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Antimicrobial materials with medical
applications
D. Sun
{1
, M. Babar Shahzad
{2
,M.Li
2
, G. Wang
1
and D. Xu*
2
Despite intensive and considerable research achievements by material scientists and biologists, the
problems of infections related to medical devices and implants remain knotty. The biofilm related
infections are much harder to eradicate due to protection of extracellular polymeric substance
secreted by the biofilms, hence shows a strong resistance to conventional antibiotics. Thus, there is a
huge challenge for researchers to seek effective methods to combat device related bacterial
infections ignited by biofilms to mitigate potential health risks and massive financial burdens to
healthcare systems. Here we review the most recent progress and work on the applications of
antibacterial biomaterials for the biomedical devices, concentrating on metals with antibacterial
coatings/surfaces, antibacterial stainless steels and other commonly used antibacterial materials.
Keywords: Antibacterial material, Devices related infection, Implant related infection, Antibacterial coatings/surfaces, Antibacterial stainless steel
This paper is part of a special issue on antimicrobial materials
Introduction
Microorganisms have diversive existence, in form of
bacteria, virus, fungi, algae and several other living
species since millions of years ago, and have unprece-
dented influence in almost every aspect of human life.
Majority of human diseases are directly and indirectly
related to infections with some kind of microorganisms.
Surface bio-contamination is being regarded a severe
problem that contributes to outbreaks of community
acquired and nosocomial infections through contiguous
fomite transmission of diseases. Each year, more than
90 000 patients died in the United States alone due to
the nosocomial infections by pathogens.
1
Biomedical devices have become a pivotal part of the
healthcare system in recent years. The usage of various stents,
heart valves and different kinds of implant devices has been
significantly increased. As a result, the demanding issue of
post-surgical bacterial infections related with implants and
medical devices generally known as device related infections
(DRIs) is posing a significant health risk to patients and
costing healthcare systems with millions of dollars.
2
Bacterial
attachment/colonisation and proliferation at the surface of
implants and biomedical devices have been regarded as a
fundamental cause of DRIs.
3,4
The simple adhesion of
planktonic bacteria to implanted device surface subse-
quently results in formation of biofilms and sessile bacterial
cells which produce an extracellular polysaccharide matrix
that protects them from the host body’s immune system and
become extremely resilient to antibiotics.
5
Multiplication
and dispersion of these bacteria in planktonic form cause
chronic infection which is hard to exterminate with
conventional antibiotics. As a matter of fact, biofilms play
a pivotal role in DRIs, and most of DRIs are biofilm based
infections. Owing to early stage diagnostics complexity of
DRIs, the extreme severity often leads to situation which
requires the removal of implanted device, putting patient’s
health at serious risk along with enormous medical costs.
Creation of the biomedical devices by antibacterial
materials lethal to bacteria and fungi can provide
prevention of biofilm based infections on implant devices
and address the urgent need of public health system. With
the achievements of the technological progress in material
science, biomedical and biological engineering, antibac-
terial biomaterials turn out to be the primary strategy to
solve device associated infections in recent years.
6–8
Antibacterial biomaterials are defined as the construction
materials for medical devices with antibacterial properties
and infection resistance ability. They are also capable of
delivering the medical substances, whose major function
is to prevent, treat, or reduce the potential or existing
infections. Injectable or implantable antibacterial bioma-
terials need to own a strong bactericidal ability to control
pre-existing infections.
9
A variety of concepts and methods have been
developed to endow the biomaterials with antimicrobial
properties. Here we review the recent progress and work
on the application of antibacterial biomaterials for
biomedical devices, concentrating on metals with anti-
bacterial coatings/surfaces and intrinsically antibacterial
materials owing to their widespread use.
Metals with antibacterial coatings/
surfaces
With technological progressions in the field of nano-
biotechnology, the quest for advanced antibacterial
1
Key laboratory of biorheological science and technology, College of
bioengineering, Chongqing University, Chongqing, 400044, China
2
Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua
Road, Shenyang 110016, China
*Corresponding author, email xudake@imr.ac.cn
{
These two authors contributed equally to this work.
ß2015 W. S. Maney & Son Ltd.
Received 3 August 2014; accepted 10 November 2014
DOI 10.1179/1753555714Y.0000000239 Materials Technology: Advanced Biomaterials 2015 VOL 30 NO B2B90
biomaterials used for medical applications as implants
and biomedical devices is continuously rising. Intensive
efforts have been focused on the development of novel
antimicrobial surfaces and the modulation of existing
biomedical devices that can eradicate or deter the
bacterial adhesion and biofilms formation on these
surfaces. Due to their potential applications in medical,
industry and even common household, exploration of
such surfaces is attracting much wider attention of
researchers. Relying on biofilms formation mechanism,
the main strategy being used for over a decade to achieve
such antibacterial (antibiofouling and bactericidal)
surfaces, which would inhibit the initial attachment of
bacteria, therefore preventing subsequent biofilms for-
mation, is through application of surface coatings (with
certain antimicrobial agents, antibiotics) and/or surface
modifications processes (chemical or physical).
10,11
The
proposed antibacterial mechanisms for antibacterial
materials, their characteristics and potential applications
are shown in Table 1 and a brief description of these
experimental approaches have been summarised in the
following subsections.
Fabrication of antibacterial surfaces by applying
surface coatings is one of the most widely used methods.
The deposition of an antibacterial material onto the
substratum surface has been regarded as a surface
coating.
23
The bactericidal activity of surface can be
achieved through two different strategies. One approach
is the release of a chemical or antibacterial agent from
the biomedical device surface which targets the sur-
rounding bacteria, in another approach, antibiotic
molecules can be grafted (covalently immobilised) on
the device surface that prevent the bacterial attachment
to the surface or kill the attached bacteria.
24
The
fabrication of antibacterial surfaces for biomedical
devices has been accomplished with various antimicro-
bial agents comprising inorganic metal ions and organic
molecules. Metals such as silver, gold, copper, and zinc
are well known for their antibacterial activities and are
used in number of in vitro and in vivo applications.
25
Here we provide a brief and comprehensive description
of antimicrobial activity and related mechanisms of
most commonly used antibacterial agents.
Silver
Silver has long history of use as an effective antimicro-
bial,
26,27
and can work in numerous formulations for
device applications, showing no toxicity to human cells in
given concentrations.
28
Owing to strong antibacterial
ability of silver cations, it has been incorporated in variety
of medical devices, such as vascular, urinary and peritoneal
catheters, vascular grafts, prosthetic heart valve sewing
rings, surgical sutures and fracture-fixation devices.
29,30
Silver have been found to be effective against various kind
of pathogens known to exist at implant sites, including
Pseudomonas aeruginosa, Escherichia coli, Staphylococcus
aureus, and Staphylococcus epidermidis.Fenget al. studied
the antibacterial effect of silver ion on E. coli and S. aureus,
and suggested a mechanism that Ag
z
ion reacts with and
disrupts the function of bacterial cell membranes and
crucial metabolic proteins and enzymes by binding to
DNA and thiol groups in proteins.
31
Currently silver has become one of the most widely
used antimicrobial agents which are being used in
diverse forms for device base applications. It is generally
coated in elemental form on the device surface,
impregnated in various forms (metallic silver particles,
silver salts, complexes, and chelates) within the device
matrix (i.e. polymer) or applied within a polymer
coating as a reservoir to control silver ion release.
Controversially, a long debate still persists over the
possible inactivation of silver mediated antibacterial
activity in physiological fluids and over the low
biocompatibility index of silver determined by the low
threshold concentration for cytotoxic effects, especially
when in form of nanoparticles.
32
Copper
The discovery of copper and its alloys (brasses, bronzes,
cupronickel, copper–nickel–zinc, and others) as a
natural antimicrobial materials that have intrinsic
properties to destroy a wide range of microorganisms
is considered innovatory in antimicrobial surfaces. The
rapid antibacterial activity of solid Cu surface has
received wide spread attention of researchers,
33,34
and it
has already been registered with US environmental
protection agency as the solid antimicrobial material. In
Table 1 Proposed antibacterial mechanisms for antibacterial materials, their characteristics and potential applications
Antibacterial
mechanism
Corresponding antibacterial
material Characteristics Prospective applications
Slow release metal
ion sterilisation
Copper, silver, metal ion
phosphate antibacterial
materials, etc.
High chemical activity provides
long term and efficient slow
release antibacterial material.
12
Widely used in medical applications,
stainless steel, water treatment.
Prevent bask in liquid coatings
and fabrics.
13
But these materials
tarnish easily and are expansive,
which limits their applications.
14
Slow release metal ion
sterilisation and photo-
catalytic sterilisation
15
Hydroxyapatite,
Ag-carrying phosphate
antibacterial materials, etc.
Phosphoric acid double salt has
a strong adsorption function,
large specific surface area,
nontoxic, stable chemical
properties; good combination of
efficiency and lasting slow-
release performance.
16
Slow release metal
ion sterilization,
photo-catalytic
sterilization and reactive
oxygen species
antibacterial mechanism
17
ZnO materials,
TiO
2
materials
Stable chemical properties,
under UV irradiation show
broad spectrum antimicrobial
properties, good pH stability,
nontoxic, abundant raw
material sources,
18,19
low cost.
20
Used in fiber, plastic, ceramic,
coating, biomedical and other fields.
21,22
Sun et al. Antimicrobial materials with medical applications
Materials Technology: Advanced Biomaterials 2015 VOL 30 NO B2 B91
further development, Cu and Cu alloys got recommen-
dation for application in hospitals and healthcare
facilities to be used as touch surfaces, where Cu alloys
used in door knobs and other touch surfaces exhibited
an in vitro antimicrobial effect against E. coli O157,
methicillin-resistant S. aureus (MRSA) and Clostridium
difficile,influenza A virus,adenovirus,andfungi in
comparison with similar ordinary stainless steel sur-
faces.
35–38
Despite lack of complete understanding and unan-
imous explanation of antibacterial mechanism of cop-
per, researchers believe that the potential antimicrobial
mechanisms for copper are as follows:
39
(i) Elevated copper levels inside a cell cause oxidative
stress and the generation of hydrogen peroxide.
Under these conditions, copper participates in the
so called Fenton type reaction – a chemical
reaction causing oxidative damage to cells
(ii) Excess copper causes a decline in the membrane
integrity of microbes, leading to leakage of
specific essential cell nutrients such as potassium
and glutamate. This leads to desiccation and
subsequent cell death
(iii) While copper is needed for many protein
functions, in an excess situation (as on a copper
alloy surface), copper binds to proteins that do
not require copper for their function. This
‘inappropriate’ binding leads to the loss of
function of the protein, and/or the breakdown
of the protein into nonfunctional portions.
Quaternary ammonium compounds
In general, surfaces having positive charge show negative
effect on cell survival. Therefore, various antimicrobial
surfaces and coating have been developed that exploit the
presence of quaternary ammonium. Quaternary ammo-
nium compounds (QACs) are widely utilised as anti-
bacterial agents and QACs coatings exhibit a contact-
based antibacterial mechanism for a persistent period of
time,
40
unlike silver ions that show release based
antibacterial mechanism.
41
Regarding their antibacterial
activity, Tiller et al. demonstrated that surfaces contain-
ing ammonium salts or quaternary ammonium groups
exhibit a damaging effect to both Gram-positive and
Gram-negative bacteria cells through disruption of cell
membrane.
42
The soluble QACs are employed in
industrial applications, water treatment, in pharmaceu-
tical and daily consumer products. These QACs are often
employed as preserving agents in cosmetic products.
Despite number of properties, certain bacterial resistance
against QACs containing surfaces and their cyto- and
bio-compatibility issue has been reported.
43,44
Hydroxyapatite (HA)
Hydroxyapatite (HA), is a naturally occurring mineral
form of calcium apatite and is a principle inorganic
componentof human hard tissues such as teeth and bones.
Many modern body implants including dental implants,
hip replacements and bone conduction implants are being
coated by Hydroxyapatite. HA coatings provide implant
surfaces with antibacterial properties. Shah et al. demon-
strated a HA based coating technique which offered an
accelerated bone tissue growth and claimed its potential
applications to a variety of orthopedic implants and
devices offering successful and lasting tissue replacement,
wound healing and joint repair.
45
HA is considered bio-
compatible as it can permeate the organic matrix of the
bone. In addition, HA-coated implants have been
reported to stimulate bone healing which helps to improve
the rate and strength of initial implant integration.
46
Unfortunately, HA coatings have the drawback that they
are mechanically weak and can be non-uniform in density
and thickness. They have also been shown to fail in long
term stability trials.
47
Polymers
So far, various surface modification approaches have been
employed to achieve surface assisted antibacterial proper-
ties. Surface functionalisation, derivatisation, or polymer-
isation are regarded as being chemical while mechanical
and surface structuring as physico-mechanical surface
modifications.
23
The grafting of functionalised polymers
on the surface can impart antibacterial activity. In other
approaches, through physicochemical adsorption mechan-
ism antibacterial agents, containing various antibacterial
polymers, enzymes and peptizes were immobilized on
substrate surface which provide different type of anti-
bacterial effect.
48–50
Polymeric molecules such as poly
(methacrylate) and poly (hexamethylene biguanidinium
hydrochloride) are just two examples of commonly
studied antibacterial agents that have been used for this
purpose. The majority of bacterial synthetic polymer and
well known natural polymer chitosan are cationic. The
polycationic polymers provide bactericidal activity by
interrupting the net negative charge of the bacteria
membrane leading to cell lysis and death. A newly
emerging class of polymers such as polynorbornenes or
poly (phenylene ethylene) derived from antimicrobial
peptides (such as magainin or defensin) has been shown
to exhibit high degrees of antibacterial activity together
with low levels of cytotoxicity.
49–51
Several surface modification approaches aimed at
introducing surface-assisted antibacterial properties have
been described so far: a scheme of the possible strategies
for antibacterial surface coatings is shown in Figure 1.
52
Despite enormous advantages, the use of surface coatings
as antibacterial agents has revealed several shortcomings.
Bacteria can develop resistance against antibiotics and
antibacterial agents. The antibiotics or antibacterial
agents can take a long time to be released from the
surface, and the concentration of the released agents may
not be sufficient to maintain effective antibacterial
activity. In addition, the durability of the target surface
may not be sufficient to maintain long term antibacterial
behaviour. Hence, the life span of antimicrobial coatings
for in-vitro and in-vivo applications is also regarded as a
crucial issue, as multiple factors pose a significant
degradation risks through various chemical, biological
and physical effects.
Intrinsically antibacterial materials
Generally, the bulk materials that perform an anti-
bacterial action without any modification can be
described as intrinsically antibacterial material.
Numerous substances possess bactericidal ability in
nature. As mentioned above in the sections on ‘Silver’
and ‘Copper’, silver and copper have been the earliest
metals to be intentionally used for its intrinsically
antibacterial properties. Polymeric materials like chit-
osan and bioactive glasses are also intrinsically anti-
bacterial materials.
Sun et al. Antimicrobial materials with medical applications
B92 Materials Technology: Advanced Biomaterials 2015 VOL 30 NO B2
In recent, the biomaterial applications of the bare
bulk metals like silver, zinc and copper are limited or
even ceased. The major concern for this is due to their
potential cytotoxicity and accumulation in organs. The
corrosion of these metals under the physiological
environment may locally release high concentrations of
active ions, resulting in cytotoxic effects. Even for the
most commonly used antibacterial metals like silver and
copper, the mechanism of how they perform antibacter-
ial activity is still far from being completely understood.
There has been much recent media attention on the ban
of UK hospitals to perform metal-to-metal hip resurfa-
cing due to corrosion and high levels of wear debris
(metallosis).
53
This is a sign to indicate that research into
novel metallic orthopdaedic materials and a variety of
applications continue to be an area of interest. In this
part, antibacterial stainless steel will be reviewed as a
novel antibacterial material.
Stainless steel has been widely used for biomedical
purpose for decades; however the lack of antibacterial
property limits its further applications in more broad
biomedical fields. Nisshin Steel (Japan) first developed
ferritic and austenitic antibacterial stainless steel con-
taining copper in 1990s.
54
Yang et al.
55–57
developed the
ferrite and austenitic antibacterial stainless steel since
2000s, and promoted the research progress of antibac-
terial stainless steel greatly in both industrial and
biomedical areas.
Nan et al.
58
found that the copper containing
antibacterial stainless steels have the broad spectrum
antibacterial features, and demonstrated that the anti-
bacterial rate against most of the Gram-negative
bacteria and Gram-positive bacteria selected in their
study reached to 99%. A type 304-Cu bearing anti-
bacterial stainless steel was demonstrated to be an
excellent alternative to the traditional orthodontic 304
stainless steel. This Cu bearing antibacterial stainless
steel exhibited strong antibacterial property against
Porphyromonas gingivalis biofilm. The cytotoxicity of
the antibacterial stainless steel to both MG-63 and KB
cells remained the same (grade 1) as those of the control
304 stainless steel. The antibacterial stainless steel
reduced the risk of implant related infections, and can
be a better material to replace the current conventional
stainless steel in orthodontic treatment.
59
Chai et al.
evaluated the antibacterial ability and biocompatibility
of a type 317L-Cu containg 4?5% copper in vitro and in
vivo using an animal model. Compared with 317L,
bacterial biofilms of both S. aureus and E. coli, the
pathogens caused implant-related infections, were sig-
nificantly inhibited by 317L-Cu in vitro and in vivo. The
317L-Cu was also biocompatible both in vitro and in
vivo, showing the strong potential of this material to be
an alternative biomaterial to reduce implant-related
infections.
60
The copper amount in cu-bearing antibac-
terial stainless steel is less than 5% wt., and the trace
amount (less than 10 ppb cm
22
day
21
) release of copper
ions by the antibacterial stainless steel is safe to the
human body.
Although intensive research on antibacterial stainless
steel is still underway, however, based on its strong
antibacterial ability and excellent bio-compatibility; it
possess huge potential to be an ideal alternate of
conventional stainless steel still largely used in biome-
dical applications. Therefore, metals as base composite
antibacterial materials, due to their inherent integrate
material characteristics, long term antibacterial proper-
ties and good biocompatibility, became an important
direction for future of biomedical antibacterial
materials.
Other antibacterial materials
Antibacterial plastics
Silver based nano-engineered materials are currently the
most commonly used in plastic commodities due to their
antimicrobial capacity. Copper, zinc and titanium
nanostructures are also showing promise in food safety
and medical field.
61
Liu et al.
62
prepared plastics with
excellent antibacterial properties by adding Ag/TiO
2
to
various kinds of resin. Matet et al. reported that they
provided a plasticised chitosan based material with good
antibacterial, mechanical properties and an appropriate
visual aspect. It may be easily scaled up and considered
for medical applications such as pharmaceutical packa-
ging.
63
Olyveira et al. presented an approach to develop
PE composite containing silver micro particles to have
an antibacterial effect. The results showed that the
incorporation of silver/titanium dioxide particles on
composites obtained systems with different dispersions.
The Ag/TiO
2
particles showed uniform distribution of
1 Surface modification approaches in medical devices aimed at obtaining antibacterial properties
52
Sun et al. Antimicrobial materials with medical applications
Materials Technology: Advanced Biomaterials 2015 VOL 30 NO B2 B93
Ag on TiO
2
particles as observed by SEM-EDX, and the
antimicrobial tests indicates its excellent antimicrobial
properties.
64
Antibacterial ceramics
The application of antimicrobial ceramics is reinvented in
medicinal applications like catheters, vascular grafts and
orthopaedic implants. Hydroxyapatite is a typical material
of antimicrobial ceramics which are widely researched for
hard tissue replacement for its good osseointegration and
biocompatibility property. Hydroxyapatite doped with
silver (Ag), CuO and ZnO can be used to improve the
antibacterial property.
65
Previous research presented that
hydroxyapatite can be doped with zinc oxide providing
novel structures with antimicrobial activity against E. coli,
S. aureus,andCandida albicans.
66
According to Mandal et
al., incorporation of Ag in HA as well as other biomaterials
leads to improved bactericidal property.
67–69
Antibacterial textile
It was reported that nano-additives was incorporated into
the antibacterial textile, endowing it with antibacterial
property, so that the textile can be applied to hospital
clothing.
70
Shalumon et al. obtained sodium alginate/
polyvinyl alcohol/zinc oxide (SA/PVA/ZnO) composite
nanofiber mats, and the cytocompatibility of bare and
composite SA/PVA fibres indicated that those with 0?5
and 1% ZnO concentrations were less toxic whereas those
with higher concentrations of ZnO was toxic in nature.
Antibacterial activity of SA/PVA/ZnO mats were exam-
ined with two different bacteria strains; S. aureus and E.
coli, and found that SA/PVA/ZnO mats showed anti-
bacterial activity due to the presence of ZnO. Their results
suggest that this could be an ideal biomaterial for wound
dressing applications once the optimal concentration of
ZnO which will give least toxicity while providing
maximum antibacterial activity.
71
Fan et al. prepared
the antibacterial fibers with good antibacterial activity
against S. aureus by the addition of silver nanoparticles.
72
Tomsˇic
ˇet al. prepared antimicrobial and washing fastness
cotton fabric through adding AgCl.
73
Conclusions
The urgent needs of novel strategies to prevent or alleviate
biomaterial associated infections are the most important
tasks for material scientists, biologists and microbiologists.
As summarised in this review, although many current
antibacterial materials are somehow effective and powerful
tools to prevent infections, but the lack of the valid
supporting data from the clinical experiments put a serious
question mark at viability of these materials for future
applications. Currently, the applications of antibacterial
materials are only examined in vitro and in preclinical
models. In the absence of well designed in vivo experiments,
it is impossible to prove their antibacterial and biocompa-
tible properties. It is also highly expected that the close
cooperation between material scientists and biologists is
indeed required to ensure that their studies are materially
and biologically meaningful. The reliable and robust
supporting data is necessarily needed to trigger the
advancement in antibacterial biomaterials study.
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Materials Technology: Advanced Biomaterials 2015 VOL 30 NO B2 B95
