, or hydrogel medium. It is observed that most manufacturers favor the incorporation of silver colloids into their products as they do not precipitate and separate, with the added benefit of acting as a preservative. Colloidal silver is defined as a mixture of silver ions and silver nanoparticles suspended in an aqueous medium. They are usually synthesized by electrolysis using a set of silver cathodes [48]. Colloidal silver was first used in 1891 by a surgeon named B.C Crede to sterilize wounds [9]. The use of silver grew in popularity between 1900 to the 1940s. Subsequently, antibiotics supplanted the use of silver [9]. Today, many products are offered not only as colloidal silver solutions, but also as personal devices suitable for home use, that synthesize colloidal silver. However, the commercialization of colloidal silver has been accompanied by inconsistencies in colloidal silver production and properties, as well as cases of unexpected side effects. Therefore, the Food and Drug Administration (FDA) has excluded any commercialized colloidal silver that claims health benefits without scientific evidence [49]. Similar action has been taken by the Therapeutic Goods Administration (TGA) in Australia [49] and the European Commission (EC) [50]. The commercial sales of colloidal silver are not banned, but claims of health benefits without scientific support are not permitted.

2.3. Antimicrobial Silver in Domestic Products

The antimicrobial applications of silver started in ancient times in domestic products like silver plates and pitchers [9]. With that in mind, there continue to be domestic applications of silver, particular for surface treatments (Table 3).
Silver is widely incorporated into surface coatings of electrical goods such as automated bathtubs (Product No. 28), laundry washing machines (Product No. 29), air purifiers with silver filters (Product No. 30) and refrigerators (Product No. 31), to produce ‘bacteria-free’ products. Application of silver nanoparticles to other household objects with frequent handling such as keyboards (Product No. 32), bath safety aids (Product No. 33), and bathroom safety handles (Product No. 34). Special stand-alone products such as containers for meat or water/wine/milk storage (Products No. 35a and 35b) are useful applications where bacterial contamination may present a health issue.
Despite the many beneficial innovations in the use of silver as an antimicrobial agent, its application in cleaning products and disposable tools such as gloves (Product No. 36), disinfectant wipes (Product No. 37), and cleaning detergent (Product No. 38) may have negative environmental impacts. Cleaning products, once used, usually end up in sewage treatment systems, and eventually the environment. This is a concern for silver nanoparticles, as there are currently no effective methods for filtering out silver nanoparticles. The release of large amount of silver products into the environment may lead to disturbances of the microbiological ecosystem, and potentially lead to bacterial resistance to silver [63]. Consequently, alternative methods of sanitization should be considered such as the application of alcohol or bleach which are sufficient for domestic purposes, or employing ‘fixed’ silver containing surfaces that reduce the risk of environmental release.
Apart from being a threat to beneficial environmental bacteria, another issue to be addressed is the possible longer-term reduction of the potency of silver in killing microbes. Since the discovery of antibiotics, the efficacy of antibiotics has been compromised by over-prescription and over-usage, leading to the current antibiotic crisis. The presence of low levels of antibiotics in the environment fosters the generation of multiple drug resistant strains [64]. Silver is not immune to the generation of bacterial resistance, with several reports in recent years [65,66]. This history suggests a need for a systemic reassessment of the usage of silver in domestic products, so that it is not used too extravagantly, or released haphazardly.

2.4. Antimicrobial Silver in Agricultural and Industrial Products

Silver has also been used for a variety of agricultural and industrial products. In industry, large scale water purification can be made cost effective by using colloidal silver for purification as it is needed only in small quantities and can purify large quantities of water, though potential environmental risk needs to be considered [67]. For agriculture use, silver has been incorporated in nylon ropes that are used to tie down plants, cover them with netting, and for various other applications. These ropes normally decay after time due to bacterial biofilm formation, so the silver prevents this decomposition [68]. Agricultural use of silver products must be carefully assessed to avoid any impact on the microbial flora and symbiosis. The growth of healthy crop plants relies heavily upon the formation of symbiotic microbes around the roots such as nitrifying bacteria and mycorrhiza [69]. Studies have shown that the contact of bioactive silver to nitrifying bacteria impedes the formation of symbiotic channels [70].
Table 4 presents patented industry and agricultural related products utilizing silver as an antimicrobial agent. An example of agricultural use is Product No. 39 which uses Ag (I) and Ag (II) to treat infections in plants, while Products No. 40 and 41 with coating of a single rope strand with silver to prolong resistance to biofilm formation. Silver coatings can be beneficial in industrial machines which require a completely sterile environment to manufacture food or medical grade products, employing silver in the parts that come in direct contact with the products (Product No. 42). Machinery parts are usually designed for prolonged periods and incorporating silver particles into these materials provides an effective means of isolation and retention of silver so that it is not released into the environment easily.
Polymers are extremely versatile and when impregnated with silver nanoparticles, they can be used for numerous applications, such as mass-produced food storage containers (Product No. 43) and industrial scale waste bins (Product No. 44). Sterility in the food and therapeutics industry is crucial, so the incorporation of silver into manufacturing equipment in contact with consumer products can be regarded as an appropriate usage. However, in the case of daily used food containers, frequent usage of silver may not be ideal as there is a risk of accumulation in the human body if the silver leaches, potentially leading to similar side effects as were observed in the middle ages when silver utensils were frequently used [9].
Products No. 45a and 45b describes a water filtration unit containing immobilized silver nanoparticles for water purification purposes. The invention and manufacture of industrial cleaning solutions containing silver (Product No. 46) is a potentially widespread application, as there is a need for instant effective sanitization to prevent bacterial transmission. However, precautions must be observed to prevent environmental release.

2.5. Overview of Patent Literature from 2007–2017

In the previous sections, applications of antibacterial silver in a variety of fields were discussed. This section presents an overview of silver-related patents on a global level for the purpose of understanding the trends, major applications as well as major contributors. Methods by which the data sets were obtained are reported in Section 3.
Tracking the number of patents disclosing antimicrobial applications of silver for each year over the past decade, as summarized in Figure 4, shows that there has been a steady upward trajectory in the number of silver patent applications in recent years. The increase may have reached a plateau in 2016/17, but it will be necessary to consider data from 2018 and onwards to confirm this hypothesis.
The data obtained from Figure 4 can be further dissected to reveal patents registered under each language, as shown in Figure 5. This can be linked to a deduction of the country of origin of these patents. This analysis demonstrates that patents claiming antimicrobial silver products are predominantly contributed by Asian countries, with China (55%), Korea (7%), and Japan (8%) comprising 70% of the chart. Patents registered in English compose 25% while another 5% are various European language patent registrations. It has been speculated that since the FDA and EMA have reduced influence in the Asian countries [49], this opens up opportunities in Asia for innovations with antimicrobial silver. Indeed, there is some basis for this speculation given the large number of silver related patents being registered in Asian languages, but additional research will be needed to establish the causes of this phenomenon. One of the potential reasons explaining the more substantial contribution of Asian countries in patented silver related innovations and consumer products is the fast-track approval pathway for new drugs in China, supported by consumer trials that are significantly cheaper than in other countries, which can be performed on higher number of participants. There is also a Chinese government strategy to commercialize non-Chinese ideas in China and financially support innovators who are willing to patent their ideas in China, with a preference to procure products whose IP is owned or registered in China. Finally, the database search may produce multiple results for a single patent that are particularly difficult to detect for Chinese applications because Chinese individuals’ names typically have only three or two characters [79].
We have also assessed the application of silver according to its field of use. Based on the analysis from Figure 6, only about 20% of the patents in each year claimed medical uses of silver. This could mean that approximately about 80% of the patented silver applications are for other usages, such as domestic, agricultural and industrial usage. If this trend continues, there is potential for damage to the ecosystem if the non-medical uses result in release to the environment. This could lead to a worrisome situation where bacteria evolve resistance to silver, one of few promising alternatives to current classes of antibiotics.

3. Materials and Methods

The patent analysis data and trend chart were generated through search results obtained from the scientific publication database, SciFinder® by the American Chemical Society. It was accessed through the University of Queensland Library portal. Results generated were accurate as of 15 June 2018.

3.1. Dataset 1—Application of Antibacterial Silver from the Global Perspective

The keywords used to generate this search were “antibacterial + silver” and “silver + medical” that narrowed down the number of silver related patents to those presenting the word “silver” in the title and describing only silver components. Therefore, patents with the general terms such as “metal nanoparticles” covering all nanomaterials with potential antibacterial applications like silver, platinum, gold, palladium, copper, zinc, and other metals, are not included here. Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 5054 hits of exact words and concepts related to its words. No duplicates were found throughout the result set. The full result was analyzed by publication year and was sorted out by natural order to reflect results in yearly order. Obtained results were used to generate a bar chart as Figure 5 by using Microsoft Word chart sketching function.

3.2. Dataset 2—Application of Antibacterial Silver from a Regional Perspective

The keywords used to generate this search were as for Dataset 1, “antibacterial + silver”. Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 5054 hits of exact words and concepts related to its words. No duplicates were found throughout the result set. The full result was analyzed by language and was sorted out by frequency of region. Results obtained were used to generate the pie chart (Figure 6) by using the Microsoft Word chart sketching function.

3.3. Dataset 3—Application of Antibacterial Silver in the Medical Field

The keywords used to generate this search were “silver + medical”. Result limiters used were publication years (2007–2017) and document type (Patent). Search results yielded 1310 hits of exact words and concept related to its words. No duplicates were found throughout the result set. The full result was analyzed by publication year and was sorted out by natural order to reflect results in yearly order. Results obtained were tabulated against dataset 1 to in order to obtain a 100% stacked bar chart presented at Figure 6 by using Microsoft Word chart sketching function.

4. Conclusions

The use of silver for its antimicrobial properties is increasing in numerous fields, including the medical, consumer, agricultural and industrial sectors. In just over 10 years, nearly 5000 new applications have been registered. The majority of the patents are from Asian countries, with Chinese language applications representing more than 50% of the global total, followed by Korean and Japanese language filings. Only about 20% of patents are registered in English.
While the potential benefits of silver are attracting increased attention, a number of publications have pointed out potential adverse effects from the overuse of silver, such as ecosystem disturbance [80], and bacterial resistance to silver [81]. Since our “armory” of antibiotics has been depleted by the rise in antimicrobial resistance, silver represents a new hope, but mindful use must be considered at an early stage to prevent a repetition of past mistakes.
We suggest that the application and commercialization of silver related products should be critically reassessed to avoid, or at least minimize, these adverse effects. In particular, while incorporation of silver products in an enclosed environment is justifiable, products which are expected to release silver into the environment should be avoided. There is ample evidence [82] that there can be adverse long-term effects from consumption or exposure to silver, so silver products should only be used in circumstances where (1) there is an absolute need for it, such as a medical intervention, and (2) in modes where silver is immobilized and containable.

Author Contributions

W.S. and Z.M.Z. designed and wrote the manuscript, Z.M.Z. coordinated the writing progress. All authors discussed the results and commented on the manuscript with the input from R.T.B. and M.A.T.B.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. National Institute of Standards and Technology. CRC Handbook of Chemistry and Physics, 81st ed.; Lide, D.R., Ed.; CRC Press: Boca Raton, FL, USA, 2000; p. 2556. ISBN 0-8493-0481-4. [Google Scholar]
  2. Hoffman, R.K.; Surkiewicz, B.F.; Chambers, L.A.; Phillips, C.R. Bactericidal action of movidyn. Ind. Eng. Chem. 1953, 45, 2571–2573. [Google Scholar] [CrossRef]
  3. Fong, J.; Wood, F. Nanocrystalline silver dressings in wound management: A review. Int. J. Nanomed. 2006, 1, 441–449. [Google Scholar] [CrossRef]
  4. Jung, W.K.; Koo, H.C.; Kim, K.W.; Shin, S.; Kim, S.H.; Park, Y.H. Antibacterial activity and mechanism of action of the silver ion in staphylococcus aureus and escherichia coli. Appl. Environ. Microbiol. 2008, 74, 2171–2178. [Google Scholar] [CrossRef] [PubMed]
  5. Morones-Ramirez, J.R.; Winkler, J.A.; Spina, C.S.; Collins, J.J. Silver enhances antibiotic activity against gram-negative bacteria. Sci. Transl. Med. 2013, 5, 190ra181. [Google Scholar] [CrossRef] [PubMed]
  6. Yakabe, Y.; Sano, T.; Ushio, H.; Yasunaga, T. Kinetic studies of the interaction between silver ion and deoxyribonucleic acid. Chem. Lett. 1980, 9, 373–376. [Google Scholar] [CrossRef]
  7. Möhler, J.S.; Sim, W.; Blaskovich, M.A.T.; Cooper, M.A.; Ziora, Z.M. Silver bullets: A new lustre on an old antimicrobial agent. Biotechnol. Adv. 2018, 36, 1391–1411. [Google Scholar] [CrossRef] [PubMed]
  8. Yamada, K. The two phases of the formation of ancient medicine. In The Origins of Acupuncture and Moxibustion, The Origins of Decoction; International Research Center for Japanese Studies: Kyoto, Japan, 1998; p. 154. [Google Scholar]
  9. Alexander, J.W. History of the medical use of silver. Surg. Infect. (Larchmt) 2009, 10, 289–292. [Google Scholar] [CrossRef] [PubMed]
  10. Davies, O. They Didn’t Listen, They Didn’t Know How; AuthorHouse: Bloomington, IN, USA, 2013; p. 805. [Google Scholar]
  11. Hill, W.R.; Pillsbury, D.M. Argyria: The Pharmacology of Silver; Williams & Wilkins Company: Philadelphia, PA, USA, 1939; p. 188. [Google Scholar]
  12. Möhler, J.S.; Kolmar, T.; Synnatschke, K.; Hergert, M.; Wilson, L.A.; Ramu, S.; Elliott, A.G.; Blaskovich, M.A.T.; Sidjabat, H.E.; Paterson, D.L.; et al. Enhancement of antibiotic-activity through complexation with metal ions—Combined ITC, NMR, enzymatic and biological studies. J. Inorg. Biochem. 2017, 167, 134–141. [Google Scholar] [CrossRef] [PubMed]
  13. Ooi, M.L.; Richter, K.; Bennett, C.; Macias-Valle, L.; Vreugde, S.; Psaltis, A.J.; Wormald, P.-J. Topical colloidal silver for the treatment of recalcitrant chronic rhinosinusitis. Front. Microbiol. 2018, 9. [Google Scholar] [CrossRef] [PubMed]
  14. Melaiye, A.; Youngs, W.J. Silver and its application as an antimicrobial agent. Expert. Opin. Ther. Pat. 2005, 15, 125–130. [Google Scholar] [CrossRef][Green Version]
  15. Hannon, D.; Gilman, T.H. Ready to Use Medical Device with Instant Antimicrobial Effect. US20150314103A1, 5 November 2015. [Google Scholar]
  16. Ostrum, R.; Hettinger, J.; Krchnavek, R.; Caputo, G.A. Use of Silver-Containing Layers at Implant Surfaces. US20130344123A1, 26 December 2013. [Google Scholar]
  17. Yang, W.-D. Medical Needles Having Antibacterial and Painless Function. WO2006088288A1, 24 August 2006. [Google Scholar]
  18. Li, Y. Fracture-Setting Nano-Silver Antibacterial Coating. CN203128679U, 14 August 2013. [Google Scholar]
  19. Ellingwood, B.A. Antimicrobial Closure Element and Closure Element Applier. US20080312686A1, 18 December 2008. [Google Scholar]
  20. Dehnad, H.; Chopko, B.; Chirico, P.; McCORMICK, R. Bone Implant and Systems that Controllably Releases Silver. WO2012064402A1, 19 May 2012. [Google Scholar]
  21. Linghu, E.; Wang, K.; Wang, Y.; Yang, J. Nanometer Silver Antibacterial Biliary Duct Bracket and Preparation Method Thereof. CN102485184A, 6 June 2012. [Google Scholar]
  22. Redler, B.M. Antimicrobial Coatings for Treatment of Surfaces in a Building Setting and Method of Applying Same. US7641912B1, 5 January 2010. [Google Scholar]
  23. Redler, B.M. Antimicrobial Coatings for Treatment of Surfaces in a Building Setting and Method of Applying Same. US8282951B2, 9 October 2012. [Google Scholar]
  24. Omray, P. Silver Nanoparticle Dispersion Formulation. WO2007017901A2, 16 February 2007. [Google Scholar]
  25. Meledandri, C.J.; Schwass, D.R.; Cotton, G.C.; Duncan, W.J. Antimicrobial Gel Containing Silver Nanoparticles. EP3359166A1, 15 August 2018. [Google Scholar]
  26. Yates, K.M.; Proctor, C.A.; Atchley, D.H. Antimicrobial Silver Hydrogel Composition for the Treatment of Burns and Wounds. WO2012151438A1, 8 November 2012. [Google Scholar]
  27. Miraftab, M. Polysaccharide Fibres for Wound Dressings. WO2013050794A1, 11 April 2013. [Google Scholar]
  28. Bowler, P.; Parsons, D.; Walker, M. Wound Dressing. US20070286895A1, 13 December 2007. [Google Scholar]
  29. Ma, R.-H.; Yu, Y.-H. Nano-Silver Wound Dressing. US20070293799A1, 20 December 2007. [Google Scholar]
  30. Lyczak, J.B.; Thompson, K.; Turner, K. Metal-Containing Materials for Treatment of Bacterial Conditions. US8425880B1, 23 April 2013. [Google Scholar]
  31. Gillis, S.H.; Schechter, P.; Stiles, J.A.R. Metal-Containing Materials. US7255881B2, 14 August 2007. [Google Scholar]
  32. Willoughby, A.J.M.; Moeller, W.D. Dental Uses of Silver Hydrosol. US9192626B2, 24 November 2015. [Google Scholar]
  33. Ruppert, K.; Grundler, A.; Erdrich, A. Antimicrobial Nano Silver Additive for Polymerizable Dental Materials. US20070213460A1, 13 September 2007. [Google Scholar]
  34. Ukegawa, S. Silver-Ion Coated Object Obtained by Microwave Irradiation and a Method for Coating a Silver-Ion Onto a Target Object. US20180245278A1, 30 August 2018. [Google Scholar]
  35. Nherera, L.M.; Trueman, P.; Roberts, C.D.; Berg, L. A systematic review and meta-analysis of clinical outcomes associated with nanocrystalline silver use compared to alternative silver delivery systems in the management of superficial and deep partial thickness burns. Burns 2017, 43, 939–948. [Google Scholar] [CrossRef] [PubMed]
  36. Banowski, B.; Garnich, F.; Simmering, R.; Device, I.E. Handset, for Performing Cosmetic and Medical Treatment for Human Skin, Has Application Surface Contacted with To-Be-Treated Skin Zone and Silver Portion, Which is Provided for Delivering Antimicrobial Silver Ions. DE102012224176A1, 26 June 2014. [Google Scholar]
  37. Su, J.; Wang, D. Antimicrobial Thermoplastic Polyurethane for Toothbrush and Preparation Method for Antimicrobial Thermoplastic Polyurethane. CN103254401A, 4 March 2015. [Google Scholar]
  38. Zhao, H. Sanitary Towel Capable of Removing Peculiar Smell and Manufacturing Method Thereof. CN102961778A, 13 March 2013. [Google Scholar]
  39. Hasegawa, S. Solid Oily Cosmetic. JP2013071914A, 22 April 2013. [Google Scholar]
  40. Miyata, S.; Kakihara, H.; Takahashi, F.; Nagaoka, H.; Kubota, T.; Ueda, G. Antimicrobial Agent. JP2010059132A, 18 March 2010. [Google Scholar]
  41. Jang, H.C. Functional Cosmetic Including Nano Silver. KR20070119971A, 21 December 2007. [Google Scholar]
  42. Zanini, D.; Alli, A.; Ford, J.; Steffen, R.; Vanderlaan, D.; Petisce, J. Antimicrobial Contact Lenses and Methods for their Production. US20030044447A1, 6 March 2003. [Google Scholar]
  43. Schuette, R.; Kreider, J.; Goulet, R.; Wiencek, K.; Sturm, R.; Canada, T. Silver-Containing Antimicrobial Fabric. US20050037057A1, 17 February 2005. [Google Scholar]
  44. Hendriks, E.P.; Trogolo, J.A. Wash-Durable and Color Stable Antimicrobial Treated Textiles. US7754625B2, 13 July 2010. [Google Scholar]
  45. Hutt Pollard, E.A.; Morham, S.; Brown, D.E.; Kray, J.S. Systems and Processes for Treating Textiles with an Antimicrobial Agent. WO2018160708, 7 September 2018. [Google Scholar]
  46. Silver, B.H. Breastpump Assemblies Having Silver-Containing Antimicrobial Compounds. US20080139998A1, 12 June 2008. [Google Scholar]
  47. Wang, X. Nano-Silver Inorganic Antibacterial Nutritional Hair Dye. CN104224617A, 24 December 2014. [Google Scholar]
  48. Panáček, A.; Kvítek, L.; Prucek, R.; Kolář, M.; Večeřová, R.; Pizúrová, N.; Sharma, V.K.; Nevěčná, T.J.; Zbořil, R. Silver colloid nanoparticles:  Synthesis, characterization, and their antibacterial activity. J. Phys. Chem. B. 2006, 110, 16248–16253. [Google Scholar] [CrossRef] [PubMed]
  49. Rulemaking History for OTC Colloidal Silver Drug Products. Available online: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/over-the-counterotcdrugs/statusofotcrulemakings/ucm071111.htm (accessed on 27 September 2018).
  50. Hartemann, P.; Hoet, P.; Proykova, A.; Fernandes, T.; Baun, A.; De Jong, W.; Filser, J.; Hensten, A.; Kneuer, C.; Maillard, J.-Y.; et al. Nanosilver: Safety, health and environmental effects and role in antimicrobial resistance. Mater. Today 2015, 18, 122–123. [Google Scholar] [CrossRef]
  51. Sasaki, H. Automatic Bathtub Washing System. JP2009268576A, 19 November 2009. [Google Scholar]
  52. Lee, Y.S. Clothes Washing Machine. US20080041117A1, 21 February 2008. [Google Scholar]
  53. Nuernberger, C.; Nienaber, R.D. Air Purifier, Useful for Neutralizing Bad Smells, Preferably for Air Purification in Refrigerators, and for Controlling Bad Smells E.G. In Textiles and Vacuum Cleaners, Comprises a Silver Zeolite with a Nanoparticulate Metallic Silver. DE102007040742A1, 5 March 2009. [Google Scholar]
  54. Kim, H.-K. Antibiotic Method for Parts of Refrigerator using Antibiotic Substance. US7781497B2, 24 August 2010. [Google Scholar]
  55. Whitchurch, B.W.; Vaillancourt, D.; Jack, P.C.I.; Chen, W.; Huang, J. Submersible Keyboard. US20090262492A1, 22 October 2009. [Google Scholar]
  56. Davis, W. Bactix Silver-Based Antimicrobial Additive in Bath Aids. US20130029029A1, 31 January 2013. [Google Scholar]
  57. Gifford, S. Bacteria-Resistant Grab Bar. US20100148395A1, 17 June 2010. [Google Scholar]
  58. Glenn, J.; Vogt, K.; Bridges, D. Antimicrobial Reusable Plastic Container. US20070189932A1, 16 August 2007. [Google Scholar]
  59. Molnár, M. Vessel with Transparent Antimicrobial Silver Coating. WO2018137725A1, 2 August 2018. [Google Scholar]
  60. Wang, X.; Gao, S. Nano-Silver Antibacterial Gloves. CN202738872U, 20 February 2013. [Google Scholar]
  61. Scheuing, D.R.; Szekres, E.; Bromberg, S. Natural Silver Disinfectant Compositions. US20100143494A1, 10 June 2010. [Google Scholar]
  62. Miner, E.O.; Eatough, C.N.; Miner, E.O.; Eatough, C.N. Antiseptic Solutions Containing Silver Chelated with Polypectate and Edta. US7311927B2, 25 December 2007. [Google Scholar]
  63. Yu, S.-J.; Yin, Y.-G.; Liu, J.-F. Silver nanoparticles in the environment. Environ. Sci. Process. Impacts 2012, 15, 78–92. [Google Scholar] [CrossRef]
  64. Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet 2001, 358, 135–138. [Google Scholar] [CrossRef]
  65. Muller, M. Bacterial silver resistance gained by cooperative interspecies redox behavior. Antimicrob. Agents Chemother. 2018, 62, e00672. [Google Scholar] [CrossRef] [PubMed]
  66. Elkrewi, E.; Randall, C.P.; Ooi, N.; Cottell, J.L.; O’Neill, A.J. Cryptic silver resistance is prevalent and readily activated in certain gram-negative pathogens. J. Antimicrob. Chemother. 2017, 72, 3043–3046. [Google Scholar] [CrossRef] [PubMed]
  67. Oyanedel-Craver, V.A.; Smith, J.A. Sustainable Colloidal-Silver-Impregnated Ceramic Filter for Point-of-Use Water Treatment. Environ. Sci. Technol. 2008, 42, 927–933. [Google Scholar] [CrossRef] [PubMed]
  68. Ingle, E.M.; Fisher, B.J.; Finney, J.W. Silver Coated Nylon Fibers and Associated Methods of Manufacture and Use. US2010166832A1, 1 July 2010. [Google Scholar]
  69. Hayat, R.; Ali, S.; Amara, U.; Khalid, R.; Ahmed, I. Soil beneficial bacteria and their role in plant growth promotion: A review. Ann. Microbiol. 2010, 60, 579–598. [Google Scholar] [CrossRef]
  70. Choi, O.; Hu, Z. Size dependent and reactive oxygen species related nanosilver toxicity to nitrifying bacteria. Environ. Sci. Technol. 2008, 42, 4583–4588. [Google Scholar] [CrossRef] [PubMed]
  71. Olson, M.E.; Harding, M.W. Method and Compositions for Treating Plant Infections. US20120219638A1, 30 August 2012. [Google Scholar]
  72. Song, Y.S.; Kim, M.H.; Won, M.H. Silver Yarn, Plied Yarn Silver Yarn, Functional Fabric Using Same, and Method for Producing Same. CN102439205A, 2 May 2012. [Google Scholar]
  73. Yabe, S. Rolling Device. JP2005201385A, 28 July 2005. [Google Scholar]
  74. Morris, M.; Kerry, J.; Cruz, M.; Cummins, E. An Antimicrobial Food Package. WO2014001541A1, 3 January 2014. [Google Scholar]
  75. Maggio, R.A.; Pearson, R.C. Rotationally Molded Plastic Refuse Container with Microbial Inhibiting Inner Surface and Method. US20080185311A1, 7 August 2008. [Google Scholar]
  76. Pradeep, T.; Chaudhary, A.; Sankar, M.U.; Rajarajan, G. Anshup Sustained Silver Release Composition for Water Purification. WO2012140520A8, 7 November 2013. [Google Scholar]
  77. Pradeep, T.; Chaudhary, A.; Sankar, M.U.; Rajarajan, G. Sustained Silver Release Composition for Water Purification. US20180186667A1, 5 July 2018. [Google Scholar]
  78. Takahashi, H.; Arakawa, H. Method for Producing Antimicrobial Agent Micro-Particle. JP2007161649A, 28 June 2007. [Google Scholar]
  79. He, Z.-L.; Tong, T.W.; Zhang, Y.; He, W. A database linking chinese patents to china’s census firms. Sci Data 2018, 5, 180042. [Google Scholar] [CrossRef] [PubMed]
  80. Tlili, A.; Jabiol, J.; Behra, R.; Gil-Allué, C.; Gessner, M.O. Chronic exposure effects of silver nanoparticles on stream microbial decomposer communities and ecosystem functions. Environ. Sci. Technol. 2017, 51, 2447–2455. [Google Scholar] [CrossRef] [PubMed]
  81. Gugala, N.; Lemire, J.; Chatfield-Reed, K.; Yan, Y.; Chua, G.; Turner, R. Using a chemical genetic screen to enhance our understanding of the antibacterial properties of silver. Genes 2018, 9, 344. [Google Scholar] [CrossRef] [PubMed]
  82. Drake, P.L.; Hazelwood, K.J. Exposure-related health effects of silver and silver compounds: A review. Ann. Occup. Hyg. 2005, 49, 575–585. [Google Scholar] [PubMed]
Figure 1. Silver’s action on a bacterial cell. 1. Silver can perforate the peptidoglycan cell wall. 2. Silver inhibits the cell respiration cycle. 3. Metabolic pathways are also inhibited when in contact with silver. 4. Replication cycle of the cell is disrupted by silver particles via interaction with DNA.
Figure 1. Silver’s action on a bacterial cell. 1. Silver can perforate the peptidoglycan cell wall. 2. Silver inhibits the cell respiration cycle. 3. Metabolic pathways are also inhibited when in contact with silver. 4. Replication cycle of the cell is disrupted by silver particles via interaction with DNA.
Antibiotics 07 00093 g001
Figure 2. Mepilex® Ag with instructions for application. Images used with permission of Mölnlycke Health care, Sweden.
Figure 2. Mepilex® Ag with instructions for application. Images used with permission of Mölnlycke Health care, Sweden.
Antibiotics 07 00093 g002
Figure 3. Commercial utilization of silver in consumer product lines, including Elastoplast (First aid bandages) and NIVEA (Shower gels and deodorants) for enhanced antimicrobial properties. Images used with permission of Beiersdorf AG, Germany.
Figure 3. Commercial utilization of silver in consumer product lines, including Elastoplast (First aid bandages) and NIVEA (Shower gels and deodorants) for enhanced antimicrobial properties. Images used with permission of Beiersdorf AG, Germany.
Antibiotics 07 00093 g003
Figure 4. Trend analysis of yearly number of patent registrations involving antimicrobial silver applications over the past decade.
Figure 4. Trend analysis of yearly number of patent registrations involving antimicrobial silver applications over the past decade.
Antibiotics 07 00093 g004
Figure 5. Analysis of language of patent registrations involving antimicrobial silver over the past decade with major contribution of Chinese (55%), English (25%), Korean (7%), Japanese (8%), and others (5%).
Figure 5. Analysis of language of patent registrations involving antimicrobial silver over the past decade with major contribution of Chinese (55%), English (25%), Korean (7%), Japanese (8%), and others (5%).
Antibiotics 07 00093 g005
Figure 6. Total patents registered globally for silver used in the medical field compared to all other applications.
Figure 6. Total patents registered globally for silver used in the medical field compared to all other applications.
Antibiotics 07 00093 g006
Table 1. List of patented medical grade products and medically related products containing silver as an antimicrobial agent.
Table 1. List of patented medical grade products and medically related products containing silver as an antimicrobial agent.
No.Patent TitleBrief Product DescriptionPatent NumberFiling DateRef.
1Ready to use medical device with instant antimicrobial effectA medical apparatus packaging designed to activate a bioactive silver coating and other bactericidal elements upon opening of package.US20150314103A15 November 2015[15]
2Use of silver-containing layers at implant surfacesThe method of coating medical implants with various forms of silver for infection prevention.US20130344123A14 March 2013[16]
3Medical needles having antibacterial and painless functionSurgical needles coated with silver nanoparticles for the prevention of infection.WO2006088288A15 January 2006[17]
4Fracture-setting nano-silver antibacterial coatingA method to coat invasive medical instruments with silver nanoparticles.CN203128679U3 April 2013[18]
5Antimicrobial closure element and closure element applierThe coating of the internal structure of a vascular portal device and the interior of its applicator.US20080312686A19 June 2008[19]
6Bone implant and systems that controllably release silverA specially designed bone implant which allows surgeons to control the release of silver ions.WO2012064402A119 May 2012[20]
7Nanometer silver antibacterial biliary duct bracket and preparation method thereofA biliary duct implant bracket made from plastic coated uniformly with silver nanoparticles to prevent biofilm formation at site of implant.CN102485184A3 December 2010[21]
8aAntimicrobial coatings on building surfacesA coating with antimicrobial silver applied to the interior surface of a building’s exterior wall.US7641912B15 January 2010[22]
8bUS8282951B29 October 2012[23]
9aSilver nanoparticle dispersion formulationA topical gel to treat dermal infections with 1% w/w silver nanoparticles as active ingredient.WO2007017901A216 February 2007[24]
9aEP3359166A115 August 2018[25]
10Antimicrobial silver hydrogel composition for the treatment of burns and woundsAn aqueous gel with a range of silver salt as its active ingredient made for the treatment of wounds specifically caused by burns.WO20120282348A15 May 2011[26]
11Polysaccharide fibers for wound dressingsThe method of coating wound dressing with a gel matrix where silver can be immobilized and applied to a wound to aid healing.WO2013050794A15 December 2012[27]
12Antimicrobial, silver-containing wound dressing for continuous releaseWound dressing capable of releasing silver ions to aid healing upon contact with fluids from the wound.US20070286895A124 August 2007[28]
13Nano-silver wound dressingA wound dressing with enhanced antimicrobial properties for improved scarring.US20070293799A19 December 2008[29]
14aMetal containing materialsSilver containing materials for treatment of bacterial conditions.US8425880B123 April 2013[30]
14bUS7255881B214 August 2007[31]
15Dental Uses of Silver HydrosolSilver suspended in aqueous gel used to reduce infection risks of dental procedures.US9192626B224 November 2015[32]
16Antimicrobial silver nanoparticle additive for polymerizable dental materialsDenture material made with the addition of silver nanoparticles for additional antimicrobial effect.US20070213460A113 September 2007[33]
17Silver ion coated products for dental and other body restoration objectsSilver coating with antimicrobial, antifouling and deodorant propertiesUS20180245278A130 August 2018[34]
Table 2. List of patented personal-care products containing silver as an antimicrobial agent.
Table 2. List of patented personal-care products containing silver as an antimicrobial agent.
No.Patent TitleBrief Product DescriptionPatent NumberFiling DateRef.
18Cosmetic and /or medical device for antimicrobial treatment of human skin with silver particlesTechnology in which shaving devices can deposit silver ions unto skin in place of traditional antiseptic medium.DE102012224176A126 June 2014[36]
19Antimicrobial thermoplastic polyurethane for toothbrush and preparation method for antimicrobial thermoplastic polyurethaneAddition of silver nanoparticles into plastic materials which are used to manufacture bristles of tooth brushes.CN103254401A28 April 2013[37]
20Sanitary towel capable of removing peculiar smell and manufacturing method thereofInfusion of silver nanoparticles into fibers of sanitary pads which prevents the growth of odor causing microbes on menstrual discharges.CN102961778A21 November 2012[38]
21Solid oil cosmetics containing antimicrobial Ag zeolites and aluminum chlorohydrateDeodorants and topical creams for the prevention of odor causing bacteria.JP2013071914A22 April 2013[39]
22Antimicrobial agents containing fine silver particle-carrying polypeptides and daikon radish fermentation products, and cosmetics containing themThe invention of a cosmetic lotion preservative consisting of silver nanoparticles.JP2010059132A18 March 2010[40]
23Functional cosmetic including nano silverAddition of silver nanoparticles into manufactured cosmetics for its antimicrobial effect which aids in the prevention of acne and pimples.KR20070119971A21 December 2007[41]
24Antimicrobial contact lenses and methods for their productionContact lenses manufactured from materials infused with silver nanoparticles for antimicrobial effects.US20030044447A16 March 2003[42]
25aSilver-containing antimicrobial fabricTextile material manufactured from fibers embedded with silver nanoparticles.US20050037057A117 February 2005[43]
25bUS7754625B213 July 2010[44]
25cWO20181607087 September 2018[45]
26Breast pump assemblies having an antimicrobial agentSuction cup segment of device coated with silver ion exchange resin to prevent possible microbial contamination into breast milk.US20080139998A112 June 2008[46]
27Nano-silver inorganic antibacterial nutritional hair dyeHair colorant having additional silver nanoparticles as preservatives.CN104224617A27 August 2014[47]
Table 3. List of patented home-use products containing silver as an antimicrobial agent.
Table 3. List of patented home-use products containing silver as an antimicrobial agent.
No.Patent TitleBrief Product DescriptionPatent NumberFiling DateRef.
28Automatic cleaning system for bathtub or pipingA cleaning system attached to a Silver ion generator which flows through hot water inlet pipe which sanitizes bathtubs as a self-cleaning function.JP2009268576A19 November 2009[51]
29Clothes washing machineLaundry washing machine consisting of a silver ion generator which will be released during each wash cycle.US20080041117A121 February 2008[52]
30Air purifier, useful for neutralizing bad smellsAn electronic air cleaning device which draws unclean air through an immobilized silver filter killing any airborne odor causing bacteria.DE102007040742A13 March 2009[53]
31Antibiotic method for parts of refrigerator using antibiotic substanceDistribute silver ions within the fridge to slow the spoilage of food spoilage.US7781497B224 March 2010[54]
32Submersible keyboardA waterproof and washable keyboard with key caps made from plastic embedded with silver ions.US20090262492A122 October 2009[55]
33Bactix silver-based antimicrobial additive in bath aidsBath safety aids made from silver impregnated polymers for long lasting antimicrobial effects.US20130029029A131 January 2013[56]
34Bacteria-resistant grab barDisability support bar paddings made out of silicone rubber impregnated with silver nanoparticles as antimicrobial additives.US20100148395A117 December 2008[57]
35aAntimicrobial reusable plastic or glass containerCollapsible food storage containers mainly for meat or water/wine/milk storage in kitchen composing of an antimicrobial silver fabric as its bottom inner layer.US20070189932A110 February 2006[58]
35bWO2018137725A12 August 2018[59]
36Nano-silver antibacterial glovesDomestic latex gloves impregnated with silver nanoparticles and other antimicrobial elements.CN202738872U20 February 2013[60]
37Natural silver disinfectant compositionsGeneral surface cleaner containing soluble silver salt for added antimicrobial effect.US20100143494A110 June 2010[61]
38Antiseptic solutions containing silver chelated with polypectate and EDTALaundry liquid having aqueous suspension of colloidal silver as additive for its antimicrobial properties.US7311927B225 December 2007[62]
Table 4. List of patented industry and agricultural related products utilizing silver as an antimicrobial agent.
Table 4. List of patented industry and agricultural related products utilizing silver as an antimicrobial agent.
No.Patent TitleBrief Product DescriptionPatent NumberFiling DateRef.
39Method and compositions for treating plant infectionsMethod of applying high valency silver to treat infection in plants of the Rosaceae family.US20120219638A121 November 2011[71]
40Silver yarn, plied yarn silver yarn, functional fabric using same, and method for producingStrong weather resistant rope for agricultural purposes made with polyester and silver-plated fiber yarn to prevent growth of biofilms.CN102439205A2 May 2012[72]
41Silver coated nylon fibers and associated methods of manufacture and useThe method and manufacture of industrialized antimicrobial fabric woven from nylon fibers impregnated with silver.US20100166832A11 July 2010[68]
42Rolling apparatus having plastic parts containing antibacterial and antifungal silver (oxides)Industry scale food grade rollers made from silver impregnated plastic for better hygiene and disease prevention.JP2005201385A28 July 2005[73]
43An antimicrobial food packageFood grade polymer containers with interiors coated with silver nanoparticles to prolong food freshness.WO2014001541A128 June 2013[74]
44Rotationally molded plastic refuse container with microbial inhibiting inner surface and methodIndustry scale plastic garbage container interiorly lined with silver nanoparticles for improved waste treatment.US20080185311A17 August 2008[75]
45aSustained silver release composition for water purificationWater filtration unit containing immobilized silver nanoparticles for water purification purposes.WO2012140520A823 March 2012[76]
45bUS20180186667A15 July 2018[77]
46Method for Producing Antimicrobial Agent Micro-ParticleAn industry cleaning liquid having silver nanoparticles as its active ingredients.JP2007161649A28 June 2007[78]
Back to TopTop