Cationic polymer–based antibacterial smart coatings

CHAPTER 21

Cationic polymer
based antibacterial smart coatings Sreyan Ghosh and Jayanta Haldar Antimicrobial Research Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India

Contents 21.1 Introduction 21.2 Modes of spreading infections and microbial biofilms 21.3 Antimicrobial surfaces to prevent infections 21.3.1 Antiadhesion approach 21.3.2 Contact killing approach 21.3.3 Release-based approach 21.4 Cationic polymer
coated smart surfaces 21.4.1 Cationic polymer
coated surfaces for contact killing of bacteria 21.4.2 Switchable cationic surfaces for kill and/or release of bacteria 21.4.3 Dual-functional (release-based and contact-based) coatings with cationic polymers and biocides 21.5 Conclusion References Further reading

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21.1 Introduction Biomaterial-associated infections have increased the rate of mortality and global healthcare costs by leaps and bounds [1,2]. These implant-related infections emerge due to adhesion of bacteria and the formation of biofilms on their surfaces [3]. To tackle implant-associated infections, administration of antibiotics has been the traditional method of treatment [4,5]. However, the emergence of drug-resistant bacteria has posed a serious threat and is becoming one of the largest causes of human fatalities [6,7]. Additionally, the formation of biofilms on implant surfaces can complicate treatment with known antibiotics. The threat of morbidity coupled with drawbacks of antimicrobial resistance and biofilm formation have led to the development of different strategies for the antimicrobial modification Advances in Smart Coatings and Thin Films for Future Industrial and Biomedical Engineering Applications DOI: https://doi.org/10.1016/B978-0-12-849870-5.00011-2

© 2020 Elsevier Inc. All rights reserved.

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of surfaces. The approach of antimicrobial surfaces has proved to be the most promising way to tackle surface-associated infections [8
11]. Anchoring different bactericidal agents to the biomaterial surfaces renders them antiinfective, therefore, markedly reducing the risk of contamination [10,11]. Among various agents used for the fabrication of antimicrobial surfaces, polymers have experienced enormous interest owing to their ease of fabrication, cost-effectiveness, and biocompatibility [11
16]. Cationic polymers have been one of the most promising choices to generate antibacterial surfaces which can kill the bacteria upon contact [17
19]. Although cationic polymer
coated surfaces show great promise in tackling surface-associated infections, they suffer from dead-cell accumulation on their surfaces reducing their antimicrobial activity over the time. To address this issue, certain cationic polymers can convert to zwitterionic or other forms, thereby switching from bactericidal to nonfouling states. To tackle the bacterial cells not only in proximity, but in the surroundings as well, dual-action (simultaneous contact and release) antimicrobial coatings have been developed by encapsulating different biocides in cationic polymeric matrices. These dual-active coatings are capable of killing microorganisms upon contact as well as by releasing antimicrobial agents into the surroundings [20]. Additionally, if the matrix is biodegradable, formation of biofilm is inhibited as the top layer of the coated surface continuously erode in a controlled manner. In this chapter, we will discuss how cationic polymers have been employed in generating smart antibacterial surfaces by employing these strategies.

21.2 Modes of spreading infections and microbial biofilms Infectious diseases can spread in many ways, such as person-to-person spread (e.g., sexual transmission, needle injection, fomites, or contaminated surfaces), common vehicle spread (food-borne, water-borne, or fecal, oral, and blood products, etc.), and via vectors (mosquitoes, flies, etc.) [21,22]. Contaminated surfaces or fomites, which are responsible for spreading most of microbial infections, can act as reservoirs of microbes. Upon being touched by a healthy individual, they can spread deadly notorious infections. When touched by an infected individual, pathogenic microbes are deposited onto the surfaces of daily-life objects such as door knobs, telephones, toys, and others, thereby infecting healthy individuals and leading to the perpetual spreading of infections. Human actions like

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coughing, sneezing, breathing, or even talking can produce aerosolizedmoisture droplets which contain bacteria. These droplets settle on different surfaces, which become potential source of pathogens [23,24]. Infectious microbes (e.g., bacteria, fungi) can also be traced to different sources in hospitals such as operating rooms, surgical equipment, medical clothing, or resident bacteria on patients’ skin [25]. Robust applications of medical devices and implants such as catheters, cardiac pacemakers, hip implants, and contact lenses, among others, can cause serious implant-associated infections, which can lead to death [26]. Even though sterilization and the use of aseptic techniques reduce the levels of bacterial contamination in hospital settings, pathogenic microorganisms are still prevalent on approximately 90% of all implants. Such nosocomial infections, including device-related ones, lead to major clinical complications, and, consequently increased healthcare costs [27]. A significant proportion of medical implant-associated infections are difficult to eradicate because the bacteria causing these infections form well-developed biofilms. A biofilm is a microbial-derived sessile community attached to a surface, embedded in a matrix of extracellular polymeric substances [28]. Infectious biofilms can be classified into surface-related (abiotic, e.g., implant surfaces, and biotic surfaces, e.g., human skin) and tissue-associated or mucus-embedded cellular aggregates [29]. Biofilms can form on any foreign object inserted into the human body, such as implants or catheters, as well as in any place in the human body, such as in the lungs of patients with cystic fibrosis, or in chronic wounds. With a protective polysaccharide coating and sequestered nutrients, microorganisms in biofilms demonstrate immense resistance to available antibiotics. In some cases, it has been found that killing bacteria in a biofilm requires roughly 1000 times the antibiotic dose necessary to achieve the same results against planktonic bacteria [28,29]. To prevent biofilm-related infections one needs to inhibit microbial colonization and subsequent biofilm formation onto surfaces [29].

21.3 Antimicrobial surfaces to prevent infections Antibacterial surfaces have emerged as a primary component of the global strategy to eliminate bacterial pathogens. Owing to the advances in materials science and biotechnology, an immense variety of options are now available to design surfaces with antibacterial properties. Various researchers have focused their interest in developing antimicrobial surfaces that

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can prevent infections. In this context, three general strategies have been adopted: (1) antiadhesion approach (nonfouling strategy), (2) contact killing approach, and (3) are lease-based approach.

21.3.1 Antiadhesion approach In the antiadhesion approach, surfaces repel microbial cells thereby preventing their adherence on the surfaces, which is the initiation step in all surface- and biofilm-associated infections. Surface immobilization of molecules that can resist protein adsorption and cell adherence as well as polyethylene glycol and different zwitterionic polymers, among others, have shown tremendous antiadhesion properties (Figs. 21.1A and 21.2) [34
37].

21.3.2 Contact killing approach Contact killing surfaces have been developed where antimicrobial compounds are anchored to the material’s surface either in a physically or chemically bounded manner. Bacteria coming into contact with the modified surfaces are believed to be killed due to disruption of their cell membrane, reaching across the microbial envelope, owing to the long hydrophobic chains present in the tethered compounds (see Fig. 21.1B) [11].

Figure 21.1 Antimicrobial strategies to prevent surface-associated infections: (A) antiadhesive surfaces reduce the adherence of bacteria to biomaterial surfaces by repelling them; (B) contact killing surfaces kill microbes upon contact by disrupting their cells; and (C) antimicrobial agents can be incorporated on surfaces and kill microbes by leaching them into the surroundings.

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Figure 21.2 Antiadhesive surfaces prevent the adherence of microbes. Various polymers are used for fabrication of antiadhesive coatings: (A) polyethylene glycol [30,31]; (B) phosphorylcholine derivatives [32,33]; (C) polysulfobetaine; and (D) polycarboxybetaine [34,35].

21.3.3 Release-based approach Release-based coatings exert their antimicrobial effects by leaching of the loaded agents from the surface, killing both adhered as well as adjacent microbes [16]. Diffusion into an aqueous medium, erosion/degradation, or hydrolysis can lead to the release of incorporated antibacterial agents. Polymeric matrices are generally employed for loading leachable biocides. Antibiotics, antimicrobial peptides, quaternary small molecules, silver, and other metal-based materials, such as nitric oxide and others are employed in release-based bacterial killing (Fig. 21.1C and Table 21.1) [16]. A simple and commonly used method to deliver these compounds is by impregnation, which is carried out by soaking a porous material or coating with the desired antibacterial agent. However, coatings developed by this method suffer from fast and uncontrolled release. Another recent approach employs noncovalent painting of polymer
biocide composites on different surfaces. Plasma-deposited polymers have been used extensively to develop carrier coatings for the release of antibacterial compounds [38]. Construction of polyelectrolyte multilayer films is another recent and effective approach for the generation of release-active coatings [9]. Hammond et al. contributed significantly in developing polyelectrolyte multilayer formulations and coatings for a new generation of antimicrobial surfaces [52
57]. There are some difficulties in tuning the release rate and for the induction of long-term immunogenic responses. A release rate-tunable biodegradable coating that leaves no residual material on the implant surface can address both problems. Hammond et al. reported a

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Table 21.1 Different biocides for release-based coatings. Type of biocide

Loaded compound

Function on release

Reference

Antibiotics

Vancomycin

Effectively kills Grampositive bacteria upon elusion from hydrogel Tackles infection upon release from orthopedic implants Mostly act by membrane pore formation

[38,39]

Affects bacterial cell wall Peptidoglycans Kills bacteria by DNA damage, enzyme inactivation, and ROS generation Kills bacteria in a controlled manner Titanium implants coated with chlorhexidine can tackle bone implantassociated infections Active against broadspectrum pathogen releasing from hydrogel Exert oxidative stress on cell membrane

[43]

Gentamicin

Antimicrobial peptides Enzymes Metal and metallic nanoparticles

Organic cationic compounds

Nonorganic compounds

Various known antimicrobial peptides Lysozyme Silver

Silver nanoparticles Chlorhexidine

Quaternary ammonium molecules Nitric oxide

[10,39,40]

[8,41,42]

[44]

[20,44
46] [47]

[48]

[5,49
51]

multilayered film formed from poly-(β-amino) esters as polycations and hyaluronic acid as polyanions incorporating gentamicin in the films [54]. The polycation poly-(β-amino) esters were hydrolyzed under physiological conditions releasing encapsulated components when exposed to an aqueous physiological environment. The total released amount was found to be monotonically increased with the number of layers. Films composed of 50
100 bilayers showed inhibition in Staphylococcus aureus growth with a zone of inhibition (ZOI) of 1.66 6 0.11 cm. However, in some cases immunogenic reactions and inflammation can result in implant or device failure. To avert this issue, medical devices designed for combined delivery of antibacterial and antiinflammatory agents to the surrounding tissues

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can be effective. In their reports, Hammond et al. developed a multilayered construct for concurrent localized delivery of antibiotic vancomycin and nonsteroidal antiinflammatory drug diclofenac with tunable release profiles [57].

21.4 Cationic polymer
coated smart surfaces 21.4.1 Cationic polymer
coated surfaces for contact killing of bacteria Attachment of microbes and their colonization on various surfaces can lead to notorious community- and hospital-acquired infections. Rendering antimicrobial properties employing different coating strategies is the most accepted approach to overcome fatal, surface-associated infections. One such strategy is to coat surfaces with cationic polymers that can kill pathogens upon contact. Among the most commonly used cationic antimicrobials, cationic polymers with quaternary ammonium groups have attracted the attention of many researchers. Quaternary derivatives of acrylic acid, poly(ester-carbonate), cellulose, and others have also been applied onto surfaces to prevent the deleterious effects exerted by pathogens. Applying these cationic polymers onto surfaces can either be executed in covalent or noncovalent ways. 21.4.1.1 Covalent coatings Physical incorporation of antibacterial molecules on the surface suffers from leaching of molecules and exhaustion of the reservoir. To avoid this loss, permanent anchoring of antimicrobial polymers has been used (Fig. 21.3A). This covalent coating of surfaces can be achieved in two ways, namely (1) the grafting-from technique and (2) the grafting-onto technique. In the grafting-from approach, reactions involve the surface and are initiated on the surface. On the other hand, in the grafting-onto technique, polymeric backbone chains are modified with different anchoring functional groups. The coupling reaction between the functional anchors and the surface are the key to the grafting-onto strategy. Grafting by anchoring linkers on the surface: Many groups have contributed significantly in developing permanently, nonleaching, antimicrobial surfaces employing different strategies for surface anchoring. Silane linkers have provided varied and effective strategies for anchoring polymers to the surface. Functionalization of surfaces by organosilanes provides several perspectives for further immobilization of different polymers, small

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Figure 21.3 Various cationic polymers employed for antimicrobial coatings: (A) cationic polymers for covalent coating for contact-based killing [29,24,34]; (B) cationic polymers for noncovalent coating for contact-based killing [48,53,58]; and (C) cationic polymers for release-based coating for leaching of biocides [20,45].

molecules, and peptides. Over the past few decades, increasing efforts have been directed toward development and applications of organosilanes as surface modifiers. The attachment is typically initiated by silylating the surface followed by immobilization of a bioactive agent. Binding to the surface is very strong and very little leakage occurs from the substrate. Considering the robust anchoring nature of silanes, Klibanov et al. developed a novel covalent coating by immobilization of poly-(4-vinylN-alkylpyridiniumbromide) on glass surfaces (Fig. 21.3A) [59]. Aminopropyltrimethoxysilane-coated glass surfaces were used. The amine (
NH2) groups were reacted with acryloyl chloride to introduce double bonds on the surface for copolymerization with 4-vinylpyridine. The final step was to incorporate a positive charge and hydrophobicity. To achieve this the pyridine rings were N-alkylated by seven linear alkyl (propyl, butyl, hexyl, octyl, decyl, dodecyl, and hexadecyl) bromides. The antibacterial activities of these modified surfaces were checked by spraying bacterial suspensions on them to mimic pathogens transmitted in air by talking, sneezing, coughing, or breathing. The immobilized poly-(4-vinyl-Nalkylpyridine) (PVP) with shorter alkyl chain lengths were found to markedly reduce the number of viable S. aureus cells with hexyl-PVP affecting a 94% 6 4% reduction. The higher activity of polymers with

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shorter chain lengths was in accordance with the fact that polymers with longer hydrophobic chains formed aggregates on the surface, resulting in an opaque appearance and elevated value of optical absorbance. Due to aggregation, the polymers with higher alkyl chains interact much less with the bacterial cells than those with shorter chains. Further, in another study, the most active hexyl-PVP was coated onto different commercial polymers such as high-density polyethylene, low-density polyethylene, nylon 6/6, and polypropylene [60]. They were found to be active against not only air-borne pathogens, but also against water-borne pathogens. The coated surface exerted 99% 6 1% reduction in viable S. aureus cells and 98% 6 1% in viable Escherichia coli cells. This demonstrates the generality of this surface coating or derivatization procedure. Another report involves maleic anhydride as a surface anchoring agent for attachment of antimicrobial polymers [60]. In this approach, maleic anhydride was attached on substrates using free-radical initiator azobisisobutyronitrile. This was followed by the attachment of polyethyleneimine (PEI). Further, PEI-modified fabric was N-hexylated and then N-methylated to introduce alkyl hydrophobicity and a positive charge on the surface. Upon spraying bacteria (S. aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and E. coli) the modified surfaces were found to be quite potent with 90%
100% reduction in viable bacterial cells. In a later report, Klibanov et al. addressed the mechanistic aspects of these hydrophobic polycation coatings [61]. Amino-glass slides derivatized with Nhexyl, methyl-PEI were used for this study. They also investigated the propensity of resistance development of pathogens against such nonleaching polycationic coatings. When bacteria were exposed to polycation immobilized slide and its unmodified predecessors, bacteria cells show strong affinity toward the polycation-derivatized surface. The fluorescence microscopy assay suggested that the polycation-derivatized antimicrobial surface apparently acts as nonselective, brute-force “permeabilizers” of bacterial cell membranes resulting in disrupted membrane integrity. Klibanov et al. reported the antibiofilm efficacy of keratoprosthetic materials made up of polymethyl methacrylate (PMMA) and titanium (Ti) covalently coated with N-hexyl, methyl-PEI [62]. For covalent derivatization of PMMA, they are hydrolyzed followed by conjugation with PEI. This conjugated PEI is further hexylated and methylated introducing hydrophobicity as well as quaternary ammonium groups on the surface. To coat titanium surfaces, they are oxidized first followed by silanization using (3-aminopropyl) triethoxysilane. They are further reacted with

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4-bromobutyryl chloride to incorporate acyl groups on the surface. These butyryl functionalities are reacted with amino (
NH2) groups of PEI. Consequent reactions of this immobilized PEI with hexyl bromide and iodomethane renders the surface quaternary and imparts hydrophobic alkyl moieties in the polymer. The coated PMMA material showed fourto eightfold inhibition in S. aureus biofilm thickness compared to that on the parent PMMA. There was also two- to fourfold less biofilm formation on modified PEI coated-Ti materials compared to that on the parent Ti. Covalent coating on PMMA did not introduce any additional toxicity when checked against human corneal limbal epithelial cells. Russell et al. developed systems for covalent antimicrobial modification of surfaces. In one of their reports, they developed an antimicrobial polymer directly on the surfaces of glass and paper using atom transfer radical polymerization (ATRP) (Fig. 21.3A) [63]. 2-Bromoisobutyryl bromide, an ATRP initiator, was immobilized on Whatmann filter paper by reacting with the
OH groups on the paper surface. ATRP of 2(dimethylaminoethyl methacrylate) was performed on this initiatormodified paper. The anchored tertiary amines were then reacted with methyl bromide, thereby giving quaternary moieties on the surface and imparting bactericidal properties to it. To check whether the coating is diffusible or not, the ZOI was checked. The lack of a zone of growth inhibition indicated that the material was not diffusing out of the paper. Lienkamp et al. reported their development of a bifunctional material containing antimicrobial and antibiofouling components [64]. Grafting using pendant linkers in the polymeric backbone: All the reports discussed above involve reactions on the substrate (surface) which require very delicate techniques as well as trained personnel, making the process a complicated one. Recent investigation has explored the incorporation of different active linkers into the polymer which can link the polymeric structure to various surfaces. This strategy provides an easier way to coat the polymers on the surfaces, mostly involving one-step fabrication. These active linkers can also be stimuli responsive so that exposure to suitable stimuli can attach them to the surfaces along with the polymeric structure. Benzophenone and dopamine and their derivatives have been enormously exploited in this approach [65,66]. Benzophenone photophores have a unique n
π excitation at 365 nm, where they form a reversible biradicaloid triplet state. This state can abstract hydrogen atoms from accessible C 2 H bonds. This leads to the recombination of radicals forming a stable, covalent C 2 C bond. This light-directed covalent

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attachment has been exploited in various fields and antimicrobial surface development has been no exception. Introduction of benzophenone photophore into the polymeric backbone can immobilize the polymer upon light irradiation making the surface modification a single-step procedure. Locklin et al. contributed significantly in developing benzophenone-conjugated polymers for antimicrobial coating [49,67
69]. In one of their reports, they developed a PEI decorated with hydrophobic alkyl chain for bacterial killing and benzophenonederivative 4-[(6-bromohexyl)oxy] benzophenone for covalent immobilization [67]. This polymer was coated on different surfaces like glass, textile, polypropylene, polyvinyl chloride, and polyethyelene by UV-irradiation. The coated surfaces showed .98% microbial death when sprayed with S. aureus or E. coli. However, the photo-cross-linking of the polymer was found to be time-consuming and inefficient. This led to development of a benzophenone-based antimicrobial quaternary small molecule (Fig. 21.3A) [68]. The rate of cross-linking was found to be 8.23 times faster than the polymer. The molecule was coated on different substrates including commercially available medically relevant ones. These coated surfaces, when sprayed with S. aureus and E. coli showed the biocidal efficiency to be 100% against both bacteria. The coating retained its antimicrobial efficacy even after 15 abrasion cycles, proving the potency of the coating for repeated use [68]. Dopamine has been a very lucrative option to researchers for its robustness and surface-independent adhesion [70
75]. Messersmith et al. contributed toward the development of dopamine-based surface anchoring strategies [70
72]. Cationic antimicrobial polymers have also been modified with dopamine for covalent surface modification. Ding et al. and Yang et al. developed various cationic polymer
based antimicrobial formulations employing dopamine as a surface-adhering moiety [74,75]. Brush-like polycarbonates were developed that contained three components: a pendant dopamine (for adhering the polymer to substrate), shortchain polyethyelene glycol (for cell-repellent property), and antibacterial cations for targeting and lysing bacterial cell membranes. Ring-opening polymerization was involved in the synthesis of the polymers [75]. Silicone rubber surfaces were coated with the polymer solutions. Upon incubation with S. aureus and E. coli, coatings were found to kill S. aureus and E. coli with 99.9% and 99.999% reduction in bacterial counts, respectively, as compared to a pristine silicone rubber surface. After incubation with S. aureus suspension for 14 days, no bacterial cell was found to be

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adhered to the optimized coated surface, proving their efficacy to exert antifouling effects when coated on long-term implant surfaces [75]. 21.4.1.2 Noncovalent coatings Covalent immobilization of coated materials on a surface can prevent its leaching, allowing durable antibacterial performance. But covalent grafting of antimicrobials also suffers from several limitations. Fabrication of a covalent coating requires trained professionals and complicated techniques and instrumentation. This called for an approach which would be devoid of complicated techniques, which led to noncovalent surface modification. In this approach, fabrication of antimicrobial surfaces can be prepared by employing simple procedures like painting or dipping. Organosoluble, antimicrobial polymers can be painted onto different surfaces rendering them antimicrobial. Evaporation of the solvent further allows these antimicrobial agents to adhere strongly to the substrate. The ease of fabrication makes this approach a very attractive strategy to develop antimicrobial surfaces. Klibanov et al. played a pioneering role in the development of noncovalent antimicrobial coatings [60,61,76
82]. Initial reports from the researchers revealed that coating with a quaternized PEI derivative, Nhexyl, N-methyl-PEI on various surfaces (such as glass or polyethylene) were capable of killing air-borne S. aureus. However, the antimicrobial surface generated by using this shorter alkyl chain-grafted PEI derivative showed reduced adherence to the surface, resulting in leaching of the polymer from the surface. The reason for this leaching was understood as lower hydrophobic moieties leading to reduced intermolecular interactions [78]. Klibanov et al. overcame this problem with the development of PEI derivatives containing higher hydrophobic moieties [79,80]. Surfaces were coated by this new PEI derivative, where the hexyl hydrophobicities were replaced with dodecyl moieties (N-dodecyl, N-methylPEI) (Fig. 21.3B). The introduction of dodecyl moieties in the polymeric architecture resulted in strong intermolecular attractions and, thus, lowered their tendency to leach out from the surface. The glass surfaces coated with this polymer showed potent activity against bacteria (S. aureus and E. coli) as well as viruses. The optimized polymer-coated glass slide showed complete killing (100%) of bacteria and viruses. The coating showed rapid virucidal activity by killing the influenza virus within minutes (B4 log reduction in the viral titer). Importantly, it also inactivated drug-resistant strains of the influenza virus, poliovirus, and rotavirus with

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high efficacy [82]. Besides painting the compound with its organosolutions, N,N-dodecyl, methyl-polyethylenimine was employed for the generation of polyelectrolyte multilayered films with microbicidal activity [48]. The layering was performed with a polyanion poly(acrylic acid) and the films were found to be effective against air-borne and water-borne E. coli and S. aureus, as well as the influenza virus [48]. Our group performed a detailed structure
activity relationship of polyethylenimine-based quaternized polymer-coated surfaces [58]. A series of quaternized polyethylenimines were prepared using precursor polymers of various molecular weights. Different long-chain alkyl bromides, such as 1-bromododecane, 1-bromohexadecane, 1-bromooctadecane, 1bromoeicosane, and 1-bromodocosane were employed for quaternization of PEIs (Fig. 21.3B). The synthesized polymers were insoluble in water, but soluble in organic solvents. Organosolutions of these polymers were used to easily coat various surfaces (Fig. 21.4). The coated surfaces showed activity against various pathogenic bacteria, including drug-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). They were also found to be active against pathogenic fungi such as Candida spp. and Cryptococcus spp. with complete killing (B5 log reduction in cell viability) of bacteria and fungi (Fig. 21.4). Even when tested in complex mammalian fluids (e.g., serum, plasma, and blood) the surfaces retained their activity. Their nontoxicity toward human red blood cells and zero propensity toward developing bacterial resistance proved the efficacy of the polymers to be developed as a “microbicidal paint” for various biomedical and household applications [58]. Recently, our group reported the development of another class of antimicrobial surfaces by coating with organosolutions of quaternized chitin derivatives (Fig. 21.3B) [83]. A series of antimicrobial water-insoluble and organosoluble quaternary chitin derivatives were synthesized by selective quaternization at the C-6 position of the sugar unit by using various N,N-dimethylalkylamines (N,N-dimethylhexadecyl amine was the optimized derivative) (Fig. 21.5) [83]. They were coated on various surfaces such as polystyrene plates, glass slides, or cover glasses by employing brush, dip, or spin-coating or drop casting from methanol solutions (Fig. 21.5). Polystyrene plates coated with these polymers showed potent activity against drug-sensitive and drug-resistant bacteria (MRSA and VRE) with minimal toxicity against mammalian cells (RBCs and embryo kidney cells). The minimum inhibitory amount (MIA) value for the polymer

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Figure 21.4 (A) Hydrophobic cationic polymers (R 5 C18H37): (i) branched N-alkyl Nmethyl PEIs and (ii) linear N-alkyl N-methyl PEIs. (B) Antibacterial activity of a polymer-coated glass surface against S. aureus. (C) Fluorescence microscopy and SEM images of bacteria (E. coli) untreated and treated with the coated surface. (D) Antifungal kinetics of (i) and (ii) coated surfaces at different concentrations (MIA and 8 3 MIA) against Candida dubliniensis: representative cross section of the yeast extract
peptone
dextrose (YPD) agar plate showing the growth of fungal colonies at different times. Reprinted with permission from J. Hoque, P. Akkapeddi, V. Yadav, G.B. Manjunath, D.S. Uppu, M.M. Konai, et al. Broad spectrum antibacterial and antifungal polymeric paint materials: synthesis, structure
activity relationship, and membraneactive mode of action. ACS Appl. Mater. Interfaces 7 (2015) 1804 2 1815. Copyright 2015, American Chemical Society.

consisting of a 48% degree of quaternization decreased from 0.48 to 0.06 μg/mm2, while the long chain was increased from
C12H25 to
C16H33. However, such a drastic increment in antibacterial efficacy was not found for E. coli, where the MIA value decreased from 7.8 to 3.9 μg/ mm2. The surface coated with these polymers also showed potent activity against P. aeruginosa, MRSA, VRE, and β-lactam-resistant Klebsiella pneumoniae. Additionally the surface coated with one of the best active polymers (quaternary chitin with hexadecyl aliphatic chain) was capable of preventing biofilm formation by S. aureus and E. coli. Importantly, medical-grade catheters coated with this polymer reduced MRSA burden by 3.7 log (compared to a noncoated catheter) in a murine model of subcutaneous infection with no biofilm development under in vivo

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Figure 21.5 (A) Quaternary hydrophobic chitin polymers (R0 5 C16H33). (B) Antibacterial activity of polymer-coated and polymer 1 poly-lactic acid (PLA) coated glass surface against S. aureus. (C) In vivo antibacterial activity of polymer-coated catheters (FESEM images). Reprinted with permission from J. Hoque, P. Akkapeddi, C. Ghosh, D.S. Uppu, J. Haldar, A biodegradable polycationic paint that kills bacteria in vitro and in vivo, ACS Appl. Mater. Interfaces 8 (2016) 29298 2 29309. Copyright 2016, American Chemical Society.

conditions (Fig. 21.5). This showed the potency of chitin-based antibacterial polymer to be developed as a coating material for the prevention of device-associated infections [83].

21.4.2 Switchable cationic surfaces for kill and/or release of bacteria A major problem with positively charged contact killing surfaces is the attachment of dead microorganisms. This deposition of bacterial dead cells blocks the antimicrobial functional groups of the surface and triggers immune responses leading to severe inflammation. Hence, as a result, there is an urgent need of surfaces that will not only kill bacteria, but also prevent their deposition. Various approaches have been pursued by researchers to address the problem of surface fouling. In one approach the incorporation of antifouling and antimicrobial components in the surface has been explored by many researchers [84
86]. Cationic polymers have been employed as the antibacterial

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component as well as functionalities having antifouling features to repel bacterial cells and preventing their attachment and deposition on the surface. In a recent report by Huang et al., antimicrobial and antifouling dual-functional block copolymer by the conjugation of polyhexanide with either allyl glycidyl ether or allyloxy polyethylene glycol were described [84]. Silicone rubber surfaces were coated with this polymer by plasma-UV-assisted surface-initiated polymerization. The coated surfaces killed both Gram-positive and Gram-negative bacteria. It also affected B5 log reduction in bacterial count when implanted in mice bodies for treatment of subcutaneous infection. However, the coexistence of antifouling and antimicrobial components on the surface may lead to a competitive resultant action diminishing the efficacy of the surface. Therefore another approach where antibacterial surfaces themselves can switch from a bactericidal state to a bacteria-releasing state in response to appropriate stimuli has gained enormous attention. Various stimuli such as pH [87
90], light [91], and potential [92] have been explored by researchers in this regard. pHtriggered switching of surfaces has received much attention. Degradable bactericidal cationic surfaces can hydrolyze to have a zwitterionic nature under suitable pH conditions. The zwitterionic feature of these surfaces leads to strong electrostatically induced hydration, thereby reducing bacterial cell adherence. Jiang et al. contributed significantly in developing zwitterionic surfaces for lowering fouling of surfaces [34
36,87,88]. They reported the development of zwitterionic carboxybetaine (CB) and sulfobetaine (SB) materials that can resist nonspecific protein adsorption in complex media. The researchers reported a polymer
surface coating that acted as an antimicrobial surface initially by killing bacteria upon contact and preventing their colonization. After the required period of bactericidal performance, the coating transformed into a bacteria-repelling one, hindering incoming live bacteria as well as deposition of dead bacteria cells [87]. This approach combines the advantages of cationic antimicrobial surfaces and nonfouling materials. In this report, they developed a switchable antimicrobial surface by immobilizing poly(N,N-dimethyl-N-(ethoxycarbonylmethyl)-N-[2ʹ(methacryloyloxy)ethyl]-ammonium bromide) (pCBMA-1 C2) on a surface. This antimicrobial cationic surface can kill . 99.9% of E. coli K12 within 1 h, and 98% of the dead bacterial cells can be released when the cationic derivatives are hydrolyzed to nonfouling zwitterionic polymers. However, the nondegradable analogue did not show any reduction in

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Figure 21.6 Graphical representation of a smart polymer coating that repeatedly switches between an attacking and defending function. Adapted from Z. Cao, L. Mi, J. Mendiola, J. Ella-Menye, L. Zhang, H. Xue, Reversibly switching the function of a surface between attacking and defending against bacteria, Angew. Chem. Int. Ed. 51 (2012) 2602 2 2605.

bacterial adherence. The transition between cationic and zwitterionic forms in the coating was irreversible, so the material was only effective for single-time use. To address this limitation, Jiang et al. developed a new polymer that was capable of reversibly switching between a cationic-ring structure and a zwitterionic-linear structure. The switching was obtained through a reversible lactonization reaction of two equilibrium states of smart polymers, a cationic N,N-dimethyl-2-morpholinone (CB-ring) and a zwitterionic carboxybetaine (CB
OH) (Fig. 21.6) [88]. Surfaces modified by the CB-ring form of the polymer showed high antibacterial activity, killing more than 99% of the bacteria sprayed on the surface within 1 h under dry conditions. On exposing the surfaces to water, rapid hydrolysis of the CB-ring form to the CB
OH form was observed, resulting in the release of the dead bacteria and the prevention of further bacterial fouling. Notably the CB
OH form easily converted back to the CB-ring form under an acidic environment, thereby regenerating the biocidal activity of the surface. Other researchers have also contributed significantly in developing established materials able to switch between bacteria-attacking and bacteria-defending functions. The emerging technologies tackling bacterial adherence to different substrates can greatly enhance the clinical outputs of medical implants and devices.

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21.4.3 Dual-functional (release-based and contact-based) coatings with cationic polymers and biocides All implanted medical devices, from transient, easily inserted, and retrieved ones such as contact lenses, endotracheal tubes, to more permanently surgically implanted hip, knee, and shoulder joints, pacemakers, and coronary stents suffer from implant-associated infections raising the need of antimicrobial coatings for implantable devices. However, quaternary polymeric coatings suffer from the problem of deposition of dead bacterial cells which renders them inactive. The dead bacterial cells, products of bacterial cell lysis, and bacterial proteins can form a layer on the antimicrobial surface, thereby masking their antimicrobial functionalities to reach the further invading pathogens. Also, surfaces capable of switching to nonfouling states lose their inherent bactericidal property. This problem necessitated the need of a strategy that will not only kill the bacteria adhered to the surface, but also the microbes in the surrounding environment over a prolonged period. Release-based coatings exert their antibacterial activity by leaching loaded-antibacterial compounds over time, which allows killing of bacteria on contact with the surface and in the surroundings over an extended period in a controlled manner. Polymeric coatings encapsulating different biocides have been employed extensively for their use in release-based killing. The polymeric network works as a platform for controlled release of the loaded biocide, which can be antibiotics, quaternary small molecules, antimicrobial peptides, metal nanoparticles, and others. The multifunctional mode of this releasebased strategy allowed further exploration. Researchers observed that not only the biocides, but also if the polymeric matrix is furnished as antimicrobial, then the polymer
biocide formulation can act as dual-action antibacterials. Various quaternary polymers have been employed for this application. These polymers can kill bacteria on contact whereas the loaded biocides can inactivate microbes in the surroundings, thereby reducing the risk of reinfection. Furthermore, if the polymer is biodegradable then gradual degradation reduces the possibility of biofilm formation by lowering the accumulation of pathogens on the surface. Hammond et al. developed a layer-by-layer (LbL) strategy to incorporate permanently microbicidal polycation into a drug-releasing, multilayered construct [53]. In one of their reports they developed a novel bifunctional LbL construct by combining a permanent microbicidal base film that can resist the formation of biofilms with a hydrolytically degradable top film that offers controlled delivery of antibiotics [53].

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The permanent base film that imparts the implantable device surface with microbicidal functionality is comprised of linear N,N-dodecyl, methylpoly(ethyleneimine) layered with poly(acrylic acid). The hydrolytically degradable layer was formed by the deposition of tetralayer architecture poly(β-amino ester)/poly(acrylic acid)/gentamicin/poly(acrylic acid) on the microbicidal base film. Another film architecture was developed for incorporation of diclofenac, an antiinflammatory drug to minimize foreign body response at the implant site. Controlled delivery of gentamicin was demonstrated over hours and that of diclofenac over days and both drugs were found to retain their efficacy after release. The bare, permanent, microbicidal base film was biocompatible showing minimal toxicity toward mammalian cells. The microbicidal base film prevented bacteria for the duration of the 2 weeks studied and retained its functionality after the biodegradable films had completely degraded. The multimodality of the polyelectrolyte multilayered films make them attractive candidates for coating implantable devices. However, in view of resistance development against conventional antibiotics, use of silver-based agents as antimicrobials has opened a new way for the development of new generation antimicrobials. Silver ions display broad-spectrum antimicrobial activity against various bacteria and other pathogens and is believed to be the active component in silver-based antimicrobials. Incorporating silver materials into polymers has been an effective approach to develop prolonged release of silver to tackle infections for a period of time. Mixing preformed silver particles with polymeric matrices has been extensively explored by researchers. However, this approach requires complicated physical techniques demanding the development of a novel approach for in situ generation of silver materials. Sen et al. reported a class of antimicrobial composites synthesized by onsite precipitation of silver bromide (AgBr) nanoparticles employing a pyridinium polymer (Fig. 21.3C) [45,46]. Various surfaces upon coating with the composites showed killing of bacteria and resisted the formation of biofilm. It is noteworthy that the antimicrobial action of these coated surfaces not only involved contact killing by the pyridinium polymer, but also killed microbes in a release-based fashion. Recently, Haldar et al. reported the development of a facile method of in situ reduction of a silver salt to silver nanoparticles in the presence of biodegradable and antimicrobial polymer N,N-dimethylhexadecyl ammonium chitin tosylate, which acted as a reducing and stabilizing agent (Fig. 21.3C) [20]. The polymer nanocomposites were coated onto glass surfaces, which were

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found to inactivate drug-sensitive and drug-resistant bacteria, including pathogenic fungi, at a much faster rate than the polymer alone. The composites released active silver ions over an extended period and displayed remarkably long-lasting activity. In addition, surfaces coated with composites effectively inhibited bacterial and fungal-biofilm formation. Catheters were coated with nanocomposites, which, upon implantation in mice bodies, showed .99.99% bacterial reduction on the catheter surface. The leaching of silver reduced the bacterial burden in surrounding tissues as well ( . 99.999% reduction). No toxicity was observed toward human erythrocytes [20]. Delivery of silver materials from a cationic
polymer matrix has also been exploited in real implants such as contact lenses [93]. The field of release-based antibacterial coatings has gained much attention over recent years to become one of the most widely studied areas of biotechnology owing to their potential importance in preventing nosocomial infections. Declining antibiotic therapies along with growing concern over bacterial resistance make them a much-needed strategy to limit pathogen colonization on biomaterial surfaces by providing a local and defined delivery of antibacterial compounds.

21.5 Conclusion Biomaterial-associated infections and the inability of antibiotic-based conventional therapies to treat notorious infections have created an alarming situation worldwide demanding the development of effective preventive strategies. Antimicrobial coatings have been the most compelling and potent method to tackle biomaterial-associated infections. Cationic polymers have been extensively used in the fabrication of antimicrobial surfaces killing bacteria by disrupting their membranes, leaving a minimal possibility for development of resistance. Cationic polymers have been anchored either by covalent linkers to different surfaces or they have been painted from their organosolutions giving a noncovalent approach to coat surfaces. LbL assembly of multilayered thin films is another method used for the formulation of antimicrobial films on surfaces. However, these cationic surfaces accumulate bacterial dead cells, thereby rendering the films ineffective. Researchers have come up with kill and/or release strategies where cationic surfaces killing bacteria upon contact converts to bacteriareleasing surfaces upon exposure to different stimuli. Another approach is to kill bacteria on the surface as well as in the surroundings by encapsulating leachable biocides in the cationic polymeric network. Besides these

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methods, employing a degradable polymer as the matrix, the formation of biofilms can be averted as continuous erosion of the dual-function coating does not allow bacterial adherence on the surface. Even though many groups have reported extensive in vitro activity data for different antimicrobial coatings, much less is known about their in vivo toxicity and activity. More in vivo studies are needed in order to realize their true therapeutic efficacy. Industrial feasibility and cost of fabrication cannot be overlooked. Another concern toward the development of antimicrobial coatings is the lack of standard experimental protocols. This allows reliable clinical studies to provide knowledge about coating stability and its efficacy in real scenarios, which will lead to myriads of innovations and make their translation into clinical research possible.

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Further reading 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. 6 (2018) 4274
4292. B.B. Hsu, A.M. Klibanov, Light-activated covalent coating of cotton with bactericidal hydrophobic polycations, Biomacromolecules 12 (2011) 6
9.