Metal-Based Antibacterial Substrates for Biomedical Applications

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Metal-based antibacterial substrates for biomedical applications Federica Paladini, Mauro Pollini, Alessandro Sannino, and Luigi Ambrosio Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.5b00773 • Publication Date (Web): 17 Jun 2015 Downloaded from http://pubs.acs.org on June 19, 2015

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Metal-based antibacterial substrates for biomedical applications Review article Federica Paladini§#, Mauro Pollini§#, Alessandro Sannino#, Luigi Ambrosio* #

Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy

*Department of Chemical Sciences & Materials Technology, National Research Council of Italy. Piazzale A. Moro, 7, 00185 Rome, Italy

*Correspondence to: Professor Luigi Ambrosio Department of Chemical Sciences & Materials Technology National Research Council of Italy. Piazzale A. Moro, 7, 00185 Rome, Italy email address: [email protected]

§

The names of the first two authors are listed in alphabetic order, indicating their equal contribution to this research work.

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Abstract

The interest in nanotechnology and the growing concern for the antibiotic resistance demonstrated by many microorganisms have recently stimulated many efforts in designing innovative biomaterials and substrates with antibacterial properties. Among the implemented strategies to control the incidence of infections associated to the use of biomedical device and implants, interesting routes are represented by the incorporation of bactericidal agents onto the surface of biomaterials for the prevention of bacterial adhesion and biofilm growth. Natural products and particularly bioactive metals such as silver, copper and zinc represent an interesting alternative for the development of advanced biomaterials with antimicrobial properties. This review presents an overview of recent progress in the modification of biomaterials as well as the most attractive techniques for the deposition of antimicrobial coatings on different substrates for biomedical application. Moreover, some research activities and results achieved by the authors in the development of antibacterial materials are also presented and discussed.

Key words: antibacterial, infection, coating, silver, biofilm.

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1. Introduction

Antibiotics have revolutionized medicine in many aspects and their discovery was a turning point in the human history1. The intensive use of antibiotics during the last 70 years has resulted in the emergence of bacterial resistance to many antimicrobial agents2 and has posed a serious concern to the global healthcare3. Throughout their evolution, bacteria have gradually adapted to resist to environmental stress and have become very efficient in tolerating external insults4. Moreover, bacteria are frequently exposed to non-lethal concentrations of drugs, and this has an important role in the evolution of the antibiotic resistance5. Bacteria can evolve by mutation and can develop several protective mechanisms to reduce their susceptibility to antibiotics6. Mutations leading to antibiotic resistance usually occur in genes encoding the targets of the antibiotic, their transporters, and the regulators that repress the expression of transporters or antibiotic-decontaminating elements7. Antibiotic resistance might arise in bacterial biofilms through genetic processes. In biofilm, bacteria have huge population sizes, thus allowing many new mutations over relatively short time scales8. The formation of biofilm, a structured community of bacteria embedded in a selfproduced polymer matrix of polysaccharide, protein and DNA, helps bacteria to survive and persist within the environment9. For numerous pathogens, biofilm formation is one of the main strategies for bacterial survival in a variety of sites within the human body10. Biofilms constitute a protected mode of growth that allows microorganisms to survival in hostile environments, being their physiology and behaviour significantly different from their planktonic counterparts11. The formation of biofilm begins with the adhesion of planktonic bacteria to the surfaces and develops into three-dimensional structures. Bacteria form a community that adhere, synthesizes extracellular matrix, matures and disperses around the site. Once bacteria adhered irreversibly, the bacterial cells colonize the site and divides12. The intrinsic resistance of biofilm infections to antimicrobial treatment poses additional challenges. While some antibiotic agents such as rifampicin have a reasonable activity against biofilm forming cells, the majority of conventional antimicrobial treatment regimens are not effective against biofilm13. Recent studies have proposed the mechanisms responsible for resistance to antibiotics. Biofilm growth is associated with an increased number of mutations leading to generation of antibioticresistant phenotypes of bacteria. The exopolysaccharide matrix produced also contributes to an increased cell survival by reducing the antimicrobial diffusion speed. Moreover, differences in bacterial density throughout the biofilm determine gradients of nutrients and oxygen availability, thus resulting in different metabolic activities among bacteria14.

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Resistance to antimicrobial agents is the most important cause of non-effective therapy of biofilmassociated infections and, importantly, it is multifactorial15. According to the National Institutes of Health, up to 80% of human bacterial infections involve biofilm-associated microorganisms. Common human diseases, such as dental caries and periodontitis, are caused by biofilm-forming bacteria. Biofilm formation has been implicated in persistent tissue infections such as chronic wound infection, chronic otitis media, chronic osteomyelitis, chronic rhinosinositis, recurrent urinary tract infection, endocarditis and cystic fibrosis-associated lung infection16. Biofilm can include bacteria, fungi, protozoa-associated bacteriophages and also viruses17-19. Bacterial, fungal, or mixed biofilm attached onto temporarily or durably implanted biomedical devices and implants leads to relevant infections17, 20. In the management of catheter-related infections (CRI), even if some measures are taken to avoid the biofilm generation, in some cases infections are so aggressive or persistent that the catheter removal and prolonged systemic antibiotic treatment result necessary, thus complicating the clinical condition of the patient and the medical assistance21. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most critical causes of healthcare-related or community-related infections, because of the multiple resistances to antibiotics and the toxins produced22. Pseudomonas aeruginosa is a gram-negative pathogen responsible for nosocomial infections such as pneumonia, bacteremia and urinary tract infections (UTIs)23. After prolonged use, BF formation on any urinary device is the rule rather than the exception. Such colonizations are mostly monobacterial with multiresistant organisms. Because these urinary devices are temporary, their use can be continued even after BF colonization, with appropriate antibiotic cover for prevention of planktonic form disseminations24. Oral bacteria have also evolved to biofilms formation on hard tooth surfaces and dental materials. The antibiofilm effect of materials used for the restoration of oral function can affect oral health25. Today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistances. Drug resistance presents an ever increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs26. Hence, the prevention of potentially infections caused by colonized biomaterials remains a key motivation for the development of antimicrobial surface coatings20.

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2. Antimicrobial agents: availability, efficacy and costs

Antibiotic-resistant infections kill around 25,000 patients in Europe each year and represent a global cost in the European Union (EU) of around €1.5 billion per year27. Despite the progress in medicine, infectious diseases caused by fungi, viruses, bacteria, and particularly by multidrug resistant bacteria, still remain a serious threats to public health28-30. Novel classes of antimicrobials are necessary to address the challenge of multidrug-resistant bacteria31, and various efforts have been made at this purpose to develop new antimicrobials with novel modes of action32. The development of a new antimicrobial drug starts by identifying an essential target for the microorganism33. The main challenge of a rational design of new drugs based on protein receptor active sites is the identification of this site and of the molecules that bind to it34. A number of new antimicrobials and an array of choice for the treatment of many infectious diseases came into clinical use in the 20th century35, when mainly synthetic derivatives of naturally produced antibiotic molecules and also a few entirely synthetic compounds have been largely adopted36. So, entire bacterial communities became exposed to antibiotics and in turn evolved towards a rapid resistance development36. Although the problem of the antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades37 and little serious progresses have been reached so far38. The lack of new and effective antibacterial compounds is due to several factors, such as the difficulty to find new antibacterial compounds with good pharmacological profiles and low toxicity. Moreover, from an economic point of view, pharmaceutical companies are more interested in developing drugs for chronic conditions than for short-term treatments39. The total cost for the development of a new anti-infective drug is estimated to be €500–800 million and usually requires more than 4–6 years after the first administration to human beings40. For more than 50 years, natural products have been employed in combating bacterial and fungal infections. Most antibiotics are natural products of microorganisms, semisynthetically produced from natural products, or chemically synthesized based on the structure of the natural products41. A multidisciplinary approach to drug discovery and the exploration of the nature as a source of novel active agents is strongly encouraged today42. Recently, there is a great tendency towards natural products and phyto-chemicals in medicine and industry to over-come antibiotic resistance and to reduce the toxicity of the synthetic drugs43. Natural products have been the reference point for anti-infective drug discovery since the early days of the antibiotic era. Then, natural resources have been abandoned in favour of synthetic chemistry and the drug discovery sector has turned increasingly to synthetic molecules44, 45. The generation of

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novel molecular diversity from natural product sources, combining synthetic methodologies and including the manipulation of biosynthetic pathways, can offer solution to the current productivity crisis in discovery and development of drugs42. Important aspects will be the diversification of screening libraries to include new natural products and the definition of effective concentrations at their target sites within the bacterial cell40. Natural products are both a fundamental source of new chemical diversity and an integral component of the pharmaceutical compendium46. Research into natural products has demonstrated significant progress in the discovery of new compounds with antimicrobial activity. In fact, nature is a generous source of compounds with the potential to treat infectious diseases and the systematic exploration of fauna and flora could provide additional antimicrobial leads and new drugs47. As an example, the rich chemical diversity in plants makes them a potential source of antimicrobials. Many in vitro studies demonstrated their therapeutic potential of phytochemical products as alternatives to antibiotics48. Plant extracts49, spices50, honey51 etc. has been reported in literature as antibacterial products. Recent research has been also devoted to the antibacterial activity of curcumin52, garlic53, and aloe vera54. Other natural bioactive agents with broad-spectrum antimicrobial properties are Copper, Zinc Oxide and Silver, either as such or dissolved in form of ion or complexes55. Thanks to the large number of preparation process available and to the novel applications that can be envisaged in several fields, research on nanomaterials containing transition metals is growing tremendously today55. The development of eco-friendly and reliable processes for the synthesis of nanoparticles has attracted considerable interest in nanotechnology56. Nanotechnology approaches using engineered nanoparticles with biocidal properties such as ZnO, Cu and Ag offer novel applications, including control of microbial colonization on diverse surfaces, prevention of biofouling, waste-water treatment, drinking water purification and the topical treatment of infectious diseases57. The antimicrobial properties of these materials have long been recognized. Even if the first biomedical practice of zinc oxide is hardly traceable, it was probably associated to the management of eyes and wounds and to the treatment of skin diseases55; copper or copper compounds were used by Greeks, Romans, Aztecs and others for the treatment of headaches, burns, intestinal worms, ear infections and for hygiene in general58; silver has a long history of usage in medicine in many cultures such as ancient Greeks, Romans and Egyptians, and also many others using silver vessels for water and other liquid storage59. ZnO has been used as an active ingredient in antibacterial creams, lotions and ointments60. Even if application of ZnO nanoparticles is very promising in controlling the spread and colonization in potential pathogens, however the use of ZnO nanoparticles is still limited because it requires the control of synthesis of the NPs and it is also limited to small-scale production61.

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Silver and copper nanoparticles gained importance as novel antimicrobial agent due to their strong antimicrobial properties against a wide range of microorganisms including multidrug-resistant organisms. In comparison with silver, copper is cheaper and the synthesis of copper nanoparticles is cost-effective62. However, the rapid oxidation of copper to CuO and Cu2O on exposure to air causes the conversion to Cu2+ during preparation and storage, so the synthesis of copper nanoparticles in an ambient environment results complicated63. In addition to the difficulties associated to technological aspects, the possible health effects and toxicology of CuO NPs have caused great concern to both the public and scientific researchers64. Even if Cu is one of indispensable elements for maintaining homeostasis in organisms, Cu ions may cause toxicity once they exceed the physiological tolerance range in vivo64. However, as compared to metals like Ag and Au, cytotoxicity of Cu has been less studied65. Among the nanomaterials, silver nanoparticles have proved to be the most effective as it has good antimicrobial efficacy against bacteria, viruses and other eukaryotic microorganisms66, 67. The current investigations support that silver ions or metallic silver as well as silver nanoparticles can be exploited in medicine for burn treatment, dental materials, coating stainless steel materials, textile fabrics, water treatment, sunscreen lotions, etc. and posses low toxicity to human cells, high thermal stability and low volatility68. The role of Ag as a superior antibacterial agent has been established69 and silver release coatings resulted more suitable for the protection of various surfaces against bacterial infection than zinc and copper equivalents70. In fact, AgNPs display enhanced broad-range antibacterial/antiviral properties, and their synthesis procedures are quite cost effective71. Silver ions and silver compounds have been known to have strong antimicrobial activity against nearly 650 types of bacteria and have potential applications in various fields like antibacterial filters, wound dressing materials, etc.72 As the most attractive nanomaterials, silver nanoparticles have been widely used in a range of biomedical applications, including diagnosis, treatment, drug delivery, medical device coating, and for personal health care. Dental instruments, contact lenses, bandages, cardiovascular implants, catheters, wound dressings, bone cements and implants, disease diagnosis and treatment are other example of interesting applications for silver nanoparticles73. Due to the growing interest in nanotechnology and to the increasing number of literature devoted to research in metal nanoantimicrobials, in the next paragraphs a special focus will be addressed to the great potential of metal nanoparticles and particularly on the biomedical application of antimicrobial silver.

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3. Techniques for antibacterial substrates deposition on materials

Different strategies has been developed to control the incidence of infections associated to the use of medical device, however interesting routes are represented by the modification of surface properties and incorporation of bactericidal agents into surfaces of biomaterials for the prevention of bacterial growth and adhesion74. The interest in nanotechnology and in metal nanoparticles such as silver, zinc and copper is growing today as a novel approach to kill or reduce the activity of a wide range of microorganisms75. Antibacterial nanoparticles can be either deposited directly on the device surface or applied in polymeric surface coatings74, and nanosilver in particular is one of the leading nanotechnology materials and products for its unique antibacterial properties76. Physical, chemical, biological and biotechnological approaches are some routes for producing and stabilizing silver nanoparticles. Laser ablation, ultrasonic and microwave assisted reactions and photo-induced syntheses are some example of physical methods through which silver nanoparticles and silver-based nanocomposites can be obtained with excellent antimicrobial properties77; the chemical approach involves the chemical reduction of silver in solution and allows the synthesis of nanoparticles with defined size and morphology77. The surface modification of a biomaterial can be performed through chemical and physical treatments78. Some of the most popular silver deposition techniques are reported in Table 1, along with a brief description of the methods and the references cited in this paragraph.

Table1. Silver deposition techniques adopted for surface modification of biomaterials TECHNIQUE SPUTTERING DEPOSITION

CHEMICAL VAPOUR DEPOSITION

SOL GEL METHOD

PHOTO-CHEMICAL DEPOSITION

DESCRIPTION Energized gas ions strike a target and cause atoms from the target to be ejected with enough energy to travel to and bond with the substrate, forming a functional coating. A reactive gas mixture is introduced in the coating region and a source of energy initiates or accelerates a chemical reaction, resulting in the growth of a coating on the target substrate. The Sol becomes gel through hydrolysis and condensation reactions. Further drying and heat treatment allow the conversion of the gel into a dense ceramic or glass particles. Nanostructured silver coatings are deposited through the in situ photo-reduction of a silver precursor.

REFS. 84-86, 88, 89, 94

97-100

91, 101-104

105-116

Silver thin films can be prepared with different physical and chemical vapor deposition techniques79.

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Cioffi et al. described electrochemical routes for the synthesis of copper and silver nanoparticles by the sacrificial anode technique, employing stabilizing agents to obtain nanometer-sized diameters and narrow size dispersions of the metal particles. The colloids mixed with a solution of an inert dispersing polymer and used to prepare nanostructured composite thin films were demonstrated effective as bioactive coatings obtained through spin-coating deposition80-82. In the same research group, ion beam sputtering (IBS) process has been optimized as deposition method of thin nanoantimicrobial coatings. Indeed, the ion beam co-sputtering of inorganic target of metal (Au, Pd, Cu) or metal oxide (ZnO) and poly-tetrafluoroethylene (PTFE) has been successfully used for the production of multifunctional coatings, which combain the antimicrobial properties of NPs with the water repellence and anti-stain characters of the PTFE matrix83. Water repellence, mechanical, electrical and antibacterial properties are just examples of functionality that can be obtained through sputter coating technologies84. During sputtering, energized gas ions strike a target and cause the ejection and travel of atoms from the target to the substrate, thus forming a functional coating. In recent years, the sputtering technology has opened new horizons in the modification of textile materials and biomedical devices 85, 86. The combination of magnetron sputtering with neutral atom beam plasma source allows the deposition of silver at pressures higher than conventional ion beam treatments. It also offers the advantage to operate at low substrate coating temperatures, thus indicating the possibility to deposit silver coatings on thermally sensitive polymeric substrates. Hence, a range of antibacterial polymer sheet and tube substrates has been developed through the deposition of silver coatings with a thicknesses ranging between 5 and 50 nm87. An additional advantage of magnetron sputtering technique is the possibility to control the size, shape and distribution of metal nanoparticles by changing the preparation parameters such as the power density, operating pressure, plasma atmosphere, substrate temperature, and deposition time88. In a recent work, Uhm et al. investigated the antibacterial properties of Ag nanostructures deposited onto a TiO2 nanotube layer using magnetron sputtering in argon plasma chamber with variable sputtering times for dental and orthopaedic applications88. Magnetron co-sputtering of Ag-containing HA coatings on titanium surfaces was proposed by Chena et al. to improve tissue compatibility and inhibit bacterial adhesion on the implant surface by preserving the mechanical properties of titanium and the bioactivity of the coated HA89. The effectiveness of ion-beam processing such as ion-beam assisted deposition (IBAD) and ion implantation has been described for biomaterials modification and adhesive bio-coatings production. Ion-beam assisted deposition (IBAD) is a vacuum deposition process that involves physical vapour deposition (PVD) and ion-beam bombardment. The IBAD process allows a good

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control of coating microstructure and chemical composition; however, its major limit is its high cost90. This technology has been proposed, for example, in the development of hydroxyapatite (HA) coatings incorporating different concentrations of silver91. In the ion implantation process, ions are accelerated to certain energy and directed toward the surface of the target materials, so that they penetrate the substrates to a depth of several hundred nanometers. Even if advantageous because of good reproducibility and cleanness for medical devices, the process is expensive and inappropriate for devices with complicated geometries90. Ion implantation has been successfully applied to orthopaedic prosthesis for metallic surface treatment and to medical polymers to reduce biofouling90. It has also been demonstrated as a powerful tool to obtain silver-containing stainless steel thanks to precise control for depositing dopant atoms into the substrate and relatively low processing temperature92. Plasma-surface modification techniques such as plasma spray, plasma polymerization and plasma immersion ion implantation & deposition (PIII&D), have been proven to be economic and effective, and have already been widely applied in biomedical industry93, 94. Silver nanoparticles can be incorporated into plasma polymers through a simultaneous deposition of silver and a plasma polymer matrix, involving the use of plasma polymerisation to form a polymeric thin film, and silver sputtering from a silver target95. Favia et al. described the plasma deposition of nanocomposite Ag/PEO-like coatings under certain conditions and in a proper RF plasma reactor where a volatile glycol was fed with argon as buffer gas and silver was sputtered from the silver RF electrode96. Chemical vapour deposition CVD has been widely used in a wide range of industrial applications to produce thin film coatings97. Single layer, multilayer, composite, nanostructured, and functionally graded coating materials with well controlled dimension and unique structure at low processing temperatures can be produced through CVD, even in case of complex shape engineering components98. As an example, the use of a CVD process would permit the coating of convoluted shapes such as tubes and polyurethane catheter surfaces designed to provide antibacterial properties99. When compared with the CVD technique, the sol–gel approach usually results in thicker films which often require post coating annealing100. However, the sol–gel method is a promising alternative technique for depositing antibacterial coatings through the entrapment of a variety of organic and inorganic compounds and biologically important molecules in various matrices101, 102. The sol is prepared with inorganic metal salts or metal alkoxides mixed with water and a mutual solvent in the presence of acid or base catalyst. Thin films can be deposited on different substrates by dip, spin and spray coating. During the sol– gel transformation, hydrolysis and condensation reactions occur and the sol becomes a rigid and

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porous network of gel. With further drying and heat treatment, the gel is converted into dense ceramic or glass particles102. Silver, copper and zinc have been adopted in doped methyltriethoxysilane (MTEOS) coatings and microtitre plate wells were coated with different volumes of liquid sol–gel and cured under various conditions at 50–70 °C70. ZnO thin films were also deposited on glass slide substrates by the sol–gel dip-coating method and the structure and antibacterial activity was evaluated101. Sol–gel based bioactive glasses have been synthesized by Palza et al. with different amount of copper and silver ions. Their results showed that the incorporation of biocide metal ions did not alter the formation of hydroxyapatite and that the bioactive glasses containing biocide metal ions presented strong antimicrobial behaviour depending on the metal used and the specific bacteria tested103. Sol gel is one of the methods used to incorporate silver nanoparticles in the coating because of some advantages such as high purity, homogeneity, and low processing temperatures. However, since the sol is usually applied to the surface by dip or spin coating, a limit of the technology is the dimension of the substrate104. Sannino et al. have developed and patented an effective technology to produce antibacterial products through the photochemical deposition of silver nanoparticles on natural and synthetic substrates for different applications105. Shortly, the method is based on the following three steps. Firstly, the impregnating silver solution is prepared by dissolving silver nitrate as precursor for metal silver in a mixture of methanol and water; then, the silver solution is deposited on the surface of the material through dip or spray coating; after that, the wet material is exposed to an ultraviolet source in order to induce the photo-reduction reaction and the in situ synthesis/deposition of the silver particles on the substrate. The silver coatings obtained are characterized by a strong adhesion to the surface of the material, and by long-term antimicrobial efficacy demonstrated against both bacteria and fungi106. Figure 1 reports scanning electron microscopy (SEM) pictures of untreated (Fig. 1a) and silver-treated (Fig. 1b) textile substrates obtained through the silver deposition technology developed by Sannino et al. The silver treated sample was subjected to several washing cycles in order to demonstrate the durability of the coating. As clearly visible in Fig. 1b, a homogeneous distribution of silver particles on the natural fibres was obtained, and the presence of the silver coating was confirmed even after the washing cycles.

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a

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b

Figure 1. SEM images showing the homogeneous distribution of silver particles deposited on natural textile substrates through in situ photo-chemical reaction (b) in comparison with the untreated sample (a). The presence of the silver coating was confirmed also after ten washings. Moreover, the ease, the versatility and the low-cost aspect are other distinctive features of the process, which can be easily translated on industrial scale and integrated in traditional production lines. The process does not require any special or expensive equipment and can be adapted to any material just by selecting the appropriate process parameters. The percentage of silver used in the preparation of the silver solution, the impregnation method and the UV exposure time can be defined as a function of the nature of the material as well as the application and the antibacterial properties expected. Thus, biomaterials such as catheters107-109, wound dressings106, 110 and surgical sutures111 have been successfully produced for biomedical application. Moreover, other antibacterial materials such as silver treated textile112-114, air filters115 and natural and synthetic leather116, 117 has been proposed by the authors to improve healthcare and to ameliorate the human life.

4. Methods for the analysis of the antibacterial properties

In clinical microbiology, sensitivity testing is difficult because of the increasing number of antibiotics. The sensitivity of bacteria to antibiotics can be tested in vitro in clinical laboratories according to two standard methods118, namely the serial dilution test and the disc test119. In dilution tests the microorganisms are tested for their ability to produce visible growth on series of agar plates (agar dilution) or in broth (broth dilution) containing dilutions of the antimicrobial agent120. Dilution methods, which represent a reference method for antimicrobial susceptibility testing, are used to determine the minimum inhibitory concentrations (MICs) of an antimicrobial

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agent121. For antimicrobial agents such as antibiotics and other substances with bactericidal or bacteriostatic activity, the minimal inhibitory concentration (MIC) is an important in vitro parameter defined as the lowest concentration of the antimicrobial agent at which no microbial growth is visible after overnight incubation under defined conditions. The determination of MIC is crucial in clinical practice in classifying the tested microorganism as clinically susceptible, intermediate or resistant to the tested drug, and also in monitoring the development of antibiotic drug resistance122,

123

. As the definition of the MIC is associated to treatment decisions for

clinicians, careful control and standardization are required for laboratory reproducibility120. In the agar dilution technique, the activity of an antimicrobial agent against bacteria is measured in vitro. Graded amounts of antibiotics are incorporated in agar plates and inoculated with the organism of interest. If the organism is susceptible to the incorporated antimicrobial agent, bacterial growth is observed proportionally to the antibiotic concentration in the agar plate59, 124. The broth dilution protocol uses liquid media with a standardized bacterial suspension and different amounts of antibiotic added. After incubation, the turbidity of the media is analysed as an indication of the bacteria growth 59, 125. Based on the final media of volume, broth dilution can be categorized as microdilution and macrodilution59, 123, 125. The main advantages of commercial microdilution systems include automated reading and rapidity; on the other hand, compared with the disk diffusion method, they have still lower sensitivities in the detection of resistance mechanisms. Since Bauer, Kirby et al. described disk diffusion in 1960s, this technique has been the point of reference for antimicrobial susceptibility testing in many clinical microbiological laboratories and still remains one of the most widely used methods in routine clinical microbiology laboratories127. The method is versatile for testing the majority of bacterial pathogens and it does not require any special equipment125, 128. Moreover, it is simple and practical and well-standardized125. The method involves the application of antibiotic solutions of different concentrations to cups, wells or paper discs, placed on the surface of or punched into agar plates seeded with the test bacterial strain129. With the diffusion of the antibiotic and the formation of an antibiotic concentration gradient into the adjacent medium, after 18-24 hours of incubation, a zone of inhibition of bacterial growth appears depending on the effectiveness of the antibiotics. The size of the inhibition zone provides an indication of the potency of the antibiotic and the MIC130. The antimicrobial gradient diffusion method is used to establish the antimicrobial concentration gradient in an agar medium. The concentration scale is indicated on the upper surface of thin plastic test strips impregnated with a dried antibiotic concentration gradient and placed on an agar plate inoculated with a standardized organism suspension. After overnight incubation, the strips are

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observed and the MIC is determined by the intersection of the lower part of the ellipse shaped growth inhibition area with the test strip125. A variety of techniques to evaluate bacteria viability has been established to determine the effectiveness of nanoparticles (diameter 100 nm) as antimicrobial agents131 and to evaluate the antimicrobial properties of antimicrobial surfaces. Agar diffusion test, inhibition zone test, microbial count test are some example of characterization techniques. In literature no standard method is advocated for the evaluation of the antimicrobial properties of medical devices and industrial products and many of the testing methods have also been modified by the test institute in terms of test organisms used, exposure times, incubation time and nutrient media132. However, some standard methods widely employed in the characterization of antimicrobial materials are described in ASTM E-2149 (American Society for Testing and Materials, 2001), JIS 2801 (Japanese Standards Association, 2000), zone of inhibition (ZOI) method, live–dead fluorescence staining and growth-based methods133. ASTM E2149-01 describes a test method for the determination of the antimicrobial activity of treated specimens under dynamic contact conditions. Samples are shaken in a concentrated bacterial suspension for one-hour contact time or other as defined by the investigator, so ensuring a good contact between bacteria and the substrates. Then, the suspension is serially diluted before and after contact and cultured. The number of viable organisms in the suspension is determined and the percentage reduction is calculated based on initial counts and untreated controls134. The testing method reported in the Japanese Industrial Standard (JIS Z 2801:2000) is one of the most common methods to assess surface antimicrobial efficiency of many products. In this test, surfaces (about 50mm × 50mm) are placed in a Petri dish and inoculated with a suspension of either E. coli or S. aureus in a nutrient broth. The bacterial suspension is then covered with a film (about 40mm × 40mm) and pressed to spread the inoculum over the film. The Petri dish is covered and incubated for 24 h at 35°C under controlled humidity. The test piece and covering film are washed and the viable bacteria in the washing solutions are counted135, 136. The general method described in ‘AATCC Test Method 100-1999, Antibacterial Finishes on Textile Materials: Assessment of’ reports the protocol for the measurement of the qualitative and quantitative antibacterial tendency of textile materials. As described in the AATCC Test Method, the textile materials are inoculated with bacteria; after incubation, the bacteria are eluted from the swatches using known volumes of extraction solution and counted. The reduction percentage by the treated specimen was calculated and used for comparison137. In 1966 Bauer et al. published a description of the standardized single-disk method for performing antimicrobial susceptibility test. The method provides the measurement of the zone of inhibition (ZOI) to bacterial growth by

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holding a ruler on the underside of a petri dish where the testing materials are placed on bacteriainoculated agar plate59,

138

. Similarly, a standardized method based on agar diffusion tests is

reported in the Swiss Standard SNV 195929-1992. The protocol consists in evaluating the width of the inhibition area to bacteria growth around and beneath the samples after incubation in contact with bacteria. The antibacterial efficacy of the testing samples is determined by evaluating the levels of antibacterial capability reported in the Standard. ZOI larger than 1 mm indicates a good antibacterial activity of the sample; if the sample is totally covered by bacteria its activity is labelled as insufficient. There also some intermediate degrees, defined as function of the ZOI dimension113. The increased use of fluorescent probes and the improvements in the quantitative and qualitative sensitivity of instruments have encouraged the use of fluorescence-based methods in a wide range of applications from industrial to environmental microbiology. The method, based on the detection of the presence of active functions or the integrity of cell structures, allows the determination of active, inactive, dead and intact cells139.

5. Applications of antibacterial products as biomaterials: actual and perspectives Nowadays, both academic research and industry are interested to the potential of antimicrobials in providing materials and products with improved quality and safety140. As an alternative to common bactericides used today, great attention has been addressed to antibacterial polymers due to their low production costs and multiple applications141, 142. The development of intrinsically antimicrobial polymers represents a novel and promising approach to reduce the emergence of drug resistant bacteria in biofilm and to contain biofilm-associated infections143. Polymeric materials with antimicrobial activity can exhibit antimicrobial capability by themselves, through chemical modifications or through the incorporation of antimicrobial organic compounds and active inorganic systems144. Antimicrobial polypeptides, for example, are characterized by the low capability to develop bacterial resistance due to their capability to bind with the bacterial wall and lead to the formation of membrane pores145. Chitosan is a natural biocide with capability in preventing bacterial growth. The bactericidal mechanism is associated to the interaction between the positively charged chitosan molecules and negatively charged microbial cell membranes, which results in the alteration of the cell permeability or disruption of the membrane integrity144. Two of the most widely studied classes of antimicrobial polymers

are

quaternary

ammonium

and

pyridinium-based

materials142;

Poly[2-(tert-

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through physical anchorage146. Indeed, some approaches involve the temporarily entrapment of biocides within the polymer matrix, other are based on the permanent attachment to the chains or the preparation of polymers with antimicrobial groups140. In comparison with those obtained by physical entrapment or coatings, polymers containing covalently bonded antimicrobial moieties present some advantages in terms of permeation of the low-molecular-weight biocides from the polymer matrices147. The polymerization of monomercontaining biocide groups, the grafting of antimicrobial agents into natural or synthetic polymers and plasma-based technologies are some approaches towards the preparation of bioactive materials for potential use in many applications148-150. Films formed by blending chitosan and PEO have been studied by Zivanovic et al. as potential antimicrobials for active packaging materials in food industry and for controlled release of active components in pharmaceutical industry. However, the influence of chitosan fraction on the properties of PEO in terms of crystallization, mechanical behaviour and permeability was demonstrated151. Also blends chitosan-polyester poly(ε-caprolactone) (PCL) were investigated by some authors in terms of anti-bacterial properties and changes in physicochemical properties of chitosan upon blending with. The degree of crystallinity of PCL resulted reduced and the surface roughness was significantly increased at nanoscale152. In the area of health care and hygiene, biocidal polymers may be incorporated or extruded into fibers and used in many biomedical applications such as sterile bandages and clothing, surgical gowns and coatings for implantation devices140,

153, 154

; another recent route emerging for the

production of a broad range of antimicrobial polymer nanocomposites is the incorporation of metal nanoparticles such as copper and silver into the polymer matrix. Polymer-metal nanocomposites can be prepared by in situ synthesis of nanoparticles or through the direct addition of the metal nanofiller dispersed into a thermoplastic matrix148, 155. Indeed, nanotechnologies and nanomaterials have opened new therapeutic horizons in medical research156 and innovative technologies are rapidly advancing for the development of new antifouling, bactericidal or antibiofilm biomaterials157. Efforts in the definition of new strategies in modifying the nanotopography of surfaces have been recently addressed to the fabrication of new generations of bactericidal biomaterials through surface coatings or surface chemistry modifications158. Infection-resistant materials can be obtained by modifying the biomaterial surface to give anti-adhesive properties, by doping the material with antimicrobial substances, and by combining anti-adhesive and antimicrobial effects in the same coating156. Microbial contamination continues to be a serious concern related to implantable and semi-implantable medical devices and healthcare products. The achievement of low bacterial adherence may also be important for

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enhancing the infection resistance of the surfaces159, so anti-biofilm coatings designed to modify the surface of medical devices for enhanced inhibition of bacterial adhesion and/or growth can lead to resistance to biofilm formation160. The modern nanotechnology has facilitated the production of silver nanoparticles with low toxicity to human and greater efficacy against bacteria. Nanoparticles are attractive alternative to antibiotics by showing improved activity against multi drug resistant bacteria161. Nanoparticles have emerged as one of the most effective antibacterial agents due to their large surface area to volume ratios. They can be used as effective growth inhibitors of various microorganisms162. Among anti-infective strategies, silver nanoparticles (AgNPs) are attracting interest for their multifaceted potential biomedical applications163. Used in dentistry for over a century, silver compounds have been demonstrated effective in prevention and arrest of caries in primary and permanent teeth164. Applied as oral antibacterial materials in form of dental restorative material, endodontic retrofill cement, dental implants, caries inhibitory solution and mouthwash, AgNPs can be used to prevent and control dental caries and periodontal disease165, 166. In dental caries management, Sevinc et al. demonstrated that the incorporation of nanosilver in dental materials was more effective than dental composites containing 10% nanozinc in reducing bacterial counts and biofilm growth, with lower detrimental effects on the colour than composite resins167. Antibacterial coatings have been designed to prevent the initial adhesion of bacteria onto the implant surface such as titanium implants168. Titanium is the most widely used material in dental and orthopaedic implants, because of the excellent properties of osteointegration. However, infection prevention is a continuous challenge as Ti is non-antibacterial inherently169 and also because of the diversity of bacterial ecosystems168. For prosthetic applications in orthopaedics and dentistry, silver nanoparticles (AgNPs) with a narrow size distribution have been synthesized by De Giglio et al. through a green procedure and immobilized on Ti implant surfaces exploiting hydrogel coatings’ swelling capabilities170. The research performed by Secinti et al. revealed that nanoparticle coatings of silver ions on artificial surfaces inhibit biofilm formation, without inducing toxicity and adverse effects on kidney, liver, brain or cornea171. The results of the studies performed by Morita et al. suggested that Ag ion coating on pure titanium and stainless steel wires inhibited the growth and pathogenic activities of oral cariogenic and periodontopathic bacteria, thus suggesting important evidence for future applications of simple Ag ion-coated dental materials and orthodontic appliances172. The results obtained by Ciobanu et al. demonstrated that silver-doped hydroxyapatite nanoparticles can offer an effective alternative to antibiotic treatments, exhibiting a specific spectrum of antimicrobial activity against both gram-positive and gram-negative bacteria173, 174. Recent works

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also suggested a combined strategy involving biomimetic approach and silver reduction process to deposit hydroxyapatite/silver layer on polyurethane scaffolds for the regeneration of the natural bone and the control of implant infections175. Co-substitution of both zinc and silver ions in HAp has also been proposed by some authors. Indeed, zinc can stimulate bone formation in low concentration and also reduce the costs of the device. Moreover, silver has demonstrated synergistic antibacterial activity with other antimicrobial agents, antibiotics and metal ions176,

177

.

Heterostructure nanoparticles ZnO-Ag/CNCs have also been synthesized and proposed by Azizi et al. for their promising applications in the pharmaceutical and nanocomposite fields because of their strong antimicrobial ability and high thermal stability178. A promising method to combine silver nanocomposites with natural compounds such as curcumin has been developed as novel antimicrobial agents for applications in medicine and particularly in wound/burns dressing179. The use of silver-containing dressings plays an important role in the reduction of wound bioburden180. Used in form of silver nitrate in the 17th and 18th centuries for the treatment of ulcers, in 1960 silver was introduced in the management of burns181. There is a range of commercially available silver dressings today, which have been shown to have a sustained, broad-spectrum antimicrobial activity against a range of clinically relevant microbes180,

181

. The application of Ag NP-based

dressings, even for a prolonged time, does not seem to negatively affect the proliferation of fibroblasts and keratinocytes, leading to the restoration of normal skin181. Silver nanoparticles can also promote the rate of wound closure by promoting proliferation and migration of the keratinocytes at the wound site. Also, silver nanoparticles can induce the differentiation of fibroblasts to myofibroblasts resulting in faster wound contraction182. Novel wound dressings have been recently developed by the authors of this review through the photochemical deposition of silver nanoparticles. The results obtained indicated that the silver deposition technology adopted allows a permanent silver coating with durable antimicrobial properties on a wide range of microorganisms including Gram-positive, Gram-Negative bacteria and also fungi 106, 110

. Other textile substrates have been developed for biomedical applications as well as improved

daily comfort, such as silver treated cotton, flax and wool110,

112-114

. Interestingly, the textile

materials developed demonstrated good antimicrobial efficacy even when treated with very low percentages of silver precursor and no effect of skin irritation and hypoallergenicity was observed in vivo115. Silver-based compounds, triclosan, silane quaternary ammonium compounds and zinc pyrithione are antimicrobials currently used in textiles183. Current textile products have been progressed and designed to control the growth and proliferation of microorganisms. Novel antimicrobial textiles are receiving great impulse because of the demand for improved hygienic conditions and for specific

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devices contributing to prevent pandemic diseases55. Among natural fibres, cotton textile has been often selected for silver deposition because it is a suitable substrate for both common and medical clothing55. Efficient, non-toxic, durable and cost effective antimicrobial cellulose fibres have been developed by Raghavendra et al. through the introduction of silver for applications in medical field184. Many other works reported in literature have been devoted to the development of functional nanotextile obtained by using inorganic nanoantimicrobials such as silver185-187, copper188, 189 and zinc190, 191. In general, a dressing has the functions to protect the wound, to promote the healing process and to provide, retain or remove the moisture. The development of innovative biomaterials capable of preventing bacterial infection, of draining exudates and of promoting wound healing is very challenging today192. In this regard, hydrogels are a very interesting class of materials widely accepted as wound dressings for the treatment of severe burns193. Hydrogel are obtained from three-dimensional natural or synthetic polymer networks with high degree of water content and can be loaded with antibiotics, metal nanoparticles, antimicrobial polymers and peptides, thus providing a moist environment and antimicrobial activity at the same time for application as medical implants coating, wound healing and skin infection treatment194-196. Moreover, hydrogel loaded with antimicrobials can be developed as stimuli-responsive polymeric coatings, where the release of the antimicrobial agent can be triggered for example by pH variations associated to bacteria growth or by ion-exchange mechanisms145, 197. Silver-releasing biomaterials obtained by self-assembling peptides and silver nanoparticles synthesized in situ have been proposed as an excellent biomaterial with low silver content, sustained silver nanoparticle release and biocompatibility for applications in wound healing198, 110. Antioxidant acacia gum and mucoadhesive carbopol hydrogels have been explored by Singh et al. in designing new hydrogel wound dressings for slow release of gentamicin199. Polyvinyl alcohol (PVA) hydrogels have been recognized as materials for potential use in burn healing. Silver nanoparticles synthesized within PVA hydrogels and silver sulfadiazine incorporated within PVA have been developed as barriers to microbial penetration, for antimicrobial topical applications and potential use in burn dressing200, 201. Novel burn wound dressing containing silver nanoparticles in a 2-acrylamido-2-methylpropane sulfonic acid sodium salt hydrogel were demonstrated effective against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus202. Nanocomposites consisting of genipin-crosslinked chitosan, poly(ethylene glycol), zinc oxide and silver nanoparticles have been prepared for biomedical applications as antibacterial wound-dressing films based on both swelling and antibacterial characteristics203. Nanosilver incorporated in

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PVP/alginate polymer matrix showed ability to prevent fluid accumulation in exudating wound and strong antimicrobial capability193. In vitro studies by Wu et al. demonstrated that nanostructural silver nanoparticles/bacterial cellulose gel membrane was a promising biomaterial as antimicrobial wound dressing with good biocompatibility to promote scald wound healing204. Brogliato et al. demonstrated that nylon threads coated with metallic silver had a satisfactory antimicrobial effect in vitro and that the dressings did not induce systemic silver absorption, toxicity in kidneys and liver and were not detrimental to the normal wound-healing process for prolonged use205. Multilayered silver-functionalized star PEG-heparin hydrogels combining antiseptic and hemocompatible properties have been developed as a versatile surface coating to fight the infection of blood contacting medical products such as central venous catheters. Specifically, a silver-free starPEG-heparin layer on top of an AgNP containing starPEG-heparin layer resulted in a hemocompatible material with durable antimicrobial functionality206. Hydrogels impregnated with nano-sized silver particles have also been proposed as effective antimicrobial lens or lens case for the reduction or elimination of infectious or inflammatory adverse responses associated to the presence of microorganisms207. Along with the applications cited above, the hydrogels have also been developed to modify the surface of urethral and urinary catheters in order to reduce the risk of encrustation, friction, protein adsorption and bacterial adhesion208,

209

.

Because of their clinical and economic significance, a variety of preventive

measures have been assessed in the treatment of urinary catheters with antimicrobial compounds. Antibiotics and antiseptics have been used as coating with different degrees of success, and literature also supports the use of catheters coated with silver alloy/hydrogel in different clinical settings210. Silver impregnated catheters showed significantly lower infection rates when compared to non-impregnated catheters211. However, even if introduced in USA about 10 years ago and about five years ago in UK, the use of silver-coated urinary catheters has been sporadic in clinical practice, probably because of cost implications212. Silver-coated catheters with long-term antibacterial capability and advantageous cost/effectiveness ratio have been developed by Sannino et al. At this purpose, the silver deposition technology described above and based on the photochemical deposition of silver nanoparticles has been applied to polyurethane catheters for haemodialysis. One of the most interesting and promising features of the technology adopted is represented by the possibility to deposit silver also onto the luminal surface of the device. Another important advantage is related to the economic aspect of the treatment. In fact, very low percentages of silver deposited on the surface on the material are able to eradicate the bacterial biofilm and to prevent the bacteria colonization of the device even for

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prolonged periods, with very low values of silver ion release and with no significant effect of cytotoxicity107-109. In Figure 2 a pilot plant specifically designed for the treatment of the catheters is reported. The system allows the treatment of four catheters at the same time and consists of two boxes respectively for the dip coating and UV irradiation of the devices (Fig 2a-c). The catheters were dipped into the first stainless steel box containing the solution made of silver nitrate dissolved in methanol or in a mixture of methanol and water (Fig. 2b); then, the catheters were placed into the second box containing UV lamps (Fig. 2c) and exposed to UV irradiation in order to induce the photo-reduction of the silver precursor and the in situ synthesis/deposition of silver nanoparticles on the surface. The treatment of the inner surface was obtained by means of a syringe through which the solution was forced to flow inside the device. In Figure 2d, a picture of a silver-treated catheter and untreated catheter is reported.

Figure 2. Pilot plant designed for the treatment of four catheters at the same time (a); immersion of the catheter into the box containing the silver solution (b); UV exposure of the catheters (c); silvertreated catheter showing the darkening of the surface in comparison with the untreated catheter (d).

At present, more research activities are also addressed by the authors to the development of silver coatings on urinary catheters, and some interesting results have been already achieved. However, further studies are in progress for the evaluation of the effectiveness of the silver coatings against a broad range of microorganisms.

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6. Conclusions and future perspectives

A concise overview of the progress in research devoted to the development of novel antimicrobials have been provided in this review article. Efforts on the definition of new drugs and technologies to incorporate antimicrobial substances in biomaterials have been recently stimulated by the necessity to overcome the growing concern for the antibiotic resistance of many microorganisms and the risk of infections associated to the clinical use of medical devices. The large number of academic studies cited and the different applications mentioned in this work demonstrate the importance of novel approaches in the management of infections. Nanotechnology and nanoantimicrobials, in particular, open new horizons in medical research and have been presented by the authors as one of the most attractive approach for the production of effective antibacterial substrates. However, the rapid expansion of nanotechnology and the increasing number of products based on nano-sized materials have also emphasized the concerns about the potential effect of nanoparticles on human health213. Nanotoxicology is emerging as sub-discipline of nanotechnology and refers to the study of interactions of nanostructures with biological systems214. Although not yet fully elucidated, the link between the toxicity of nanomaterials and their small size has been assessed and related to their reactive surface area and the ease to enter the human body, cross biological membranes and accessing cells, tissue and organs214. Size, dose, exposure time, shape, surface chemistry and cell types are important factors in mediating cellular responses. A proper cell model for studying the biological effects of AgNPs in vivo still remains a challenge215, 216. Because of the different possibilities in the synthesis of nanoparticles, the different sizes, the presence or absence of capping agents, and the diverse kinds of toxicity evaluation tests, a trend in citotoxicity and genotoxicity of silver nanoparticle is very hard to determine. Moreover, additional difficulties in the evaluation of genotoxicity are related to the different cell cultures, organisms or animals. Some authors demonstrated that the most resistant organism to genotoxicity is human cell cultures; silver nanoparticles exhibit lower toxicity in comparison with silver ions and the nanoparticle encapsulation lowers its toxicity217. However, the genotoxic studies have not yet elucidated the possible connection between the DNA binding properties of NPs and their genotoxic potential218. The size-dependent cytotoxicity of AgNPs was recently investigated and only the 10 nm particles affected the cell viability of human lung cells through a mechanism associated with intracellular silver release. Particle agglomeration in cell medium, cellular uptake, intracellular localization and Ag release were studied and, even if different agglomeration patterns were observed between silver nanoparticles coated with PVP and citrate, no evident difference was observed in the uptake or intracellular localization of the citrate and PVP coated AgNPs219.

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Differences in toxic concentrations between nanoparticles of different sizes have been observed as well as higher toxicity in silver ions than silver nanoparticles; however, for both silver ions and silver nanoparticles, the concentrations for cytotoxicity were considered much higher than those reported for antimicrobial activity. This indicates a margin of safety between exposure for antimicrobial applications of silver nanoparticles and adverse effects on human cells. Also the addition of silver onto implantable medical devices for antibacterial applications resulted in greater toxicity towards bacteria than towards human cells220, 221. Although some authors assessed the cytotoxic and genotoxic potential of AgNPs even at small concentration, in other works toxic effects to mammalian cells were associated to very high doses of nanoparticles, i.e. only in cases of accumulated nanosilver in specific organs222, 223. This indicates that, despite the rapid progresses in nanobiotechnology, the potential for adverse health effects due to prolonged exposure at various concentration levels in humans and environment has not been established yet223. Public debate on the toxicological and environmental effects of direct and indirect exposure to metal-based antimicrobial materials is emerging and there is still a critical lack of understanding in environmental and ecotoxicological studies224, 225. Toxicity of metal nanoparticles to aquatic organisms seems to be related to their physical and chemical properties and to processes of dissolution, aggregation and agglomeration of the particles in aquatic media. Although the production of these particles has increased considerably in recent years, data on their toxicity on microalgae still remain insufficient226 and also, concentration and form of nanomaterials in the environment are difficult to quantify225. Although metal-based antimicrobials hold great promise, their potential for toxicity in humans limits their current use224.

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Moreno-Garrido,

I.;

Pérez,

S.;

Blasco,

J.

Mar.

Environ.

Res.

2015,

doi:

10.1016/j.marenvres.2015.05.008.

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