Control of Bacterial Infections after Knee Joint Replacement

Abstract

Background: Knee joint replacement is an effective method to decrease pain and improve knee function in
patients with advanced knee joint arthritis. However, there are some factors leading to the failure of the
treatment, such as infection, mechanical failure of the replaced joint, and destruction or loosening of the
implant, which may lead to the need for revision surgery. The aim of this study was to assess new methods to
improve the longevity of the knee arthroplasty, as well as finding measures to decrease infection-related failures.
Methods: Databases such as PubMed and Science Direct as well as the Material Journal were searched to
find articles about infections of bone implant surgeries. 76 articles were retrieved; of them, 41 articles were
used for this review.
Results: Of the 41 articles, 33 were about the non-antibiotic treatment of bone implant infections, five articles
had evaluated in vivo non-antibiotic treatment and its effect on bone tissue and four other articles were
related to a combination of these agents with antibiotics and their increased effects after surgery.
Conclusion: Using non-antibiotic agents to prevent post total knee surgery infections and biofilm formation
is recommended to prevent antibiotic resistance. Currently, polymethyl meta-acrylate cement mixed with
antibiotics such as vancomycin and gentamycin is used in such operations but biofilm formation and
microbial resistance can occur, which may lead to acute infection. In this review, we evaluated technologies
that can enhance the functions of orthopedic implants so that total knee joint surgery infections can be
decreased. Reports show that combined various technologies can enhance preventing microbial infections.
Keywords: implants, infections; Antimicrobial therapy; Knee joint surgery, Anti-adhesion biomaterial,

Full text

Iranian Journal of Orthopaedic Surgery
Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71 Control of Bacterial Infections after…
65
Control of Bacterial Infections after Knee Joint Replacement
*** Tala Asgari,MSc ; ****Azad Aliahmadi,MSc ; **Hamid Mahdavi Mohtasham,MSc ;
*Seyyed Morteza Kazemi, MD
Having considered the increased rate of infection after knee joint
arthroplasty, it is recommended to use implants with approved
antimicrobial properties. Such infections are not limited to patients with
immunodeficiency or those at risk of infections because they can occur in
all patients. So preventive measures cover all patients undergoing such
treatments. Although it is more reasonable to use antimicrobial measures
for patients at higher risk of infection, as antimicrobial implants are used
to decrease the costs and increase the efficiency, all patients undergoing
knee joint arthroplasty can use them(1). Reports published since 2010
show that infection is the most prevalent cause of re-do surgery in the
next two years after the primary surgery. After that period non-infectious
causes are responsible for re-do surgeries, which have been shown in
National Joint Registry(2). Various measures have been considered to
prevent such resistance, such as restricting bacteria at the site of adhesion
to the implant in order to prevent the primary infection(3). Antibacterial
plates are another solution to actively destroy bacteria contacted to the
implant. Many antibacterial strategies have been assessed and reported
but some of them have had limited efficacy and some others are not
suitable to be located in osseous tissue(4).
Abstract
Background: Knee joint replacement is an effective method to decrease pain and improve knee function in
patients with advanced knee joint arthritis. However, there are some factors leading to the failure of the
treatment, such as infection, mechanical failure of the replaced joint, and destruction or loosening of the
implant, which may lead to the need for revision surgery. The aim of this study was to assess new methods to
improve the longevity of the knee arthroplasty, as well as finding measures to decrease infection-related failures.
Methods: Databases such as PubMed and Science Direct as well as the Material Journal were searched to
find articles about infections of bone implant surgeries. 76 articles were retrieved; of them 41 articles were
used for this review.
Results: Of the 41 articles, 33 were about non-antibiotic treatment of bone implant infections, five articles
had evaluated in vivo non-antibiotic treatment and its effect on bone tissue, and four other articles were
related to combination of these agents with antibiotics and their increased effects after surgery.
Conclusion: Using non-antibiotic agents to prevent post total knee surgery infections and biofilm formation
is recommended to prevent antibiotic resistance. Currently polymethyl meta-acrylate cement mixed with
antibiotics such as vancomycin and gentamycin is used in such operations but biofilm formation and
microbial resistance can occur, which may lead to acute infection. In this review we evaluated technologies
that can enhance the functions of orthopedic implants so that total knee joint surgery infections can be
decreased. Reports show that combined various technologies can enhance preventing microbial infections.
Keywords: implants, infections; Antimicrobial therapy; Knee joint surgery, Anti-adhesion biomaterial,
Antibiofilm, Antimicrobial biomaterial
Received: 5 months before printing; Accepted: 3 month before printing
Introduction
*
Orthopedic surgeon, Shahid
Beheshti University of medical
sciences, Tehran, Iran
** MSc. Sports Injuries and
Corrective exercise - Director
of Research Affairs at Bone,
Joint and Related Tissue
Research Center (BJRTrc)
*** Ph.D. student
Microbiology – Bone, Joint and
Related Tissue Research
Center (BJRTrc)
**** MSc. Clinical
Biochemistry– Bone, Joint and
Related Tissue Research
Center (BJRTrc)
Corresponding author: S M
Kazemi, Bone, Joint, and
Related Tissue Research
Center, Shahid Beheshti
University of Medical Sciences,
Teharn, Iran .
Email:
Seyyedmortezakazemi@yahoo
.com

Iranian Journal of Orthopaedic Surgery
Asgari, MSc; Aliahmadi, MSc et al. Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71
66
Factors to cause infections in bone implants
include contamination at the site of the
implant, transfer of the contamination from
the surgeon’s or the staff’s hands, transfer
from the skin or mucus membrane of the
patient, or transfer from the other patients,
which by controlling them infections can be
decreased(5).
“Primary microbial adhesion” as the main
cause of infection
The process of bacterial adhesion can be
divided into two basic phases; reversible and
irreversible. The reversible phase has less
stability compared with the second phase and
is caused by the non-specific cellular and
molecular reactions of the bacteria with the
surface of the implant(6). Bacteria attached to
the implant sometimes express biofilm gene,
which leads to secret a preventive sluggish
material (biofilm) that leads to resistance of
the bacteria and enhances its dissemination(7).
Bacteria use various ways for pathogenesis. So
there are many parameters for biofilm
formation by them. Preventing bacteria from
primary adhesion to the surface (for example
using anti-adhesion surfaces) can be one of the
measures to control infection(8,9).
Surfaces with anti-adhesion properties
Polysaccharides with bacterial anti-adhesion
properties (antibiofilm):
One of the most cost effective and simplest
ways to prevent biofilm formation is to
prevent the bacteria from adhesion to the
surfaces by using anti-adhesion covers(10).
Bacterial adhesion is a complex process that
can be influenced by many factors such as
physical and biochemical properties of the
materials’ surfaces, cellular characteristics of
the bacteria including its hydrophobia,
electrical charge of the cellular surface,
environmental factors (ionic potential), and
presence of organic material and electricity
flow. Having considered that the electrical
charge of the specified cellular wall of bacteria
is negative in neutral PH, it is usually seen that
hydrophilic materials have less bacterial
adhesion compared with hydrophobic
materials (11). Although there are controversies
in this regard, it is overall accepted that
hydrophilic surfaces in contact with mediators
with organic molecules such as proteins are
against producing an anchor for the bacteria to
start the bacterial adhesion process and
biofilm formation. So anionic polysaccharides
with hydrophilic properties are possible
candidates to produce anti-adhesion
surfaces(12).
Currently, hyaluronic acid has been studied as
one of the polysaccharides to be used as
antibiofilm cover. Recently antibacterial
property of hyaluronic acid has been reported
by finding the decreased adhesion of
staphylococcus aureus to surfaces with
titanium covered by hyaluronic acid compared
with surfaces with titanium but without
coverage with the acid(13).
Heparin is another natural polysaccharide with
anti-adhesion properties that has been studied
recently. Heparin as an anticoagulant is used in
implants with direct contact with the blood
such as surgical catheters, and stents(14).
Reports show that staphylococcus aureus
changes fibrinogen to fibrin by secretion of
coagulase, and then fibrin works as a
preservative network for bacteria and
facilitates bacterial adhesion to the implant’s
surface. By using tissue plasminogen activator
as a molecular cover in bone implants, such
proteins can transform the host’s plasminogen
to active plasmin leading to direct fibrinolytic
activity on the implant’s surface (where the
fibrin contaminated with the bacteria exists)
and destroy the contaminated fibrin by
degrading the fibrin and consequently destroy
the bacterial anchor for adhesion to the
surface(15).
In some strains of staphylococcus aureus,
decreased biofilm formation by tissue
plasminogen activator and its strong effect has
been reported. It has also been mentioned in
the report that coagulation inhibitors such as
vit K, heparin, and hydroin may theoretically

Iranian Journal of Orthopaedic Surgery
Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71 Control of Bacterial Infections after…
67
prevent biofilm formation but they cannot
prevent fibrin sediment formation by
staphylococcus aureus and destroy fibrin
contaminated with bacteria. It was also
reported that heparin even increased biofilm
formation in staphylococcus aureus(16).
Staphylokinase existed in staphylococcus
aureus functions similar to tissue plasminogen
activator but it is not related to biofilm
formation in this bacterium. It is sometimes
secreted heavily in biofilm former strains(17).
Polymer covers with anti-adhesion
characteristics
Some polymer covers such as hydrophilic poly
meta-acrylic acid, polyethylene oxide, and
protein resistant polyethylene glycol can be
attached to titanium implants(18). They can
significantly inhibit bacterial adhesion. Even if
some of such covers disturb osseous tissue
function, malfunction of the cells can be
restored and alleviated by using active
biomolecules such as sericin protein(19,20).
Dextran
There are other synthetic and biopolymers
with anti-adhesion properties(21). Dextran is a
polysaccharide that is widely used for
biomedical applications because of its very
high compatibility(22). It is reported that this
polysaccharide has anti-adhesion as well as
protein inhibiting properties similar to
hydrophilic polyethylene glycol, for which it
has been widely studied(23).
Dextran has some adhesion points to bacterial
cell surface, along the polymeric chain, to
inhibit the protein formation of micro-
organisms. It is while polyethylene glycol has
only one active terminal adhesion point. It
does not have reactivity along the whole
polymeric chain. That is why dextran is
potentially a good alternative for polyethylene
glycol to deactivate active biomolecules
because more inactivated bacterial active
biomolecules can be achieved by that
compared with polyethylene glycol cover(24).
Antimicrobial peptides
Antimicrobial peptides can be good
alternatives for antibiotics because of low
toxicity and causing low bacterial resistance(25).
They have hydrophilic and hydrophobic
regions, are water soluble, and can pass the
bacterial lipid rich membranes(26).
Their residuals that have positive charge can
disturb bacterial membrane processes by
interacting with negative loaded microbial cell
wall particles (lipopolysaccharides in gram
negative and teichoic acid in gram positive
bacteria)(27). This property is useful for
designing antimicrobial surfaces, where
primary adhesion and bacterial contact can
occur(28).
Chitosan
Currently, chitosan is used as a practical
material in antimicrobial compounds, as well
as food, cosmetic, and water and sewage
industries. That is why in recent years
antimicrobial properties of chitosan and its
derivatives against various types of micro-
organisms have been noticed(29).
Chitosan has various advantages over other
antiseptics such as high antimicrobial
properties covering a wide range of organisms
and low toxicity for mammalian cells. Its
capability to destruct biofilms formed by
bacteria has also been approved, although its
antimicrobial properties tend to decrease
because of its low water solubility. Nowadays
antimicrobial and biological compatibility of
chitosan can be enhanced by producing water
soluble chitosan (hydroxypropyl trimethyl
chloride chitosan)(30).
Surely there is always a concern that
combining chitosan with bone cement may
affect its mechanical properties(31). To solve
this issue, nanoparticles of the chitosan or
chitosan ammonium quaternary can be used.
Such nanoparticles also enhance the
antibacterial function of bone cements mixed
with gentamycin (these particles present
loaded surface density to interact with
bacteria leading to destruction of bacterial cell

Iranian Journal of Orthopaedic Surgery
Asgari, MSc; Aliahmadi, MSc et al. Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71
68
wall hence eliminating bacteria)(32). As chitosan
nanoparticles can mix uniformly with bone
cement, mechanical properties will not be
seriously affected if the ratio of powder to
weight is considered(30).
Regardless of using antibiotics such as
gentamycin mixed with bone cements, they
are not much effective to prevent the
infection. So in some studies chitosan in the
form of propyl methyl ammonium chloride
mixed with polymethyl meta-acrylate bone
cements (which has been evaluated in vivo)
could considerably inhibit infection caused by
methicillin resistance staphylococcus
epidermidis and this method had a promising
role to control the infection(33).
Metallic nanoparticles with antimicrobial
properties
High area to volume ratio and ease of
production has made nanoparticles an
important treatment modality against
bacterial biofilms(34). There are various reports
explaining multi-potentiality of nanoparticles
as antimicrobial elements. Capability of metals
to target different parts of organisms make
them superior to routine antibiotics against
infection so using metallic nanoparticles can
be an important and practical measure to
prevent infection(35).
Although recent studies show safety of using
nanoparticles in different treatments, these
nanoparticles can affect human body
according to their compositions. Factors such
as volume of nanoparticles, size, shape,
duration of exposure, and chemical surfaces
can affect their functions(36).
Silver
Recently, silver nanoparticles have been
considered very much to design implant
surfaces. This is important because such
particles have antimicrobial properties and
strong anti-biofilm potential with low toxicity
for mammalian cells. Silver nanoparticles can
effectively inhibit bacterial growth including
highly resistant strains with very low densities,
and do not show any acute cytotoxicity(34).
Although bacterial resistance has been
reported for silver ion, there is not such a
report for silver nanoparticles. So having
considered that bacterial resistance has been
changed to an international crisis using such
non-antibiotic measures can help to control
such a crisis(35). In a study, silver nanoparticles
combined with vancomycin and titanium
nanotubes showed high antibacterial
properties against methicillin resistant
staphylococcus aureus and bacterial adhesion
was prevented for 28 days by the combination.
The report concluded that using
nanotechnology in implant surfaces and
combining a non-organic bacteriocidal agent
such as silver nanoparticle with an organic
antibiotic such as vancomycin was an effective
method to prevent the infection and injury to
the soft tissue specifically when external
implants are used in the body.
Titanium implants having silver nanoparticles
can destroy floating bacteria as well as
bacteria attached to the surfaces with the
same mechanism during 1, 4, and 12 days. On
the other hand, reports show that sensitivity of
floating bacteria to silver nanoparticles can
decrease bio-film formation(37). Nowadays
silver nanoparticles are used with the
combination of other therapeutic measures
but there are always concerns regarding its
toxicity and blood transmission. Toxicity of
silver nanoparticles is related to environmental
and biological changes such as surface
oxidation, silver ion dissemination, and
reactions with biological macromolecules. And
it is always a challenge to diagnose how much
silver ion in the form of nanoparticles may
cause toxicity because by decreasing the
density the antimicrobial effect will also
decrease. Silver nanoparticles can connect to
membranous proteins and inhibit cellular
replication by activation of messenger
pathways. They can also enter the cells
through endocytosis or dissemination and
disturb mitochondrial function leading to

Iranian Journal of Orthopaedic Surgery
Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71 Control of Bacterial Infections after…
69
injury to intracellular proteins or nucleic
acids(38).
Copper
Low expense and easy use of copper on other
metallic surfaces has led to its practical use(38).
Antibacterial effect of copper on titanium
through decreasing the adhesion of bacteria
such as staphylococcus aureus and epidermidis
has been reported. Although such densities
can make toxicity in mammalian cells,
decreasing the amount and using
nanoparticles can be the remedy for such a
problem(39). Copper nanoparticle is an effective
factor against herbal and animal pathogenesis
that is why it is used as pesticide and growth
enhancer in agricultural industry. Copper
nanoparticles are also used as antimicrobial
cover on medical instruments to prevent
bacterial contaminations(40).
There are some reports about biofilm
prevention by copper nanoparticles against
bacteria such as E. Coli, pseudomonas
aeruginosa, and methicillin resistant
staphylococcus aureus. High potential of these
particles for absorption, penetration, and easy
access has led to introducing them as
antibiofilm material. But toxicity and blood
transmission of copper is also a challenge
similar to what exists for silver(41).
Gold
Gold nanoparticles are considered as practical
nanoparticles because of their high potential
for strong absorption and high conductivity.
Gold particles can easily penetrate to bacterial
cells (because of their small size) and compress
bacterial cell DNA. This process can prevent
genome replication, so the cell loses its
capability to replicate leading to bacterial
death. In addition to this, penetration of gold
nanoparticles into the cell wall inactivate
enzymes and produce hydrogen peroxide,
which its toxicity can kill the bacteria(41). Gold
metal shows weak antimicrobial properties
against wide spectrum of microbes and can
only kill bacteria in specific densities so using
this metal is not practical.
This research is a general evaluation of studies
that had been done about the effects of
biological materials and other non-antibiotic
treatments to be used as antimicrobial
materials and bacterial antibiofilms in artificial
knee joint surgeries. Data gathering was done
by searching in both Persian and English
language articles published from 2003 to 2016.
Databases such as Scopus, google, PubMed,
and google scholar were searched using
related keywords to find articles that had
required information about infection of
artificial joints and the ways of prevention of
such infections. New and practical methods
mentioned in those articles were briefly
reported in this review.
In this paper, we have tried to find the various
strategies regarding the prevention of deep
infections around the implants.
Among the factors introduced, biological
materials naturally reliable, durable, non-toxic
and safe and can prevent bacterial adhesion
and biofilm formation at implant surface.
Currently, Heparin is natural polysaccharide
with anti-adhesion properties which is used as
an anti-adhesion of the blood cells to implants
such as surgical catheters and stents.
Some polymer covers with anti-adhesion
properties like Dextran that is widely used to
inhibit the protein formation of
microorganisms.
Antimicrobial peptides such as chitosan and
nanoparticles of metal such as silver, copper
and gold are coatings that can be used as
antimicrobial agents. Recently, the use of
heparin polysaccharide in stents is practically
used as an anti-adhesive property, and then
chitosan is considered as an anti-adhesive
polymer coating and more attention has been
Results
Methods

Iranian Journal of Orthopaedic Surgery
Asgari, MSc; Aliahmadi, MSc et al. Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71
70
paid to the antimicrobial properties of silver
nanoparticles for the design of implant
surfaces.
In order to prevent infection, post knee joint
surgery treatments should be in a way that by
decreasing the infection rate, no limitation
occurs in merging the osseous tissue in the
region, no disorder happens in the bone tissue,
biostability exists at the surgical site, and
mechanical properties of the implant is not
altered.
Basically, all materials used for producing bone
implants can lead to bacterial biofilm
formation; hence to inflammation and necrosis
of the host’s tissue. High dose antibiotics are
prescribed to prevent infection-related
complications. Currently mixing antibiotics
with bone cements that is used by orthopedic
surgeons in knee arthroplasties is considered
as a potentially effective method to dispense
the drug at the site of surgery. But irregular
distribution of the antibiotics, short life, and
more importantly resistance of some strains of
bacteria against the wide range of antibiotics
have made some problems.
Since prevention is the best response to
infection, creating safe and non-toxic biological
materials and Metallic nanoparticles to prevent
bacterial adhesion and biofilm formation can be
a solution to these infections.
1. Bozic KJ, Kurtz SM, Lau E, Ong K, Chiu V, Vail TP, et
al. The epidemiology of revision total knee arthroplasty
in the United States. Clinical Orthopaedics and Related
Research®. 2010;468(1):45-51.
2. Khan M, Osman K, Green G, Haddad F. The
epidemiology of failure in total knee arthroplasty:
avoiding your next revision. Bone Joint J. 2016;98(1
Supple A):105-12.
3. Koh IJ, Cho W-S, Choi NY, Kim TK, Group KKR.
Causes, risk factors, and trends in failures after TKA in
Korea over the past 5 years: a mulcenter study. Clinical
Orthopaedics and Related Research®. 2014;472(1):316-
26.
4. Rosenthal VD, Maki DG, Graves N. The International
Nosocomial Infection Control Consortium (INICC): goals
and objectives, description of surveillance methods, and
operational activities. American journal of infection
control. 2008;36(9):e1-e12.
5. Knetsch ML, Koole LH. New strategies in the
development of antimicrobial coatings: the example of
increasing usage of silver and silver nanoparticles.
Polymers. 2011;3(1):340-66.
6. Neoh KG, Hu X, Zheng D, Kang ET. Balancing
osteoblast functions and bacterial adhesion on
functionalized titanium surfaces. Biomaterials.
2012;33(10):2813-22.
7. Furneri PM, Garozzo A, Musumarra MP, Scuderi AC,
Russo A, Bonfiglio G. Effects on adhesiveness and
hydrophobicity of sub-inhibitory concentrations of
netilmicin. International journal of antimicrobial agents.
2003;22(2):164-7.
8. Fux C, Costerton JW, Stewart PS, Stoodley P. Survival
strategies of infectious biofilms. Trends in microbiology.
2005, 13(1);34-40.
9. Junter G-A, Thébault P, Lebrun L. Polysaccharide-
based antibiofilm surfaces. Acta biomaterialia.
2016;30:13-25.
10. Zhang X, Wang L, Levänen E. Superhydrophobic
surfaces for the reduction of bacterial adhesion. Rsc
Advances. 2013;3(30):120, 20-30.
11. Jacobs T, Morent R, De Geyter N, Dubruel P, Leys C.
Plasma surface modification of biomedical polymers:
influence on cell-material interaction. Plasma Chemistry
and Plasma Processing. 2012;32(5):1039-73.
12. Harris L, Richards R. Staphylococcus aureus
adhesion to different treated titanium surfaces. Journal
of Materials Science: Materials in Medicine.
2004;15(4):311-4.
13. Hu X, Neoh K-G, Shi Z, Kang E-T, Poh C, Wang W. An
in vitro assessment of titanium functionalized with
polysaccharides conjugated with vascular endothelial
growth factor for enhanced osseointegration and
inhibition of bacterial adhesion. Biomaterials.
2010;31(34):8854-63.
14. Kwiecinski J, Na M, Jarneborn A, Jacobsson G,
Peetermans M, Verhamme P, et al. Tissue plasminogen
activator coating on implant surfaces reduces
Staphylococcus aureus biofilm formation. Applied and
environmental microbiology. 2016;82(1):394-401.
15. Akiyama H, Ueda M, Kanzaki H, Tada J, Arata J.
Biofilm formation of Staphylococcus aureus strains
isolated from impetigo and furuncle: role of fibrinogen
and fibrin. Journal of dermatological science.
1997;16(1):2-10.
16. Wimley WC. Describing the mechanism of
antimicrobial peptide action with the interfacial activity
model. ACS chemical biology. 2010;5(10):90 ۵-١٧.
17. Masako K, Hideyuki I, Shigeyuki O, Zenro I. A novel
method to control the balance of skin microflora: Part 1.
Attack on biofilm of Staphylococcus aureus without
antibiotics. Journal of dermatological science.
2005;38(3):197-205.
18. Darouiche RO .Treatment of infections associated
with surgical implants. New England Journal of
Medicine. 2004;350(14):1422-9.
19. Shi Z, Neoh KG, Kang E-T, Poh C, Wang W. Titanium
with surface-grafted dextran and immobilized bone
References
Conclusion

Iranian Journal of Orthopaedic Surgery
Vol 15, No 2 (Serial No 57), Spring 2017, p 65-71 Control of Bacterial Infections after…
71
morphogenetic protein-2 for inhibion of bacterial
adhesion and enhancement of osteoblast functions.
Tissue Engineering Part A. 2008;15(2):417-26.
20. Romanò CL, Scarponi S, Gallazzi E, Romanò D,
Drago L. Antibacterial coating of implants in
orthopaedics and trauma: a classification proposal in an
evolving panorama. Journal of orthopaedic surgery and
research. 2015;10(1):157.
21. Zhang F, Zhang Z, Zhu X, Kang E-T, Neoh K-G. Silk-
functionalized titanium surfaces for enhancing
osteoblast functions and reducing bacterial adhesion.
Biomaterials. 2008;29(36):4751-9.
22. Braem A, Mellaert L, Mattheys T, Hofmans D,
Waelheyns E, Geris L, et al. Staphylococcal biofilm
growth on smooth and porous titanium coatings for
biomedical applications. Journal of biomedical materials
research Part A. 2014;102 24.-215:(1).
23. Kaper HJ, Busscher HJ, Norde W. Characterization of
poly (ethylene oxide) brushes on glass surfaces and
adhesion of Staphylococcus epidermidis. Journal of
Biomaterials Science, Polymer Edion. 2003;14(4):313-24.
24. Bronk JK, Russell BH ,Rivera JJ, Pasqualini R, Arap
W, Höök M, et al. A multifunctional streptococcal
collagen-mimetic protein coating prevents bacterial
adhesion and promotes osteoid formation on titanium.
Acta biomaterialia. 2014;10(7):3354-62.
25. Necula B, Van Leeuwen J, Fratila-Apachitei L, Zaat
S, Apachitei I, Duszczyk J. In vitro cytotoxicity evaluation
of porous TiO2–Ag antibacterial coatings for human
fetal osteoblasts. Acta biomaterialia. 2012;8(11):4191-7.
26. Rujanapun N, Aueviriyavit S, Boonrungsiman S,
Rosena A ,Phummiratch D, Riolueang S, et al. Human
primary erythroid cells as a more sensitive alternative in
vitro hematological model for nanotoxicity studies:
Toxicological effects of silver nanoparticles. Toxicology
in Vitro. 2015;29(8):1982-92.
27. Albrecht MA ,Evans CW, Raston CL. Green
chemistry and the health implications of nanoparticles.
Green chemistry. 2006;8(5):417-32.
28. Kong M, Chen XG, Xing K, Park HJ. Antimicrobial
properties of chitosan and mode of action: a state of the
art review. International journal of food microbiology.
2010;144(1):51-63.
29. Tan H, Peng Z, Li Q, Xu X, Guo S, Tang T. The use of
quaternised chitosan-loaded PMMA to inhibit biofilm
formation and downregulate the virulence-associated
gene expression of antibiotic-resistant staphylococcus.
Biomaterials. 2012;33(2):365-77.
30. Shi Z, Neoh K, Kang E, Wang W. Antibacterial and
mechanical properties of bone cement impregnated
with chitosan nanoparticles. Biomaterials.
2006;27(11):2440-9.
31. Mu H, Guo F, Niu H, Liu Q, Wang S, Duan J .Chitosan
improves anti-biofilm efficacy of gentamicin through
facilitating antibiotic penetration. International journal
of molecular sciences. 2014;15(12):22296-308.
32. Tan H-l, Ao H-y, Ma R, Lin W-t, Tang T-t. In vivo Effect
of Quaternised Chitosan-loaded PMMA Bone Cement on
Methicillin-resistant Staphylococcus Infection of the Tibial
Metaphysis in a Rabbit Model. Antimicrobial Agents and
Chemotherapy. 2014:AAC. 03489-14.
33. Kvitek L, Panáček A, Soukupova J, Kolář M,
Večeřová R, Prucek R, et al. Effect of surfactants and
polymers on stability and antibacterial activity of silver
nanoparticles (NPs). The Journal of Physical Chemistry C.
2008;112(15):5825-34.
34. Baker C, Pradhan A, Pakstis L, Pochan DJ, Shah SI.
Synthesis and antibacterial properties of silver
nanoparticles. Journal of nanoscience and
nanotechnology. 2005;5(2):244-9.
35. Hussain S, Hess K, Gearhart J, Geiss K, Schlager J. In
vitro toxicity of nanoparticles in BRL 3A rat liver cells.
Toxicology in vitro. 2005;19(7):975-83.
36. Wang J, Li J, Qian S, Guo G, Wang Q, Tang J, et al.
Antibacterial surface design of titanium-based biomaterials
for enhanced bacteria-killing and cell-assisting functions
against periprosthetic joint infection. ACS applied materials
& interfaces. 2016;8(17):11 -162-78.
37. Beer C, Foldbjerg R, Hayashi Y, Sutherland DS,
Autrup H. Toxicity of silver nanoparticles—nanoparticle
or silver ion? Toxicology leers. 2012;208(3):286-92.
38. Stranak V, Wulff H, Rebl H, Zietz C, Arndt K,
Bogdanowicz R, et al. Deposition of thin titanium–
copper films with antimicrobial effect by advanced
magnetron sputtering methods. Materials Science and
Engineering: C. 2011;31(7):1512-9.
39. Ruparelia JP, Chatterjee AK, Duttagupta SP,
Mukherji S. Strain specificity in antimicrobial activity of
silver and copper nanoparticles. Acta biomaterialia.
2008;4(3):707-16.
40. LewisOscar F, MubarakAli D, Nithya C, Priyanka R,
Gopinath V, Alharbi NS, et al. One pot synthesis and
anti-biofilm potential of copper nanoparticles (CuNPs)
against clinical strains of Pseudomonas aeruginosa.
Biofouling. 2015;31(4):379-91.
41. Ahmed RA, Fadl-allah SA, El-Bagoury N, El-Rab
SMG. Improvement of corrosion resistance and
antibacterial effect of NiTi orthopedic materials by
chitosan and gold nanoparticles. Applied Surface
Science. 2014;292:390-9.