Chapter 1

Antimicrobial Materials—An Overview

Shaheen Mahira,a Anjali Jain,a Wahid Khan*a and Abraham J. Dombb
a Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. E-mail:
b School of Pharmacy-Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Infectious disease management has become an increasing challenge in recent years. According to the Centers for Disease Control and Prevention and the World Health Organization, microbial infections are a top concern. Pathogenic microorganisms are of main concern in hospitals and other healthcare locations, as they affect the optimal functioning of medical devices, surgical devices, bone cements, etc. Combatting microbial infections has become a serious health concern and major challenging issue due to antimicrobial resistance or multidrug resistance and has become an important research field in science and medicine. Antibiotic resistance is a phenomenon where microorganisms acquire or innately possess resistance to antimicrobial agents. New materials offer a promising antimicrobial strategy as they can kill or inhibit microbial growth on their surface or within the surrounding environment with superior efficacy, low toxicity and minimized environmental problems. The present chapter focuses on classification of antimicrobial materials, surface modification and design requirements, their mode of action, antimicrobial evaluation tests and clinical status.

1.1 Introduction

The presence of harmful microorganisms in the area of human health has become a great concern, due to the variety of infections and diseases. Rapid antibiotic resistance further worsens the situation.1 Microbial contamination, adhesion, persistence and colonization of surfaces have become detrimental to health and society. Biofilms are microbial aggregates that adhere to a substrate and these account for 80% of infections that lead to increased patient morbidity and medical expenses.2 According to Neely and Maley, vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus (MRSA) can survive for a day on materials used in healthcare systems and some microbes can survive for more than 90 days.3 To overcome these issues, materials that can provide antimicrobial activity are being explored for biomedical use to reduce hospital-acquired infections.4 Disinfectants such as hydrogen peroxide, hypochlorite, etc. have a short duration of action and environmental toxicity issues.5 Antimicrobial materials are capable of inhibiting or killing the microbes on their surface or within their surroundings,6 but clinically they have significant shortfalls such as poor antimicrobial activity, issues with microbial resistance and difficulty of functioning in a dynamic environment. Thus, there is a need for effective and long-term antibacterial and biofilm-preventing materials to meet the demands in biomedicine.2 With that said, new macromolecules with antimicrobial activity as well as structural modification of polymers to achieve desirable physicochemical and biological properties are being developed.7

Biofilms are a bacterial defense mechanism that protect bacteria from being washed away and make bacteria less susceptible or ineffective towards toxins. Biomedical devices are commonly used in hospitals as part of medical practice. They can be a source of microbial infections via contact with body fluids and tissues and due to openings in protective barriers, such as the skin, leading to nosocomial or hospital-acquired infections. Out of 150 million intravascular devices used annually in the USA, 200 000–400 000 result in nosocomial bloodstream infections. So prevention of these infections becomes necessary to reduce patient suffering and huge associated medical costs.8 Related to this, there is an increased need to explore long-lasting, broad-spectrum and more efficient antimicrobial agents, due to unceasing global emergence of new infectious agents.9

Antimicrobial polymers have wide applications in the biomedical field, especially when they are in direct contact with the human body. They should possess certain requirements and meet regulations for safe use within the body. Firstly, they should be biocompatible, unreactive to the body with good stability and resistance to bodily fluids. Moreover, as previously mentioned, higher content of microbes in biofilms can result in serious infections and health issues. Therefore, selecting appropriate polymers against microbes is essential for biomedical applications.10 Microbes can acquire resistance easily upon use of conventional antimicrobials, and can lead to environmental contamination and toxicity to humans due to biocidal diffusion.11,12 Antimicrobial polymeric materials can address these problems by promoting antimicrobial efficacy and reducing residual toxicity.13,14 Some described polymeric systems can belong to more than one section in this chapter. However, the purpose of the chapter is to provide a handy overall vision of the field of antimicrobial materials.

1.2 Antimicrobial Materials

1.2.1 Antimicrobial Polymers

Antimicrobial polymers have emerged as promising candidates against microbial contamination owing to their properties. Their versatile macromolecular chemistry facilitates the tailoring of polymer physicochemical properties to be used for various applications in the biomedical field.15 Polymers with Intrinsic Antimicrobial Activity

In nature, most materials possess antimicrobial ability. Materials that exhibit antimicrobial action without any modification are known as intrinsic antimicrobial materials.16 Natural Polymers Chitosan

Chitosan was discovered by Rouget in 1859 and is the most widely used polymer in biomedicine, with its broad-spectrum antibacterial activity, first proposed by Allan and Hadwinger.17,18 It is a linear, polycationic heteropolysaccharide composed of (1–4)-2-acetamido-2-deoxy-βd-glucan (N-acetyl d-glucosamine) and (1–4)-2-amino-2-deoxy-β d-glucan (d-glucosamine) units obtained by partial alkaline N-deacetylation of chitin.19 The physicochemical and biological properties of this biopolymer depend on its number of amine groups, thus favoring site-specific modification and providing versatility for more applications. Its antimicrobial activity can be explained by two main mechanisms. Firstly, positively charged chitosan can interact with negatively charged microbial cell surfaces and will either prevent the transport of essential materials into cells or result in leakage of cellular contents. In the second mechanism, chitosan binds with cellular DNA (via protonated amine moieties) and results in microbial RNA synthesis inhibition.20,21

Chitosan acts on various types of bacteria and fungi (Table 1.1) and its activity in turn depends on the polymer-related factors (molecular weight, charge density, hydrophilic/hydrophobic character, concentration and chelating capacity), pH, ionic strength, temperature, and the type of microbe.22 Copolymers with zwitterionic properties were obtained by grafting the mono (2-methacryloyloxyethyl) acid phosphate and vinyl sulfonic acid sodium salt upon chitosan. They showed the optimum antimicrobial activity at 5.75 pH towards Candida albicans.23 The antimicrobial activity of quaternary ammonium salts of chitosan increased with an increase in the alkyl chain length that was attributed to the increased lipophilic properties of the derivatives.24 Chitosan-based biomedical materials are gaining much attention due to their biodegradability, biocompatibility, non-toxicity and antimicrobial effects. In addition, hydrophilicity and their structural similarity to glycosaminoglycans make them versatile materials for tissue engineering.25,26 These properties account for wide applications as excipients for drug delivery and gene delivery in wound healing and tissue engineering.27 Cross-linked, quaternized chitosan/polyvinylpyrrolidone electrospun mats were found to be attractive materials for wound dressings as they were more efficient in inhibiting Gram-positive and Gram-negative bacterial growth.28 Novel composite scaffolds based on α-chitin/nanosilver29 and β-chitin/nanosilver30 exhibited profound antibacterial activity towards Staphylococcus aureus and Escherichia coli.

Table 1.1 Minimum growth inhibitory concentration for chitosan antibacterial and antifungal activity.
Microorganism Minimum inhibitory concentration (ppm) Ref.
Antibacterial action
Salmonella enterica 2000 31
Bacillus cereus 1000 32
Klebsiella pneumoniae 700 33
Erwinia species 500 33
Xanthomonas campestris 500 34
Erwinia carotovora 200 33
Vibrio cholerae 200 32
Escherichia coli 100 32
Staphylococcus aureus 20 33
Corynebacterium michiganensis 10 33
Antifungal action
Byssochlamys spp. 1000–5000 35
Trichophyton equinum 2500 33
Trichophyton mentagrophytes 2200 36
Aspergillus fumigatus >2000 32
Microsporum canis 1100 36
Candida albicans 500 32
Fusarium oxysporum 100 33
Botrytis cinerea 10 33 Heparin

Heparin, a highly sulfated glycosaminoglycan, is widely applicable in the field of hemocompatible biomaterials.37 The antimicrobial mechanism has not been clearly defined for heparin. However, due to heparin binding with calcium, it seems likely that it acts by chelation of cations that are essential for bacterial growth. Other possible mechanisms might be the inhibition of transport/intracellular utilization of cations. Warren and Graham reported the antimicrobial activity of heparin against Staphylococcus aureus and Erwinia stewartii at a concentration of 150 U mL−1, when they were grown in protein-free medium.38,39 Heparin binding or coating has prevented microbial adhesion and colonization in vitro and in vivo by its ability to favor albumin adsorption and reduced fibrinogen adsorption. In a randomized pilot study, 20 ureteral stents with and without heparin coating were inserted into obstructed ureters for 2–6 weeks and evaluated for encrustation and biofilm formation. About 33% of uncoated stents were colonized by bacteria, while no biofilms were detected on heparin-coated stents. There was a significant decrease in catheter-related infections with heparinized central venous catheters (CVCs) and dialysis catheters that was confirmed by randomized study of heparin-coated and uncoated non-tunnelled CVCs inserted in 246 patients as well as in a retrospective study of coated and uncoated tunnelled dialysis catheters.37 ε-Polylysine

ε-Polylysine (ε-PL) is a hydrophilic linear polyamide composed of 25–30 residues of l-lysine with ε-amino and α-carboxyl group linkage.40 Shoji Shima, Heiichi Sakai, and co-workers first described the production of ε-polylysine by natural fermentation resulting in a compound with wide antibacterial spectrum and lethal effect on bacteria, yeast, mould, viruses etc.41 Its antimicrobial activity depends on the number of l-lysine residues, with >10 residues being necessary to exhibit proper antimicrobial action.40 It has good antibacterial effect on Gram-negative bacteria that are difficult to control. In addition, it is adsorbed electrostatically to bacterial cell surfaces that have negatively charged lipopolysaccharide, causing the stripping of their outer membrane. This eventually leads to abnormal cytoplasmic distribution and cell death.41

Naturally available ε-PL is edible, biodegradable, non-toxic and soluble in water. ε-PL derivatives can be used as emulsifiers, drug carriers, biodegradable fibers, highly water-absorbable hydrogels, biochip coatings, etc.42 ε-PL was studied as an antimicrobial agent in platelet concentrates for the first time in Japan, where it was shown to completely inhibit the growth of Staphylococcus epidermis, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus in platelet concentrates after 8 days at 100 µg mL−1. ε-PL and polycaprolactone (PCL) copolymer showed a broad-spectrum antibacterial action towards Escherichia coli, Staphylococcus aureus and Bacillus subtilis.43 Polymers Containing Quaternary Nitrogen Atoms

Most bacterial cells are negatively charged, hence most antimicrobial polymers are positively charged to drive their interaction. In addition, the ones with quaternary ammonium moieties are mostly explored as polymeric biocides. Polycationic biocides act by destructive interaction with the bacterial cell wall.44 Antimicrobial activity of quaternary ammonium compounds (QAC) depends on the length of their N-alkyl chain.45 For bacteria and fungi, the optimum chain length of QACs is different (14 carbons for Gram-positive bacteria, 16 carbons for Gram-negative bacteria and 12 carbons for yeast and filamentous fungi).46,47 Antifungal activity of QACs is attributed to their electrostatic interaction with fungal cell membrane resulting in cell lysis. The antifungal activity may also involve the impediment of formation of hyphae.48 The virucidal mechanism of QACs for enveloped viruses involves disruption or detachment of the viral envelope, with subsequent release of nucleocapsid.49 Polymers with Aromatic or Heterocyclic Groups

Cationic polymers with quaternary ammonium groups and aromatic or heterocyclic rings are synthesized from polystyrene and polyvinylpyridine. Imidazole derivatives offer good chemical stability, with resistance to hydrogenation, and undergo numerous substitution reactions for providing functional derivatives. Random and block copolymers containing quaternized poly (4-vinylpyridine) (P4VP) and polystyrene showed good antibacterial action. P4VP possesses reactive pyridine groups that form pyridinium-type antimicrobial polymers.50,51 The antimicrobial activity and biocompatibility of N-hexylated P4VP was improved by copolymerization with poly(ethylene glycol) methyl ether methacrylate. Due to increased surface wettability, the antibacterial property of these polymers was found to be 20 times higher than the quaternized homopolymer, without causing any hemolysis.52

In general, the antifungal mechanism of action of gemini QACs involves lysis of cell membrane and cell organelles. Gemini QACs contain two pyridinium residues [3,3-(2,7-dioxaoctane) bis(1-decylpyridinium bromide)] per molecule, that cause respiration inhibition and cytoplasmic leakage of adenosine triphosphate as well as magnesium and potassium ions in Saccharomyces cerevisiae.53d-Glucosamine QA derivatives have potent antifungal activity towards Coriolus versicolor and Poria placenta by forming complexes with essential elements to block/reduce their fungal growth.54 Zephiran (alkyl dimethyl benzylammonium chloride) also effectively inactivates enveloped viruses such as vaccinia virus and some non-enveloped viruses such as reovirus and bacteriophages. However, it is not effective against small, non-enveloped viruses such as picorna viruses.55,56 Polyacrylamides and Polyacrylates

Among cationic synthetic polymers, polyacrylamides and polyacrylates with tertiary or quaternary amine groups are the most investigated antimicrobial polymers due to their wide versatility and ease of synthesis. Physicochemical properties and antimicrobial activity can be properly modulated by varying the type of monomers, type of counter ion of charged groups, polymer amphiphilicity and alkyl chain length attached to the cationic groups.57

Methacrylate polymers with tertiary butylamine groups are considered to be potent antimicrobials.58 Most of the quaternary polyelectrolytes are obtained from methacrylic monomers such as 2-(dimethylamino) ethyl methacrylate.59 Antimicrobial properties of modified glycidyl methacrylate polymers with quaternary ammonium and phosphonium groups were tested against Gram-positive bacteria (Bacillus subtilis and Bacillus cereus), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhae and Shigella sp.) and fungus (Trichophyton rubrum). These polymers showed prominent antimicrobial properties against Gram-negative bacteria and fungi at 24 h contact time.24 Palermo and Kuroda synthesized copolymers based on polymethacrylate and polymethacrylamides, where the hydrophobic groups, polymer composition and length were varied to get antimicrobials with non-hemolytic properties. Methacrylamides with alkyl pyridinium pendant groups and temperature-responsive N-isopropylacrylamides were also synthesized as biocides.59

In 1960, Wichterle and Lim first described the use of poly-2-hydroxyethylmethacrylate (PHEMA) for contact lens applications.60 It got FDA approval in 1971 and was sold by Bausch & Lomb.61 HEMA/N-vinyl-2-pyrrolidone hydrophilic copolymer is used to make soft contact lenses that cover the entire cornea and present good oxygen permeability with great comfort. By contrast, hydrophobic polymers such as poly(methyl methacrylate) (PMMA) and poly(hexa-fluoroisopropyl methacrylate) are widely used for hard contact lenses.62–64 pH- and thermal-sensitive hydrogels of PHEMA and itaconic acid copolymers have potential biomedical applications, mainly for dermatological treatments and wound dressings. Porphyrin-crosslinked poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) copolymers were used for preventing endophthalmitis.65 Quaternized chitosan-loaded PMMA has been shown to inhibit MRSA and exhibits excellent physical properties and osteogenic activity.52 Polysiloxanes

Polysiloxanes with quaternary ammonium and imidazolium groups, as well as polysilsesquioxanes with quaternary ammonium groups, have activity against Gram-positive and Gram-negative bacteria. Polysiloxane polymers with pendant quaternary ammonium salt (QAS) groups show antibacterial action via interaction with bacterial membranes.58 Generally, these polymer systems show the lowest adhesion and best foul release of biofouling, based on a repeating unit (–Si–O–), with saturated organic groups linked to two non-backbone valencies of the silicon. Moreover, the Si–O bond is stronger (108 kcal mole−1) than C–C bonds (83 kcal mole−1) and is extremely durable, providing long-term control of fouling.66

Polysiloxanes with quaternary ammonium groups are gaining interest due to high flexibility of polymer chains that makes the contact of microbe and polymer easier. Their hydrophilic inorganic and hydrophobic organic groups augment the quaternary moiety in the vicinity of the microbial cell wall. Polysiloxanes with N,N-dialkylimidazolium salt showed higher antibacterial power. Imidazolium-substituted polysiloxane has higher thermal stability compared to alkyl ammonium functionalized polymers.67 Poly-dimethyl-siloxane (PDMS) is the most commonly used silicone polymer. PDMS with QAS moieties will facilitate contact-killing antimicrobial properties of the materials.68 Polyionenes

Polyionenes are polymer electrolytes with quaternized nitrogens in the polymer backbone.69,70 In general, their antimicrobial efficacy depends on chain rigidity, pendant substituents and alkyl chain length.71–73 When compared to ionenes with flexible spacers, the rigid spacers exhibit greater interaction with lipidic bilayers resulting in their phase separation. Ionenes with low charge density and longer lipophilic chains exhibit effective biocidal activity against yeast, indicating that their hydrophobicity is the predominant factor for cell wall disruption.9,71 Tiller's group synthesized N,N,N′,N′-tetramethyldiamine- and α,ω-dibromoalkane-based polymers and found that they have excellent antimicrobial activity with non-hemolytic properties.72,73 Polyoxazolines

Polyoxazolines are pseudopeptides obtained by ring-opening reactions.74,75 Their properties can be tuned by controlling the end functional groups during initiation and termination chain reactions and by varying the monomer side chain. Due to lower toxicity and functional versatility they are known as biocide end-functionalized polymers.76

Polyoxazolines represent a valuable type of macromolecules and are mainly investigated in the biomedical field due to their biocompatibility, blood clearance and protein adsorption. A series of polymethyloxazolines with different satellite groups including hydroxyl-, primary amine- and double bond-containing groups were synthesized. It was found that the functional satellite groups greatly controlled the minimum inhibitory concentration (MIC) towards Staphylococcus aureus and Escherichia coli at a range of 10–2500 ppm.77,78 Hyperbranched and Dendritic Polymers

Branched polyethylene imine (PEI) in its quaternized form adsorbs on the bacterial cell membrane and causes cell death by disrupting the cell membrane and releasing the intracellular contents, thereby showing outstanding antibacterial activity.79 Its antibacterial properties depend on dendrimer size, length of hydrophobic chains in quaternary ammonium groups and counter anions.79 The main drawback of branched and hyperbranched polymers is the polydispersity and functional heterogeneity that makes it difficult to rationalize and understand their behavior with microbes. This led to the emergence of dendrimers with compact structure, monodisperse molecular weights and availability of many end groups. Their biocidal properties depend on dendrimer size, hydrophobic chain length, surface porosity and counter anions. Poly(propyleneimine) and poly(amidoamine) (PAMAM) dendrimers are widely used in drug delivery and gene therapy.80 Polyethylene glycol diacrylate (PEGDA)-based dendrimers are made by reacting PEGDA with ethylene diamine and diethyl amine. Quaternary dendrimer-based copolymers showed antimicrobial action based on the amount of quaternary ammonium moieties and surface porosity.52,81 Polymers with Guanidine Groups

Polyguanidines and polybiguanides possess high water solubility, a broad antimicrobial spectrum and non-toxicity, thereby attracting considerable attention as antimicrobial compounds.82 They can be synthesized by polycondensation or polyaddition and the starting materials can consist of monomeric guanidines, isocyanide dihalides, guanido acid esters, cyanogen halides or dicyanamides. In the 1940s, the first patent for oligoguanidine compounds as antibacterial agents was filed.83 Earlier findings suggested that an average molecular weight of 800 Da is required for efficient antimicrobial action.84 Polyhexamethylene biguanide is a broad-spectrum antimicrobial biocide that kills bacteria, fungi, parasites and certain viruses. It has biguanidine units linked with hexamethylene hydrocarbon chains, thereby providing an amphipathic structure.85 Its antimicrobial activity is attributed to bacterial cell wall disruption. It binds with lipid membranes, causing increased membrane fluidity and permeability and subsequent microbial death. It has also been reported to bind bacterial DNA, altering the transcription process and causing lethal damage to DNA.86 Polymers Mimicking Natural Peptides

Antimicrobial peptides (AMPs) are the main components of host defense against various infections; they display remarkable activity against bacteria, fungi, viruses and parasites.87,88 They have roles in immunomodulation and inflammation processes. They kill bacteria by different mechanisms such as cell membrane disruption, interference with metabolism and targeting cytoplasmic components.89 They usually have hydrophilic and hydrophobic groups that enable the molecule to be solubilized in aqueous environments and pass through the lipidic membranes. However, their utility has been hindered due to high manufacturing costs, susceptibility to proteolysis and poor pharmacokinetic profile.90 Additionally, the complexity of the native structure imposes difficulty in studying their bioactivity. All these reasons have led to an increase in research interest in synthesizing AMPs.76

AMPs can serve as promising candidates for new-generation antimicrobials and are of great interest due to a low risk of bacterial resistance, broader spectra of action, target specificity, high efficacy and synergistic action with classical antibiotics.91 Extensive research has been done in the area of making synthetic peptides, maintaining the natural peptide skeleton (l-α-amino acids) and non-naturally occurring structures (d-α-amino acids, β-peptides or peptoids). Solid-phase synthesis and solution coupling are the common methods to prepare AMPs. Analogs of idolidicin were synthesized to give less toxic polymers with higher antimicrobial properties.92 Similarly, grasitin analogs exhibited potent action against Gram-positive and Gram-negative bacteria with significant reduction in hemolysis.93 β-Peptides are a class of polyamides mimicking AMPs that can show various helical conformations and resistance to degradation by proteases when compared to conventional peptides. Arylamide and phenylene ethynylene oligomers and polymers were made by simple and inexpensive synthetic methods.94 Polynorbornene derivatives prepared by various synthetic strategies with high molecular mass afford good antibacterial action with minimal cytotoxicity to humans. Ilker et al. found that upon increasing the amine groups on such polymers, hemolytic activity decreased significantly.13 The fungal cell wall contains mannan, chitin and glucans that are absent in other microbes, making them potential targets for therapeutics. Antifungal peptides target fungal cell walls via peptide binding to chitin. Moreover, they show lethal effects by disrupting membrane integrity, promoting membrane fluidity or by creating pores.95 A list of antimicrobial peptides and their antibacterial action is given in Table 1.2.

Table 1.2 List of antimicrobial peptides.
Antimicrobial peptide Chemical ring Antimicrobial action Ref.
Magainin α-Helix Active against bacteria, fungi and viruses 97–99
Cecropin α-Helix Active against bacteria, fungi and viruses 100–102
Brevinin-1 α-Helix Active against fungi and viruses 103, 104
PMAP-23 α-Helix Active against fungi 96, 97
Protegrin β-Sheet Active against bacteria and viruses 98, 99
Dermaseptin β-Sheet Active against viruses 100, 101
Tachyplesin β-Sheet Active against viruses 102, 103
Polyphemusin β-Sheet Active against viruses 104, 105
Tenecin-3 Extended turn Active against fungi 106
PR-39 Extended Active against bacteria 107 Polymers Containing Halogens Polymers Containing Fluorine

Polymers containing fluorine are most attractive, due to their unique properties such as oil and water repellence due to lower polarizability and high electronegativity of fluorine atoms; higher chemical, thermal and weather resistance; lower dielectric constant and lower surface energy.76 2-[(4-Fluorophenyl)amino]-2-oxoethyl-2-methylacrylate was synthesized by free-radical copolymerization. It was found to be more prominent in inhibiting microbial growth due to high fluorine content.108 By replacing two leucine residues in buforin II with more hydrophobic hexafluoro-leucine residues, antibacterial activity was enhanced without significantly impacting hemolytic activity.109 Moon et al. synthesized a polymer with quinolone and a fluorine atom that proved its capacity to kill bacteria.110 Guittard's group developed Quaterfluo®, in which perfluoro alkyl groups were incorporated into the gemini structure. The results showed their potent antimicrobial activity after 1 h of contact time.111 Polymers Containing Chlorine

Kugel et al. modified triclosan with an acrylate functionality followed by copolymerisation with different compositions of ethyl and butyl acrylates. Results showed that antimicrobial properties improved upon increasing triclosan groups without any leaching of triclosan.112 It acts by deactivation of fatty acid synthesis of bacteria by inhibiting enoylacyl carrier protein reductase.49 N-Halamine Compounds

N-Halamines are formed by halogenation of amide, imide or amine groups by covalent bonding. They are the most promising candidates as antimicrobials, due to their fast and total killing action against various microbes without any environmental concerns and long-term stability, and it is highly unlikely that microbes will establish resistance to them.24 They promote the direct transfer of active moiety to the target site or by dissociating into free halogen in aqueous media, resulting in inactivation/inhibition of microbial growth.76N-halamine acrylamide monomers were copolymerized and used as antimicrobial coatings that exhibited 8-log inactivation of both Gram-positive and Gram-negative bacteria following a 5 min short contact time.113 Imparting Antimicrobial Activity to Polymer by Chemical Modification Covalent Incorporation of Lower Molecular Weight Antimicrobials

Poly(4-vinylphenol) (PVPh) was modified by sulfonation followed by electrospinning and MIC values were measured against a variety of bacteria, where modified polymers exhibited greater antimicrobial action at lower concentration than unmodified PVPh.114 Worley and co-workers incorporated N-chloramine moieties (hydantoins, oxazolidinones and imidazolidinones) into polyester and nylon fabrics by covalent conjugation. The resulting antimicrobial activity suggested that they are highly effective with 7-log reduction in 10 min in case of hydroxymethyl hydantoin functional group incorporation.115,116 Badrossamay and Sun grafted nitrogen-containing monomers (acrylamide, methacrylamide, N-tert-butylacrylamide and N-tert-butylmethacrylamide) into polyethylene and polypropylene, where they showed good antibacterial activity at 30 min contact time, even at concentration of bacteria above 107 CFU mL−1.117,118 Coupling of Antimicrobial Peptides

Cationic polymers that are hydrophobic can be used as antimicrobial coating materials and they are capable in inhibiting bacteria and human-pathogenic fungi.119 They interact with bacterial and fungal cell walls, disrupting the integrity of the lipid membrane, and impairing the transportation of compounds, ultimately leading to cell lysis. In fungal cells, cationic amphipathic peptides such as magainin cause membrane lysis and interfere with the DNA integrity of fungi cells.95,120

Polyethylene glycol-grafted polystyrene beads were covalently linked to AMPs with specific sequences. The results showed that their antimicrobial action was dependent on exposure time and concentration of modified polystyrene.121 2-(2-Methoxyethoxy) ethyl methacrylate and hydroxylated oligoethylene glycol methacrylate copolymer were functionalized with magainin I, and the results showed strong biocidal activity and biofilm prevention, even at low degrees of peptide coupling.76 Grafting Other Antimicrobial Polymers

To infer antimicrobial activity, natural polymers can be grafted to synthetic polymers. Yang et al. grafted chitosan onto polypropylene modified with acrylic acid and found that with increasing acrylic acid grafting, cell viability decreased.122 Lysozyme was immobilized to polyvinyl alcohol cross-linked films and the antimicrobial property was directly proportionate to the amount of enzyme incorporated.123 Poly(ethylene terephthalate) films were copolymerized and quaternized with hexyl bromide to yield pyridinium groups that were found to be more effective when the surface concentration was larger than 1.5×10−4 mol mol−1 m−2.124

1.2.2 Antimicrobial Nanomaterials Organic Nanoparticles

Polymeric nanoparticles can kill microbes by contact-killing cationic surfaces (quaternary ammonium compounds, quaternary phosphoniums or alkyl pyridiniums) or by releasing antimicrobial agents and antimicrobial peptides. The antibacterial activity of polycations depends on the ability of multiple charges to attach and interact with the bacterial cell wall.2,125 Non-covalent Incorporation of Lower Molecular Weight Antimicrobials

Lu et al. incorporated triclosan, a widely used antimicrobial, into cyclodextrin and subsequently into PCL or nylon films. By this modification, the antimicrobial agent was protected against higher temperatures during processing.126 Sulfamethoxazole was introduced into PAMAM dendrimers as drug carriers in aqueous media. Diuron or 3-(3,4-dichlorophenyl)-1,1-dimethylurea was embedded in poly(ester anhydride) composed of sebacic acid, ricinoleic acid, terephthalic acid and isophthalic acid, by which release of the compound was observed for about 25 days.76,127 Incorporation of Mixture of Antimicrobials Non-covalently

Polymers can be mixed with natural or synthetic antimicrobial polymers. Quaternized PEI at 1% or 2% w/w can be added to the composite resins. Data from antibacterial assays demonstrated that the antibacterial properties were retained up to 3 months with complete growth inhibition of Enerococcus faecalis, Staphylococcus aureus and Streptococcus mutans and a reduced growth of Staphylococcus epidermis and Pseudomonas aeruginosa.128,129 Jones et al. blended PCL with poly(N-vinylpyrrolidone)-iodine which imparted antibacterial properties to the biomaterials without altering mechanical or rheological properties. Moreover, PCL degradation also favored the anti-adherence of Escherichia coli.130 Inorganic Nanoparticles

Organic antibacterials are usually less stable at higher temperatures when compared to inorganic materials, which poses difficulties in designing materials that are stable and able to withstand harsh processing conditions. In order to overcome these problems, inorganic nanosized materials are often used as antimicrobial materials.2,6 Various coating techniques are listed in Table 1.3. A list of metal and metal oxide nanoparticles and their antimicrobial action is presented in Table 1.4. The antimicrobial mode of action of metal oxide nanoparticles is explained in Figure 1.1 and different approaches for surface modification are shown in Figure 1.2.

Table 1.3 Different methods of surface modification of biomaterials.
Method Description Ref.
Sputter deposition Atoms from the target are ejected from the energized gas ions that travel and bind with the substrate forming a coat 144–146
Electrostatic spray deposition Process of liquid automization by means of electrical forces 131
Electrophoretic deposition Involves motion of charged particles towards the oppositely charged electrode and deposit formation under the influence of applied electric field 132
Chemical vapor deposition Reactive mixture of gas is moved to the coating area from a chemical reaction thus forming a coat on the target substrate 149–151
Pulsed laser deposition Laser ablate a target material and condense it on the surface of a substrate 133
Photo-chemical deposition Photo-reduction of a silver precursor results in nanostructured silver coatings 153–155
Sol–gel method By hydrolysis and condensation, the sol becomes gel. Further drying and heating converts gel into denser particles 134, 135
Table 1.4 Antimicrobial activity of metal oxide nanoparticles.a
Metal oxide NPs Test organism Antimicrobial action Ref.
Aluminium oxide (Al2O3) NPs Escherichia coli Growth inhibition of Escherichia coli 136
Antimony trioxide (Sb2O3) NPs Escherichia coli, Bacillus subtilis and Staphylococcus aureus Toxic to all the three microbes 137
Bismuth oxide (Bi2O3) NPs Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli No effect against all tested microbes 138
Calcium oxide (CaO) NPs Lactobacillus plantarum Higher bactericidal activity 139
Cerium oxide (CeO) NPs Escherichia coli, Shewanella oneidensis and Bacillus subtilis No effect on Shewanella oneidensis 140
Cobalt oxide (Co3O4) NPs Staphylococcus aureus and Escherichia coli Showed antimicrobial activity on tested bacteria 141
Copper oxide (CuO) NPs MRSA, Staphylococcus epidermis, Pseudomonas aeruginosa, Proteus sp. Staphylococcus aureus, Bacillus subtilis, Escherichia coli; fish pathogens: Aeromonas hydrophila, Pseudomonas fluorescens, Flavobacterium sp. and Branchiophilum sp. Active against all the tested microbes 142–145
Magnetite (Fe3O4) NPs Escherichia coli Concentration-dependent bacteriostatic action 146
Iron oxide (FeO) NPs Staphylococcus aureus, Shigella flexneri, Escherichia coli, Bacillus licheniformis, Bacillus subtilis, Brevibacillus brevis, Vibrio cholerae, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermis Moderate antibacterial activity against 6 Gram-positive and 2 Gram-negative bacteria 147
Magnesium oxide (MgO) nanowires Escherichia coli and Bacillus spp. Lower bacteriostatic activity 148
Titanium dioxide (TiO2) NPs MRSA Exhibited antimicrobial effect on tested isolates 149
Zinc oxide (ZnO) NPs MSSA, MRSA and MRSE, Streptococcus agalactiae, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Salmonella paratyphi, Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium smegmatis, Mycobacterium bovis, Klebsiella pneumoniae, Enterobacter aerogenes, Candida albicans, Malassezia pachydermatis, Bacillus megaterium, Bacillus pumilus and Bacillus cereus Active on tested microbes 150–156
Zinc/iron oxide composite NPs Escherichia coli and Staphylococcus aureus Exhibited greater antibacterial activity with higher Zn/Fe weight ratio 157
ZnO-loaded PA6 nanocomposite Staphylococcus aureus and Klebsiella pneumoniae Dose-dependent antibacterial action 158
Nanosilver-decorated TiO2 nanofibres Staphylococcus aureus and Escherichia coli Increased antimicrobial effect 159
Hybrid CH-α-Fe2O3 nanocomposite Staphylococcus aureus and Escherichia coli Improved antibacterial activity 160
Zinc-doped CuO nanocomposite Escherichia coli, Staphylococcus aureus and MRSA Remarkable biocidal activity 161
PEI-capped ZnO NPs Escherichia coli Exhibited better antibacterial activity 162
Chitosan-based ZnO NPs Candida albicans, Micrococcus luteus and Staphylococcus aureus Showed biofilm inhibition against Micrococcus luteus and Staphylococcus aureus 163
Carvone functionalized iron oxide Staphylococcus aureus and Escherichia coli Inhibited colonization and biofilm formation 164
Silver-decorated titanium dioxide (TiO2 : Ag) NPs MRSA and Candida sp. Conferred antimicrobial effect on tested microbes 165
Graphene oxide modified ZnO NPs Escherichia coli, Bacillus subtilis, Salmonella typhimurium and Escherichia faecalis Excellent antibacterial activity 166
a NPs: nanoparticles; MRSA: methicillin-resistant Staphylococcus aureus; MRSE: methicillin-resistant Staphylococcus epidermidis; MSSA: methicillin-sensitive Staphylococcus aureus; PEI: polyethyleneimine.
Fig. 1.1 Mechanism of antimicrobial action by metal oxide nanoparticles (MO-NPs): MO-NPs cause cell membrane damage by electrostatic interaction. Their accumulation dissipates the proton motive force, disrupting the chemiosmosis process, thereby causing proton leakage. They induce reactive oxygen species generation which damages organic biomolecules (carbohydrates, lipids, proteins and nucleic acids) finally causing microbial death. They bind with mesosomes and alter cellular respiration, cell division and the DNA replication process. Dephosphorylation of phosphotyrosine residues inhibits signal transduction and ultimately obstructs bacterial growth. Protein carbonylation leads to loss of catalytic activity of enzymes, ultimately triggering protein degradation. Photosensitized transition MO-NPs cause alteration in cell membrane, Ca2+ permeability, diminution in superoxide dismutase activity, DNA damage and abnormal cell division.
Fig. 1.2 Approaches for surface modification in medical devices to impart antimicrobial properties. Polymer coating is preferable for controlled drug release of organic or inorganic antimicrobial compounds, whereas in inorganic coatings both antimicrobial compound release and intrinsic antibacterial activity are possible.

1.2.3 Antimicrobial Plastics

Bioplastics are biopolymers obtained from proteins and are widely explored for their uses in medicine. They exhibit antimicrobial properties by creating anti-adhesive surfaces, disrupting cell-to-cell communication or leading to cell membrane lysis, thereby killing bacteria.167 Soya, albumin and whey protein serve as the source of raw materials for producing bioplastics that act as promising materials for fabricating implants. Albumin shows antimicrobial activity by its enzyme lysozyme, which causes cell wall lysis. Albumin from hen egg whites is of particular interest in medical device fabrication due to its inherent antibacterial nature.168 Albumin-based plastics reduce the growth of Escherichia coli and Bacillus subtilis on their surface.169 Glycomacropeptides and immunoglobulins present in whey protein bind the toxin and prevent microbial infection.170 Different test methods are available that can be performed to determine whether albumin or whey plastics can be used in medical applications, based on the intended use in areas such as packaging medical products (ASTM F2097-10: Standard Guide for Design and Evaluation of Primary Flexible Packaging for Medical Products) and infection testing for medical applications (ASTM F813-07(2012): Standard Practice for Direct Contact Cell Culture Evaluation of Materials for Medical Devices).171

Currently, silver-based nanoengineered materials are widely applicable in plastic commodities because of their antimicrobial abilities. In medicine and for food safety, titanium-, copper- and zinc-based nanostructures also show promising antimicrobial effects.172 Liu et al. prepared plastics with excellent antibacterial activity by adding Ag/TiO2 to resins.173 Matet et al. synthesized plasticized chitosan-based polymers containing good antibacterial properties and mechanical strength with easy scale-up.174 de Olyveira et al. developed a polyethylene composite containing silver microparticles.16,175

1.2.4 Antimicrobial Ceramics

Hydroxyapatite is a biocompatible and bioactive material in common use as an implant in bone tissue regeneration and as a drug carrier in drug and gene delivery systems. Due to its structural flexibility, various metal ions can be substituted in order to improve solubility, antibacterial activity and mechanical strength for bone implantation.176,177 In addition, it is a potential candidate for use in cell targeting, fluorescence labeling, imaging and diagnosis materials.178 Denser hydroxyapatite bioceramics can be used to create middle ear and eye implants, percutaneous device implants and inner dialysis systems. Hydroxyapatite doped with silver, copper oxide and zinc oxide can be used to improve antibacterial properties.179,180

1.3 Ideal Features of Antimicrobial Materials

An ideal antimicrobial polymer should have following characteristics:7 highly stable over long periods of time; easily and inexpensively synthesized; should not decompose or emit toxic products; should be water insoluble for disinfection of water; should possess broad spectrum of antimicrobial activity; should be non-toxic and non-irritating.

1.4 Factors Affecting Antimicrobial Activity

1.4.1 Effect of Molecular Weight

Molecular weight has an important role in determining antimicrobial activity.7 Chen et al. synthesized polypropylenimine dendrimers functionalized with quaternary ammonium groups and found that the antimicrobial properties have parabolic dependence on molecular weight.79 In the case of polyacrylates and polymethylacrylates with biguanide groups, the optimal range of molecular weight was reported to be from 5×104 to 1.2×105 Da, with variance above and below this range significantly reducing efficacy.181 Similarly, poly(tributyl 4-vinylbenzyl phosphonium chloride) also showed optimal antimicrobial action within a range of 1.6×104 to 9.4×104 Da.182 However, the bacteriostatic action of fractioned quaternary ammonium salts against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus had little dependence on molecular weight.7,183

1.4.2 Effect of Counter Ions

Counter ion effect on antimicrobial properties is not clearly known, except where they change or alter the solubility of host polymers. Kanazawa et al. investigated the counter anion dependence of poly[tributyl (4-vinylbezyl) phosphonium] salts where the antimicrobial activity is in the order hexafluorophosphate<perchlorate<tetrafuoride<chloride, which can be correlated with the solubility products of those polymers.182 Chlorides and bromides exhibit the highest antimicrobial activity in the case of quaternary ammonium compounds. Counter ions with strong binding affinity towards quaternary compounds show lower antibacterial action because of slow and reduced release of free ions in the medium.79

1.4.3 Charge Density

Usually, a positive charge density can impart better polymeric electrostatic interaction with negatively charged bacterial cell walls. For chitosan, with increasing degrees of deacetylation, the charge density increase enhances the electrostatic interaction of the polymer and thus antimicrobial property. Higher charge density groups were incorporated in chitosan to form guanidinylated chitosan and asparagine N-conjugated chitosan oligosaccharide, which resulted in high antimicrobial action, whereas N-carboxyethyl chitosan did not show any antimicrobial action due to a lack of free amino groups.206–208

1.4.4 Effect of Spacer Length and Alkyl Chain Length

Spacer length affects the interaction of antimicrobial agents with the bacterial cytoplasmic membrane due to changes in charge density and conformation of the polymer.184 The antimicrobial activity of quaternary ammonium chlorides depends on the hydrophilic–lipophilic balance. Poly(trialkyl vinyl benzyl ammonium chloride) with the longest carbon chain (C12) showed higher antimicrobial activity.7

1.4.5 pH Effect

The pH effect can be seen mostly in amphoteric polymers and chitosan. At acidic pH, chitosan exhibits maximum antimicrobial activity because of polycation formation and better solubility. However, at basic pH, there are no reports of its antimicrobial effect.185

1.4.6 Hydrophilicity

Hydrophilic nature is considered an important prerequisite for any antimicrobial agent to show activity. Tailoring of hydrophobic group content and molecular weight in amphiphilic polymethacrylate derivatives showed improvements in antimicrobial activity.186 In the same manner, compared to the original form, the water-soluble chitosan derivatives synthesized by alkylation, metallization, quaternization and saccharization displayed greater antimicrobial action.187,188

1.5 Methods to Evaluate Antimicrobial Properties

Due to the high number of antibiotics in clinical microbiology, sensitivity testing becomes difficult. However, there are two standard testing methods: the serial dilution test and the disc test, by which sensitivity of bacteria to antibiotics can be tested in vitro.189,190 In serial dilution tests, visible microbial growth is tested on a series of agar plates (agar dilution method) or broth (broth dilution method) that contain dilutions of antimicrobial agent.191 It acts as a reference method for testing antimicrobial susceptibility, which in turn determines the MIC of antimicrobial agents.192 Determination of MIC has an important role by which the tested microorganism is categorized as clinically susceptible, intermediate or resistant to a tested drug. Antibiotic drug resistance can also be monitored by MIC.193,194 The disc diffusion method involves the use of different concentrations of antibiotic solutions in paper wells, cups or discs that are placed over the surface or punched into seeded agar plates containing a test bacterial strain.195 Some of the characterization methods, such as test for microbial count, agar diffusion test and zone of inhibition (ZOI) test are used to determine and evaluate the effectiveness of nanoparticles as antimicrobial agents.196

No standard method is advocated in the literature to evaluate the antimicrobial activity of industrial products and medical devices. Moreover, the researchers modify the testing conditions as per their experimental design.197 There are widely used standardized methods to characterize the antimicrobial materials described in ASTM E-2149 (American Society for Testing and Materials, 2001), JIS 2801 (Japanese Standards Association, 2000), ZOI method, live–dead fluorescence staining and growth-based methods.198 The ASTM E-2149-01 test method determines the antimicrobial property of treated specimens under dynamic contact conditions.199 In the JIS Z 2801 : 2000 (Japanese Industrial Standard) testing method, surfaces (50×50 mm) are inoculated with Escherichia coli or Staphylococcus aureus suspension in a nutrient broth placed in petri dishes.200,201 In 1966, Bauer et al. performed a test by the measurement of the zone of bacterial growth inhibition, with the testing materials placed on bacteria-inoculated agar plates, through the use of a ruler on the underside of the petri dish.202,203 Fluorescence methods are based on the detection of intact cell structures and determination of inactive, active, dead and intact cells.204 A standardized method is reported in Swiss Standard SNV 195929-1992 based on an agar diffusion test, which evaluates the width of bacterial growth inhibition area, around and beneath the samples after incubation with bacteria.171,205

1.6 Clinical Trials

Clinical trials for antimicrobial polymers are described in Table 1.5.

Table 1.5 Clinical trials for antimicrobial polymers.a
Title Indication Comments Phase Status
Efficacy and Safety of a Biofunctional Textile in the Management of Atopic Dermatitis AD Purpose is to study the use of biofunctional textile coated with chitosan. Shows improved quality of life and diminishes skin colonization with Staphylococcus aureus and skin moulds 2 Ongoing
USF Hemostasis: Usage of HemCon for Femoral Hemostasisafter Percutaneous Procedures Coronary angiography Used as an adjunct to manual compression for better control of vascular access site bleeding and reduce time to hemostasis after percutaneous coronary angiography 4 Completed
Trial of a Novel Chitosan Hemostatic Sealant in the Management of Complicated Epistaxis Epistaxis Purpose is to evaluate applicability of sealant in spontaneous epistaxis and its healing effect on nasal mucosa Completed
The Effects of a Polyethyleneimine-coated Membrane (oXiris™) for Hemofiltration Versus Polymyxin B- Immobilized Fibre Column (Toraymyxin™) for Hemoperfusion on Endotoxin Activity and Inflammatory Conditions in Septic Shock—A Randomized Controlled Pilot Study Septic shock It is hypothesized that positively charged inner surface of the membrane allows the absorption of negatively charged bacterial products which leads to activation of pro- and anti-inflammatory mediators at the early stage of sepsis Not started
A Clinical Study: the Antibacterial Effect of Insoluble Antibacterial Nanoparticles (IABN) Incorporated in Dental Materials for Root Canal Treatment Endodontic treatment The effect of antibacterial nanoparticles, incorporated in root canal sealer material and in provisional restoration to be examined 2 Recruiting
Antimicrobial peptides
Antimicrobial Peptides in Periodontitis: A Pilot Study Chronic periodontitis Studied the level of expression of genes coding those peptides by studying periodontal smears Completed
Analysis of the Response of Subjects with Atopic Dermatitis to Oral Vitamin D3 by Measurement of Antimicrobial Peptide Expression in Skin and Saliva AD, psoriasis Examined whether administration of oral vitamin D3 given over 21 days will change the AMP expression in the skin or saliva of subjects with AD Completed
Role of Antimicrobial peptides in Host Defense Against Vaccinia Virus AD Compared smallpox virus replication, number of AMPs and other antiviral molecules in people with AD, as compared to psoriasis or asthma or healthy individuals Completed
Clinical Study of Antibacterial Nanoparticles Incorporated in Composite Restorations Oral health Evaluated the antibacterial effect of alkylated PEI nanoparticles incorporated into flowable and hybrid composite resin disks 2 Completed
Topical Application of Silver Nanoparticles Reduced Oral Pathogens in Mechanically Ventilated Patients: A Randomized Controlled Clinical Trial Critical illness Silver nanoparticles are effective to reduce potential pathogen microbial loads in mechanical ventilation patients Completed
Antibacterial Properties of Silicon Incorporated with Quaternary Ammonium Polyethylenimine Nanoparticles Head and neck carcinoma Aim is to evaluate the antibacterial activity of quaternary ammonium PEI nanoparticles (1–2% w/w) when compared to commercial soft liner material 1 Not yet recruiting
a AD: atopic dermatitis; AMP: antimicrobial peptide; PEI: polyethylenimine.

1.7 Conclusion and Future Developments

In this chapter, a concise overview on the research and development of novel antimicrobials has been provided. In order to synthesize and incorporate antimicrobial substances in biomaterials, various methods and recent technologies have been stimulated by the need to overcome antibiotic resistance and the risk of infections associated with the clinical use of medical devices.171 Antimicrobial polymers have various application in the areas of water filtration systems, fibers, food packaging, surgical industries, surfactants and detergents and pharmaceuticals.6 Nanoantimicrobials can provide new horizons in medical research and it is one of the most interesting areas of development for producing effective antibacterial substrates.171 Intrinsically antimicrobial polymers represent a promising and novel approach by reducing the drug-resistant bacteria in biofilm.206 Antimicrobial properties can be incorporated into polymeric materials by chemical modifications or by imparting inorganic/organic antimicrobial agents.76 There is reduced opportunity for bacterial resistance with antimicrobial polypeptides as they bind with the bacterial cell wall and form pores in the membrane.207 Short-term activity and environmental toxicity displayed by small molecular weight antimicrobial agents can be overcome by antimicrobial polymers. To obtain materials and products with improved quality and safety, industrial and academic research should come on board to develop innocuous materials that are environmentally friendly and reusable, with a broad range of potent, long-lasting and antimicrobial properties.6,171


Antimicrobial peptide
Minimum inhibitory concentration


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