The Chemistry and Applications of Antimicrobial Polymers: A State-of-the-Art Review

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The Chemistry and Applications of Antimicrobial

Polymers: A State-of-the-Art Review
Article in Biomacromolecules · May 2007

DOI: 10.1021/bm061150q · Source: PubMed
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May 2007 Published by the American Chemical Society Volume 8, Number 5
© Copyright 2007 by the American Chemical Society
Reviews
The Chemistry and Applications of Antimicrobial Polymers: A
State-of-the-Art Review
El-Refaie Kenawy,*,† S. D. Worley,‡ and Roy Broughton§
Department of Chemistry, Polymer Research Group, Faculty of Science, University of Tanta, Tanta 31527,
Egypt, and Department of Chemistry and Biochemistry, and Department of Polymer and Fiber Engineering,
Auburn University, Auburn, Alabama 36849
Received December 4, 2006; Revised Manuscript Received February 20, 2007
Microbial infection remains one of the most serious complications in several areas, particularly in medical devices,
drugs, health care and hygienic applications, water purification systems, hospital and dental surgery equipment,
textiles, food packaging, and food storage. Antimicrobials gain interest from both academic research and industry
due to their potential to provide quality and safety benefits to many materials. However, low molecular weight
antimicrobial agents suffer from many disadvantages, such as toxicity to the environment and short-term
antimicrobial ability. To overcome problems associated with the low molecular weight antimicrobial agents,
antimicrobial functional groups can be introduced into polymer molecules. The use of antimicrobial polymers
offers promise for enhancing the efficacy of some existing antimicrobial agents and minimizing the environmental
problems accompanying conventional antimicrobial agents by reducing the residual toxicity of the agents, increasing
their efficiency and selectivity, and prolonging the lifetime of the antimicrobial agents. Research concerning the
development of antimicrobial polymers represents a great a challenge for both the academic world and industry.
This article reviews the state of the art of antimicrobial polymers primarily since the last comprehensive review
by one of the authors in 1996. In particular, it discusses the requirements of antimicrobial polymers, factors
affecting the antimicrobial activities, methods of synthesizing antimicrobial polymers, major fields of applications,
and future and perspectives in the field of antimicrobial polymers.
1. Introduction infections usually requires removal of the implant. Because the

Contamination by microorganisms is of great concern in a success of treatment in these cases is poor, emphasis has been
variety of areas, such as medical devices, healthcare products, placed on ways to prevent catheter-related infections. Infection
water purification systems, hospitals, dental office equipment, in sites such as the brain or cerebrospinal fluid (CSF) can be
food packaging, food storage, household sanitation, etc.1,2 more serious, because many antibiotics cannot effectively cross
Bacterial contamination of biomedical devices, for example, the blood-brain barrier to achieve therapeutic concentrations.
permanent catheters or implants, is a major problem in those Antimicrobial agents are those materials capable of killing
medical disciplines employing biomaterials.3 pathogenic microorganisms.5 Antimicrobial agents of low mo-
The use of long-term catheters can lead to serious implant- lecular weight are used for the sterilization of water, as
associated infections.4 In fact, medical implants account for antimicrobial drugs, as food preservatives, and for soil steriliza-
nearly one-half of all nosocomial infections. These infections tion.6 However, they can have the limitation of residual toxicity
are especially serious because bacteria that are often resistant even when suitable amounts of the agent are added.7,8
to multiple antibiotics usually cause them. Resolution of these Various kinds of plastics are usually sterilized by means of
either dry/wet heat, or ionizing radiation.9 However, these
* Corresponding author. E-mail: [email protected].
† University of Tanta. polymers can be contaminated or infected by microorganisms
‡ Department of Chemistry and Biochemistry, Auburn University. such as bacteria if they are exposed to the atmosphere.
§ Department of Polymer and Fiber Engineering, Auburn University. Therefore, there is a definite need for new materials with
10.1021/bm061150q CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/11/2007
1360 Biomacromolecules, Vol. 8, No. 5, 2007 Kenawy et al.
antimicrobial activities. It is apparent that, in principle, the ideal

solution of this problem is a method for rendering biomaterials
resistant to microbial colonization. Antimicrobial polymers can
provide a very convenient way for achieving this goal.
An area of polymer research that presents great current
interest, yet has received insufficient attention, is that of the
development of polymers with antimicrobial activities, generally
known as polymeric biocides. In the area of health care and
hygienic applications, biocidal polymers may be incorporated Figure 1.
into fibers, or possibly extruded into fibers themselves, and used
for contact disinfectants in many biomedical applications such stable in long-term usage and storage at the temperature of its
as sterile bandages and clothing. For example, antimicrobial intended application, (3) not soluble in water for a water-
surgical gowns and antifungal polymeric coatings on surfaces disinfection application, (4) does not decompose to and/or emit
such as shower walls and many kinds of tubing minimize the toxic products, (5) should not be toxic or irritating to those who
problems of biofouling and the release of pathogenic microor- are handling it, (6) can be regenerated upon loss of activity,
ganisms into streams of flowing fluids.10 and (7) biocidal to a broad spectrum of pathogenic microorgan-
The use of antimicrobial polymers offers promise for enhanc- isms in brief times of contact.
ing the efficacy of some existing antimicrobial agents and
minimizing the environmental problems accompanying con- 3. Factors Affecting the Antimicrobial Activity
ventional antimicrobial agents by reducing the residual toxicity
of the agents, increasing their efficiency and selectivity, and There are many factors for antimicrobial polymers that can
prolonging the lifetime of the antimicrobial agents. Also, affect their antimicrobial activity and mechanism of activity such
polymeric antimicrobial agents have the advantage that they are as molecular weight, spacer length between active site and
nonvolatile and chemically stable and do not permeate through polymer, hydrophilic-hydrophobic balance, and nature of
skin. Therefore, they can reduce losses associated with vola- counterions.27,28
tilization, photolytic decomposition, and transportation. In the 3.1. Effect of Molecular Weight. The molecular weight plays
field of biomedical polymers, infections associated with bio- an important role in determining the antimicrobial properties.
materials represent a significant challenge to the more wide- Therefore, many research groups have studied the molecular
spread application of medical implants.11-15 Infection is the most weight dependence. Ikeda and his co-workers investigated the
common cause of biomaterial implant failure in modern antimicrobial activity of homopolymers of polyacrylates and
medicine. Antimicrobial polymers play an important role in polymethyl acrylates with side-chain biguanide groups and their
reducing the incidences of such failures. Catheters made from copolymers with acrylamide (Figure 1).29,30
a polymer that slowly releases an antibiotic could save the lives They found that the biocidal action of the polymethyl acrylate
of many hospital patients who are subjected to infections every with pendent biguanide groups against S. aureus was markedly
year. Antimicrobial polymers could also thwart infections around dependent on the molecular weight.
more permanent implants, such as pacemakers. In the field of A molecular weight region between 5 × 104 and 1.2 × 105
textiles, work has been performed with the aim of developing Da was optimal for the required action. When the molecular
new textile products with antimicrobial finishes for medical weight was lower than 5 × 104 Da, the antimicrobial property
applications. Significant advances in the past three decades have increased with molecular weight, while the antibacterial activity
been made in the synthesis and applications of polymers to decreased sharply with the increase of the molecular weight of
prevent microbial attack and degradation for diverse end uses.16 the polymer over 1.2 × 105 Da. The dependence of antimicrobial
One method of achieving antimicrobial polymers is to add properties was explained on the basis of the permeability through
an organic or inorganic biocide to the polymers during process- the cell wall. The molecular weight dependence of poly-
ing of the material.10,17 (trialkylvinylbenzylammonium chloride) (Figure 2) against S.
Another method is to endow a biocidal function to the aureus was also evaluated.31
polymer after processing.10,18,19 A different approach for the The bactericidal properties were found to increase monotoni-
preparation of polymers bearing groups with antimicrobial cally with molecular weight up to 7.7 × 104 Da, the highest
activity is the preparation of polymerizable monomer-containing molecular weight tested during the study. However, bacteriso-
biocide moieties and then polymerizing subsequently or copo- tatic activities of the fractionated polymeric quaternary am-
lymerizing with another monomer.10,20-26 The grafting of monium salts against S. aureus, B. subtilis, E. coli, A. aerogenes,
antimicrobial agents into natural occurring or synthetic polymers and P. aeruginosa were shown to have little molecular weight
is yet another approach to the problem of the preparation of dependence.
bioactive materials with a potential use in various applications. Kanazawa and co-workers32 investigated the molecular weight
The current review is focused on the recent developments in dependence of poly(tributyl 4-vinylbenzyl phosphonium chlo-
the field of antimicrobial polymers primarily over the past 10 ride) (Figure 3) against S. aureus in saline solution and
years and subsequent to the previous review of Worley and discovered that the antibacterial properties increased with the
Sun.10 The review is organized into sections discussing the basic increase of molecular weight from 1.6 × 104 to 9.4 × 104 Da.
requirements, factors affecting the antimicrobial activity of the The higher antimicrobial activity of the polymers may be
polymer, and the various approaches and major applications of accounted for by the contribution of the polymers to each
the antimicrobial polymers. elementary process in the cidal action. For example, the
sequence of elementary events in the lethal action of the cationic
2. Basic Requirements for Antimicrobial Polymers
biocides may be considered as follows:29 (1) adsorption onto
The ideal antimicrobial polymer should possess the following the bacterial cell surface, (2) diffusion through the cell wall,
characteristics: (1) easily and inexpensively synthesized, (2) (3) adsorption onto the cytoplasmic membrane, (4) disruption
The Chemistry of Antimicrobial Polymers Biomacromolecules, Vol. 8, No. 5, 2007 1361
Figure 4. Generation 2 poly(propyleneimine) dendrimer quaternary

ammonium biocides with eight QAC groups on the surface.
Table 1. Comparison among Molecules Biocides, via Their

Interaction with Bacteria
small
molecule polymer dendrimer
step biocides biocides biocides
(1) initial adsorption weak strong strong
Figure 2. Structures of some quaternary ammonium and phospho- (2) diffusion to the high low medium
nium salts with bioactivity. cytoplasmic membrane
(3) binding to the membrane low medium high
(4) disruption and disintegration low medium high
of the membrane
one needs to take into consideration the bacteria structure.

Depending on the sophistication of the cell wall structure,
bacteria can be divided into two classes, Gram-positive (e.g.,
S. aureus) and Gram-negative (e.g., E. coli). Gram-positive
bacteria tend to have a loose cell wall, while Gram-negative
bacteria have an outer membrane structure in the cell wall
forming an additional barrier for foreign molecules. Most of
the investigations that were summarized above deal with the
molecular weight dependence on S. aureus eradication. Studies
Figure 3. Tributyl(4-vinylbenzyl)phosphonium salt monomer. indicated that molecules with molecular weight up to 5 × 104
to 9 × 104 Da do not seem to have problems diffusing across
of the cytoplasmic membrane, (5) leakage of the cytoplasmic the cell wall of the Gram-positive bacterium S. aureus. For
constituents, and (6) death of the cell. Gram-negative bacteria, such as E. coli, the question of diffusion
It is well known that the bacterial cell surface is usually to the cell membrane is even more complicated due to the
negatively charged as evidenced by its susceptibility to elec- existence of an outer membrane.
trophoresis. Adsorption of polycations onto the negatively 3.2. Effect of Counterion. Kanazawa and co-workers
charged colloidal surface is expected to take place to a greater investigated the counteranion dependence of poly[tributyl(4-
extent than that of monomeric cations. Therefore, it is reasonable vinylbenzyl)phosphonium] salts (Figure 3) against S. aureus.
to assume that in the elementary process step (1) is enhanced The antibacterial activity was found to be affected by the
for polymers as compared to that for monomers. structure of the counter anions.20 The activity was low for a
Ikeda and co-workers synthesized polycationic biocides with counteranion, which tends to form a tight ion-pair with
pendent phosphonium salts and compared their antibacterial phosphonium ion, while it was high for those facilitating ionic
activity with the corresponding monomers (Figure 2). They also dissociation to free ions. The antimicrobial properties were in
demonstrated that the activity is increased in the order of the order of chloride > tetraflouride > perchlorate > hexafluo-
increasing molecular weight.25,29,33-36 rophosphate, which could be correlated with the solubility
Chen and co-workers synthesized quaternary ammonium- products of the polymers.
functionalized poly(propyleneimine) dendrimers (Figure 4).37 The antimicrobial activity of the quaternary ammonium
They found that the antimicrobial properties of these den- dendrimers synthesized by Chen et al. showed dependence on
drimer biocides have parabolic dependence on molecular weight. the counterion. They found that the biocides with bromide anions
Tokura and co-workers38 found similar results. are more potent than those with chloride anions.37 However,
A very interesting comparison of small molecule biocides, the work carried out by Panarin and co-workers on the synthesis
polymer biocides, and dendrimer biocides with regard to their of homopolymers of vinylamine and methyl methacrylate with
interactions with bacteria is quantitatively summarized in Table pendent quaternary ammonium groups showed no effect for
1.37 counter anions on the antibacterial activities among chloride,
However, Panarin and co-workers reported that the bacte- bromide, and iodide.39 It is not clear why counterions should
riostatic properties had no molecular weight dependence for their have an effect on antimicrobial activity except where they alter
copolymers of vinylamine, methyl acrylate, and N-vinyl pyr- solubilities of their host polymers.
rolidone with pendent quaternary ammonium groups.39 To 3.3. Effect of Spacer Length and Alkyl Chain. It is quite
explain properly the discrepancy of the trends in these data, reasonable that the antimicrobial activity is dependent on the
Scheme 1. Reaction of 2-(3-Acrylamidopropyldimethylammonio)

Ethanoate [APDMAE] with Fluoroalkanoyl Peroxides
Figure 5. Structure of monomer SMPM.
Scheme 3
Scheme 2. Synthesis of METR-NIPAAm Copolymer
short alkyl substituents or (2) different aggregational behavior

for long and short hydrophobes.37
4. Preparation and Activities of Antimicrobial

Polymers
By attaching bioactive substrates to synthetic or naturally
occurring macromolecules, it is expected to increase their
therapeutic efficiencies while lowering their potential toxicities.
Various approaches, which can achieve this attachment, are
discussed as follows.
4.1. Preparation of Polymerizable Monomer-Bearing
spacer length due to the change in both conformation and charge Groups with Antimicrobial Activity. Antimicrobial agents that
density of the polymer, which consequently affect the mode of contain reactive functional groups such as hydroxyl, carboxyl,
interaction with the cytoplasmic membrane.27 For a polymeric or amino groups can be covalently linked to a wide variety of
quaternary ammonium chloride biocide, the hydrophilic- polymerizable derivatives. Most of the synthesized drug mono-
lipophilic balance influences the antimicrobial properties. mers and their polymers are acrylic types of pharmaceutically
Although Panarin et al.39 discovered that the antimicrobial active compounds. The advantages of acrylic-type drug conju-
activities of their polymers did not show differences with gate monomers are that these can be copolymerized to vary the
different chain lengths, Ikeda et al. studied poly(trialkylvinyl- drug concentration and that they can be used to prepare different
benzylammonium chloride) and discovered that the antimicrobial hydrophilic/hydrophobic functionalities in the polymer drug
activity was the highest with the longest chain (C12) that they conjugates for different purposes in the pharmaceutical industry.
investigated.28 In this context, Reddy et al.43 synthesized antimicrobial drugs
Sawada and co-workers prepared perfluoro-propylated and containing monomers (AMBS, MMBS) by reacting acryloyl
perfluoro-oxaalkylated end-capped 2-(3-acrylamidopropyldim- chloride and methacryloyl chloride with 4-amino-N-(5-methyl-
ethylammonio)ethanoate (APDMAE) (Scheme 1).40 3-isoxazolyl)benzenesulfonamide in the presence of triethyl
These fluorinated APDMAE polymers have been evaluated amine, Scheme 3.
for their antibacterial activities against S. aureus and P. Another monomer, N-[4-sulfamido-N-(5-methyl-3-isoxazolyl)-
aeruginosa. It was found that prefluoro-oxaalkylated APDMAE phenyl]maleimide (SMPM) (Figure 5), was prepared by reacting
polymer, because of its longer chain, was more active against maleic anhydride with 4-amino-N-(5-methyl-3-isoxazolyl)ben-
both S. aureus and P. aeruginosa. zenesulfonamide.
Recently, Nonaka and co-workers synthesized methacryloyl- The three monomers were polymerized using benzoyl per-
ethyl trialkyl phosphonium chlorides/N-isopropylacrylamide oxide as a free radical initiator under nitrogen atmosphere at
copolymers (Scheme 2). 70 °C. The polymers were soluble in DMSO, DMF, and THF
They found that the antibacterial activity of the copolymers and insoluble in nonpolar solvents. The antifungal screenings
against E. coli was increased with increasing the alkyl chain of these monomers and their polymers were achieved for two
length in the phosphonium groups in the copolymer.41,42 fungi, A. niger and C. albicans. The authors used a method to
Rationalization of the parabolic relationship between antibacte- measure the zone of inhibition of monomers and polymers. Zone
rial properties and alkyl chain lengths has been debated. It has of inhibition is generally a circular zone around the antimicrobial
been attributed to (1) dual binding sites on the surface for which polymer or the antibiotic, for example, in which growth of the
the relative binding affinities at each site differ for long and microorganism susceptible to the tested material is inhibited.
Figure 7. Structure of monomeric biocides.
Figure 6. Monomers and copolymers based on N-TBTM and

m-TBTM.
The zone of inhibition of different concentrations of monomers

and polymer conjugates reveals that SMPM and its polymer
poly(SMPM) have significant antifungal activities with both C.
albicans and A. niger. The polymer-drug conjugate showed
superior anti-microbial activity over the monomer at all
concentrations. There are no data concerning the mode of actions
of these polymers reported by the authors; however, they may
function as a drug delivery system by slowly releasing the drug Figure 8. Structure of the polymeric biocide synthesized from
to the media. 2-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiopropyl methacrylate.
Al-Diab and co-workers44 have recently reported the synthesis
of two novel organotin monomers, (N-tri-n-butyltin)maleimide
(N-TBTM) and m-acryloylamino-(tri-n-butyltinbenzoate) (m-
AATBTB) (Figure 6).
Copolymerization of these two monomers with styrene was
carried out in bulk at 65 °C in sealed tubes under nitrogen
atmosphere using azobisisobutyronitrile as the free radical
initiator (Figure 6). The antibacterial activities of the synthesized
organotin monomers and copolymers toward various types of Figure 9. Structure of MQ.
Gram-positive and Gram-negative bacteria were investigated
after 24 h contact time. The results showed that Gram-positive derivatives, which are proposed to inhibit the cytochrome P-450
bacteria were more sensitive to the two monomers (m-AATBTB monooxygenase.
and N-TBTM) and their styrene copolymers than were the Recently, the same group reported the synthesis of monomers
Gram-negative bacteria. They also reported that copolymeriza- containing the quinoline moiety, 1-ethyl-6-fluoro-7-{4-[2-hy-
tion of monomers with styrene decreased the potency of the droxy-3-)2-methylacryloyloxy)propyl] piperazin-1-yl}-4-oxo-
monomers (m-AATBTB and N-TBTM) against Gram-positive 1,4-dihydroquinolin-3-carboxylic acid (MQ) (Figure 9).46 The
and Gram-negative bacteria. This is expected due to the decrease quinoline-containing monomer was polymerized by a free
of active functional groups in the polymer chain by introducing radical polymerization technique with azobisisobutyronitrile
styrene, which has no antimicrobial activity in the chain. The (AIBN) as an initiator in dimethylformamide solution.
authors did not discuss the mode of actions of these materials, The antibacterial activity of the monomer MQ against Gram-
but it could be due to the presence of the tin moiety on the positive as well as Gram-negative bacteria was explored by the
polymer surface, which may interact with the cell wall leading shake-flask method,46 which is one of the testing methods
to the death of the microorganism. commonly used for evaluating the biocidal activity of materials.
Moon and co-workers synthesized vinyl acryl monomers with The results indicated that it was antibacterial after 24 h contact
azole moieties (Figure 7).45 time. The antimicrobial activity of the polymer PQ, synthesized
Polymerization of monomers a-e (Figure 7) was attempted. by the polymerization of MQ, was determined, and the results
However, only polymerization of 2-hydroxy-3-(5-methyl-1,3,4- indicated that it was a reasonably potent antimicrobial agent.
thiadiazol-2-yl)thiopropyl methacrylate (Figure 7e) was suc- This polymer could be functioning as a drug delivery system,
cessful in giving the corresponding polymer (Figure 8). It is releasing the norfloxacin, which is known to inhibit bacterial
interesting to observe that the polymer was a more effective DNA gyrase and cell growth.
antibacterial agent than was the monomer after 24 h contact. Cho et al.23,47 reported the synthesis of the bactericidal
No report on the mode of action of these materials is described, monomer 2,4,4′-trichloro-2′-acryloyloxydiphenyl ether (AcDP)
but it might be due to the presence of the bezimidazole from acryloyl chloride and 2,4,4′-trichloro-2′-hydroxydiphenyl
Scheme 4. Synthesis of AcDP
Scheme 5
Figure 10.
The monomer (ACTMIO) was copolymerized with several

monomers such as acrylonitrile (AN), methyl methacrylate
(MMA), and vinyl acetate (VAC). After regular chlorine bleach
Figure 11. treatment, N-halamine derivatives of the corresponding poly-
meric materials exhibited antimicrobial properties against Es-
ether (DP) in the presence of triethylamine in dry tetrahydrofuran cherichia coli, and these properties were durable and refreshable
(THF) at 20 °C (Scheme 4). with chlorine bleaching. The results of biocidal efficacy for the
The AcDP monomer was either homopolymerized or copo- halogenated polymers showed that PVAC-co-ACTMIO pro-
lymerized with methylmethacrylate (MMA), styrene (St.), or vided 99.9% reduction of E. coli after 30 min of contact,
acrylic acid (AA).23,47,48 The antimicrobial activities of the whereas for PMMA-co-ACTMIO and PAN-co-ACTMIO, the
monomer AcDP and the prepared copolymers were tested reduction provided was 99% and 90%, respectively, for the same
against Pseudomonas aeruginosa and Staphylococcus aureus. time of contact. The halogenated polymers were tested for
The results showed a general trend that the monomer was more biocidal efficacy against E. coli in forms of films or powders.
active toward the test organisms than were the homopolymer The results showed that the powdered halogenated copolymers
and copolymers. The results of these studies indicated clearly demonstrated a total kill against E. coli at a flow rate of 0.2-
that the hydrophilicity of the copolymer affects the antibacterial 0.6 mL/min, while the polymer films needed a contact time of
activity. less than 30 min to perform the total kill. No significant
Vinyl monomers with phenol and benzoic acid as pendent differences could be noticed in the antibacterial properties for
groups were synthesized by Park and co-workers (Figure 10).49 the copolymers, indicating the similar functions possessed by
the N-halamine structures.55 It was reported that if the haloge-
Some of these monomers were polymerized (Figure 11). The nated polymers were stored at 25 °C for 3 months, the
antimicrobial activities of the polymers were explored using the antibacterial properties of the samples did not essentially change.
halo zone test after a contact time of 72 h at 28 °C. Surprisingly, This indicated that the polymers possessed proper stability in
the polymerization of the monomers decreased their antimicro- the dry state and that the N-halamine structures in all of the
bial activities significantly. polymer samples were very stable. The mode of action of the
The above-mentioned authors stated that, even though the N-halamine polymers is described as direct transfer of oxidative
antimicrobial activity of the polymers is much lower than that halogen (Cl+ or Br+) from the N-halamine nitrogen to the cell
of the corresponding monomers, they could be coated on glassy wall of the organism by direct contact followed by oxidation,
polymers. The concentration of antimicrobial agent on the coated rather than dissociation of X+ into water followed by diffusion
polymeric material surface could be higher than that on the over to a cell.
surface of the polymer compound with low molecular weight It is known that 8-hydroxyquinoline derivatives have anti-
antimicrobial agent showing identical or even superior antimi- microbial activity.56 Bankova and co-workers reported the
crobial activity. synthesis of 5-chloro-8-quinolinyl acrylate (AQ) by reacting
Recently, a relatively new class of biocidal polymers known 5-chloro-8-hydroxyquinoline with the acid chloride of acrylic
as cyclic N-halamines demonstrated superior properties including acid (Scheme 6).21,22
biocidal efficacy, long-term stability, and rechargeability once The monomer AQ was polymerized (PAQ) and copolymer-
the efficacy had been consumed during use. Several such ized with acrylic acid (PAA-co-AQ). The antimicrobial activities
materials have been prepared and tested for antimicrobial of AQ, PAQ, and P(AA-co-AQ) were tested against E. coli,
properties.50-53 and the results showed that AQ is more active than the
Sun and co-workers reported the synthesis of cyclic amine homopolymer and the copolymer.21 The antimicrobial activities
monomer, 1-acryloyl-2,2,5,5-tetramethylimidazolidin-4-one (ACT- here are displayed by the release of 8-hydroxyquinoline (HQ)
MIO) (Scheme 5), by the reaction of acryloyl chloride with moieties; the release studies showed correlation between the
2,2,5,5-tetramethylimidazolidin-4-one (TMIO).54 copolymer microstructure and hydrolysis behavior. The lower
Scheme 6. Synthesis of 5-Chloro-8-quinolinyl Acrylate (AQ)
Figure 12. Structure of some sulfonium salts.
is the content of the HQ, the higher is the release rate, and the
higher are the antimicrobial activities. In these kinds of
antimicrobial polymers, the antimicrobial activities should
increase with time due to the release of more active agent; Figure 13. Structure of MDPB.
however, after a certain time, they may become inactive because
of releasing the entire active ingredient. In a subsequent
publication, the same group reported the synthesis of other
copolymers based on the monomer AQ.24 They reported the
synthesis of copolymers of monomer AQ with acrylamide
P(AM-co-AQ) and N-vinyl-2-pyrrolidone P(VP-co-AQ). The
antimicrobial activities of the monomer AQ, the homopolymer
PAQ, and the prepared copolymers P(VP-co-AQ), P(AM-co-
AQ), and P(AA-co-AQ) were tested against S. aureus and S.
tiphimurium. In general, the antimicrobial activities of the tested
materials increased in the order: P(VP-AQ) < P(AM-co-AQ)
< P(AA-co-AQ). Increasing the acrylic acid content of the
copolymer P(AA-co-AQ) to 95% caused an increase in the Figure 14. Homo-polymer of MDPB, and copolymer of MDPB with
antibacterial activity of the copolymer to be almost similar to acrylamide.
that of the monomer AQ.
Endo and co-workers reported the synthesis and the antibac-
terial activity of polymeric sulfonium salts to explore the effect
of R-heteroatoms on the antibacterial activity of polymeric
onium salts.25 The polymeric sulfonium salt was obtained by
polymerization of p-vinylbenzyltetramethylenesulfonium tet-
rafluoroborate (Figure 12) at 60-80 °C in acetonitrile with Figure 15. Methacrylate monomers containing pendent quaternary
AIBN as an initiator. ammonium moieties based on 1,4-diazabicyclo-[2.2.2]-octane (DAB-
Polymeric sulfonium salts exhibited a high antibacterial CO).
activity against Gram-positive bacteria. It was found that the
activity of the polymeric sulfonium salts was much higher than with K2CO3. The salt was reacted with ECMA (ethyl R-chlo-
that of the model compound, p-ethylbenzyl tetramethylene romethyl acrylate) to yield the methacrylate monomer with two
sulfonium tetrafluoroborate. However, the use of the sulfonium quaternary ammonium groups (Figure 15). The monomer was
salts as disinfectants may be rather limited because of their low polymerized by free radical polymerization. The antimicrobial
thermal stability. activities of the prepared polymers were screened against S.
Imazato et al.57,58 prepared a new monomer, methacryloy- aureus and E. coli as test organisms. The results showed that
loxydodecyl pyrimidinium bromide (MDPB) (Figure 13). A the monomers were not active against the test organisms, while
water-soluble homopolymer of MDPB and copolymer of MDPB the polymers showed moderate activities against the test
with acrylamide were prepared (Figure 14). The bactericidal organisms in polymer concentrations ranging from 1 mg/mL
activity against oral Streptococci was investigated. However, to 3.9 µg/mL. The minimum inhibitory concentration (MIC)
cured resin incorporating MDPB, which is a water-insoluble value for the polymer with the butyl group was 250 µg/mL,
form, had little bactericidal activity. Higher concentrations of while this value was reduced to 62.5 µg/mL with increasing
the MDPB were more effective; for example, a concentration the alkyl chain length to 6 carbons as in the case of the hexyl
of 500 µg mL-1 killed 99.999% within 1 min, while at 100 µg group. The lethal actions of these biocides are believed to follow
mL-1, even after 480 min, the killing was slow. The mechanism the mode of action of cationic biocides, as they target the
of action for these quaternary compounds is believed to be due cytoplasmic membranes. It is believed that the incorporation
to the direct cationic binding to cell wall components, which of the DABCO group into the polymer might enhance its
leads to disruption of the cell wall membrane, and subsequently diffusion into the cell wall due to similarities of the polymer
leads to leakage of critical cell contents and cell death. pendent group and the lipid layer. As a result, there is a
Mathias et al.35 synthesized new methacrylate monomers combination of both ionic and van der Waals interactions, which
containing pendent bi-quaternary ammonium moieties based on should increase the binding of the polymers to the cytoplasmic
(DABCO) [1,4-diazabicyclo-[2.2.2]-octane] (Figure 15).35 The membrane of the bacteria.
monomer was prepared by reacting DABCO with bromoalkanes Singh et al.59 described the synthesis of iodine containing
such as with butyl and hexyl chains to be attached to one quaternary amine methacrylate copolymers. The monomers were
nitrogen of DABCO. The other nitrogen of DABCO was treated synthesized via a two-step reaction: the first step was the
with 11-bromoundecanoic acid. The carboxylic group of the reaction of ethylene glycol dimethacrylate (EGDMA) with
produced product was transferred to sodium salt by reacting it piperazine in methanol at 35 °C for 6 h. The second step was
Scheme 7. Synthesis of Quaternary Amine Methacrylate (QAMA)
Figure 16.
Figure 17.
Scheme 8. Synthesis of
Poly(2,4-dichlorophenylmethacrylate-co-vinyl Acetate)
The antimicrobial activities of the homopolymer and copoly-
mers were evaluated against bacterial strains (B. subtilis, E. coli,
and S. citreus), fungi (A. niger, S. pulVerulrmtum, and T.
lignorum), and yeasts (C. utilis, S. cereVisiae, and P. stipitis).
The results showed that the antibacterial activity of the
homopolymer corresponded to the lowest growth (20%), and
the other copolymers exhibited 20-38% growth. The antifungal
and the anti-yeast activities of the homopolymer showed 18-
38% growth. The authors did not report antimicrobial activity
for the monomer.
The monomer 3-triethoxysilylpropyl-5,5-dimethylhydantoin
has been described and polymerized by the Worley group.61
the quaternization of the synthesized monomer with 1-iodooc- It was polymerized on the surfaces of sand particles to
tane (Scheme 7). The quaternized monomer was copolymerized produce an adhered film that, upon chlorination with dilute
with 2-hydroxyethyl methacrylate (HEMA) by free radical sodium hypochlorite bleach, became biocidal (Figure 16). The
polymerization using ammonium persulfate and N,N,N′,N′- biocidal efficacy of this coated sand has been demonstrated in
tetramethyl ethylenediamine as a redox initiator. Copolymers a cartridge filter experiment against the bacterial pathogens
with various ratios of the quaternized monomers (QAMA) were Staphylococcus aureus and Escherichia coli. Complete inactiva-
synthesized. The antimicrobial activities of the QAMA contain- tion was observed within 1 min of contact for the former
ing copolymers were evaluated against E. coli and S. aureus. bacterium and in the interval of 1-5 min for the latter. Upon a
The results showed that all of the bacteria were killed by the loss of biocidal activity due to the depletion of bound chlorine,
next day after the incubation. In case of 40% content of QAMA the coated sand particles could be recharged by further exposure
in the copolymer, only a contact time of 10 min was required to dilute bleach. Potential uses of biocidal sand include
to show 100% kill. It was observed that increasing the QAMA disinfection and odor control in water treatment facilities and
content in the copolymer reduced the contact time required for recirculating baths.
killing E. coli. 4.2. Immobilized Antimicrobial Agent on Synthetic Pre-
Endo and co-workers described the synthesis and polymer- formed Polymers. The synthesis of cross-linked copolymers
ization of trialkyl-3-[(and 4-)vinylbenzyl]phosphonium chloride based on copolymerization of vinylbenzyl chloride (VBC) either
(Figure 2) by reaction of 3- (and 4-) chloromethylstyrene with with 2-chloroethyl vinyl ether (CEVE) or with methylmethacry-
trialkylphosphine. The polymerization was carried out in toluene late (MMA), using divinylbenzene (DVB) as a cross-linker, was
at room temperature under an atmosphere of nitrogen.33,60 Low reported.62 The cross-linked copolymers were further modified
molecular weight model compounds of similar structure were by quaternization with triphenylphosphine (Figure 17) and
synthesized (Figure 2). The results of the antibacterial activity triethylamine.
study showed that the polymers, in general, were more active The antimicrobial activities of the modified copolymers were
than the corresponding model compounds. evaluated against various microorganisms (Staphylococcus
Patel and co-workers synthesized homo- and copolymers from aureus, Escherichia coli, Bacillus subtilis, Aspergillus flaVus,
2,4-dichlorophenyl acrylate (2,4-DMA).1 The monomer 2,4- Fusarium oxysporum, and Candida albicans). The antimicrobial
DMA was prepared by reacting methacryloyl chloride and 2,4- activities of the modified copolymers were also evaluated against
dichlorophenol. Homo- and copolymers of 2,4-DMA and vinyl C. albicans SC5314, A. flaVus, and F. oxysporum as fungal
acetate (VAC) were prepared in DMF using 2,2′-azobisisobu- organisms. It was found that the diameter of the inhibition zone
tyronitrile (AIBN) as an initiator (Scheme 8). varied according to the active group in the copolymer and also
Figure 19.
Scheme 9. Coupling Reaction between Ampicillin and a

Polymeric Carrier
Figure 18.
the examined microorganism. In general, the copolymers showed

antimicrobial activity against the tested microorganisms. How-
ever, the compound with the triphenylphosphonium salt of the
modified copolymer was the most effective against bacteria and
fungi species. A concentration of 20 mg/mL of triphenylphos-
phonium salt of the modified copolymer killed 100% of C.
albicans. However, this polymer activity toward A. flaVus was
lower and gave 44% of the organism surviving at 20 mg/mL.
Although the polymer shown in Figure 17 has very interesting
structural features and a facile synthesis, the test method
described was not the best way to evaluate these polymers. It
would be preferable to pump the inocula through a column filter
containing the polymer to ensure maximum contact and accurate not be used for long-term applications where water exposure
contact time measurements. would occur.
Some polymers containing an antimicrobial pharmacophore Patel et al.64 reported the synthesis of poly (styrene-co-maleic
can be prepared by the chemical anchoring of the pharmacoph- anhydride) (PS-MA) with surface-containing functional anhy-
ore to the polymers. The polymers having phenolic hydroxyl dride groups of different percentages by solution polymerization.
moieties were prepared by the reaction of amine-functionalized The biologically active compound (BAC), ampicillin, was
copolymers (RAAS-4G) with p-hydroxybenzoic acid, 2,4- bound on the surface of this matrix by a coupling reaction
dihydroxybenzoic acid, and 3,4,5-trihydroxybenzoic acid (Figure (Scheme 9).
18).63 The amount of ampicillin chemically bound to the matrix
The antibacterial activities of the polymers were evaluated was spectroscopically characterized. The in vitro release rate
against E. coli and S. aureus during 15-24 h contact time, and of ampicillin in weak basic medium was studied along with
they increased in the order of the increasing number of the the determination of its antimicrobial activity. The study
hydroxyl groups.63 The activities were attributed to the phenolic indicated that the rate of drug release could be controlled by
hydroxyl groups in the resin. However, the exact mechanism the amount of the incorporated anhydride. To study the
of destruction of the surface of the cells due to the contact with antimicrobial activity of the prepared polymers, Patel et al. ran
these polymers has not been investigated by the authors. a control experiment, that is, only culture without the drug,
Park et al. introduced a 2-benzimidazolecarbamoyl moiety which showed a higher growth rate than the experiment in the
(CBZ) to poly(ethylene-co-vinyl alcohol) (Figure 19). presence of the drug. The presence of the drug alone reduced
The antifungal activity of the synthesized EVOH-CBZ was the growth rate from the beginning. Bound drug was unable to
evaluated after incubation for 72 h at 28 °C against Aspergillus show an effect in the beginning. However, after a delay of 8-16
fumigatus and Penicillium pinophilum and showed antifungal h, bacterial growth was inhibited. This could be due to the
activity. The inhibition zone diameter increased with increasing release of the drug, which means that this system works as a
CBZ concentration.2 The effect here was mainly from CBZ controlled release system for the drug, and, once released, the
moieties. The authors mentioned when they complexed the ampicillin released begins to function according to the known
polymer, EVOH-CBZ, with isophoronediamine, the cured mode of action of this class of antibiotics.
DGEBA-CBZ complex sheet did not show any appreciable Poly(styrene-co-maleic anhydride) (PS-MA) was used by Lee
antifungal activity, indicating that release of CBZ units is needed and co-workers as a carrier for active agents containing amino
to exhibit antifungal activity. Therefore, CBZ supported poly- or hydroxyl groups.65
mers will be of little potential use because large weight In this context, 4-aminophenol (AP) was reacted with PS-
percentages are required for activity and because they could MA to obtain SMA-AP conjugate (Scheme 10). SMA-AP
Scheme 10. A Route of Chemical Synthesis for SMA-AP
Scheme 11. Reaction Pathway Outlining the Preparation of the Figure 20.
Target Sulfopropylbetaine Copolymers
Figure 21.
phosphonium chloride (MET-R) (Scheme 2) and N-isopropy-
lacrylamide (NIPAAm).41 The copolymer [METO-NIPAAm],
with octyl substituents in phosphonium groups (R ) C8H17
[METO]), was found to have a high antibacterial activity against
E. coli. However, there is no report about the antimicrobial
properties of the monomer itself to compare with the copoly-
mers.
Lowe et al.66 prepared a series of statistical copolymers
derived from 2-(dimethylamino)ethyl methacrylate with four
different hydrophobic monomers (ethyl, butyl, cyclohexyl, and
octyl methacrylates) via free radical copolymerization under bulk
conditions using AIBN as an initiator at 60 °C. The synthesized
copolymers were modified with 1,3-propanesultone (Scheme
11) to yield polysulfopropylbetaine derivatives. The antimicro-
bial activities of the sulfopropylbetaine copolymers were tested
against S. aureus and E. coli using the broth dilution method.
The results showed that all of the copolymers showed bacte-
riostatic activity against the test organisms. However, the
activities were mainly dependent on the copolymer composition
and the test organism. The MIC values for S. aureus and E.
coli were in the range of 1125-2000 µg/mL, which is about 2
orders of magnitude higher than those of the antibiotics
exhibited bacterial activity against E. coli and S. aureus. The ampicillin and erythromycin.
reduction in the number of the cells of E. coli was 95.3%, while Polymeric phosphonium salts with different side-chain lengths
it was 99.9% for S. aureus. The relatively lower activity of between the main chain and the reactive group, poly[4-(2-
SMA-AP toward E. coli as compared to S. aureus is due to tributylphosphonioethyl) styrene chloride-co-4-(2-chloroethyl)-
the outer membrane barrier in E. coli. No free AP was detected styrene], Figure 20, and poly[4-(3-tributylphosphoniopropyl)-
from the polymer incubated under similar conditions. Therefore, styrene chloride-co-4-(3-chloropropyl)styrene], Figure 21, were
it was concluded that SMA-AP may be bactericidal by itself, prepared by Kanazawa and Endo.26
and its bactericidal activity may last for a fairly long period of The polymeric phosphonium salts were prepared by reacting
time under neutral conditions. However, there was no bacteri- tributylphosphine with the copolymers in toluene at room
cidal mechanism suggested for SMA-AP, but it is possible that temperature under nitrogen atmosphere for 20 h. The antimi-
it was due to the phenolic hydroxyl group, which may attack crobial activity of the polymer phosphonium salts was tested
the cell membrane, which leads to cell death. One advantage against S. aureus and E. coli, and the results showed high
of this kind of antimicrobial system is that there is no release activity of the synthesized polymers.
of active agent into the environment; it has bactericidal activity They found that the antibacterial activity decreased as the
itself. side-chain length increased. However, in the two examples
Probably the class of the antimicrobial polymers that has studied, there is only a difference of one carbon between the
received the most attention over the years has been that of the lengths of the two chains. Therefore, this difference in activity
polymeric quaternary “onium” salts. is probably due to other factors.
Nonaka and co-workers synthesized water-soluble polymers Nonaka and co-workers prepared copolymer beads bearing
having a phosphonium group from methacryloyloxyethyl trialkyl quaternary ammonium groups (Figure 22).67
Scheme 13. Antimicrobial Polymers Prepared by the

Immobilization of Ammonium and Phosphonium Groups onto the
Chloroacetylated Poly(glycidyl methacrylate)
Figure 22. Resins containing quaternary ammonium groups.
Figure 23.
Scheme 12. Preparation of Polymer-Grafted Phosphonium Salts

by Quaternization of Styrene-7% Divinylbenzene
trioctylphosphine is attributed to the strong interaction between

The beads were prepared by the treatment of glycidyl the resins and bacteria.
methacrylate (GMA)-1,4-divinylbenzene copolymer beads with Popa and co-workers synthesized quaternary phosphonium
hydrogen chloride and then were treated with various amines salts grafted on an insoluble “gel-type” styrene-7% divinyl-
such as triethylamine, N,N-dimethyloctylamine, N,N-dimethyl- benzene copolymer (Scheme 12).69 The quaternary phosphonium
dodecylamine, and N,N-dimethylhexadecylamine. The antibacte- salts were prepared from chloromethylstyrene-divinylbenzene
rial activities of the resins were examined against E. coli and copolymer and the corresponding phosphine in N,N-dimethyl-
S. aureus. The results showed that the antibacterial activity formamide by reacting for 2 h under stirring at room temperature
increased with the increase of the amount of quaternary to allow the copolymer beads to swell, and then refluxing at
ammonium groups in the resins. The activity of the resins was 110 °C for 72 h (Scheme 12).
not affected by the chain length of the alkyl groups. The antibacterial activities of the products were tested against
Another similar copolymer system based on glycidyl meth- S. aureus, E. coli, and P. aeruginosa. The copolymers were
acrylate and a divinylbenzene-bearing phosphonium group was minimally active against the test organisms after incubation for
prepared by Nonaka and co-workers (Figure 23).68 18 h at 37 °C. They may have bacteriostatic properties because
The copolymer beads, having 2-chloro-3-hydroxypropyl, were the best copolymer showed 40% reduction of the colony units
prepared by treating glycidyl methacrylate-1,4-divinylbenzene after 18 h of exposure.
copolymer beads with hydrogen chloride. The produced modi- Modified glycidyl methacrylate polymers having quaternary
fied beads were further treated with triethylphosphine, tribu- ammonium and phosphonium groups were prepared.18 Three
tylphosphine, and trioctylphosphine. The antibacterial activities different antimicrobial polymers were prepared (Scheme 13),
were examined against E. coli and S. aureus by measuring the and the antimicrobial activities of these polymers were tested
decrease in the number of viable cells in bacteria suspension against Gram-negative bacteria (E. coli, P. aeruginosa, Shigella
after contact with the resin for a prescribed time. The beads sp., and Salmonella typhae), Gram-positive bacteria (Bacillus
with trioctylphosphine exhibited high antibacterial activity subtilis and B. cereus), as well as the fungus Trichophytun
against E. coli and S. aureus in water; however, the beads with rubrum. The tested polymers showed significant antimicrobial
triethylphosphine and tributylphosphine did not. activity against Gram-negative bacteria and the fungus after 24
Nonaka and his co-workers noticed that there is a relationship h contact time, whereas these polymers were less active against
between the adsorption ability of the resins for the anionic Gram-positive bacteria. It was reported that the tributyl phos-
compounds such as dodecylbenzenesulfonic acid and the honium salt was able to kill 100% of the fungus Trichophytun
antibacterial activity. They found that the resin with high rubrum at a concentration of 10 mg/mL and a contact time of
adsorption ability has high antibacterial activity. Therefore, in 24 h. Polymer with triphenylphosphonium salt was able to kill
their subsequent work, they studied the interaction between the 100% P. aeruginosa at a lower concentration of 5 mg/mL; the
resins and bacteria by preparing resins having various phos- same concentration of polymer with ammonium salt was able
phonium groups.42 Uemura et al. studied the adsorption and to kill 100% P. aeruginosa at the same contact time. Generally,
elution behavior of the resins toward anionic surfactants as a it was found that the diameter of the inhibition zone varied
model of the interaction between the resins and bacteria. It was according to the active group in the polymer and the test
found that the resin showing the highest antibacterial activity bacteria. The polymer with tributylphoshonium salt is the most
had the highest adsorption ability for anionic surfactants; effective against both Gram-positive and Gram-negative bacteria
therefore, the higher activity of copolymer beads having as compared to salts of triethylamine and triphenylphosphine.18
Scheme 14. Synthesis Scheme for the Generation 3 Quaternary

Ammonium Dendrimers with C12 Hydrophobe
Figure 24.
coli, P. aeruginosa, Shigella sp., and Salmonella typhae), Gram-

positive bacteria (B. subtilus and B. cereus), and the fungus
trichophyton rubrum. The results showed that the three copoly-
mers were highly active against the test organisms after
incubation for 24 h at 30 °C. The copolymer with tributylphos-
phonium salt was the most effective one against the test
organisms. Generally polymers with phosphonium salts showed
excellent antimicrobial activity after 24 h incubation at 30 °C
against T. rubrum; they killed 100% of T. rubrum at a
concentration of 2.5 mg/mL. However, T. rubrum required a
concentration of 10 mg/mL polymer with ammonium salt to
Figure 25. kill 100% of T. rubrum. To kill 100% of E. coli, it required a
concentration of 10 mg/mL polymer with triphenylphosphine
or 5 mg/mL polymer with tributylphoshine. Polymer with
triphenylphosphine proved to be able to kill 100% of E. coli,
97% of P. aeruginosa, and 48% of B. subtilis at a concentration
of 10 mg/mL at the same contact time. The modes of actions
of these polymers are similar to the mode of action of polyquats
previously explained. In conclusion, it seems that these materials
could be promising candidates for preventing biomaterial-related
infections. The latter results are in agreement with the previously
reported results.6,18
Recent advances in polymer chemistry seem to provide an
ideal system for bioactive materials. Dendrimers are novel highly
Figure 26. branched three-dimensional macromolecules that emanate from
a central core.70 They can be tailored to generate uniform or
discrete functionalities and possess tunable inner cavities, surface
moieties, sizes, molecular weight, and solvent interactions.
Generation 4 poly (propyleneimine) dendrimer has attracted
much attention as a potential antimicrobial agent because of its
compact structure and the availability of many end groups.
Cooper and co-workers37 modified the commercially available
poly(propylene imine) dendrimers with 32 surface primary
amine groups (Figure 27) to introduce the quaternary ammonium
function on the dendrimers. The amine-funtionalized dendrimers
were modified in two steps (Scheme 14). The first step was by
reacting the primary amine group either with 2-chloroethyl
isocyanate or with 2-bromoethyl isocyanate. The second step
involved the reaction of halogen-containing dendrimers pro-
duced from the first step with tertiary amines to form the
quaternary ammonium-functionalized poly(propylene imine)
Figure 27. Commercially available generation 4 poly(propyleneimine) dendrimers. The antimicrobial properties of the modified
primary amine-terminated dendrimers.
dendrimers were evaluated using a bioluminescence method.
Recently, quaternary ammonium and phosphonium salts were They extensively studied the effect of the other factors such as
immobilized on a modified copolymer of glycidyl methacrylate the size of the dendrimers, length of the hydrophobic chain in
and 2-hydroxyethyl methacrylate (Figures 24-26).6 the quaternary groups, and the effect of counterion.37 The results
Three copolymers were prepared by reacting the modified showed that the higher generations of the dendrimer showed
poly(glycidyl methacrylate-co-2-hydroxyethyl methacrylate) higher antibacterial activities. The results also showed that the
with triethylamine, triphenylphosphine, and tributylphosphine, antimicrobial activity is proportionally dependent on the mo-
respectively (Figures 24-26). The antimicrobial activities of lecular weight. Also, the counterion studies showed that the
the copolymers were studied against Gram-negative bacteria (E. dendrimers with bromine as counterion were more potent than
Scheme 15. Preparation of Polymer Poly[1,3,5-trichloro-6-methyl-

6-(4′-vinylphenyl)-1,3,5-triazine-2,4-dione]
Figure 28.
polymer filter. After a long period of storage at ambient

Figure 29.
temperature, their activity continued, and none were ineffective.
The polymers with general structure shown in Scheme 15
are polystyrene triazinediones synthesized by Sun, Worley, and
co-workers.73-75 These polymers are synthesized from com-
mercial polystyrene; the first step was a Friedel-Crafts acylation
using an acid chloride such as acetyl chloride in the presence
of aluminum chloride. The formed polystyrene ketone was then
reacted with dithiobiuret in the presence of HCl to form a
polystyrene triazinethione. The thione was oxidized to the ketone
using hydrogen peroxide in base, and halogenation was per-
formed by exposure to aqueous free halogen (chlorine and
bromine) in a reaction flask or in a packed column.10,72
Figure 30.
The antimicrobial activity of the polymer described in Scheme
those with chloride, although the reason for this observation is 15 was tested against the bacterium Staphylococcus aureus in
not clear. The dependence on the hydrophobic chain of the a water-filter application by packing a small column with the
quaternary ammonium structure is similar to conventional polymer and passing through it an aqueous solution of S. aureus
polymer biocides, and shows a parabolic relationship, with bacterial suspension. The contact time of flow was 30 s, and
dendrimer biocides carrying the C10 hydrophobe being the most the aliquots of effluent were plated on nutrient agar. The plates
potent. These results are consistent with our previous discussion were incubated at 37 °C for 48 h before examination for viable
about the effect of the counterion on the antimicrobial properties. organisms. It was found that no bacteria survived.
The mode of actions of these dendrimer biocides was explained Recently, Worley et al. have reported a very interesting and
to be similar to the mode of action of cationic biocides. In this important comparison between the polymeric quaternary am-
case, the dendrimers’ initial adsorption onto the negatively monium materials and N-chlorinated polymers.75 They described
charged bacterial cell surfaces is more rapid than the small the synthesis of three systems based on poly(styrene) derivatives;
molecule biocides due to their polycationic nature. Also, due that is, the three systems have the same polymer backbone, but
to the compact structure of these dendrimers, their permeability only differed in their biocidal derivative moieties (Figure 30).
into the cell is higher than that for the polymeric biocides. The first system was based on the chlorinated methylated
Therefore, the dendrimers can disrupt and disintegrate the cell polystyrene hydantoin beads. It was prepared by reacting the
wall to a higher extent than do the small molecules. potassium salt of 5,5-dimethylhydantoin with chloromethylated
Worley and co-workers synthesized two poly(ethyleneglycol- polystyrene beads in DMF at 100 °C for 12 h. The functionalized
N-halamine) polymers (Figure 28).19 Dichlorohydantoins and beads were suspended in a flask containing 5.25% sodium
chloroimidazolidin-4-ones were attached to a methoxy-poly- hypochlorite to produce the chlorinated beads (PHY). The other
(ethylene glycol)-terminated amine. two systems were quaternary ammonium salts that were
The resulting water-soluble polymers have inactivated bacteria produced on the same chloromethylated polystyrene, which was
(S. aureus) over a prolonged period of time after 10 min contact made to react either with dimethyldodecylamine to yield PQ1
time. The polymer containing the hydantion moiety showed or with N,N,N′,N′-tetramethylethylenediamine in ethanol at
better activity and stability than did the chloroimidazolidin-4- reflux temperature for 12 h followed by reaction with dodecyl
one polymer. bromide to yield PQ2. The antimicrobial efficacies of the three
Materials of general structure (Figure 29), polystyrene hy- systems were tested, and the results showed that the N-
dantoin, were synthesized by Worley and co-workers.71 chlorinated polymeric beads were much more efficacious in an
The biocidal activities of these polymers were tested against aqueous disinfection application against the bacteria S. aureus
S. aureus. These polymers were capable of killing S. aureus in and E. coli than was that of the structurally similar polymeric
contact times of 1 s or less, most with one pass through the quaternary ammonium salts (PQ1 and PQ2).
Scheme 16. Schiff Base Formation between MPA and Various

Aldehydes
Figure 31.
Scheme 17. Modification of MPA with Various Esters
Figure 32.
Grunlan et al. reported on the antimicrobial behavior of

polyelectrolyte multilayer films containing cetrimide and silver.78
They described six antimicrobial thin film systems, based upon
polyethyleneimine (PEI), poly(acrylic acid) (PAA), silver nitrate
(AgNO3), and containing cetrimide. Film deposition was carried
out on poly(ethylene terephthalate) (PET) film, with a thickness
of 175 µm; the antimicrobial thin films were highly effective.
Corona treatment of PET substrates prior to thin film deposition
yielded a more effective film than did those with no surface
treatment. It is believed that the strong negative surface charge
imparted by the corona led to a more concentrated deposition
Figure 33. Ammonium and phosphonium groups immobilized on the of the positively charged antimicrobial agents. Another useful
copolymer of CEVE and VBC. discovery was an enhanced antimicrobial efficacy in films made
with cetrimide, an organic quaternary ammonium molecule,
Worley et al. synthesized a very intriguing series of hydan- relative to films containing only silver.
toinyl/quat siloxane copolymers containing both N-halamine and Shyu et al. prepared hydrogel membranes with a polyelec-
quaternary salt functionalities simultaneously (Figure 31).76 The trolyte method, based on homogenizing an interpolyelectrolyte
copolymers are adequately soluble in water to be used for complex, a chitosan-alginate sponge with high stability.79 The
coating cotton swatches. spongelike chitosan-alginate hydrogels exhibited superabsor-
All of the biocidal polymer coatings were effective against bent properties. The result of the antimicrobial activities after
E. coli O157:H7 and Staphylococcus aureus. However, it is 24 h contact suggests that the PEC sponges containing antimi-
evident that the coatings containing hydantoinyl siloxane crobial agents should effectively suppress bacterial proliferation
functional groups (PHS and PHQS (1:1)) were much more to protect wounds from bacterial invasion.
effective against Gram-negative E. coli O157:H7 than was PQS. Recently, Kenawy’s group modified polyacrylamide by
The monomer 5,5-dimethyl-3-(3-triethoxysilylpropyl) hydan- introducing an amino group in the side chain of the polymer
toin and its hydrolysis product polymer poly[3-(5,5-dimethyl- by reacting it with ethylenediamine.80 The amine-modified
hydantoinylpropyl)hydroxysiloxane were employed by the same polymer was reacted with two classes of active compounds. The
group to functionalize the surfaces of silica gel particles to first group was aromatic aldehydes containing active groups such
produce an adhered film that became biocidal upon chlorination as p-hydroxybenzaldehyde, vanillin, p-chlorobenzaldehyde, and
with dilute sodium hypochlorite bleach (Figure 32).77 The anisaldehyde. The second group was phenolic ester derivatives
biocidal efficacy of the functionalized silica gel was demon- such as p-hydroxymethylbenzoate, 2,4-dihydroxymethylben-
strated in a cartridge filter experiment against the bacterial zoate, 2-hydroxymethylbenzoate, and 3,4,5-trihydroxypropyl-
pathogens Staphylococcus aureus and Escherichia coli O157: benzoate.
H7. Complete 6 log inactivations of the two bacterial species The modified polymers (Schemes 16 and 17) showed
were observed within 30 s of contact. Moreover, upon loss of antimicrobial activity against Staphylococcus aureus, Escheri-
biocidal activity due to depletion of bound chlorine, the coated chia coli, Bacillus subtilis, Aspergillus flaVus, Fusarium ox-
silica gel particles could be recharged by further exposure to ysporum, and Candida albicans. The tests were carried out by
dilute bleach. Potential uses of the biocidal silica gel include the cut plug method after incubation for 36 h. The polymer
disinfection and odor control in water treatment facilities and derivative of p-chlorobenzaldehyde was the most effective
recirculating baths. against bacteria and fungi species. Also, the phenol-modified
Scheme 18. Preparation of Chitosan from Chitin
Figure 34. Electron scanning micrograph of (A) normal-control

Staphylococcus aureus, and (B) and (C) treated Staphylococcus
aureus cell (ref 81).
polymers showed high antimicrobial activities at the same

contact time and concentration of 20 mg/mL. The mode of
action here is related to the phenolic moieties. This may be due
to the fact that phenols damage cell membranes and cause
release of intracellular constituents. Phenols also cause intrac-
ellular coagulation of cytoplasmic constituents, leading to cell
death or inhibition of cell growth.
Various copolymers were prepared by the copolymerization
of 2-chloroethylvinyl ether (CEVE) with vinylbenzyl chloride
(VBC).81 The copolymers were quaternized by reaction of the
copolymers with triethylamine, triphenylphosphine, and tribu-
Scheme 19. Preparation Route to N-Alkyl Chitosan Derivatives
tylphosphine (Figure 33).
The antimicrobial activities of the quaternized copolymers
were tested against fungal organisms (C. albicans, Aspergillus
flaVus) and bacterial organisms (B. subtilis, E. coli, and S.
aureus). The results showed that the phosphonium-containing
polycationic biocides were more effective than were the
quaternary ammonium salts. The antimicrobial activity of
polymer with triphenylphosphonium salt against the selected
microorganisms was high. It killed 71-98% of the microorgan-
isms at a concentration of 5 mg/mL. However, a concentration
of 10 mg/mL killed 98-100% of the tested fungi. Decreasing
the polymer concentration to 2.5 mg/mL decreased the inhibition
potency of the polymer to 50% inhibition for Staphylococcus
aureus. It is quite clear that this polymer is a potent inhibitor
for C. albicans where it performed 100% inhibition of growth
for that organism at 10 mg/mL concentration and 98%, 96%,
and 71% of organism growth inhibition at concentrations of 5,
2.5, and 1.25 mg/mL of the polymer, respectively. This
selectivity of growth inhibition of polymer for C. albicans might
be due to the interaction between this poly(cationic) biocide
with the charged organism membrane. Examination of the S.
the alkyl substituent; this increased activity was ascribed to the
aureus polymer-treated cells by electron microscopy indicated
contribution of the increased lipophilic properties of the
disruption for the cytoplasmic membrane (Figure 34), causing
derivatives.
a release of potassium ions as shown by the assay of potassium
leakage. Huh et al. modified poly(ethylene terephthalate) (PET) texture
by exposing it to an oxygen plasma glow discharge to produce
4.3. Immobilized Antimicrobial Agent on Naturally Oc- peroxides on its surface.86 These peroxides were then used as
curring Polymers. Chitin is the second-most abundant biopoly- catalysts for the polymerization of acrylic acid (AA) to prepare
mer in nature. It is found in the shells of crustaceans, the cuticles a PET with a carboxylic acid group (PET-A) (Scheme 20).
of insects, and the cell wall of fungi.82 Chitosan, a deacetylated Chitosan and quaternized chitosan (QC) were then coupled with
product of chitin, has many interesting properties, such as the carboxyl groups on the PET-A to obtain chitosan-grafted
antimicrobial activity and nontoxicity. It is obtained from shrimp PET (PET-A-C) and QC-grafted PET (PET-A-QC), respectively
and crab shell chitin by alkaline deacetylation (Scheme 18).83 (Schemes 21 and 22). The PET-A was dipped in 1-ethyl-3-(3-
Many attempts have been made to use chitosan in several dimethylaminopropyl)carbodiimide (WSC) aqueous solution to
fields such as the food, medical, cosmetic, and textile indus- activate the carboxyl groups on the surface, and it was
tries.84 subsequently transferred into the chistosan solution to obtain
N-Alkyl chitosan derivatives were prepared by introducing chitosan-grafted PET (PET-A-C) (Scheme 21).
alkyl groups into the amine groups of chitosan via a Schiff’s QC-Grafted PET (PET-A-QC) was prepared by dipping the
base intermediate.85 Quaternization of the N-alkyl chitosan activated PET-A in QC solution (Scheme 20). The antibacterial
derivatives with methyl iodide produced water-soluble cationic activity of the chitosan-grafted PTEs was high against S. aureus
polyelectrolytes (Scheme 19). and showed a high growth inhibition after laundering. The
The antimicrobial activities of the chitosan quaternary am- antimicrobial activity is attributed to the possibility of the release
monium salts increased with the increase in the chain length of of the chitosan from the PET surface during shaking in the flask
Scheme 20. Oxygen Plasma Treatment of PET and Graft Scheme 23. Preparation of Grafted Chitosan Copolymers
Polymerization of Acrylic Acid (AA) on PET
Scheme 21. Formation of Chitosan-Grafted PET (PET-A-C) Scheme 24. Reaction Scheme for the Synthesis of HTCC
Scheme 22. Quaternization of Chitosan and Its Immobilization

onto PET-A
However, this is expected because it is known that high acidic

and high basic media have effect on the microorganisms, and
the studies showed pH variations up to 6.2 only.
N-(2-Hydroxy)propyl-3-trimethylammonium chitosan chloride
(HTCC) was synthesized by the reaction of glycidyltrimethy-
lammonium chloride (GTMAC) and chitosan (Scheme 24).88
The modified chitosan (HTCC) showed excellent antimicro-
bial activity; it was stronger than the unmodified chitosan due
to the quaternary ammonium groups. HTCC was blended with
polyacrylonitrile (PAN) using NaSCN aqueous solution as a
and to the presence of the quaternary ammonium ions of the common solvent. The PAN/HTCC blend fibers were prepared
grafted chitosan. Therefore, the mode of action could be due to via a wet spinning and drawing process. Addition of 0.5%
disruption of cell membrane function, which consequently leads HTCC to the blend fiber showed nearly 100% reductions in
to the cell death. Even though these systems showed reasonable bacteria.
antimicrobial activity, the possibility that they lose the antimi- New polymeric derivatives of dipyridyl were synthesized by
crobial activity after time is high due to the release of grafted Avram and co-workers.89 These compounds were synthesized
chitosan. It is always preferable to find self-sterilized materials by reaction of chloroacetylated cross-linked dextran micropar-
(SSM), which remain active for longer periods of time and ticles with dipyridyl compounds as 4,4′-dipyridyl, N-n-octyl-
which do not release the active agent at high rate. dipyridinum chloride, and N-benzyldipyridinum chloride (Schemes
Two anionic monomers, mono (2-methacryloyloxyethyl) acid 25 and 26).
phosphate (MAP) and vinylsulfonic acid sodium salt (VSS), Preliminary studies concerning the antimicrobial activities of
were grafted onto chitosan to obtain copolymers with zwitte- these polymeric dipyridyl compounds were performed, and the
rionic properties (Scheme 23).87 Results of the antimicrobial results showed that the polymeric dipyridyl conjugates have
activities of the modified chitosan samples against Candida improved antimicrobial activity over the small molecular
albicans, Trichophyton rubrum, and Trichophyton Violaceum compounds.
showed that optimum antimicrobial activities result at pH ) Ion exchange fibers, with quaternary ammonium, phospho-
5.75 against Candida albicans. The antimicrobial activities of nium, or thiol groups, were prepared by graft copolymerization
chitosan-g-MAP and chitosan-g-VSS were 95% and 75%, of vinyl monomers on loofah fiber, which is one of the natural
respectively, over 48-72 h contact time. The polymers showed fibers.90 Methacryloyloxyethyl trimethyl ammonium chloride
the dependence of the antimicrobial activities on the pH; when (METAC), tributyl-4-vinylbenzyl phosphonium chloride (TRVB),
the pH was changed to 6.2, the activities dropped to 10-15%. and 2,3-epithiopropyl methacrylate (ETMA) were used as vinyl
Scheme 25. Reaction of Chloroacetylated Cross-linked Dextran

with Dipyridyl (MQ, Monoquaternized; BQ, Biquaternized)
Scheme 26. Reaction of Chloroacetylated Cross-linked Dextran

with N-n-Octyldipyridinium Chloride and N-Benzyldipyridinium
Chloride Figure 35. Structure of grafted loofah fibers.
Scheme 27. Schiff Base Formation between Chitosan (CTS) and Figure 36. Polyketones.
Different Aldehydes
Ion exchange fibers LE and LE-TTA had high adsorption
ability for silver ions. Fibers LE and LE-TTA were stirred with
AgNO3 solution to produce silver ions adsorbed on both fibers
(LE-Ag and LE-TTA-Ag). The antibacterial activity of the fibers
was tested against E. coli and S. aureus. LE-TTA-Ag exhibited
high antibacterial activity against E. coli and S. aureus, but LE-
Ag did not. On the other hand, L-g-METAC and L-g-TRVB
also exhibited high antibacterial activity against E. coli and S.
aureus. However, the best results in this work were shown by
the fiber L-g-TBVB, which has a tributylphosphonium group
in the side chain. The fiber L-g-TBVB showed the highest
activity against S. aureus, with a total kill after less than 2 h.
The mechanism here is expected to be due to the quaternary
ion and its known mode of action. Also, the silver adsorbed on
Scheme 28. Schiff Base Formation between Chitosan (CTS) and
fiber (LE-TTA-Ag) showed antimicrobial activity against S.
Different Esters aureus. The clear mode of action for this system was not
clarified by the authors, but it could be due to the interaction
of Ag+ with cell enzymes after penetration of the cell wall,
which leads to the cell death.
Chitosan has an amino group at C-2, which is important
because amino groups are nucleophilic and readily react with
electrophilic reagents. Chitosan modified under mild conditions
often results in regioselectivity. In our laboratory, biologically
active moieties were introduced into the amino groups of
chitosan to yield antimicrobial chitosans. Specifically, vanillin,
p-hydroxybenzaldehyde, p-chlorobenzaldehyde, anisaldehyde
(Scheme 27), methyl 4-hydroxybenzoate, methyl 2,4-dihydroxy-
benzoate, propyl 3,4,5-trihydroxybenzoate, and 2-hydroxym-
ethylbenzoate (Scheme 28) were attached.91
The anti-microbial activities of these modified chitosans were
explored against fungi such as Candida albicans SC5314,
Aspergillus flaVus, and Fusarium oxysporium. Also, they were
monomers. Methacryloyloxyethyl trimethyl ammonium chloride tested against bacteria such as Bacillus subtilis, Escherichia coli,
(METAC) was grafted on loofah fiber by reacting it in deionized and Staphylococcus aureus after 24 h contact time. These
water using ammonium cerium nitrate as an initiator to yield modified chitosans were found to be generally highly active
loofah-grafted METAC (L-g-METAC). A similar method was toward fungi species (more than bacterial species). However,
used to prepare TBVB and ETMA grafted on loofah fibers to for polymer CTS1 (Scheme 27), concentrations of 20 mg/mL
yield L-g-TBVB and L-g-ETMA (LE) (Figure 35). Further were able to kill 100% of Bacillus subtilis, Escherichia coli,
modification for the ETMA grafted on loofah fiber L-g-ETMA and Staphylococcus aureus. A lower concentration of 10 mg/
(LE) was carried out by reacting it with triethylenetetramine mL was able to kill 100% of Staphylococcus aureus. Also,
(TTA) to yield an ion exchange fiber LE-TTA (Figure 35). polymer CTS2 showed total kill of 100% for Aspergillus flaVu
Scheme 29. Synthesis of Drug Polymer
and Fusarium oxysporium at a concentration of 20 mg/mL; a The authors studied the hydrolysis rate of bithionol-containing
lower concentration of 10 mg/mL killed 98% of Staphylococcus polymers at 37 °C in buffer solution at pH 7.4. It releases
aureus at the same contact time. The mode of action could be bithionol at about 1% per day. There was no specific antimi-
due to the phenolic hydroxyl groups. crobial study for the prepared polymers reported.
4.4. Preparation of Hydrolyzable Antimicrobial Agents
as Part of the Polymer Main Chain. A number of chemical 5. Major Fields of Applications of Antimicrobial
reactions can be employed to incorporate antimicrobial agents Polymers
into polymeric backbones. Polymers with biologically active
groups in the main chain are considered desirable as they may 5.1. Water Treatment. Chlorine or water-soluble disinfec-
be hydrolyzed to active drugs and small innocuous molecules. tants are used for sterilizing water. However, soluble disinfec-
Prime candidates for polymer structures in these categories are tants have the problems of residual toxicity of the agents, even
polyamides, polyesters, and polyurethanes.92 Polyketones have if suitable amounts of the agents are used.63 With the use of
been prepared by reacting benzene, chloroacetyl chloride, 1,2- these disinfectants or antimicrobial agents, the problem of
dichloroethane, and dichloromethane using anhydrous aluminum residues cannot be avoided, bringing about more serious
chloride as a catalyst and nitrobenzene as a solvent (Figure 36).93 consequences. Their residues can become concentrated in the
All of the samples of the polyketones showed inhibitory food chain in the environment. In addition, because free chlorine
effects on the growth of Bacillus substilis and Pseudomonas and other related chemicals can react with organic substances
fluorescens. They also showed antifungal activity against in the water to yield trihalomethane analogues that are suspected
Aspergillus niger and Trichoderma Viride. of being carcinogenic, their use should be avoided. These
A model drug polymer was synthesized using 1,6-hexane drawbacks can be solved by the removal of microorganisms
diisocyanate (HDI), polycaprolactone diol (PCL), and a fluo- from water with insoluble substances.8,96 One approach is the
roquinolone antibiotic, ciprofloxacin (Scheme 29). The study use of insoluble contact disinfectants that can inactivate, kill,
showed that an antibiotic could be polymerized into the or remove target microorganisms by mere contact without
backbone of a polymer and that the polymer could be degraded releasing any reactive agents to the bulk phase to be disinfected.
by an inflammatory cell-derived enzyme cholesterol esterase.94 Polymeric disinfectants are ideal for applications in hand-
Analysis of the solutions showed that ciprofloxacin was released, held water filters, surface coatings, and fibrous disinfectants,
and it was able to inhibit the growth of P. aeruginosa. The because they can be fabricated by various techniques and can
degradation products containing ciprofloxacin bonded to frag- be made insoluble in water. Several workers in the past few
ments of PCL and HDI and did not display antimicrobial decades have attempted to produce insoluble polymeric disin-
activity. The mechanism of action is similar to quinolones, which fectants for use in water treatment. A water-insoluble matrix
inhibit the activity of the bacterial DNA gyrase, which leads to based on iodinated poly(methyl methacrylate-co-N-vinyl-2-
bacterial cell death. However, for these systems, the complete pyrrolidone) was synthesized by Tyagi et al.97 The copolymer
degradation of the polymer backbone is necessary to release was synthesized from methyl methacrylate (MMA) and N-vinyl-
the known active formula of the drug. 2-pyrrolidone with a 1:1 (w/w) ratio and using 0.5% AIBN (w/
Albertsson and co-workers described the incorporation of the w) as an initiator. The copolymer was sieved in particle size
known antimicrobial agent, bithionol[2,2′-thiobis(2,4-dichlo- range 250-500 µm and was treated with molecular resublimed
rophenol)], in the polymer main chain.95 Bithionol was found iodine at 37 °C for 24 h to yield the iodinated copolymer. This
to react with phosgene to give the bischloroformate, and the copolymer was used in the specially designed cartilage for
latter was used for the preparation of alternating copolycarbon- testing the antimicrobial activity of the iodinated copolymer
ates, polyurethanes, or copolycarbonate/polyurethane (Figure (Figure 38). As shown in Figure 38, the system was connected
37). to a water tap via a water flow regulator. A known concentration
Figure 37.
Figure 39.
Table 2. Microbial Counts with Respect to Water Flow through

the Column
microbial density/100 L of water passed
species initial up to 5000 L 5000-8000 L
S. aureus 2× 105 nil 1(1
E. coli 2 × 105 nil 5(2
Candida 1.5 × 105 nil 1(1
the efficacy has been consumed during use.50 Worley et al. at

Auburn University have prepared several of such materi-
Figure 38. Diagram of the refill cartridge (ref 97).
als.50,99,100 Of particular value for water and air disinfection
applications are the N-halamine polymers that are prepared in
of microbial cells composed of E. coli, S. aureus, and Candida
the form of highly cross-linked porous beads. Functionalization
spp. was inoculated into the water reservoir. The eluting water
of methylated polystyrene by halogenated hydantoin and imi-
was tested at regular interval for the microbes. A volume of
dazolidinone derivatives was reported. The structures of the
8000 L of contaminated water was used. The microbial count
several types of functionalized polymeric beads are shown in
with water flow was as shown in Table 2. The results indicated
Figure 39.
that the iodinated polymer remained effective against the test
Column filter biocidal efficacy tests were conducted for
microorganisms until 5000 L of water had passed.
aqueous suspensions of the Gram-positive bacterium S. aureus
Tan and co-workers prepared modified polypropylene (PP) and Gram-negative bacterium E. coli for four types of beads in
nonwoven cloths by radiation-induced grafting of 4-vinylpyri- this study (Figure 39). Glass columns were packed with beads
dine (4-VP) onto PP nonwoven cloths and followed by of PHY-Cl, PHY-Br, PMHY-Cl, and PI-Cl. The suspensions
quaternization with a halohydrocarbon such as benzyl bromide, of pathogenic bacteria were pumped through the columns. The
benzyl chloride, ethyl bromide, butyl bromide, or hexadecyl results showed the efficacies of the bead columns for inactivation
bromide.98 The activity results showed that the modified PP of S. aureus and E. coli. The PHY-Cl and PHY-Br polymer
nonwoven cloths possessed the ability to capture the bacterial beads were able to exhibit complete inactivation of both species
cell alive. It was found that the quaternization with benzyl in the contact time interval of 1-2 s. In contrast, the polymer
bromide was the highest in the extent of removal of E. coli. labeled Poly1-Cl in Figure 42 has been shown to accomplish
There were no morphological changes of the adhered cells the same task in less than 1 s. The PMHY-Cl polymer also
observed by SEM; thus, the surface of the modified PP completely inactivated both species of bacteria in a contact time
nonwoven cloths may not be bactericidal, but bacteriostatic. of less than or equal to 1 s. The PI-Cl polymer beads inactivated
Cyclic N-halamines have superior properties including bio- S. aureus in a contact time between 2 and 3 s. The various
cidal efficacy, long-term stability, and recharge ability, once polymeric beads will be particularly useful in the disinfection
Figure 43. Quaternized hydroxyethyl cellulose polymer.
As schematically illustrated in Figure 40, the expected drug

concentration profiles vary drastically according to the different
Figure 40. Theoretical plasma drug concentration after administration methods of drug administration. Briefly, the drug concentration
of various dosage forms: (a) standard oral dose; (b) oral overdose; in blood reaches a maximum very rapidly after administration
(c) intravenous injection; and (d) controlled release system. of a standard dosage (curve a), and then decreases to a minimum.
At this point, repeated administration becomes necessary. Often
the initial maximum concentration is above the therapeutically
desirable level, increasing the risk of side effects, as it may reach
the toxic level (curve b). On the other hand, the minimum
concentration may be below the therapeutically effective level.
In this way, standard dosage forms can result in a drug regimen
in which the patient oscillates between alternating periods of
drug overdose and drug inefficacy (curve c). Controlled release
systems ideally smooth the peaks and valleys in the drug
concentration in blood, providing a more effective drug regimen
(curve d).
Antimicrobial polymers are powerful candidates for polymeric
drugs with high activities, which can be ascribed to their
characteristic nature of carrying the high local charge density
of the active groups in the vicinity of the polymer chains.
Figure 41. Antimicrobial electrospun sheet (ref 102).
Electrospun fibers containing tetracycline hydrochloride based
on poly(ethylene-co-vinyl acetate), poly(lactic acid), and blend-
ing were prepared to use as an antimicrobial wound dress-
ing.102,104 Figure 41 shows the antimicrobial electrospun sheet.
The release of tetracycline hydrochloride from the electrospun
mats was studied and showed a smooth release of the drug over
5 d.
Chitosan and its derivatives have been reportedly used as film
formers in hair products, setting agents, hair conditioners, and
Figure 42. Hydroxypropyl trimethylammonium chitosan chloride.
shampoos.105 Recently, hydroxypropyl trimethylammonium chi-
tosan chloride was synthesized for evaluation in a cosmetic
application (Figure 42).105
of potable water and moist air flowing through cartridge fillers
containing them. Cellulose derivatives are commonly used in cosmetics as skin
and hair conditioners. Quaternary ammonium cellulose deriva-
5.2. Medicine and Healthcare Products. Most pharmaco- tives are of particular interest as conditioners in hair and skin
logically active agents are low molecular weight compounds, products (Figure 43).
which readily penetrate into all cell types and are often rapidly Gentamicin-loaded poly(methyl methacrylate) beads consti-
excreted from the body. Consequently, large and repeated doses tute an effective drug delivery system for local antibiotic therapy
must be given to maintain a therapeutic effect, and, in addition, in bone and soft tissue infections, as they enable gentamicin
when specificity is limited, drugs invariably display a range of concentrations at the site of the infection to become much higher
deleterious side effects. Attachment of drugs such as antimi- than can be achieved with systemic application.106 The beads
crobial agents to macromolecular carriers alters their rate of were implanted in a patient in infected joint arthroplasty, and it
excretion from the body and provides the possibility for was found that a high level of antibiotics was achieved through
controlled release over a prolonged period.101 Controlled the implant. The beads were left in situ for 5 years. Gentamicine-
delivery systems are used to improve therapeutic efficacy and release testing revealed residual antibiotic release after being 5
safety of drugs by delivering them at a rate dictated by the need years in situ. Gentamicin implants were impregnated in sheep
of the physiological environment.102 and showed that the system is promising for the treatment of
The most attractive approach is the synthesis of new local infections in veterinary patients.107
polymeric drugs based on well-known pharmacons or drugs Implants of cross-linked high amylase starch containing
bound covalently to a macromolecular biodegradable or soluble various ratios of ciprofloxacin antibiotic were prepared.108 The
support.103 The advantage of this kind of system over the implants were applied to rabbits along the femur between the
traditional delivery system, which is based on physical combi- quadriceps and biceps femoris muscles. The results showed that
nation, is mainly that the “polymeric drug” may display the implants having ciprofloxacin have a considerable potential
pharmacological activity by itself, but at the same time may be as a drug delivery system for local prevention and treatment of
used as a carrier for the pharmaceutical agent. bone and soft tissue infections.
Table 3. Functional Groups in Polymers Commonly Used for Food Packaging Material (Reference 114)
Antimicrobial sutures were prepared by the radiation grafting no reduction in mechanical properties occurred even after
of 2-hydroxyethyl methacrylate monomer (HEMA) on polypro- storage for a long period in a wet environment.58,112
pylene monofilament.109 The poly(HEMA) hydrogel grafted 5.3. Food Applications. Microbial contamination reduces the
sutures were used for the immobilization of 8-hydroxy quinoline shelf life of foods and increases the risk of food-born illness.
as an antimicrobial drug. It was found that the modified sutures The demand for minimally processed, easily prepared, and ready
exerted an antimicrobial activity against S. aureus. to eat “fresh” food products, as well as globalization of food
Recently, concerns have been raised regarding the therapeutic trade, and distribution from centralized processing, pose major
effects exhibited by dental restorative materials.110 Several challenges for food safety and quality.113 The interested reader
attempts at modification of the resin matrix phase or filler to is also referred to the review by Appendini and Hotchkiss, which
provide antimicrobial effects have been reported by Imazato represents a very interesting discussion of the need for antimi-
and co-workers.111 They reported the synthesis of an antibacterial crobial food packaging.113
monomer, 12-methacryloyloxydodecylpyridinium bromide The food-borne microbial outbreaks are driving a search for
(MDPB) (Figure 13). The monomer (MDPB) was synthesized innovative ways to inhibit microbial growth in the foods while
by combining quaternary ammonium dodecylpyridinium with maintaining quality, freshness, and safety. Traditional methods
a methacryloyl group, so that the bactericide was immobilized of preserving foods from the effect of microbial growth include
in the resin matrix by copolymerization of MDPB with other thermal processing, dry freezing, refrigeration, irradiation, and
monomers. The resin composites incorporating MDPB demon- adding antimicrobial agents or salts. Unfortunately, some of
strated inhibition of dental plaque formation on the surface, and these techniques cannot be applied to some food products, such
as fresh meats and ready-to-eat products.114 Also, there is a Scheme 30. Preparation of the Broad-Spectrum Antimicrobial
growing demand for foods without chemical preservatives.115 Fiber Based on PVA
Antimicrobial packing is a form of active packing in which the
package interacts with the product or the head space between
the package and food system to obtain a desired outcome.116
Antimicrobial substances incorporated into packaging materi-
als can control microbial contamination by reducing the growth
rate and maximum growth population and/or extending the lag-
phase of the target microorganisms or by inactivating the
microorganisms by contact.117 Antimicrobial polymers can be
used in several food-related applications including packaging.118
One of these applications is to extend the shelf life and promote
safety by reducing the rate of growth of specific microorganisms
by direct contact of the package with the surface of solid foods,
for example, meat, cheese, etc., or in the bulk of the liquid, for
example, milk or meat exudates. Second, antimicrobial packag-
ing materials greatly reduce the potential for recontamination
of processed products and simplify the treatment of materials
to eliminate product contamination. For example, self-sterilizing ing materials for increased fruit and vegetable shelf life.124
packaging might eliminate the need for peroxide treatment in Examples of ionic and covalent immobilization of antimicrobials
aseptic packaging. Third, at least in concept, this could result onto polymers or other materials have been reviewed in this
in self-sterilizing foods, especially liquids. This might be work. This type of immobilization requires the presence of
particularly useful for high acid products such as fruit juices. functional groups both on the antimicrobial agent as well as on
Antimicrobial polymers might also be used to cover surfaces the polymer. Examples114 of polymers used for food packaging
of food processing equipment so that they self-sanitize during that have functional groups are shown in Table 3. Application
use. Examples include filler gaskets, conveyers, gloves, gar- of antimicrobial polymers in food is gaining interest from
ments, and other personal hygiene equipment. The target researchers due to its potential to provide quality and safety
microorganism and the food composition must be considered benefits. Currently, development is limited due to the availability
in antimicrobial packaging. of antimicrobials, new polymeric materials, and testing methods.
With the advent of new materials and more information, this
As with any antimicrobial agent, those to be incorporated
may change.
into polymers have to be selected on the basis of their spectrum
Future work in this field will focus on the use of biologically
of activity, mode of action, chemical composition, and the rate
active derived antimicrobial compounds bound to polymers. The
of growth and physiological state of the targeted microorgan-
need for the new antimicrobials with a wide spectrum of activity
isms.119 Antimicrobial moieties attached to the polymer, how-
and low toxicity will increase. Also, antimicrobial dendrimers
ever, need to be active while attached to the polymer. This
may play an important role in this field of application. It is
activity is related to the mode of action. If, for example, the
possible that research and development of “intelligent” or smart
mode of action is on the cell membrane or wall of the
antimicrobial food packages will follow. These will be materials
microorganism, it is possible that the attached antimicrobial
that sense the presence of microorganisms in the food. It may
agent will act on the cells. This is likely not to be the case if it
be also interesting to use the idea of pro-drugs in the
needs to enter the cytoplasm.
antimicrobial polymeric food preservatives and packaging.
Examples of polymers with high antimicrobial activity in 5.4. Textile Products. Antimicrobial treatment is rapidly
growth media and low activity in foods include triclosan in becoming a standard finish for some categories of textile
plastics.120 Further considerations in antimicrobial packaging products such as for medical, institutional, and hygienic uses.
choice are the concentration of antimicrobials in the polymer Recently, it became popular in sportswear, women’s wear, and
film, the effect of film thickness on activity, and the physical aesthetic clothing to impart anti-odor or biostatic properties.125,126
and mechanical properties of the polymers after conversion to Textiles and fibrous materials are subjected to various
the final product. For example, antimicrobial activity of finishing techniques to afford (a) protection for the user of textile
compounds coated or immobilized on the surface of polymer materials against bacteria, yeast, dermatophytic fungi, and other
films may be independent of film thickness. However, if the related microorganisms for aesthetic, hygienic, or medical
antimicrobial is entrapped into the bulk of the material, the film purposes; (b) protection of the textile itself from biodeterioration
thickness will play a role in the diffusion and concentration at caused by mold, mildew, and rot-producing fungi; and (c)
the surface of the film.121 protection for textiles from insects and other pests.119,120
Some polymers are inherently antimicrobial and have been Basically, there are three mechanisms by which antimicrobial
used in films and coatings. Cationic polymers such as chitosan agents provide protection to textiles and the wearer. The majority
promote cell adhesion.122 Because charged amines interact with of antimicrobial protective finishes function by the controlled-
negative charges on the cell membrane, they can cause leakage release mechanism. An excellent example of a controlled-release
of intracellular constituents. Chitosan has been used as a coating mechanism is the fiber with broad-spectrum antimicrobial
and appears to protect fresh vegetables and fruits from fungal properties based on poly(vinyl alcohol) (PVA) (Scheme 30).
degradation. Although the antimicrobial effect is attributed to The fiber was prepared by reaction of 5-nitrofurylacrolein with
antifungal properties of chitosan, it may be possible that the poly(vinyl alcohol) in the presence of an acid catalyst.16 The
chitosan acts as a barrier between the nutrients contained in the antimicrobial activity was produced by slow release of the nitro
produce and microorganisms.123 compound in the presence of moisture.
Bacterial acrylic polymers made by copolymerizing acrylic Shin and co-workers investigated the effect of the molecular
protonated amine co-monomers have been proposed as packag- weight on antimicrobial activity of chitosan-treated cotton
of the antibiotic for wool dyed at high temperature was attributed

to greater penetration of Doxy into the wool at high temperature,
making Doxy difficult to release from the fiber interior. The
sorption of antibiotics on nylon may be comparable to that on
wool, but the resulting infection-resistant properties were much
lower than those of wool and did not provide a sustained release.
Also, the ZOI of hydrolyzed wool dyed with Doxy was greater
than that of unhydrolyzed wool.
Polyurethane-chitosan blended polymer was used to improve
shrinkage and antimicrobial properties of woolen fabrics.131 The
blended polymers were used to treat woolen fabric. The
experimental results indicated an improvement in both the
shrink-proof and the antimicrobial properties of the fabric.
However, the yellowing and softness tendency of the fabric
shifted toward an unfavorable outcome. Much more effort
should be done in this field because it represents a very
important area of application for antimicrobial polymers. The
innovative work of Sun and co-workers concerning attaching
Figure 44. N-halamine functional groups to cellulose to render textile
materials biocidal has been discussed in earlier sections of this
fabrics.125 Three different molecular weights for chitosan were review.52-55,73,74,126
used. The results of the antibacterial activity of the chitosan-
treated fabrics showed that the reduction rate increased as the 6. Future and Perspectives
molecular weight increased. However, the antimicrobial activity Undoubtedly, the use of polymers in the medical field has
of chitosan-treated fabrics seems to be more affected by the reduced the suffering of humans and offered them a better hope
treatment concentration than by molecular weight. for a better life. The range of application has been extended to
Polyamide fibers (PA6) with antibacterial properties were include many fields such as artificial organs, drugs, health care
prepared by the graft polymerization of the acrylic acid on PA6 products, implants, bone replacement and other prostheses,
yarn.129 The resultant fibers, containing carboxylic groups in wound-healing, food, textile industry, and water treatment, etc.
their structure, were additionally modified with penicillin, The field of antimicrobial polymers, which has progressed
neomycin, and gentamycin to obtain antimicrobial fibers. The steadily, but slowly, over the past years, appears to be on the
activity was tested against S. aureus, E. coli, and P. aeruginosa, verge of rapid expansion, as evidenced by a broad variety of
and the modified fibers showed strong biocidal effects on the new classes of compounds that have been prepared and studied
Gram-positive microorganism S. aureus and the Gram-negative in the past few years. For example, a very novel approach to
E. coli. isolating biocidal moieties on the surfaces of polymers has
Choi and co-workers reported the dyeing of wool with recently been reported by Wynne and co-workers.132 This may
antibiotic to develop novel infection-resistant materials for be due to the current awareness about the spread of viruses such
external biological end uses.130 They were prepared by using a as HIV and hepatitis and by contact with contaminated surfaces
“dyelike” interaction of two antibiotics, Doxycycline (Doxy) that lead to more stringent health and medical regulation to treat
and ciprofloxacin (Cipro), which are highly active against Gram- most material with microbiocides. Modification of polymers and
negative and Gram-positive bacteria and the only antibiotics fibrous surfaces, and changing the porosity, wettability, and
approved for treatment of anthrax (Bacillus anthracis) infection other characteristics of the polymeric substrates, should produce
by the Center for Disease Control and Prevention (Atlanta, implants and biomedical devices with greater resistance to
GA).130 The chemical structures of the two selected antibiotics microbial adhesion and biofilm formation. A number of
are as shown in Figure 44. polymers have been developed that can be incorporated into
Nylon was used as a synthetic control. The results showed cellulose and other materials, which should provide significant
that the sorption of Doxy was much higher in wool than in advances in many fields such as food packaging, textiles, wound
nylon, whereas sorption of Cipro was similar in both fibers. To dressing, coating of catheter tubes, and necessarily sterile
investigate the effect of hydrolysis on sorption of antibiotics surfaces. The greater need for materials that fight infection will
by wool, wool was hydrolyzed at 40 °C for different times. give incentive for discovery and use of antimicrobial polymers.
The fabric strength decreased only slightly, and the hydrolysis Of course, it should be kept in mind that newly developed
of wool considerably increased the sorption of both Doxy and biocidal polymers must strive to possess the attributes suggested
Cipro. For comparison, Nylon also was hydrolyzed, and the in section 2 of this review. For example, biocidal polymers
studies showed that the sorption of Doxy was slightly greater requiring contact times of the order of hours to provide
on hydrolyzed nylon, whereas sorption of Cipro had substantially substantial reductions in viable pathogens, such as some of those
increased by hydrolysis for 1 h. Nevertheless, sorption of Cipro referenced in this review, really have no practical value; seconds,
was always lower in hydrolyzed nylon than in hydrolyzed wool. or minutes at most, should be the contact time goal for a real
The zone of inhibition (ZOI) test revealed the infection application. Furthermore, if the structural modification to the
characteristics of antibiotic-dyed substances. Interestingly, wool polymer caused by biocidal functionalization adversely affects
fabrics dyed by Doxy at lower temperature, for example, 45 the intended use pattern, the polymer will be of no importance.
and 65 °C, showed greater ZOI than the fabric dyed at high For example, if a fiber that must be exposed to aqueous bleach
temperatures. Measurement of Doxy release from wool indicated to render it antimicrobial (an N-halamine polymer) is weakened
that low-temperature-dyed wool resulted in better-sustained by that exposure, or its dye is bleached, it will have limited
release of Doxy than high-temperature-dyed wool. Low release use.
Future work should focus on the development of new GTMAC ) glycidyltrimethylammonium chloride
polymeric antimicrobial materials to be used for soil sterilization METAC ) methacryloyloxyethyl trimethyl ammonium chlo-
to replace the toxic materials currently in use such as methyl ride
bromide. Many interesting ideas were formulated through TRVB ) tributyl-4-vinylbenzyl phosphonium chloride
writing this review. Of particular interest were the use of ETMA ) 2,3-epithiopropyl methacrylate
dendrimers as antimicrobial polymers and the use of N-halamine HDI ) 1,6-hexane diisocyanate
polymers as biocides. If one could combine both ideas by PCL ) polycaprolactone diol
preparation of the dendrimer on an insoluble support and then 4-VP ) 4-vinylpyridine
modification of it to form N-halamines, this could be a very PP ) polypropylene
promising development. HEMA ) 2-hydroxyethyl methacrylate
Participation and collaboration of research institutes, industry, PVA ) poly(vinyl alcohol)
and government regulatory agencies will be the key for the ZOI ) zone of inhibition
success of antimicrobial polymeric materials. MIC ) minimum inhibitory concentration
Abbreviations References and Notes

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1. Introduction infections usually requires removal of the implant. Because the

antimicrobial activities. It is apparent that, in principle, the ideal

Figure 4. Generation 2 poly(propyleneimine) dendrimer quaternary

Table 1. Comparison among Molecules Biocides, via Their

one needs to take into consideration the bacteria structure.

Scheme 1. Reaction of 2-(3-Acrylamidopropyldimethylammonio)

Figure 5. Structure of monomer SMPM.

short alkyl substituents or (2) different aggregational behavior

4. Preparation and Activities of Antimicrobial

Figure 7. Structure of monomeric biocides.

Figure 6. Monomers and copolymers based on N-TBTM and

The zone of inhibition of different concentrations of monomers

Scheme 4. Synthesis of AcDP

The monomer (ACTMIO) was copolymerized with several

Scheme 6. Synthesis of 5-Chloro-8-quinolinyl Acrylate (AQ)

Figure 12. Structure of some sulfonium salts.

Scheme 7. Synthesis of Quaternary Amine Methacrylate (QAMA)

Scheme 9. Coupling Reaction between Ampicillin and a

the examined microorganism. In general, the copolymers showed

Scheme 10. A Route of Chemical Synthesis for SMA-AP

Scheme 13. Antimicrobial Polymers Prepared by the

Figure 22. Resins containing quaternary ammonium groups.

Scheme 12. Preparation of Polymer-Grafted Phosphonium Salts

trioctylphosphine is attributed to the strong interaction between

Scheme 14. Synthesis Scheme for the Generation 3 Quaternary

coli, P. aeruginosa, Shigella sp., and Salmonella typhae), Gram-

Scheme 15. Preparation of Polymer Poly[1,3,5-trichloro-6-methyl-

polymer filter. After a long period of storage at ambient

Scheme 16. Schiff Base Formation between MPA and Various

Scheme 17. Modification of MPA with Various Esters

Grunlan et al. reported on the antimicrobial behavior of

Scheme 18. Preparation of Chitosan from Chitin

Figure 34. Electron scanning micrograph of (A) normal-control

polymers showed high antimicrobial activities at the same

Scheme 22. Quaternization of Chitosan and Its Immobilization

However, this is expected because it is known that high acidic

Scheme 25. Reaction of Chloroacetylated Cross-linked Dextran

Scheme 26. Reaction of Chloroacetylated Cross-linked Dextran

Scheme 29. Synthesis of Drug Polymer

Table 2. Microbial Counts with Respect to Water Flow through

the efficacy has been consumed during use.50 Worley et al. at

Figure 43. Quaternized hydroxyethyl cellulose polymer.

As schematically illustrated in Figure 40, the expected drug

of the antibiotic for wool dyed at high temperature was attributed

Abbreviations References and Notes

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