Antifouling, Antibacterial, and Bioactive Polymer Coatings

Anna Sienkiewicz and Piotr Czub

Cracow University of Technology

Introduction

Bacterial contamination relates to various surfaces including both medical (e.g., medical devices, implants, wound dressings) and industrial applications (e.g., food packages, industrial pipes, separation membranes, and marine). It is a globally serious problem, leading to health issues or threat to the limited efficiency and lifetime of appliances. In general, bacteria adhere on these surfaces and are able to survive by the formation of so-called biofilms. The development of these sessile-structured communities is shown in Figure 14.1. The environment of biofilms provides ideal conditions for the bacteria living, allowing for safe metabolism and increased resistance to antibiotics and host immunological defense. Because of the complex exopolysaccharides matrix protecting the attached microorganisms from the antimicrobial agents, even 1000-fold compared to bacteria growing in suspension (Campoccia, Montanaro and Arciola, 2013), the created biofilm is difficult to destroy (Davies, 2003). Mainly due to this reason, all actions leading to inhibition of microorganisms’ proliferation process and the creation of the pathogens’ biofilm are extremely important (Glinel et al., 2012). In the process of bacterial adhesion, two main stages can be distinguished: (1) interaction between the bacterial cell surface and the material surface (rapid and easily reversible) and (2) interplay between the so-called adhesion proteins on bacterial cell wall (fimbriae or bacterial pilli) and binding molecules of the surface material (relatively slow, reversible, and often termed irreversible process) (Lichter, Van

Illustration of bacterial adhesion during the process of biofilm formation. (Sufficiently adapted, modified, and redrawn based on Davies, 2003 and Lichter, Van Vliet and Rubner. 2009.)

FIGURE 14.1 Illustration of bacterial adhesion during the process of biofilm formation. (Sufficiently adapted, modified, and redrawn based on Davies, 2003 and Lichter, Van Vliet and Rubner. 2009.)

Vliet and Rubner, 2009). It is worth nothing that not one specific feature, but a variety of different factors have their influence on the process of bacterial adhesion. They include both specific and nonspecific characteristics of pathogenic microorganisms, the surface properties, and environmental conditions including temperature, concentrations of glucose and oxygen, and sustained fluid shear flows.

Antibacterial Polymer Coatings

Numerous medical interventions require the introduction of a medical device into the body. This procedure, on the one hand, is beneficial for the health improvement; on the other hand, it increases the risk of numerous complications, which include infection, inflammation, and initiation of a wound-healing response. Therefore, the research on antibacterial polymer coatings is focused on designing layers, which will be characterized by one of the following features: antibacterial agent release, contact killing, and antiadhesion/bacteria-repelling (Cloutier, Mantovani and Rosei, 2015).

Antibacterial Agent Release Coatings

The main role of antibacterial agent release coatings is discharging (via diffusion into the aqueous medium, followed by erosion/degradation or hydrolysis of covalent bonds) the antibacterial compounds over time. This way, a high antibacterial dose is delivered just in the specific areas where it is needed the most. Antibiotics or antiproliferative drugs are released from the surface in therapeutic concentrations to the certain areas, at the same time avoiding the toxic effects of drugs on the whole body system, as well as tailoring selection of antibiotics toward specific pathogens associated with exact implant infections. Antibiotic release is achieved using a wide variety of coatings, both non- and biocompatible polymer coatings. However, it is worth noting that due to the difficult diffusion through the pores of the polymer, releasing the antibiotics from nonbiocompatible materials is limited to just a certain portion of loaded amount, and additionally, after the procedure is completed, nonbiodegradable polymer matrices have to be removed. On the other hand, biodegradable polymers allow for the delivery of higher doses of antibiotics, and in most cases, their degradation products are common metabolites. Among the variety of biodegradable coatings obtained for the controlled delivery of antibiotics, the most often mentioned in the literature are poly(propylencfumarate/methylmethacrylate), collagen, polyanhydrides, polyorthoesters, and polylactide-co-glycolide.

An interesting example of polymer coatings, characterized by good durability and flexibility in terms of antibacterial agent release, is a mixture of poly(butylmethacrylate) and poly(ethylene-co-vinyl acetate) copolymers (Chudzik et al., 2005). These coatings were designed to release the antimicrobial (e.g., antibiotics such as vancomycin or norfloxacin) and/or antithrombotic agents (e.g., heparin, hirudin and coumadin) and are recommended both for self-expanding/balloon-expandable stents and urinary catheters. The authors of this invention claim the total combined concentrations of both polymers in the coating composition between 0.25% and about 70% by weight, with the bioactive agent dissolved or suspended in the coating mixture at a concentration of 0.01%-90% by weight. The medical device is covered by the polymer coating by dipping or spraying, and allowed to cure by solvent evaporation.

Another noteworthy study on the agent release polymer coatings presents biomi- metic trilayer polymeric coatings that combine controlled NO release with surface- immobilized active heparin (Zhou and Meyerhoff, 2005). The coating, containing a dense polymer bottom layer, a middle layer (polymer matrix) doped with a lipophilic diazeniumdiolate-type NO [diazeniumdiolated dibutylhexanediamine (DBHD/N20,)], and an aminated polymer (PVC or PU) top-coating allowing for the direct attachment of heparin, is synthesized to mimic the nonthrombogenic properties of the endothelial cell (EC) layer that lines the inner wall of healthy blood vessels. This invention combines the antiplatelet adhesion and activation, which are characteristics of NO release polymers, with the reduction of thrombosis by the immobilization of heparin. Figure 14.2 shows the synthesis of aminated polyurethane and covalently binding of heparine and aminated polymer through l-ethyl-3-(3-dimethylaminopropyl)carbodi- imidehydrochloride (EDC) and (A-hydroxysuccinimide) NHS as coupling agents.

Contact-Killing Polymer Coatings

The contact-killing task of polymer coatings is performed through disrupting microorganisms’ cell membranes by antimicrobial compounds, which are covalently anchored to the material surface by flexible, hydrophobic polymeric chains. This way, the antibacterial function is performed constantly without the risk of running out of

Schematic representation of

FIGURE 14.2 Schematic representation of (a) the synthesis of aminated polyurethane, (b) covalent binding of aminated polymer and heparin through EDC and NHS as coupling agents, and (c) dual acting biomimetic coating with combined NO release and surface-bound heparin (top layer: aminated polymer with surface-bound heparin; middle layer: a polymer matrix with NO donor DBHD/N,0,, and bottom layer: dense polymer). (Sufficiently adapted, modified, and redrawn based on Zhou and Meyerhoff, 2005.)

released antimicrobial compounds. The killing of bacteria is performed by either release-killing of antibacterial moiety from a matrix (such as antibiotics, phenols, and heavy metals using various methods such as spray or dip coating and hydrogel trapping) (Chung, Papadakis and Yam, 2003; Li et ah, 2006) or contact killing of antibacterial surfaces (Wu et ah, 2016). The most effective compounds for contactkilling coatings are either cationic compounds (quaternary ammonium compounds, chitosan, antimicrobial peptides, phosphonium salts, titanium oxide particles, etc.) or enzymes (Popa et ah, 2003; Green, Fulghum and Nordhaus, 2011; Munoz-Bonilla and Fernandez-Garcia, 2012).

Figure 14.3 shows 3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride (QAS), quaternized poly(4-vinyl-/V-alkylpyridinium bromide) (PVP) and quaternized poly(2-(dimethylamino)ethyl methacrylate (PDMAEMA), examples of intensively studied synthetic biocidal quaternary ammonium compounds (QACs), which are used as contact-based bactericidal surfaces.

Although the mechanism of action of QACs is not fully discovered, they exhibit strong contact-killing activity toward both Gram-positive and Gram-negative bacteria through (1) destabilization of the intracellular matrix of a bacterium by the ion-exchange mechanism with Ca2+ and Mg2+ ions in the cytoplasmic membrane and (2) destructive influence on the cytoplasmic membrane causing the leakage of intracellular fluid

Chemical structures biocidal QACs used as contact-based bactericidal surfaces. (Sufficiently adapted, modified, and redrawn based on Yu, Wu, and Chen, 2015.)

FIGURE 14.3 Chemical structures biocidal QACs used as contact-based bactericidal surfaces. (Sufficiently adapted, modified, and redrawn based on Yu, Wu, and Chen, 2015.)

(Yu and Wu, 2015). The antimicrobial effect of QACs is related to strong affinity and damaging interactions between the positively charged quaternary nitrogen of QACs and the negatively charged head groups of acidic phospholipids in microorganisms’ membranes (Elena and Miri, 2018).

On the other side, it is important to highlight that the technique using leachable biocides is characterized by two main disadvantages: termed application and generating the increasing drug resistance throughout the microbial species. So, in order to achieve biocidal effect without releasing biocide into the environment, antimicrobial moieties are irreversibly (covalently) affixed to the surface of material. Polymeric antimicrobial compounds such as tertiary amine 2-(dimethylamino)ethyl methacrylate (DMAEMA) can be attached to the surfaces of common materials including glass and paper using atom transfer radical polymerization and applied as antibacterial treatment of food packaging, everyday household items, and military applications (Lee et al., 2004). Figure 14.4 presents the synthetic pathway for the atom transfer radical polymerization (ATRP) and subsequent quaternization of DMAEMA on solid surfaces. The process involves the reaction of 2-bromoisobutyryl bromide with the hydroxyl groups of the cellulose in filter paper and the free amine groups on amino glass slides via, respectively, esterification and amidation. Throughout this reaction, the active initiator of ATRP is obtained and subsequently used to polymerize DMAEMA to the initiated surfaces in the presence of Cu(I)Br and the ligand 2,2'-bipyridine as catalysts. Additionally, as shown in Figure 14.4b, propionyl bromide can be mixed with stoichiometrically varying amounts of 2-bromoisobutyryl to differ the density of active ATRP initiation sites on the paper.

Another important issue toward preventing microbial contamination is inhibiting the microbial colonization on surfaces. Recently, it is mostly performed by application of water-soluble antimicrobial compounds, leading unfortunately to rapid development of resistant strains and environmental problems in the short time. Therefore, the invention of the coating materials based on polyethylenimine (PEI) that can kill pathogenic microorganism and stay bound to surfaces seems very promising (Hoque et al., 2015). Figure 14.5 presents the synthesis of colorless branched (V-alkyl-A- methyl PEIs by E. Clarke methylation of branched PEIs and subsequent quatemiza- tion with alkyl bromide.

Obtained coatings display excellent compatibility with both medically relevant polymer, such polylactic acid, and commercial paints. Most of all they are effective

The atom transfer radical polymerization and subsequent quaternization of DMAEMA on solid surfaces. (Sufficiently adapted, modified, and redrawn based on Lee et al., 2004.)

FIGURE 14.4 The atom transfer radical polymerization and subsequent quaternization of DMAEMA on solid surfaces. (Sufficiently adapted, modified, and redrawn based on Lee et al., 2004.)

The synthesis of water-insoluble and organo-soluble PEI derivatives. (Sufficiently adapted, modified, and redrawn based on Hoque et al., 2015.)

FIGURE 14.5 The synthesis of water-insoluble and organo-soluble PEI derivatives. (Sufficiently adapted, modified, and redrawn based on Hoque et al., 2015.)

as contact-killing compounds, showing five log reduction with respect to control toward, for example, human pathogenic bacteria including drug-resistant strains [e.g., methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and beta lactam-resistant Klebsiella pneumoniae] and pathogenic fungi (Candida spp. and Cryptococcus spp.). Additionally, it was found that linear polymers were more active and exhibit a higher killing rate than the branched one.

Antiadhesion/Bacteria-Repelling Polymer Coatings

Antiadhesion/bacteria-repelling polymer coatings prevent formation of microbial biofilm via the noncytotoxic mechanisms. It might be realized by introducing, for example, highly negatively charged polymers (electrostatic repulsion), similar hydrogel forming polymers (steric repulsion) mostly based on polyethylene glycol), or special polymers w'ith low surface energy (ultrahydrophobic repulsion) (Chen et al., 2016).

Based on performed studies (Venkateswaran et al., 2014), polymers with antiadhesive characteristics against a range of clinically important Gram-negative and Gram-positive bacteria were selected from the library of 381 polyacrylates/acryl- amides and polyurethanes. The tests performed against both individual microbe or microbial mixtures revealed that PA13, copolymer of methylmethacrylate and dimethylacrylamide (9:1 monomer ratio); PA515, copolymer of methoxyethylmethacrylate, diethylaminoethylacrylate, and methylmethacrylate (6:1:3 monomer ratio); and PU83, polyurethane synthesized from poly(ethyleneglycol)900 and 4,4'-methylen ebis(cyclohexylisocyanate), with 1,4-butanediol as a chain extender (1:2:1 monomer ratio) exhibit the best antiadhesion/bacteria-repelling properties. In Figure 14.6, the chemical structures of copolymers PA13 and PA515 are presented. Additionally, it was found that coatings of a polyurethane-based and a silicone-based intravenous catheter with PA 13 significantly reduce bacterial binding, which makes it potential antibiotic-free bacteria-repellent coatings for medical devices.

A recently presented, very interesting approach (Lin et al., 2018) is based on obtaining durably antibacterial and bacterially antiadhesive cotton fabrics coated with antibacterial cationic fluorine-containing polymers. The fabrics are prepared by spray coating of antibacterial quaternary ammonium monomers with different alkyl chain lengths and fluorine-containing monomers. Figure 14.7 shows the synthesis route for the antibacterial and bacterially antiadhesive cotton fabric.

Presented antibacterial monomers, polymers, and fabrics exhibit good antibacterial activities against both S. aureus and Escherichia coli, and slightly better for S. aureus. Moreover, alkyl chain length and contents of the antibacterial monomers, as well as the add-on percentage of polymer, has greater influence on the antibacterial properties of the fabrics. Furthermore, it was found that incorporation of fluorine component into the polymer enhances the antibacterial activity and bacterial antiadhesion of the treated fabrics due to the low surface energy-induced hydrophobicity.

Another very important group of coating materials are obtained in order to prevent microbial infection causing the implant failure. During the surgery, implants are susceptible to bacterial contamination from both skin and mucous membranes. The most critical pathogenic moment leading to development of infection on biomaterials is the formation of biofilm, starting with bacterial adhesion. There are two stages

Examples of copolymers with antiadhesive characteristics against Gramnegative and Gram-positive bacteria. (Sufficiently adapted, modified, and redrawn based on Venkateswaran et al., 2014.)

FIGURE 14.6 Examples of copolymers with antiadhesive characteristics against Gramnegative and Gram-positive bacteria. (Sufficiently adapted, modified, and redrawn based on Venkateswaran et al., 2014.)

Synthesis route for the antibacterial and bacterially antiadhesive cotton fabric. (Sufficiently adapted, modified, and redrawn based on Lin et al., 2018.)

FIGURE 14.7 Synthesis route for the antibacterial and bacterially antiadhesive cotton fabric. (Sufficiently adapted, modified, and redrawn based on Lin et al., 2018.)

of bacterial adhesion: (1) the initial interaction between bacterial cell surfaces and material surfaces and (2) interactions between proteins on the bacterial surface structures and binding molecules on the material surface (Chouirfa et al., 2019). Among the tested solutions, applied mainly for titanium implants, coating with a thermore- sponsive polymer /V-isopropylacylamide (PIPAAM) is very promising. The antiadhesive titanium surface is obtained by coating with polyglycidyl methacrylate using the initiated chemical vapor deposition technique, and in the next stage, grafting with an amine group terminated PIPAAM by the ring-opening reaction (Lee et al., 2015). The in vitro tests performed on the samples of titanium coated with PIPAAM indicate that bacteria causing peri-implantitis and nosocomial infections are effectively detached by lowering the temperature.

 
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