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Applications and challenges of smart antibacterial coatings
CHAPTER 20
Applications and challenges of smart antibacterial coatings Debirupa Mitra, En-Tang Kang and Koon Gee Neoh Department of Chemical and Biomolecular Engineering, National University of Singapore, Kent Ridge, Singapore
Contents 20.1 Introduction 20.1.1 Bacterial contamination: a global concern 20.1.2 Smart antibacterial coatings: a promising approach 20.2 Smart antibacterial coatings for various applications and their associated challenges 20.2.1 Medical devices 20.2.2 Healthcare facilities 20.2.3 Textiles 20.2.4 Food packaging 20.2.5 Water treatment and industrial equipment 20.3 Conclusion References
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20.1 Introduction 20.1.1 Bacterial contamination: a global concern The attachment of bacteria to surfaces and their subsequent colonization leads to several undesired consequences. One of the most detrimental consequences is the occurrence of hospital-associated infections (HAIs) in patients, which results in high morbidity and even mortality. According to the Centre for Disease Control and Prevention (CDC) on any day one out of three hospitalized patients has at least one HAI. There were an estimated 687,000 HAIs in US acute care hospitals in 2015 and B72,000 hospital patients with HAIs died during their hospitalizations [1]. It has been reported that 45% of HAIs are associated with bacterial colonization of implants or medical devices [2]. Implant infections are often accompanied by biofilm formation on the implant surface, and these infections are Advances in Smart Coatings and Thin Films for Future Industrial and Biomedical Engineering Applications DOI: https://doi.org/10.1016/B978-0-12-849870-5.00013-6
© 2020 Elsevier Inc. All rights reserved.
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resistant to antibiotics and host defenses and frequently persist until the implant is removed, which is the standard therapy [2]. Apart from insertion of implants and other invasive medical procedures, the inanimate environment in healthcare facilities also contributes to the spread of HAIs [3]. Infection can spread to patients via contact with bacteriacontaminated surfaces. Cross-contamination among patients may also occur via healthcare workers who are, in turn, in contact with these surfaces. In addition to different prone-to-contamination surfaces (e.g., bedrails, bedside tables, equipment, and wash faucets), hospital textiles provide an excellent substrate for bacterial colonization at appropriate temperature and humidity [4]. Patients shed bacteria and contaminate their apparel and bed sheets, following which the bacteria proliferate. Furthermore, bed making in hospitals releases large quantities of microorganisms into the air, which contaminate the immediate and nonimmediate surroundings, thereby contributing to HAIs. Another major health concern is bacterial contamination of food. With food production becoming increasingly automated, the number of food-contacting surfaces and, hence, the potential for cross-contamination has substantially increased [5]. Although these surfaces are sanitized, a clean surface can get soiled instantaneously by any contaminated product leading to cross-contaminations throughout the remaining processing run. Microbial contamination is, thus, a challenge to food safety, quality, and security. Bacterial contamination of drinking water is another important problem, especially in developing or underdeveloped countries. Drinking water may be contaminated anywhere between its source and point-ofuse by a contaminated water-contacting surface, and this is often the cause of widespread, water-borne diseases [6]. In a different scenario, bacterial attachment to marine vessels, water pipes, and other industrial watercontacting equipment has been a long-unsolved problem that causes biofouling [7]. Biofouling is often associated with biofilms and subsequent bacteria-mediated corrosion that results in shorter service life and increased energy and maintenance costs in marine and other industries. It is, therefore, evident that bacterial contamination of surfaces is undoubtedly an issue of global concern and potential remedies are of utmost necessity. A promising approach is the use of antibacterial coatings that either inhibit the adhesion of bacteria (antiadhesive) and/or exhibit bactericidal properties. Antiadhesive coatings prevent nonspecific interactions between the surface and the biological environment, thereby inhibiting bacterial attachment and biofilm formation in the early stages after
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contact. However, “perfectly” antiadhesive coatings are extremely hard to achieve and, hence, they inevitably become contaminated [8]. On the other hand, bactericidal coatings are capable of reducing the bioburden by effective killing of bacteria, but are generally prone to accumulation of dead bacteria.
20.1.2 Smart antibacterial coatings: a promising approach A number of bactericidal coatings have been developed over the past few decades that have been shown to be effective against a wide range of bacteria under laboratory testing. Traditional bactericidal coatings exhibit continuous activity, which may not be necessary in the absence of harmful doses of bacteria. Additionally, in certain scenarios, continuous activity can lead to adverse effects of the biocide on the surrounding environment. For example, in the absence of an infection, high amounts of released biocide from an implant surface may induce undesired immune response or even local toxicity. Thus the ideal coating would be one that exhibits activity only when required such as in the presence of significant bacterial colonization and remains “inert” otherwise [8]. As mentioned in Section 20.1.1, another limitation of traditional bactericidal coatings is the accumulation of dead bacteria on the surface that results in cloaking of the biocidal moieties and progressive loss of efficacy. An ideal antibacterial coating should possess bacteria-releasing characteristics or “self-cleaning” to avoid accumulation of dead bacteria on the surface. To realize such ideal antibacterial coatings, the development of “smart” coatings has garnered much research interest. While the definition of smart coatings is broad and not yet standardized, smart antibacterial coatings in this chapter would be considered as those capable of exhibiting or altering their antibacterial activity in response to a stimulus. There are two types of smart antibacterial coatings. The first are coatings whose bactericidal activity is triggered in the presence of one stimulus or several stimuli. This is mostly realized through the triggered release of loaded or encapsulated biocides. Examples of released biocides include antibiotics, antimicrobial peptides (AMP), metal (or metal oxide) nanoparticles (NPs), quaternary ammonium compounds (QAC), cationic dendrimers, and hydrogen peroxide [8]. Activity could also be achieved through a stimuli-responsive generation of reactive oxygen species (ROS) or conformational changes of a grafted biocide. The second kind of smart antibacterial coatings are those capable of “switching” or altering their
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antibacterial activity in response to stimuli. A classic example is the “kill and release” coating, which can switch between bactericidal and bacteriareleasing functionalities wherein the stimulus acts as the trigger for the switch. For either kind of smart antibacterial coating, possible stimuli include pH, temperature, light, magnetic field, electric field, mechanical force (pressure or touch), ultrasound, ionic strength, and concentration of biochemical agents (i.e., chemicals secreted by bacteria or chemicals present inside the human body at a particular site of infection such as enzymes, glucose, toxins, urea, etc.) [9]. Among these, the most commonly investigated stimulus in the design of smart antibacterial coatings is pH, followed by temperature, light, and biochemical concentration.
20.2 Smart antibacterial coatings for various applications and their associated challenges 20.2.1 Medical devices Prevention of device or implant-associated infections is purportedly the most important application of smart antibacterial coatings. A significant amount of smart coating research so far has been dedicated to potential application in medical devices. Bacterial infections are almost always associated with reduction in environmental pH due to the secretion of acidic metabolites, following which the pH at the site of infection can be reduced to as low as 5.5 [10]. This difference between physiological pH (7.4) and acidic pH at the site of infection is, hence, the most commonly capitalized trigger to initiate antibacterial activity from the smart coating. From a materials perspective, pH-responsive coatings are often fabricated using carboxyl group containing polymers in combination with cationic moieties forming layer-by-layer (LbL) coatings or electrostatically-complexed hydrogel coatings. Biocides can be loaded into the LbL or hydrogel coating, or in a different scenario the cationic moiety itself could be the biocide. At pH below the pKa of the acid, the carboxyl groups are protonated. This leads to ionic imbalance which destabilizes the LbL or hydrogel structure releasing the biocide. Carboxyl groupcontaining polymers can also be combined with alcohol group containing ones by forming ester bonds that are stable at physiological pH, but are hydrolyzed at low pH. For example, Liu et al. have reported the fabrication of vancomycin (Van) encapsulated poly(vinyl alcohol)/poly (lactide-glycolide acid) (PLGA) NPs grafted on biomedical titanium through a silane linker (Fig. 20.1). At physiological pH, the coating
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Figure 20.1 pH-triggered drug release from hybrid PLGA NPs. Reprinted with permission from Z. Liu, Y. Zhu, X. Liu, K.W.K. Yeung, S. Wu, Construction of poly(vinyl alcohol)/ poly(lactide-glycolide acid)/vancomycin nanoparticles on titanium for enhancing the surface self-antibacterial activity and cytocompatibility, Colloids Surf. B: Biointerfaces 151 (2017) 165 177. Copyright 2017, Elsevier.
releases small amounts of Van continuously due to the slow swelling of polymer chain segments. At acidic pH (6.4, 5.4, and 4.5), Van release is substantially increased and the coating exhibited the highest antibacterial efficacy at the lowest pH of 4.5. At the same time, mammalian-cell attachment and proliferation were not hindered [11]. Another strategy is the use of Schiff base which cleaves into the carbonyl and amino groups under acidic conditions. A pH-responsive hydrogel fabricated via Schiff base linkage between oxidized dextran (dextran-CHO) and cationic polyethyleneimine (PEI) dendrimers with encapsulated silver (Ag) NPs has been fabricated (Fig. 20.2). While B6% each of Ag and dendrimer were released at pH 7.4, the release increased to B18% and 13% for Ag and the dendrimer, respectively, at pH 5. The hydrogel showed potent antibacterial activity against both Gram-negative and Gram-positive bacteria, while no obvious hemolytic toxicity, cytotoxicity, and biochemical toxicity were observed for the antibacterial hydrogel after incubation with cells or after implantation [12]. Other strategies include the use of
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Figure 20.2 Dendrimer and Ag release from Schiff base containing hydrogel with a decrease in environmental pH. Reprinted with permission from T. Dai, C. Wang, Y. Wang, W. Xu, J. Hu, Y. Cheng, A nanocomposite hydrogel with potent and broadspectrum antibacterial activity, ACS Appl. Mater. Interfaces 10 (17) (2018) 15163 15173. Copyright 2018, American Chemical Society.
pH-responsive imine [13], boronic ester bond [14], or coordination bond [15] for the release of biocides. In one study, antibiotics and Ag NPs were loaded into titania nanotubes and then sealed with coordination polymers bonded to metal ions such as zinc (Zn) or Ag. These metal polymer coordination bonds are sensitive to pH and release of Ag and antibiotics occurred at acidic pH with enhanced antibacterial efficacy compared to physiological pH [15]. Another interesting study reported Znincorporated silicate glass coatings for orthopedic stainless steel. The authors hypothesized that Zn oxide is incorporated in the silicate network, forming acid-hydrolysable Si O Zn bonds. At physiological pH, Zn release was low (,10%), but increased dramatically under acidic (pH 4.5) conditions (B90%) and was proportional to the Zn oxide content in the glasses [16]. However, the antibacterial efficacy was not investigated and, hence, its potential for application has not yet been determined. In addition to acidic metabolites, bacteria may secrete other substances during their metabolism such as enzymes (e.g., phosphatase,
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Figure 20.3 Enzymatic degradation of self-assembled multilayer films of montmorillonite (MMT)/hyaluronic acid (HA) gentamicin (GS) with antibiotic release. Reprinted with permission from B. Wang, H. Liu, L. Sun, Y. Jin, X. Ding, L. Li, et al., Construction of high drug loading and enzymatic degradable multilayer films for self-defense drug release and long-term biofilm inhibition, Biomacromolecules 19 (1) (2018) 85 93. Copyright 2018, American Chemical Society.
hyaluronidase, chymotrypsin, and extracellular lipases) and toxins, which can be exploited as stimuli for triggering antibacterial activity from smart coatings [8,17]. A study reported self-assembled LbL films of montmorillonite/hyaluronic acid gentamicin that gradually degraded in hyaluronidase solutions or a bacterial infection microenvironment, which caused the responsive release of gentamicin (Fig. 20.3). While only B5 wt.% antibiotic was released from the film in phosphate-buffered saline (PBS) after 48 h of immersion, the amount rapidly increased to 30 wt.% in 105 CFU/mL of Escherichia coli. Although the smart antibiotic release contributed to efficient antibacterial properties, with the progressive peeling off of the films, long-term biofilm inhibition is unlikely to be achieved [18]. Other than pH and enzymes, body temperature (37°C) could also be used as a stimulus for antibacterial coatings intended for medical devices. In this case, the most widely employed strategy is the use of thermoresponsive polymer poly(N-isopropyl acrylamide) (PNIPA) or its copolymers, whose lower critical solution temperature (LCST) can be adjusted to slightly below body temperature. At body temperature ( . LCST) PNIPA-based hydrogels compact or collapse owing to their coil-to-globe transition following the release of entrapped biocides [19]. For example, Ag NPs entrapped within PNIPA functionalized surfaces having LCST below body temperature showed good antibacterial activity against E. coli at 37°C, but, at this temperature surface hydrophobicity led to fouling.
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Figure 20.4 Temperature-triggered switching between bactericidal and bacteriarepelling functionalities. Reprinted with permission from X. Wang, S. Yan, L. Song, H. Shi, H. Yang, S. Luan, et al., Temperature-responsive hierarchial polymer brushes switching from bactericidal to cell repellency, ACS Appl. Mater. Interfaces 9 (46), 2017, 40930 40939. Copyright 2017, American Chemical Society.
The authors showed that lowering the temperature to below the LCST caused PNIPA chains to swell and release the dead bacteria [20]. Although temperature-triggered Ag release may have potential application for medical devices, the triggered release of dead bacteria at temperatures lower than the body temperature is not practical for devices implanted in the body. Another PNIPA-based surface that exhibited bactericidal activity at room temperature and antiadhesive property at body temperature has been reported by Wang et al. (Fig. 20.4). This coating comprised a top layer of PNIPA-based copolymer with conjugated Van and a bottom layer of antiadhesive poly(sulfobetaine methacrylate) (PSBMA). At room temperature, the Van was exposed and exerted activity due to the swollen PNIPA. When temperature was increased to 37°C the PNIPA chains collapsed concealing the Van and revealing the PSBMA which repelled bacteria [21]. Although it is a novel temperature-triggered smart coating, it is not suitable for implants or devices where the temperature cannot be lowered below 37°C. While PNIPA has been the go-to polymer for
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temperature-responsive surfaces, poly(N-vinylcaprolactam) (PVCL) is another polymer that undergoes temperature-induced phase separation in an aqueous environment [22]. Aqueous PVCL gels exhibit two temperature-induced transitions, namely (1) a low-temperature transition at 31.5°C, attributed to microsegregation of hydrophobic domains and (2) a higher temperature transition at B37.5°C, representing the collapse of the gel volume [23]. The latter transition can be capitalized for the release of antibacterial agents. However, body temperature-responsive coatings would be triggered as soon as they are placed inside the body independent of the presence of bacteria unlike pH and enzyme-responsive ones, unless they can be fabricated from polymers which show transition temperatures at higher temperatures (fever) caused by an infection. Even if the latter could be done, a major limitation would be that not all fevers are a symptom of an infection and conversely not all infections may result in increased body temperature [24]. Despite recent advancements, several challenges are yet to be overcome in the fabrication of smart coatings for medical devices. First, the choice of materials has to be such that it is entirely nontoxic to mammalian cells. Second, it is extremely challenging to develop coatings that have high activity only in the presence of a harmful concentration of bacteria, but are totally inert otherwise. Most coatings show gradual release of biocides even in the absence of stimuli, which may be undesirable for this application. Continuous activity in the absence of an infection may lead to adverse immune responses and toxicity, similar to the drawback of traditional antibacterial coatings. Release of biocides in sublethal doses may also contribute to development of antimicrobial resistance. Even in the presence of stimuli, fine control of the release pattern of the biocide is difficult to achieve for such in vivo applications. Third, medical devices are usually implanted for long-term treatments and, hence, smart coatings need to be durable as well as effective for the entire duration of the implant, which may range from a few days for a catheter to few months for orthopedic implants and even lifelong in the case of heart implants. Among research done so far, most studies have not investigated long-term durability and efficacy of these coatings in a simulated physiological environment. Furthermore, as with any device meant for biomedical use, there are limitations of in vitro tests in simulating the complex in vivo environment. Cell surface interactions in the presence of a stimulus are complex and immensely difficult to simulate. Hence, the translation from successful laboratory developments to clinical practice would unlikely be a
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straightforward process. Last, challenges in scale-up would also complicate the translation to commercial products for smart coatings in any field of application.
20.2.2 Healthcare facilities Surface contamination in healthcare facilities is a major reason for the spread of HAIs, as mentioned in Section 20.1.1. Smart antibacterial coatings for this important application have not been as widely investigated as those for medical devices. The only kind of stimuli-responsive coatings reported so far are based on light activation. These coatings can be fabricated using either immobilized photosensitizers (such as various dyes) or photocatalysts (such as titanium dioxide) both of which can generate ROS when illuminated by light in the presence of molecular oxygen [3,25,26] as shown in Fig. 20.5. The biggest advantage of such coatings is that with the proper choice of photoactive materials, the antibacterial activity can be tuned to be continuous or discontinuous, as desired. For example, with the use of photosensitizers whose wavelength of absorption falls in the range of visible or indoor white light, continuous bacterial killing can be achieved. Such continuously antibacterial coatings are suited for surfaces that are high-touch or prone to very frequent contamination such as bedrails and door handles. In one report, light-activated cellulose
Figure 20.5 Mechanism of action of light-activated antibacterial surfaces fabricated using (a) photosensitizer-embedded and (b) photocatalyst-deposited substrate. Reprinted with permission from S. Noimark, C.W. Dunnill, I.P. Parkin, Shining light on materials—a self-sterilising revolution, Adv. Drug Deliv. Rev. 65 (4) (2013) 570 580. Copyright 2013, Elsevier.
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acetate coatings containing Toluidine Blue O and Rose Bengal showed continuous antibacterial activity when illuminated with a 28 W domestic fluorescence lamp for 6 h [27]. On the other hand, discontinuous activity can be obtained by the use of infrared (IR) or ultraviolet (UV)-active materials. These coatings can be applied on certain equipment such as stethoscopes or thermometers that need to be disinfected only after use. In one study a smart coating was fabricated on a wide range of substrates by sequential deposition of a gold NP layer and phase-transitioned lysozyme film. Due to the photocatalytic effect of gold NP, the coating exhibited very high antibacterial efficacy under near-IR laser irradiation. Moreover, the topmost lysozyme layer could be degraded and detached from the surface by immersion in vitamin C solution for a short period, leading to removal of the dead bacteria and exposure of the gold NP layer below, over multiple cycles [28]. Although an interesting laboratory work, degradation of layers with each cycle will limit possible long-term use. The major challenge associated with the design of smart coatings for use in healthcare facilities is the lack of appropriate stimuli in the indoor ambient environment apart from light. No other stimuli have been investigated so far for this application. While light-responsive coatings seem attractive, long-term efficacy is very hard to achieve owing to bleaching of the photoactive materials. Additionally, coatings for hospital use would have to be durable against dry and wet friction because surfaces are frequently wiped as part of daily cleaning and disinfection protocols. This also means that the effectiveness of these coatings after contact with liquid disinfectants would need to be evaluated. As with coatings for medical devices, practical considerations necessary for translating to clinical practice like durability and long-term efficacy are seldom investigated. Another issue is that photoactivity also depends on the intensity of light. Most works carried out so far have utilized an intensity of B3500 lx. However, hospital-light intensity may vary from 200 lx in corridors to 50,000 lx in operating theaters [29] and, thus, coatings would need to be tuned as per their precise site of application. Furthermore, objects in the healthcare environment are varied, ranging from metals to ceramics to plastics and glass, and from small objects to large surfaces like walls. Thus within the healthcare environment, different methods of surface treatment may be required for applying smart coatings on different substrates in a costeffective manner. Nevertheless a light-responsive coating technology based on titanium dioxide co-doped with fluorine and copper [30] has
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now been commercialized (KASTUS Technologies). The advantages of this coating are that it is transparent, can be activated by indoor, visible light and also possesses dark activity due to the presence of copper. However, this coating technology uses sol gel deposition at 550°C and thus is limited to glass or ceramic substrates. Although the coating is claimed to be “permanent” [31], information on its long-term effectiveness in a clinical setting is currently lacking.
20.2.3 Textiles Antibacterial textiles find use as fabrics for hospital bed linen, patient and staff uniforms, curtains, and wound dressing. It has been established that antibacterial textiles can indeed result in a significant reduction in the microbial burden [4]. While traditional bactericidal coatings on textiles have been developed for many years, limited research has been carried out on smart antibacterial coatings. Smart textiles that have been studied so far often use temperature or pH-responsive hydrogel coatings with loaded biocides [32]. pH-responsive chitosan hydrogel coatings have been studied wherein pH-sensitivity as well as antibacterial activity is imparted by chitosan [33]. Chitosan chains are in extended or coiled states in acidic or alkali solutions, respectively, and subsequently higher antibacterial activity is observed in its extended state. Wound dressings are an important application of antibacterial textiles. While biocide-releasing and chitosan-containing wound dressings are commercially marketed, a smart one is yet to be commercialized. Cornelius et al. suggested that cotton modified with pH- and temperature-sensitive microgel (fabricated from PNIPA copolymerized with methacrylic acid) loaded with biocides can potentially be used as a smart wound dressing [34]. Although the microgel showed an increase in volume (swelling) with an increase in pH between 3 and 7, the biocide release remained unchanged at 32 °C. Furthermore, temperature-sensitivity was not investigated and hence its application as a smart wound dressing cannot be asserted. In another study, a combination of PNIPA/chitosan microgel and silane QAC was coated over cotton to impart pH and temperature-responsive antibacterial as well as moisturemanagement properties [19]. Antibacterial activity was maintained after five laboratory washings. Apart from pH and temperature, light-activated textiles have also been studied. Manna et al. fabricated a bioinspired mineralization route to prepare self-cleaning cotton by surface functionalization with nano Ag@ZnO. ZnO has photocatalytic antibacterial activity in
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the UV region and the addition of Ag NPs not only aided in the antibacterial activity, but also caused a shift in the ZnO’s photocatalytic activity to the visible light region [35]. In an interesting study, Kulaga et al. prepared a new type of mechanically responsive material on polypropylene surgical mesh. A first layer of plasma polymer-containing Ag NPs was followed by a second plasma polymer layer that acted as a barrier to spontaneous release of Ag NPs. Controlled release of Ag was achieved by applying tensile stress (elongation of the coated mesh), which induced mechanically reversible fragmentations (or crack formation) in the top layer of the deposited plasma polymer [36]. The main challenge in the design of smart antibacterial coatings for textiles is the lack of appropriate stimuli. Although temperature and pH-responsive coatings have been developed their suitability for textile applications is limited. For example, body temperature may be a suitable stimulus for wound dressings as the antibacterial activity will be triggered only when placed in contact with a skin wound, although the release will occur regardless of the presence or absence of infection. However, it is challenging to identify an ideal stimulus for hospital bed sheets or patient uniforms. Additionally for textiles in direct contact with the skin, careful consideration has to be made while choosing coating materials in order to avoid any irritation or sensitization of the skin. Another challenge of coated textiles, whether smart or traditional, is their stability to laundering. As with most coatings, the durability of coated textiles under appropriate conditions has not been well investigated and, hence, their suitability for practical applications is uncertain. Similar to coatings for medical devices, achieving fine control over the release of biocides and long-term efficacy are also major issues.
20.2.4 Food packaging Smart antibacterial coatings have received very limited attention in food packaging research, although “active” food packaging (incorporating active but not environment-responsive agents within the packaging material) [37] and responsive or “intelligent” packaging (containing sensing interfaces in the form of flexible printed electronics) [38,39] for food safety and monitoring have already been individually demonstrated in the lab. Active packaging with antibacterial functionality is usually fabricated by incorporating “safe” biocides such as plant-derived essential oils, natural-occurring organic acids such as citric acid or naturally derived
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polymers like chitosan [40]. Chemical sensors integrated with packaging films [39] have responsive coatings which are usually fabricated from selfassembled NPs, hydrogels, grafted polymers, LbL, or supramolecular materials [41]. Hydrogel coatings in responsive packaging shrink, swell, or degrade in response to temperature, moisture, light, or pH. Some selfassembled monolayers or polymer films currently used as sensing surfaces respond to the presence of biological molecules. These ideas, in principle, could be further extended to fabricate smart antibacterial coatings that exert activity in response to pH, moisture, temperature, light, biogenic compounds like enzymes or toxins, or other contaminants present in food. In a futuristic perspective these stimuli can be used to trigger biocide release from smart antibacterial coating as well as generate a signal for consumers to determine the food’s quality, as shown in Fig. 20.6. A difficult challenge would be the necessity for coating materials and biocides that have no toxicity and no or minimal effect on food taste, smell, and color while prolonging the shelf life of the food. Safety regulations are stringent for food (similar to those for medical devices) [37] and precise control of response to stimuli would be required in order to avoid unnecessary or untimely release of biocides into food. If biogenic compounds or food analytes are to be used as stimuli, the coating would have to be very specific to the type of food or the type of microorganisms present. A wide range of coatings tailored to respond to such specific triggers would then have to be developed. Like other applications, challenges in translation from prototype to commercial product exist mostly because of the complex nature of foods. For instance, the presence of complex
Figure 20.6 Design of a smart antibacterial food packaging. Food-quality indicators can act as stimuli to trigger the release of biocides from a responsive packaging.
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constituents (e.g., lipids, proteins, and ions) may alter the biocide release from what was obtained using standard food simulants in the laboratory. Although existing technologies on antibacterial packaging and responsive packaging can be integrated, careful considerations have to be made in order to achieve smart antibacterial food packaging.
20.2.5 Water treatment and industrial equipment Biofouling of equipment is a severe menace in many industries. Although much research has been carried out on antiadhesive coatings to prevent biofouling, smart antiadhesive coatings dedicated for this application have not yet been developed. Since bactericidal coatings are also prone to fouling, surface coatings that can switch from being bactericidal to bacteriareleasing (biofouling detachment) when triggered by stimuli may be an alternative to self-cleaning or regenerating surfaces. For example, Yan et al. developed pH-responsive hierarchical polymer brush coatings where an outer layer of poly(methacrylic acid) (PMA) is hydrolyzed at low pHtriggering release of AMPs that are covalently immobilized on the inner layer (Fig. 20.7). The PMA, when hydrated, is hydrophilic and resistant to initial bacterial attachment. When fouled, reduction in pH causes the PMA chains to collapse, exposing the AMP to kill bacteria. Additionally
Figure 20.7 pH-triggered switching between a bacteria-repellent and bactericidal surface based on hydration of PMA layer. Reprinted with permission from S. Yan, H. Shi, L. Song, X. Wang, L. Liu, S. Luan, et al. Nonleaching bacteria-responsive antibacterial surface based on a unique hierarchical architecture, ACS Appl. Mater. Interfaces 8 (37) (2016) 24471 24481. Copyright 2016, American Chemical Society.
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the dead bacteria can be released once the PMA chains resume their hydrophilicity when the environmental pH is increased again [42]. In another study a smart supramolecular surface capable of switching functions reversibly between bactericidal and bacteria-releasing ability in response to UV 2 visible light was developed [43]. This surface was fabricated using azobenzene (Azo) groups and a biocidal β-cyclodextrin derivative conjugated with quaternary ammonium salt groups (CD QAS). The Azo groups, in their trans form, were incorporated into CD QAS forming an inclusion complex to achieve a bactericidal surface while, upon irradiation with UV light, the Azo groups switched to cis form, resulting in dissociation of the Azo/CD QAS inclusion complex and release of dead bacteria from the surface (Fig. 20.8). The surface could be easily regenerated by irradiation with visible light and reincorporation of fresh CD QAS. Similar to smart coatings for inhibiting biofouling, point-of-use water treatment filters can also be coated with kill and release coatings for bactericidal activity followed by fouling release. For this application, a major challenge would be the lack of appropriate stimuli for triggering the “switching” behavior at the site of application. In comparison to other smart coatings it would be even more difficult to maintain long-term activity for kill and release type coatings. These coatings would only have a limited number of switching cycles and
Figure 20.8 Light-triggered switching bacteria-repellent and bactericidal surface based on photoactive inclusion complex. Reprinted with permission from T. Wei, W. Zhan, Q. Yu, H. Chen, Smart biointerface with photoswitched functions between bactericidal activity and bacteria-releasing ability, ACS Appl. Mater. Interfaces 9 (31) (2017) 25767 25774. Copyright 2017, American Chemical Society.
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substrates would have to be recoated frequently, which is impractical and costly. For industrial use such as coating water pipes or equipment with large surface areas, the coating technology would need to be scalable and cost-effective. For drinking water treatment, the biggest challenge would be to achieve antibacterial efficacy without leaching any toxic components into the drinking water.
20.3 Conclusion In view of their promising potential, smart antibacterial coatings have gained substantial research interest over the past two decades and areas of possible application include medical devices, contamination-prone surfaces in the healthcare environment, textiles, food packaging, and water treatment or other industrial water-contacting equipment. Interest in this field stems from the need to develop antibacterial coatings that can exert activity only when desired, thereby overcoming the limitations of traditional bactericidal coatings. The success of smart antibacterial coatings depends on two main aspects, namely (1) choice of the right stimuli and (2) fabrication of coating using materials that can respond effectively to the stimuli. While advances in synthetic chemistry have indeed promoted the development of responsive materials, further research is required to be able to finely control the response behavior in the presence, as well as absence, of stimuli. Currently, smart antibacterial coatings are mainly in the laboratory testing phase and in order to translate any laboratory success to possible commercial use, a number of challenges need to be addressed, such as the ability to test efficacy under conditions that simulate the real scenario, durability and long-term efficacy of the coatings, fabrication processes that can be readily scaled-up, and compliance with human and environmental safety standards.
References [1] https://www.cdc.gov/hai/data/portal/index.html (accessed 15.02.19). [2] J.M. Schierholz, J. Beuth, Implant infections: a haven for opportunistic bacteria, J. Hosp. Infection 49 (2) (2001) 87 93. [3] K. Page, M. Wilson, I.P. Parkin, Antimicrobial surfaces and their potential in reducing the role of the inanimate environment in the incidence of hospital-acquired infections, J. Mater. Chem. 19 (23) (2009) 3819. [4] G. Borkow, J. Gabbay, Biocidal textiles can help fight nosocomial infections, Med. Hypoth. 70 (5) (2008) 990 994.
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[5] L.J. Bastarrachea, A. Denis-Rohr, J.M. Goddard, Antimicrobial food equipment coatings: applications and challenges, Ann. Rev. Food Sci. Technol. 6 (2015) 97 118. [6] J. Wright, S. Gundry, R. Conroy, Household drinking water in developing countries: a systematic review of microbiological contamination between source and point-of-use, Trop. Med. Int. Health 9 (1) (2004) 106 117. [7] S. Coetser, T.E. Cloete, Biofouling and biocorrosion in industrial water systems, Crit. Rev. Microbiol. 31 (4) (2005) 213 232. [8] T. Wei, Q. Yu, H. Chen, Responsive and synergistic antibacterial coatings: fighting against bacteria in a smart and effective way, Adv. Healthcare Mater. 3 (2019) e1801381. [9] A. Cavallaro, S. Taheri, K. Vasilev, Responsive and “smart” antibacterial surfaces: common approaches and new developments (review), Biointerphases 9 (2) (2014) 029005. [10] H.-P. Simmen, J. Blaser, Analysis of pH and pO2 in abscesses, peritoneal fluid, and drainage fluid in the presence or absence of bacterial infection during and after abdominal surgery, Am. J. Surg. 166 (1) (1993) 24 27. [11] Z. Liu, Y. Zhu, X. Liu, K.W.K. Yeung, S. Wu, Construction of poly(vinyl alcohol)/poly(lactide-glycolide acid)/vancomycin nanoparticles on titanium for enhancing the surface self-antibacterial activity and cytocompatibility, Colloids Surf. B: Biointerfaces 151 (2017) 165 177. [12] T. Dai, C. Wang, Y. Wang, W. Xu, J. Hu, Y. Cheng, A nanocomposite hydrogel with potent and broad-spectrum antibacterial activity, ACS Appl. Mater. Interfaces 10 (17) (2018) 15163 15173. [13] L. Pichavant, G. Amador, C. Jacqueline, B. Brouillaud, V. Héroguez, M.-C. Durrieu, pH-controlled delivery of gentamicin sulfate from orthopedic devices preventing nosocomial infections, J. Control. Rel. 162 (2) (2012) 373 381. [14] C. Ding, Z. Yan, J. Ren, X. Qu, Autonomous and continuous stimuli-responsive polymer surface for antibacterial application through enzymatic self-propagating reactions, Chem. Eur. J. 23 (59) (2017) 14883 14888. [15] T. Wang, X. Liu, Y. Zhu, Z.D. Cui, X.J. Yang, H. Pan, et al., Metal ion coordination polymer-capped pH-triggered drug release system on titania nanotubes for enhancing self-antibacterial capability of Ti implants, ACS Biomater. Sci. Eng. 3 (5) (2017) 816 825. [16] X. Chen, D.S. Brauer, N. Karpukhina, R.D. Waite, M. Barry, I.J. McKay, et al., ‘Smart’ acid-degradable zinc-releasing silicate glasses, Mater. Lett. 126 (2014) 278 280. [17] X. Li, B. Wu, H. Chen, K. Nan, Y. Jin, L. Sun, et al., Recent developments in smart antibacterial surfaces to inhibit biofilm formation and bacterial infections, J. Mater. Chem. B 6 (26) (2018) 4274 4292. [18] B. Wang, H. Liu, L. Sun, Y. Jin, X. Ding, L. Li, et al., Construction of high drug loading and enzymatic degradable multilayer films for self-defense drug release and long-term biofilm inhibition, Biomacromolecules 19 (1) (2018) 85 93. ˇ ˇ [19] D. Stular, J. Vasiljevi´c, M. Colovi´ c, M. Mihelˇciˇc, J. Medved, J. Kovaˇc, et al., Combining polyNiPAAm/chitosan microgel and bio-barrier polysiloxane matrix to create smart cotton fabric with responsive moisture management and antibacterial properties: influence of the application process, J. Sol Gel Sci. Technol. 83 (1) (2017) 19 34. [20] H. Yang, G. Li, J.W. Stansbury, X. Zhu, X. Wang, J. Nie, Smart antibacterial surface made by photopolymerization, ACS Appl. Mater. Interfaces 8 (41) (2016) 28047 28054.
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[21] X. Wang, S. Yan, L. Song, H. Shi, H. Yang, S. Luan, et al., Temperature-responsive hierarchical polymer brushes switching from bactericidal to cell repellency, ACS Appl. Mater. Interfaces 9 (46) (2017) 40930 40939. [22] B. Wang, Z. Ye, Q. Xu, H. Liu, Q. Lin, H. Chen, et al., Construction of a temperature-responsive terpolymer coating with recyclable bactericidal and self-cleaning antimicrobial properties, Biomater. Sci. 4 (12) (2016) 1731 1741. [23] A. Laukkanen, F.M. Winnik, H. Tenhu, Pyrene-labeled graft copolymers of Nvinylcaprolactam: synthesis and solution properties in water, Macromolecules 38 (6) (2005) 2439 2448. [24] M.J. Kluger, W. Kozak, C.A. Conn, L.R. Leon, D. Soszynski, Role of fever in disease, Ann. N.Y. Acad. Sci. 856 (1) (1998) 224 233. [25] R. Cahan, Conjugated and immobilized photosensitizers for combating bacterial infections, Recent Pat. Anti-infective Drug Discov. 8 (2) (2013) 121 129. [26] S. Noimark, C.W. Dunnill, I.P. Parkin, Shining light on materials—a self-sterilising revolution, Adv. Drug Deliv. Rev. 65 (4) (2013) 570 580. [27] V. Decraene, J. Pratten, M. Wilson, Novel light-activated antimicrobial coatings are effective against surface-deposited Staphylococcus aureus, Curr. Microbiol. 57 (4) (2008) 269 273. [28] Y. Qu, T. Wei, J. Zhao, S. Jiang, P. Yang, Q. Yu, et al., Regenerable smart antibacterial surfaces: full removal of killed bacteria via a sequential degradable layer, J. Mater. Chem. B 6 (23) (2018) 3946 3955. [29] V. Decraene, J. Pratten, M. Wilson, Assessment of the activity of a novel lightactivated antimicrobial coating in a clinical environment, Infect. Control Hosp. Epidemiol. 29 (12) (2008) 1181 1184. [30] N.S. Leyland, J. Podporska-Carroll, J. Browne, S.J. Hinder, B. Quilty, S.C. Pillai, Highly efficient F, Cu doped TiO2 anti-bacterial visible light active photocatalytic coatings to combat hospital-acquired infections, Sci. Rep. 6 (2016) 24770. [31] http://www.kastus.com/ (accessed 15.02.19). [32] J. Hu, H. Meng, G. Li, S.I. Ibekwe, A review of stimuli-responsive polymers for smart textile applications, Smart Mater. Struct. 21 (5) (2012) 053001. [33] D. Jocic, H. Kadoglu, E. Perrin Akcakoca Kumbasar, P. Celik, C. Okan Afrikan, A. Cay, et al., The perspective of stimuli-responsive surface modifying systems in developing functionalized textile, Paper Presented at 9th AUTEX World Textile Conference 2009, Ege University, 2009. [34] V.J. Cornelius, N. Majcen, M.J. Snowden, J.C. Mitchell, B. Voncina, Preparation of SMART wound dressings based on colloidal microgels and textile fibres, Smart Mater. IV (2006). 64130X. [35] J. Manna, S. Goswami, N. Shilpa, N. Sahu, R.K. Rana, Biomimetic method to assemble nanostructured Ag@ZnO on cotton fabrics: application as self-cleaning flexible materials with visible-light photocatalysis and antibacterial activities, ACS Appl. Mater. Interfaces 7 (15) (2015) 8076 8082. [36] E. Kulaga, L. Ploux, L. Balan, G. Schrodj, V. Roucoules, Mechanically responsive antibacterial plasma polymer coatings for textile biomaterials, Plasma Proc. Polym. 11 (1) (2014) 63 79. [37] B.G. Werner, J.L. Koontz, J.M. Goddard, Hurdles to commercial translation of next generation active food packaging technologies, Curr. Opin. Food Sci. 16 (2017) 40 48. [38] J.H. Han, C.H.L. Ho, E.T. Rodrigues, 9—Intelligent packaging, in: J.H. Han (Ed.), Innovations in Food Packaging., Academic Press, London, 2005. [39] M. Vanderroost, P. Ragaert, F. Devlieghere, B. De Meulenaer, Intelligent food packaging: the next generation, Trends Food Sci. Technol. 39 (1) (2014) 47 62.
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[40] M.A. Del Nobile, A. Lucera, C. Costa, A. Conte, Food applications of natural antimicrobial compounds, Front. Microbiol. 3 (2012) 287. [41] J. Brockgreitens, A. Abbas, Responsive food packaging: recent progress and technological prospects, Comp. Rev. Food Sci. Food Safety 15 (1) (2016) 3 15. [42] S. Yan, H. Shi, L. Song, X. Wang, L. Liu, S. Luan, et al., Nonleaching bacteriaresponsive antibacterial surface based on a unique hierarchical architecture, ACS Appl. Mater. Interfaces 8 (37) (2016) 24471 24481. [43] T. Wei, W. Zhan, Q. Yu, H. Chen, Smart biointerface with photoswitched functions between bactericidal activity and bacteria-releasing ability, ACS Appl. Mater. Interfaces 9 (31) (2017) 25767 25774.
Applications and challenges of smart antibacterial coatings Debirupa Mitra, En-Tang Kang and Koon Gee Neoh Department of Chemical and Biomolecular Engineering, National University of Singapore, Kent Ridge, Singapore
Contents 20.1 Introduction 20.1.1 Bacterial contamination: a global concern 20.1.2 Smart antibacterial coatings: a promising approach 20.2 Smart antibacterial coatings for various applications and their associated challenges 20.2.1 Medical devices 20.2.2 Healthcare facilities 20.2.3 Textiles 20.2.4 Food packaging 20.2.5 Water treatment and industrial equipment 20.3 Conclusion References
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20.1 Introduction 20.1.1 Bacterial contamination: a global concern The attachment of bacteria to surfaces and their subsequent colonization leads to several undesired consequences. One of the most detrimental consequences is the occurrence of hospital-associated infections (HAIs) in patients, which results in high morbidity and even mortality. According to the Centre for Disease Control and Prevention (CDC) on any day one out of three hospitalized patients has at least one HAI. There were an estimated 687,000 HAIs in US acute care hospitals in 2015 and B72,000 hospital patients with HAIs died during their hospitalizations [1]. It has been reported that 45% of HAIs are associated with bacterial colonization of implants or medical devices [2]. Implant infections are often accompanied by biofilm formation on the implant surface, and these infections are Advances in Smart Coatings and Thin Films for Future Industrial and Biomedical Engineering Applications DOI: https://doi.org/10.1016/B978-0-12-849870-5.00013-6
© 2020 Elsevier Inc. All rights reserved.
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resistant to antibiotics and host defenses and frequently persist until the implant is removed, which is the standard therapy [2]. Apart from insertion of implants and other invasive medical procedures, the inanimate environment in healthcare facilities also contributes to the spread of HAIs [3]. Infection can spread to patients via contact with bacteriacontaminated surfaces. Cross-contamination among patients may also occur via healthcare workers who are, in turn, in contact with these surfaces. In addition to different prone-to-contamination surfaces (e.g., bedrails, bedside tables, equipment, and wash faucets), hospital textiles provide an excellent substrate for bacterial colonization at appropriate temperature and humidity [4]. Patients shed bacteria and contaminate their apparel and bed sheets, following which the bacteria proliferate. Furthermore, bed making in hospitals releases large quantities of microorganisms into the air, which contaminate the immediate and nonimmediate surroundings, thereby contributing to HAIs. Another major health concern is bacterial contamination of food. With food production becoming increasingly automated, the number of food-contacting surfaces and, hence, the potential for cross-contamination has substantially increased [5]. Although these surfaces are sanitized, a clean surface can get soiled instantaneously by any contaminated product leading to cross-contaminations throughout the remaining processing run. Microbial contamination is, thus, a challenge to food safety, quality, and security. Bacterial contamination of drinking water is another important problem, especially in developing or underdeveloped countries. Drinking water may be contaminated anywhere between its source and point-ofuse by a contaminated water-contacting surface, and this is often the cause of widespread, water-borne diseases [6]. In a different scenario, bacterial attachment to marine vessels, water pipes, and other industrial watercontacting equipment has been a long-unsolved problem that causes biofouling [7]. Biofouling is often associated with biofilms and subsequent bacteria-mediated corrosion that results in shorter service life and increased energy and maintenance costs in marine and other industries. It is, therefore, evident that bacterial contamination of surfaces is undoubtedly an issue of global concern and potential remedies are of utmost necessity. A promising approach is the use of antibacterial coatings that either inhibit the adhesion of bacteria (antiadhesive) and/or exhibit bactericidal properties. Antiadhesive coatings prevent nonspecific interactions between the surface and the biological environment, thereby inhibiting bacterial attachment and biofilm formation in the early stages after
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contact. However, “perfectly” antiadhesive coatings are extremely hard to achieve and, hence, they inevitably become contaminated [8]. On the other hand, bactericidal coatings are capable of reducing the bioburden by effective killing of bacteria, but are generally prone to accumulation of dead bacteria.
20.1.2 Smart antibacterial coatings: a promising approach A number of bactericidal coatings have been developed over the past few decades that have been shown to be effective against a wide range of bacteria under laboratory testing. Traditional bactericidal coatings exhibit continuous activity, which may not be necessary in the absence of harmful doses of bacteria. Additionally, in certain scenarios, continuous activity can lead to adverse effects of the biocide on the surrounding environment. For example, in the absence of an infection, high amounts of released biocide from an implant surface may induce undesired immune response or even local toxicity. Thus the ideal coating would be one that exhibits activity only when required such as in the presence of significant bacterial colonization and remains “inert” otherwise [8]. As mentioned in Section 20.1.1, another limitation of traditional bactericidal coatings is the accumulation of dead bacteria on the surface that results in cloaking of the biocidal moieties and progressive loss of efficacy. An ideal antibacterial coating should possess bacteria-releasing characteristics or “self-cleaning” to avoid accumulation of dead bacteria on the surface. To realize such ideal antibacterial coatings, the development of “smart” coatings has garnered much research interest. While the definition of smart coatings is broad and not yet standardized, smart antibacterial coatings in this chapter would be considered as those capable of exhibiting or altering their antibacterial activity in response to a stimulus. There are two types of smart antibacterial coatings. The first are coatings whose bactericidal activity is triggered in the presence of one stimulus or several stimuli. This is mostly realized through the triggered release of loaded or encapsulated biocides. Examples of released biocides include antibiotics, antimicrobial peptides (AMP), metal (or metal oxide) nanoparticles (NPs), quaternary ammonium compounds (QAC), cationic dendrimers, and hydrogen peroxide [8]. Activity could also be achieved through a stimuli-responsive generation of reactive oxygen species (ROS) or conformational changes of a grafted biocide. The second kind of smart antibacterial coatings are those capable of “switching” or altering their
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antibacterial activity in response to stimuli. A classic example is the “kill and release” coating, which can switch between bactericidal and bacteriareleasing functionalities wherein the stimulus acts as the trigger for the switch. For either kind of smart antibacterial coating, possible stimuli include pH, temperature, light, magnetic field, electric field, mechanical force (pressure or touch), ultrasound, ionic strength, and concentration of biochemical agents (i.e., chemicals secreted by bacteria or chemicals present inside the human body at a particular site of infection such as enzymes, glucose, toxins, urea, etc.) [9]. Among these, the most commonly investigated stimulus in the design of smart antibacterial coatings is pH, followed by temperature, light, and biochemical concentration.
20.2 Smart antibacterial coatings for various applications and their associated challenges 20.2.1 Medical devices Prevention of device or implant-associated infections is purportedly the most important application of smart antibacterial coatings. A significant amount of smart coating research so far has been dedicated to potential application in medical devices. Bacterial infections are almost always associated with reduction in environmental pH due to the secretion of acidic metabolites, following which the pH at the site of infection can be reduced to as low as 5.5 [10]. This difference between physiological pH (7.4) and acidic pH at the site of infection is, hence, the most commonly capitalized trigger to initiate antibacterial activity from the smart coating. From a materials perspective, pH-responsive coatings are often fabricated using carboxyl group containing polymers in combination with cationic moieties forming layer-by-layer (LbL) coatings or electrostatically-complexed hydrogel coatings. Biocides can be loaded into the LbL or hydrogel coating, or in a different scenario the cationic moiety itself could be the biocide. At pH below the pKa of the acid, the carboxyl groups are protonated. This leads to ionic imbalance which destabilizes the LbL or hydrogel structure releasing the biocide. Carboxyl groupcontaining polymers can also be combined with alcohol group containing ones by forming ester bonds that are stable at physiological pH, but are hydrolyzed at low pH. For example, Liu et al. have reported the fabrication of vancomycin (Van) encapsulated poly(vinyl alcohol)/poly (lactide-glycolide acid) (PLGA) NPs grafted on biomedical titanium through a silane linker (Fig. 20.1). At physiological pH, the coating
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Figure 20.1 pH-triggered drug release from hybrid PLGA NPs. Reprinted with permission from Z. Liu, Y. Zhu, X. Liu, K.W.K. Yeung, S. Wu, Construction of poly(vinyl alcohol)/ poly(lactide-glycolide acid)/vancomycin nanoparticles on titanium for enhancing the surface self-antibacterial activity and cytocompatibility, Colloids Surf. B: Biointerfaces 151 (2017) 165 177. Copyright 2017, Elsevier.
releases small amounts of Van continuously due to the slow swelling of polymer chain segments. At acidic pH (6.4, 5.4, and 4.5), Van release is substantially increased and the coating exhibited the highest antibacterial efficacy at the lowest pH of 4.5. At the same time, mammalian-cell attachment and proliferation were not hindered [11]. Another strategy is the use of Schiff base which cleaves into the carbonyl and amino groups under acidic conditions. A pH-responsive hydrogel fabricated via Schiff base linkage between oxidized dextran (dextran-CHO) and cationic polyethyleneimine (PEI) dendrimers with encapsulated silver (Ag) NPs has been fabricated (Fig. 20.2). While B6% each of Ag and dendrimer were released at pH 7.4, the release increased to B18% and 13% for Ag and the dendrimer, respectively, at pH 5. The hydrogel showed potent antibacterial activity against both Gram-negative and Gram-positive bacteria, while no obvious hemolytic toxicity, cytotoxicity, and biochemical toxicity were observed for the antibacterial hydrogel after incubation with cells or after implantation [12]. Other strategies include the use of
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Figure 20.2 Dendrimer and Ag release from Schiff base containing hydrogel with a decrease in environmental pH. Reprinted with permission from T. Dai, C. Wang, Y. Wang, W. Xu, J. Hu, Y. Cheng, A nanocomposite hydrogel with potent and broadspectrum antibacterial activity, ACS Appl. Mater. Interfaces 10 (17) (2018) 15163 15173. Copyright 2018, American Chemical Society.
pH-responsive imine [13], boronic ester bond [14], or coordination bond [15] for the release of biocides. In one study, antibiotics and Ag NPs were loaded into titania nanotubes and then sealed with coordination polymers bonded to metal ions such as zinc (Zn) or Ag. These metal polymer coordination bonds are sensitive to pH and release of Ag and antibiotics occurred at acidic pH with enhanced antibacterial efficacy compared to physiological pH [15]. Another interesting study reported Znincorporated silicate glass coatings for orthopedic stainless steel. The authors hypothesized that Zn oxide is incorporated in the silicate network, forming acid-hydrolysable Si O Zn bonds. At physiological pH, Zn release was low (,10%), but increased dramatically under acidic (pH 4.5) conditions (B90%) and was proportional to the Zn oxide content in the glasses [16]. However, the antibacterial efficacy was not investigated and, hence, its potential for application has not yet been determined. In addition to acidic metabolites, bacteria may secrete other substances during their metabolism such as enzymes (e.g., phosphatase,
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Figure 20.3 Enzymatic degradation of self-assembled multilayer films of montmorillonite (MMT)/hyaluronic acid (HA) gentamicin (GS) with antibiotic release. Reprinted with permission from B. Wang, H. Liu, L. Sun, Y. Jin, X. Ding, L. Li, et al., Construction of high drug loading and enzymatic degradable multilayer films for self-defense drug release and long-term biofilm inhibition, Biomacromolecules 19 (1) (2018) 85 93. Copyright 2018, American Chemical Society.
hyaluronidase, chymotrypsin, and extracellular lipases) and toxins, which can be exploited as stimuli for triggering antibacterial activity from smart coatings [8,17]. A study reported self-assembled LbL films of montmorillonite/hyaluronic acid gentamicin that gradually degraded in hyaluronidase solutions or a bacterial infection microenvironment, which caused the responsive release of gentamicin (Fig. 20.3). While only B5 wt.% antibiotic was released from the film in phosphate-buffered saline (PBS) after 48 h of immersion, the amount rapidly increased to 30 wt.% in 105 CFU/mL of Escherichia coli. Although the smart antibiotic release contributed to efficient antibacterial properties, with the progressive peeling off of the films, long-term biofilm inhibition is unlikely to be achieved [18]. Other than pH and enzymes, body temperature (37°C) could also be used as a stimulus for antibacterial coatings intended for medical devices. In this case, the most widely employed strategy is the use of thermoresponsive polymer poly(N-isopropyl acrylamide) (PNIPA) or its copolymers, whose lower critical solution temperature (LCST) can be adjusted to slightly below body temperature. At body temperature ( . LCST) PNIPA-based hydrogels compact or collapse owing to their coil-to-globe transition following the release of entrapped biocides [19]. For example, Ag NPs entrapped within PNIPA functionalized surfaces having LCST below body temperature showed good antibacterial activity against E. coli at 37°C, but, at this temperature surface hydrophobicity led to fouling.
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Figure 20.4 Temperature-triggered switching between bactericidal and bacteriarepelling functionalities. Reprinted with permission from X. Wang, S. Yan, L. Song, H. Shi, H. Yang, S. Luan, et al., Temperature-responsive hierarchial polymer brushes switching from bactericidal to cell repellency, ACS Appl. Mater. Interfaces 9 (46), 2017, 40930 40939. Copyright 2017, American Chemical Society.
The authors showed that lowering the temperature to below the LCST caused PNIPA chains to swell and release the dead bacteria [20]. Although temperature-triggered Ag release may have potential application for medical devices, the triggered release of dead bacteria at temperatures lower than the body temperature is not practical for devices implanted in the body. Another PNIPA-based surface that exhibited bactericidal activity at room temperature and antiadhesive property at body temperature has been reported by Wang et al. (Fig. 20.4). This coating comprised a top layer of PNIPA-based copolymer with conjugated Van and a bottom layer of antiadhesive poly(sulfobetaine methacrylate) (PSBMA). At room temperature, the Van was exposed and exerted activity due to the swollen PNIPA. When temperature was increased to 37°C the PNIPA chains collapsed concealing the Van and revealing the PSBMA which repelled bacteria [21]. Although it is a novel temperature-triggered smart coating, it is not suitable for implants or devices where the temperature cannot be lowered below 37°C. While PNIPA has been the go-to polymer for
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temperature-responsive surfaces, poly(N-vinylcaprolactam) (PVCL) is another polymer that undergoes temperature-induced phase separation in an aqueous environment [22]. Aqueous PVCL gels exhibit two temperature-induced transitions, namely (1) a low-temperature transition at 31.5°C, attributed to microsegregation of hydrophobic domains and (2) a higher temperature transition at B37.5°C, representing the collapse of the gel volume [23]. The latter transition can be capitalized for the release of antibacterial agents. However, body temperature-responsive coatings would be triggered as soon as they are placed inside the body independent of the presence of bacteria unlike pH and enzyme-responsive ones, unless they can be fabricated from polymers which show transition temperatures at higher temperatures (fever) caused by an infection. Even if the latter could be done, a major limitation would be that not all fevers are a symptom of an infection and conversely not all infections may result in increased body temperature [24]. Despite recent advancements, several challenges are yet to be overcome in the fabrication of smart coatings for medical devices. First, the choice of materials has to be such that it is entirely nontoxic to mammalian cells. Second, it is extremely challenging to develop coatings that have high activity only in the presence of a harmful concentration of bacteria, but are totally inert otherwise. Most coatings show gradual release of biocides even in the absence of stimuli, which may be undesirable for this application. Continuous activity in the absence of an infection may lead to adverse immune responses and toxicity, similar to the drawback of traditional antibacterial coatings. Release of biocides in sublethal doses may also contribute to development of antimicrobial resistance. Even in the presence of stimuli, fine control of the release pattern of the biocide is difficult to achieve for such in vivo applications. Third, medical devices are usually implanted for long-term treatments and, hence, smart coatings need to be durable as well as effective for the entire duration of the implant, which may range from a few days for a catheter to few months for orthopedic implants and even lifelong in the case of heart implants. Among research done so far, most studies have not investigated long-term durability and efficacy of these coatings in a simulated physiological environment. Furthermore, as with any device meant for biomedical use, there are limitations of in vitro tests in simulating the complex in vivo environment. Cell surface interactions in the presence of a stimulus are complex and immensely difficult to simulate. Hence, the translation from successful laboratory developments to clinical practice would unlikely be a
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straightforward process. Last, challenges in scale-up would also complicate the translation to commercial products for smart coatings in any field of application.
20.2.2 Healthcare facilities Surface contamination in healthcare facilities is a major reason for the spread of HAIs, as mentioned in Section 20.1.1. Smart antibacterial coatings for this important application have not been as widely investigated as those for medical devices. The only kind of stimuli-responsive coatings reported so far are based on light activation. These coatings can be fabricated using either immobilized photosensitizers (such as various dyes) or photocatalysts (such as titanium dioxide) both of which can generate ROS when illuminated by light in the presence of molecular oxygen [3,25,26] as shown in Fig. 20.5. The biggest advantage of such coatings is that with the proper choice of photoactive materials, the antibacterial activity can be tuned to be continuous or discontinuous, as desired. For example, with the use of photosensitizers whose wavelength of absorption falls in the range of visible or indoor white light, continuous bacterial killing can be achieved. Such continuously antibacterial coatings are suited for surfaces that are high-touch or prone to very frequent contamination such as bedrails and door handles. In one report, light-activated cellulose
Figure 20.5 Mechanism of action of light-activated antibacterial surfaces fabricated using (a) photosensitizer-embedded and (b) photocatalyst-deposited substrate. Reprinted with permission from S. Noimark, C.W. Dunnill, I.P. Parkin, Shining light on materials—a self-sterilising revolution, Adv. Drug Deliv. Rev. 65 (4) (2013) 570 580. Copyright 2013, Elsevier.
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acetate coatings containing Toluidine Blue O and Rose Bengal showed continuous antibacterial activity when illuminated with a 28 W domestic fluorescence lamp for 6 h [27]. On the other hand, discontinuous activity can be obtained by the use of infrared (IR) or ultraviolet (UV)-active materials. These coatings can be applied on certain equipment such as stethoscopes or thermometers that need to be disinfected only after use. In one study a smart coating was fabricated on a wide range of substrates by sequential deposition of a gold NP layer and phase-transitioned lysozyme film. Due to the photocatalytic effect of gold NP, the coating exhibited very high antibacterial efficacy under near-IR laser irradiation. Moreover, the topmost lysozyme layer could be degraded and detached from the surface by immersion in vitamin C solution for a short period, leading to removal of the dead bacteria and exposure of the gold NP layer below, over multiple cycles [28]. Although an interesting laboratory work, degradation of layers with each cycle will limit possible long-term use. The major challenge associated with the design of smart coatings for use in healthcare facilities is the lack of appropriate stimuli in the indoor ambient environment apart from light. No other stimuli have been investigated so far for this application. While light-responsive coatings seem attractive, long-term efficacy is very hard to achieve owing to bleaching of the photoactive materials. Additionally, coatings for hospital use would have to be durable against dry and wet friction because surfaces are frequently wiped as part of daily cleaning and disinfection protocols. This also means that the effectiveness of these coatings after contact with liquid disinfectants would need to be evaluated. As with coatings for medical devices, practical considerations necessary for translating to clinical practice like durability and long-term efficacy are seldom investigated. Another issue is that photoactivity also depends on the intensity of light. Most works carried out so far have utilized an intensity of B3500 lx. However, hospital-light intensity may vary from 200 lx in corridors to 50,000 lx in operating theaters [29] and, thus, coatings would need to be tuned as per their precise site of application. Furthermore, objects in the healthcare environment are varied, ranging from metals to ceramics to plastics and glass, and from small objects to large surfaces like walls. Thus within the healthcare environment, different methods of surface treatment may be required for applying smart coatings on different substrates in a costeffective manner. Nevertheless a light-responsive coating technology based on titanium dioxide co-doped with fluorine and copper [30] has
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now been commercialized (KASTUS Technologies). The advantages of this coating are that it is transparent, can be activated by indoor, visible light and also possesses dark activity due to the presence of copper. However, this coating technology uses sol gel deposition at 550°C and thus is limited to glass or ceramic substrates. Although the coating is claimed to be “permanent” [31], information on its long-term effectiveness in a clinical setting is currently lacking.
20.2.3 Textiles Antibacterial textiles find use as fabrics for hospital bed linen, patient and staff uniforms, curtains, and wound dressing. It has been established that antibacterial textiles can indeed result in a significant reduction in the microbial burden [4]. While traditional bactericidal coatings on textiles have been developed for many years, limited research has been carried out on smart antibacterial coatings. Smart textiles that have been studied so far often use temperature or pH-responsive hydrogel coatings with loaded biocides [32]. pH-responsive chitosan hydrogel coatings have been studied wherein pH-sensitivity as well as antibacterial activity is imparted by chitosan [33]. Chitosan chains are in extended or coiled states in acidic or alkali solutions, respectively, and subsequently higher antibacterial activity is observed in its extended state. Wound dressings are an important application of antibacterial textiles. While biocide-releasing and chitosan-containing wound dressings are commercially marketed, a smart one is yet to be commercialized. Cornelius et al. suggested that cotton modified with pH- and temperature-sensitive microgel (fabricated from PNIPA copolymerized with methacrylic acid) loaded with biocides can potentially be used as a smart wound dressing [34]. Although the microgel showed an increase in volume (swelling) with an increase in pH between 3 and 7, the biocide release remained unchanged at 32 °C. Furthermore, temperature-sensitivity was not investigated and hence its application as a smart wound dressing cannot be asserted. In another study, a combination of PNIPA/chitosan microgel and silane QAC was coated over cotton to impart pH and temperature-responsive antibacterial as well as moisturemanagement properties [19]. Antibacterial activity was maintained after five laboratory washings. Apart from pH and temperature, light-activated textiles have also been studied. Manna et al. fabricated a bioinspired mineralization route to prepare self-cleaning cotton by surface functionalization with nano Ag@ZnO. ZnO has photocatalytic antibacterial activity in
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the UV region and the addition of Ag NPs not only aided in the antibacterial activity, but also caused a shift in the ZnO’s photocatalytic activity to the visible light region [35]. In an interesting study, Kulaga et al. prepared a new type of mechanically responsive material on polypropylene surgical mesh. A first layer of plasma polymer-containing Ag NPs was followed by a second plasma polymer layer that acted as a barrier to spontaneous release of Ag NPs. Controlled release of Ag was achieved by applying tensile stress (elongation of the coated mesh), which induced mechanically reversible fragmentations (or crack formation) in the top layer of the deposited plasma polymer [36]. The main challenge in the design of smart antibacterial coatings for textiles is the lack of appropriate stimuli. Although temperature and pH-responsive coatings have been developed their suitability for textile applications is limited. For example, body temperature may be a suitable stimulus for wound dressings as the antibacterial activity will be triggered only when placed in contact with a skin wound, although the release will occur regardless of the presence or absence of infection. However, it is challenging to identify an ideal stimulus for hospital bed sheets or patient uniforms. Additionally for textiles in direct contact with the skin, careful consideration has to be made while choosing coating materials in order to avoid any irritation or sensitization of the skin. Another challenge of coated textiles, whether smart or traditional, is their stability to laundering. As with most coatings, the durability of coated textiles under appropriate conditions has not been well investigated and, hence, their suitability for practical applications is uncertain. Similar to coatings for medical devices, achieving fine control over the release of biocides and long-term efficacy are also major issues.
20.2.4 Food packaging Smart antibacterial coatings have received very limited attention in food packaging research, although “active” food packaging (incorporating active but not environment-responsive agents within the packaging material) [37] and responsive or “intelligent” packaging (containing sensing interfaces in the form of flexible printed electronics) [38,39] for food safety and monitoring have already been individually demonstrated in the lab. Active packaging with antibacterial functionality is usually fabricated by incorporating “safe” biocides such as plant-derived essential oils, natural-occurring organic acids such as citric acid or naturally derived
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polymers like chitosan [40]. Chemical sensors integrated with packaging films [39] have responsive coatings which are usually fabricated from selfassembled NPs, hydrogels, grafted polymers, LbL, or supramolecular materials [41]. Hydrogel coatings in responsive packaging shrink, swell, or degrade in response to temperature, moisture, light, or pH. Some selfassembled monolayers or polymer films currently used as sensing surfaces respond to the presence of biological molecules. These ideas, in principle, could be further extended to fabricate smart antibacterial coatings that exert activity in response to pH, moisture, temperature, light, biogenic compounds like enzymes or toxins, or other contaminants present in food. In a futuristic perspective these stimuli can be used to trigger biocide release from smart antibacterial coating as well as generate a signal for consumers to determine the food’s quality, as shown in Fig. 20.6. A difficult challenge would be the necessity for coating materials and biocides that have no toxicity and no or minimal effect on food taste, smell, and color while prolonging the shelf life of the food. Safety regulations are stringent for food (similar to those for medical devices) [37] and precise control of response to stimuli would be required in order to avoid unnecessary or untimely release of biocides into food. If biogenic compounds or food analytes are to be used as stimuli, the coating would have to be very specific to the type of food or the type of microorganisms present. A wide range of coatings tailored to respond to such specific triggers would then have to be developed. Like other applications, challenges in translation from prototype to commercial product exist mostly because of the complex nature of foods. For instance, the presence of complex
Figure 20.6 Design of a smart antibacterial food packaging. Food-quality indicators can act as stimuli to trigger the release of biocides from a responsive packaging.
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constituents (e.g., lipids, proteins, and ions) may alter the biocide release from what was obtained using standard food simulants in the laboratory. Although existing technologies on antibacterial packaging and responsive packaging can be integrated, careful considerations have to be made in order to achieve smart antibacterial food packaging.
20.2.5 Water treatment and industrial equipment Biofouling of equipment is a severe menace in many industries. Although much research has been carried out on antiadhesive coatings to prevent biofouling, smart antiadhesive coatings dedicated for this application have not yet been developed. Since bactericidal coatings are also prone to fouling, surface coatings that can switch from being bactericidal to bacteriareleasing (biofouling detachment) when triggered by stimuli may be an alternative to self-cleaning or regenerating surfaces. For example, Yan et al. developed pH-responsive hierarchical polymer brush coatings where an outer layer of poly(methacrylic acid) (PMA) is hydrolyzed at low pHtriggering release of AMPs that are covalently immobilized on the inner layer (Fig. 20.7). The PMA, when hydrated, is hydrophilic and resistant to initial bacterial attachment. When fouled, reduction in pH causes the PMA chains to collapse, exposing the AMP to kill bacteria. Additionally
Figure 20.7 pH-triggered switching between a bacteria-repellent and bactericidal surface based on hydration of PMA layer. Reprinted with permission from S. Yan, H. Shi, L. Song, X. Wang, L. Liu, S. Luan, et al. Nonleaching bacteria-responsive antibacterial surface based on a unique hierarchical architecture, ACS Appl. Mater. Interfaces 8 (37) (2016) 24471 24481. Copyright 2016, American Chemical Society.
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the dead bacteria can be released once the PMA chains resume their hydrophilicity when the environmental pH is increased again [42]. In another study a smart supramolecular surface capable of switching functions reversibly between bactericidal and bacteria-releasing ability in response to UV 2 visible light was developed [43]. This surface was fabricated using azobenzene (Azo) groups and a biocidal β-cyclodextrin derivative conjugated with quaternary ammonium salt groups (CD QAS). The Azo groups, in their trans form, were incorporated into CD QAS forming an inclusion complex to achieve a bactericidal surface while, upon irradiation with UV light, the Azo groups switched to cis form, resulting in dissociation of the Azo/CD QAS inclusion complex and release of dead bacteria from the surface (Fig. 20.8). The surface could be easily regenerated by irradiation with visible light and reincorporation of fresh CD QAS. Similar to smart coatings for inhibiting biofouling, point-of-use water treatment filters can also be coated with kill and release coatings for bactericidal activity followed by fouling release. For this application, a major challenge would be the lack of appropriate stimuli for triggering the “switching” behavior at the site of application. In comparison to other smart coatings it would be even more difficult to maintain long-term activity for kill and release type coatings. These coatings would only have a limited number of switching cycles and
Figure 20.8 Light-triggered switching bacteria-repellent and bactericidal surface based on photoactive inclusion complex. Reprinted with permission from T. Wei, W. Zhan, Q. Yu, H. Chen, Smart biointerface with photoswitched functions between bactericidal activity and bacteria-releasing ability, ACS Appl. Mater. Interfaces 9 (31) (2017) 25767 25774. Copyright 2017, American Chemical Society.
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substrates would have to be recoated frequently, which is impractical and costly. For industrial use such as coating water pipes or equipment with large surface areas, the coating technology would need to be scalable and cost-effective. For drinking water treatment, the biggest challenge would be to achieve antibacterial efficacy without leaching any toxic components into the drinking water.
20.3 Conclusion In view of their promising potential, smart antibacterial coatings have gained substantial research interest over the past two decades and areas of possible application include medical devices, contamination-prone surfaces in the healthcare environment, textiles, food packaging, and water treatment or other industrial water-contacting equipment. Interest in this field stems from the need to develop antibacterial coatings that can exert activity only when desired, thereby overcoming the limitations of traditional bactericidal coatings. The success of smart antibacterial coatings depends on two main aspects, namely (1) choice of the right stimuli and (2) fabrication of coating using materials that can respond effectively to the stimuli. While advances in synthetic chemistry have indeed promoted the development of responsive materials, further research is required to be able to finely control the response behavior in the presence, as well as absence, of stimuli. Currently, smart antibacterial coatings are mainly in the laboratory testing phase and in order to translate any laboratory success to possible commercial use, a number of challenges need to be addressed, such as the ability to test efficacy under conditions that simulate the real scenario, durability and long-term efficacy of the coatings, fabrication processes that can be readily scaled-up, and compliance with human and environmental safety standards.
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