Surface & Coatings Technology 404 (2020) 126424

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Surface & Coatings Technology

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Surface engineered biomaterials and ureteral stents inhibiting biofilm T

formation and encrustation
Todorka G. Vladkovaa, , Anna D. Stanevab, Dilyana N. Gospodinovac
⁎

a
Laboratory for Advanced Materials Research (LAMAR), Dept. of Polymer Engineering, University of Chemical Technology and Metallurgy (UCTM), Sofia, Bulgaria
b
Dept. of Technology of Silicates, University of Chemical Technology and Metallurgy, Sofia, Bulgaria
c
Dept. of Electrical Apparatus, Technical University-Sofia, Bulgaria

ARTICLE INFO ABSTRACT

Keywords: Protection of ureteral stents against infections is a significant current challenge raised by increasing the number
Antimicrobial of stentings and infections, microbial resistance to conventional antibiotics and multi-drugs treatments, side
Ureteral stents effects for the patients like damage of surrounding tissue and high morbidity. Surface engineered biomaterials
Biofilm and ureteral stents, reducing biofilm formation and encrustation would contribute to mitigation of the problem.
Urinary tract infection
The aim of this review is to present the progress during the last 5 years in the development of surface engineered
antimicrobial biomaterials and stents with expectation to raise some new fruitful ideas in this direction. Strategies
aimed at preventing, disrupting, or removing adherent microbes and biofilms from biomaterials and ureteral stents
are its main subject. Various antibacterial agents, modifications, and coatings as well as preparation, deposition and
characterization techniques are among the topics covered. A brief market analysis is also included covering the
significance of ureteral stents associated infections and a mode of development of a biofilm.
The review of the progress during the last 5 years shows a continuing interest in surface modification and coating
employing three principal anti-biofilm strategies: 1) mechanical detachment; 2) killing microbial cells and 3) creation
of low-adhesive surfaces. The known surface engineering solutions report a reduced, to some extent, biofilm formation
and encrustation of biomaterials and ureteral stents, but none of them is able to totally stop their development.
Some new trends are observed, such as complementary antimicrobial protection by coating and flow dy­
namic; biodegradable coatings releasing antimicrobial agent; quasi irremovable surface coatings, delivering drug
or antimicrobial agent as well as new carbon and biodegradable materials; bacteriophages and phage cocktails,
etc. Almost all of them are under intense in vitro studies; only few of them were studied in vivo animal models and
none in humans. Some of the liquid infused coatings, already tested in animal models, seem to be the closest to
clinical application but so far no one has been applied to ureteral stents.
This review outlines some future research directions and major challenges in the surface engineered bio­
materials and ureteral stents. It gives ideas how, by surface engineering, to approach more closely the “clean”
ureteral stent to not allow microbial adhesion and encrustation and thus sharply reduce the ureteral stents
associated infections and stent dysfunction.
The most important prerequisite of the non-toxic “clean” surface is to be low adhesive. Its anti-biofilm per­
formance could be improved by including bio-surfactant and/or inhibitor of quorum sensing (QS) and/or in­
hibitor of the crosslinking of the exopolymeric substances (EPSs). The key to identifying a “universal” surface
that would repel/release all microbial cells is maybe hidden in the in-depth understanding of the mechanism of
the initial reversible adsorption of the EPSs secreted by microbial cells, since it initiates the whole biological
cascade of biofilm development.

1. Introduction associated infections, microbial resistance to conventional antibiotic

and multi drugs treatments, high economical price of the stenting, side
Protection of urinary stents against infections is a significant current effects for the patients, like damage of surrounding tissue and high
challenge raised by increasing number of stentings and stents- morbidity [1].

⁎
Corresponding author at: University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria.
E-mail address: tgv@uctm.edu (T.G. Vladkova).

https://doi.org/10.1016/j.surfcoat.2020.126424
Received 23 June 2020; Received in revised form 11 September 2020; Accepted 12 September 2020
Available online 14 September 2020
0257-8972/ © 2020 Elsevier B.V. All rights reserved.
T.G. Vladkova, et al.
Fig. 1. Anatomy of the renal system in a female.
Approximately 92,000 ureteral stents were implanted every year
until 2011 and their horizon is expanding [1,2]. The annual con­
sumption of urological tubes around the world was over 100 million in
2016, according to the European Centre for Disease Prevention and
Control [3]. Worldwide kidney transplants increased by 6.5% in 2016
as compared to 2015 [4]. According to Bloomberg [5] the global ur­
eteral stents market is expected to surpass US$ 564.4 million by 2026.
Key industry producers [6] expect this market to reach $ 696.5 million
by 2024.
Some problems in the renal system (see Fig. 1), such us complica­
tions from different medical procedures, kidney or ureter stones, tu­
mors, tear or rupture of the ureter from surgery or trauma, infection,
blood clots, pressure on the ureter from nearby structures require
stenting.
As it is evident on Fig. 2, the ureteral stent is placed in the upper
urinary tract whereas the urinary catheter is in the lower urinary tract.
Due to their different positions the ureteral stent and the urinary ca­
theter are under different urodynamic conditions, the latter being of
importance for carrying away the microbial cells by the urine flow.
If the ureter is narrowed or becomes blocked it can slow or stop the
urine flow. The urine backs up in the kidneys and makes it difficult for
the kidneys to work properly. The backup of urine can also cause da­
mage to the kidneys and lead to more severe illness. A stent can help
keep a narrow or blocked ureter open. It may also be used to support a
damaged ureter while it heals.
Heavy clinical problems due to microbial extra- and intraluminal
biofilm development and encrustation occur at varying degrees on al­
most all stents but it is more expressed at long-time indwelling stents
that are responsible for approximately 65% of nosocomial infections
[7–9]. The growing microbial resistance against antibiotics is set to
cause 30 million deaths by 2050 and to cause an economic impact on
healthcare providers, around 100 Trillion US$, a significant part of
them due to ureteral stents associated infections [10]. High economic
burden of ureteral-stents-related problems was demonstrated in 2016:
more than one hundred US dollars per patient per day, including the
costs of ureteral stent, drugs, consultation of healthcare professionals,
hospitalization, stent extraction and work incapacity due to stent-re­
lated problems [11].
Antibiotic therapy alone is, in most cases, insufficient to eradicate
biofilm infections. Development of surface engineered biomaterials and
ureteral stents, inhibiting biofilm formation and encrustation is a
strategy to mitigate the problem [6,12–14].
2
Surface & Coatings Technology 404 (2020) 126424
Main artery from heart
Brings blood with wastes
Left kidney
Ureteral stone
Ureter
Carries urine
Female bladder
Collect urine
Urethra
Some key considerations have to be taken into account when anti­
microbial biomaterials and ureteral stents are developed: they work in
urine environment with microbial cells cocktail; shear forces are dif­
ferent for the ureteral and urethra stents being in the upper or in the
lower part of the urinary tract, respectively; the indwelling duration is a
couple of days to couple of months; surface characteristics (surface
chemistry, topography, roughness, energy and elastic modulus) of
materials by which they are fabricated: polymers, metals, biodegrad­
ables are different [15].
No migration is achieved by stent design: collars, wings, flanges, barbs
and a double ‘pig-tail’ [16]. Metallic stents, preferable for long-term
stenting offer superior durability and reduced need for frequent changes.
316LCu-bearing stainless steel (316LCu-SS) was studied as a novel ureteral
stents material with antibacterial and encrustation reducing properties.
The in vitro immersion test showed that 316LCu-SS not only inhibited
proliferation of bacteria and formation of biofilm, but had also less en­
crustation. Its antibacterial effectiveness against E. coli reached to 92.7% in
the artificial urine for 24 h and 90.3% in the human urine for 6 h. The
percentage of the encrustation surface coverage was 30.2% by 12 weeks,
which was nearly one half of that on NiTi alloy. The in vitro tests showed
that 316LCu-SS had no toxicity, and promoted the migration of urethral
epithelial cells [17,18]. The complexity of insertion and removal, as well
as the stent-associated infections are gaps [19] of the metalic stents. The
relatively new biodegradable materials usually reduce encrustation, im­
prove patient comfort, can be safely removed or the removal can be
avoided [20,21]. Lock et al. [22] investigate magnesium and its alloys as a
novel class of biodegradable and anti-bacterial materials for ureteral stent
applications. They demonstrate that magnesium alloys decrease E. coli
viability and reduce the colony forming units over a 3-day incubation
period in artificial urine when compared to the currently used commercial
polyurethane stent but their clinical translation needs further studies. The
mechanical properties of the biodegradables are usually insufficient; they
need exact adjustment of the degrading period, etc. The biodegradables
still need further improvement [23–28]. Protection of metallic and poly­
meric stents against both biofilm formation and encrustation is usually
made by surface engineering [29] that is in the focus of this review.
2. Biofilm formation and encrustation
Pathogenic microbial cell biofilms are the leading cause of ureteral
stents-associated infections (USAIs). Mono- and multi-specie biofilms
are extremely capable to self-reproduction on biological and non-
T.G. Vladkova, et al. Surface & Coatings Technology 404 (2020) 126424

Kidney

Ureter

Ureteral stent

Male Bladder

Catheter balloon

Intraluminal

Catheter Extraluminal

Fig. 2. Anatomical cross section of the renal system in a male depicting the position of a ureteral stent in the upper urinary tract and a urinary catheter in the lower
urinary tract.

biological surfaces and resist traditional means of planktonic bacteria

killing [30–33]. The generally accepted mode of biofilm development
includes several stages presented in Fig. 3. 1. Reversible adsorption of
Initially, planktonic cells reversibly attach to the surface (reversible planktonic cells
adhesion) and remain in this state until signaled by an environmental
cue to form a less ephemeral relationship. Once microorganisms begin
to secrete exopolymeric substances (EPSs), biofilm develops to an ir­
reversible process due to cross-linking. In the mature biofilm, the cells Environmental cues
are already engaged in an extracellular matrix (ECM), composed of (chemical messages) signaling
proteins, exopolysaccharides and extracellular DNA (eDNA). The ma­
2. Transient stage
trix traps nutrients, various biologically active molecules, such as cell
communication signals, and enzymes that are able to degrade various EPS secretion
matrix components, any nutrients and other substrates [33]. Every
specie has a specific set of environmental signals, many of them che­
mical messages, for intercellular signaling within a population to co­ 3. Irreversible adhesion
ordinate altered gene expression in response to the population density,
(cross-linking, ECM formation)
a phenomenon known as “quorum sensing” (QS) [34]. Many current
studies, aimed at the development of non-toxic antibiofilm approaches,
are focused on this phenomenon [35,36].
Knowledge about competitive relationships in multi-species biofilms
also opens perspectives for new approaches to reducing the biofilm 4. Mature biofilm dispersal and
formation based on non-biocide compounds: bio-surfactants/dis­ dissemination
persants, enzymes, and other, produced by microorganism metabolites
[36]. Biofilm dispersal activation is discussed now as a novel mode of
action for identification of anti-biofilm compounds [37,38]. Fig. 3. General mode of a biofilm development.
Any stage of the biofilm development can be a target of an anti-

3
T.G. Vladkova, et al.
Living bacteria
Microbial cells
Fig. 4. Principle of the biomechanics (mechanical detachment).
biofilm treatment but it is the easiest at the initial stage, i.e. during the
reversible attachment (adhesion) of planktonic microbial cells. The
combat with biofilms and encrustation is complicated by several phe­
nomena: secretion of different EPSs by the different microbial species as
well as by one and the same microbial cells on different surfaces; the
versatile nature of adhesive proteins using different adsorption me­
chanisms in front of complementary surfaces; concurrent adsorption of
EPSs constituents (similar to the Vromann effect at an adsorption of
mixes proteins), etc. The adherence of microbial cells to the stent is
always the event, initiating each step in the pathogenesis of the urinary
tract infections and maybe the key to their prevention is hidden here
[39–41].
Microbial strains, specific for uropathogenic biofilms, are:
Escherichia coli, Proteus, Staphylococcus, Pseudomonas, Klebsiella,
Enterobacters, Enterococci, Candida, Serratia, rarely Delftia tsuruhatensis,
Achromobacter xylosoxidans and few others with predominance of E. coli
[42,43]. The long term indwelling ureteral stent biofilms are often
multi-microbial with Proteus mirabilis as a major pathogen [44,45]. P.
mirabilis forms crystalline biofilms causing not only infections but
partial or in some cases, total blockage of the urine flow. A real-time
imaging demonstrates that the initial cell adherence occurs in less than
1 h of exposure to P. mirabilis followed by accumulation of additional
material (carbohydrate) and highly elongated, motile cells; a con­
ditioning film develops after 24 h and within 4 days the surface is
covered with crystalline deposits [46]. This is associated with the in­
crease of urinary pH due to generation of ammonia, promoting mineral
crystals formation (hydroxyapatite, magnesium ammonium phosphate
and others), contributing to an increased morbidity [42,47–49]. P.
mirabilis characterizes by several virulence factors promoting adhesion
and biofilm formation that can be utilized in personalized therapies
targeting specific virulence pathways [49].
Unique characteristics of the flow dynamics were revealed in ob­
structed and stented ureters by a biomimetic artificial model [50].
Artificial urine accelerated encrustation [51] and poly-microbial in­
fection models [52] were created to compare in vitro encrustation of
variety of polymeric materials and to search for anti-biofilm strategies.
Quartz crystal microbalance (QCM) was used for online monitoring of
encrustation [53]. Factors influencing the initial bacterial adhesion
should be taken into account when anti-biofilm and anti-encrustation
biomaterials and ureteral stents are developed: material surface char­
acteristics [15]; indwelling time, urine composition, urodynamic and
ureteral stent design [48,54].
3. Principle strategies for the creation of anti-biofilm and anti-
encrustation biomaterials and stent surfaces
Large variety of approaches focused on coatings and surface mod­
ifications are under study to counteract the biofilm formation and en­
crustation [55]. Analysis of the market by products shows several ma­
terials of interest for stent coating: hydrophilic polymers; antimicrobial
4
Surface & Coatings Technology 404 (2020) 126424
Living bacteria
carried away by
the urine flow
peptides; specific drugs and biodegradables [56]. Surfaces with hy­
drogels, antibiotics, nanoparticles, enzymes, QS inhibitors, anti-adhe­
sion agents, bacteriophages, etc., all of them are considered as experi­
mental [29,48,57–59]. Three fundamental strategies to control biofilm
formation and encrustation are in use currently:
1) Mechanical detachment;
2) Killing microbial cells and
3) Creation of low-adhesive surfaces.
Complex approaches (mechanical detachment and killing, low ad­
hesion and killing, etc.) are a current trend since the biofilm formation
and encrustation is a complex phenomenon.
3.1. Mechanical detachment
Mechanical detachment of the microbial cells is the idea of bio­
mechanics based approaches (Fig. 4).
Urinary tract devices capable of repeated removal of biofilms via
active deformation offer a potential for non-biologic, non-antibiotic
method to biofilms removal. Combination of finite-element modeling
and prototype devices development show repeatedly removal of a
mixed biofilm of P. mirabilis and E. coli. [59]. A stent-on-chip micro­
fluidic model and occluded ureter stent study demonstrate a significant
reduction of encrustation at a combination of optimal stent wall
thickness and side-hole shape [14].
3.2. Killing of microbial cells
The killing of microbial cells in contact with antibiotics or other
antimicrobial agents, grafted on (contact killing), or delivered by ma­
terial surface, is a largely used surface engineering approach to the
reduction of biofilm formation and encrustation.
Variety of antimicrobial agents and techniques for surface mod­
ification and coatings deposition are in use. A number of nano-com­
posites are discussed in detail (composition, physical and chemical
properties as well as biological activity) as suitable alternatives of an­
timicrobial agents [60].
Molecules that interfere with bacterial signaling systems, anti­
microbial peptides, bacteriophages, hydrogels with or without anti­
biotics, silver nanoparticles, anti-adhesion agents, naturally derived
compounds, etc. show promise in vitro. It is expected that their im­
plementation in complementary therapies could contribute to eradicate
resilient biofilm infections but the ureteral stents associated infections
(USAIs) remain a clinical problem [40,41,61–66].
Wet chemistry, plasma treatment, or both plasma treatment and wet
chemistry, physical vapor deposition (PVD), chemical vapor deposition
(CVD) and other techniques are employed in the surface engineering of
antimicrobial biomaterials and ureteral stents. Plasma-assisted surface
functionalization, grafting and coating are current approaches in the
T.G. Vladkova, et al.
Living
bacteria
Contact killing
surface
Fig. 5. Contact killing approach.
solvent-free chemistry [63,67].
3.2.1. Contact killing surfaces
Contact killing surfaces exhibit antimicrobial activity without re­
leasing antibiotics or other biocidal substances, as it is evident in Fig. 5.
Nano-materials, carbon materials, polymer–nanoparticles, polymer
brushes and hydrogels, fluorinated amphiphilic polymers, polymers
tethered with antibiotics such as ciprofloxacin, antimicrobial cationic
polymers and peptides, naturally occurring antimicrobials, etc. based
modifications and coatings are studied for the creation of contact killing
surfaces. Different mechanisms take place in the contact activity of such
surfaces depending on their chemistry [64].
3.2.1.1. Nano-materials-based approaches. Metal-, metal oxide, or
composite nanoparticles (NPs), polymer/ceramic NPs with entrapped
bioactive agents and other approaches are studied currently [60,65].
Inside the cells, NPs either by themselves or by the released ions
interact with proteins, inhibiting essential cellular functions. Both NPs
binding to preferential sites of proteins and enzymes as well as
generating reactive oxygen species (ROS) induce cell damage and
death [62,66]. It is known that the formation of hybrid polymer-
metal NPs increases significantly the stability of the NPs,
biocompatibility and antibacterial activity. Permanent immobilization
of hybrid polymer-metal NPs onto different surfaces is of interest for
durable anti-biofilm effect. For example, enzymatically surface grafted,
hybrid Ag/chitosan system, synergistically inhibits S. aureus and E. coli
bacterial growth in vitro as it was found by Ivanova [66]. One-step
synthesis of Ag NPs on polydopamine-coated sericin/polyvinyl alcohol
composite antimicrobial films was developed Exhibition of inhibitory
effect against biofilm forming bacteria was found for biosynthesized Ag,
AgJ NPs and silver nanoparticles containing coatings as tested in vitro
[68–70]. Zare et al. [71] demonstrated effective prevention of bacterial
growth and biofilm formation of silver/hydrophilic poly(p-xylylene)
composite coated urinary catheters tested in synthetic urine at a body
temperature of 37 °C. Ex vivo study of Carvalho et al. [72] demonstrated
that Ag clusters, incorporated in a:C (Ag/a:C) matrix, produced by
plasma gas condensation process reduce the friction coefficient of
stents. A proof of concept study demonstrates that antifouling coating
prepared with alternate layers of polydopamine and AgNP on silicone
urinary catheter restricts in vivo infection in animal model. Preparation
of nanocomposite films, containing metal nanoparticles (such as silver,
copper, zinc oxide and other) by the use of non-thermal plasmas at low
and atmospheric pressure is accepted as a promising approach to
manufacturing of biomaterials with high antimicrobial activity [67].
Vladkova et al. demonstrated [74] that magnetron co-sputtered TiO2/
SiO2/Ag nanocomposite coatings, tested in vitro (including in urine flow
with E. coli) sharply reduce bio-adhesion and biofilm formation. It was
also shown that silver nanoparticles with high biocide activity can be
5
Surface & Coatings Technology 404 (2020) 126424
Dead
bacteria
biologicaly active
substance
produced by CVD or atomic layer deposition (ALD) [75]. Baiee et al.
[76] demonstrated high activity against E. coli in laboratory tests of
ultra-fine Ag NPs (2 to 10 nm), prepared by laser ablation of Ag target.
TiO2 layers, deposited on AISI 316LVM steel by low temperature ALD
process are referred also as useful for antimicrobial protection of
urological devices [77]. The high antimicrobial activity of Ag and Ag
ions against both Gram-positive and Gram-negative bacteria is often
proved in vitro. Ag-based coatings and silver nanoparticles (AgNPs)
becoming increasingly common as antibacterial agents are
commercially employed within the medical field with limited success
in vivo. But such antimicrobials were not reported during the last five
years for antimicrobial protection of ureteral stents that are of use in the
medical practices.
The reason for failure in vivo of silver- or other antimicrobial agent
containing materials is probably that in work conditions the microbial
cells act ‘in concert’, as a mixture, whereas the tests in vitro are against
single microbial strains, i.e. the test and work conditions are different.
In addition, in the human body the medical devices (including ureteral
stents) are in contact with human tissues and fluids where some non-
desirable interactions are possible. Mimicking the work conditions in
laboratory testing is complicated and usually approach these conditions
to some extent only. Therefore, the testing in vivo is of critical im­
portance when evaluating antimicrobial activity and generally the
performance of biomaterials.
It was reported that the incorporation of CuO, cetyl trimethy­
lammonium bromide (CTAB)-capped CuO, and ZnO NPs as nano-filler
renders PDMS surface antibacterial as well as that low concentrations of
magnesium-doped zinc oxide NPs affect the development of P. mirabilis
biofilm: reduce bacteria number and extracellular material and there­
fore are advised as a potential antimicrobial agent for urological de­
vices [78,79]. Bankier et al. [60] reports synergestic antmicrobial ef­
fects of metal nanoparticles combinations.
3.2.1.2. Carbon materials-based approaches. Surface coatings with
carbon materials: graphene, carbon nanotubes (CNTs), diamond-like
carbons (DLCs) are of increased interest because they combine
antimicrobial activity and low toxicity to human cells. Nanomaterials
such as graphene, whether these materials are active on the surface or
whether they achieve antimicrobial activity through releasing traces
into the aqueous phase is not yet resolved, but their activity in
microbial suspensions is clearly demonstrated. The most frequently
proposed mechanisms of action fall under four categories: (i) oxidative
stress induction, (ii) protein dysfunction, (iii) membrane damage, and
(iv) transcriptional arrest [80]. The mechanism of action depends on
the concentration of the graphene oxide (GO): low GO concentrations
cut membranes of the micro-organisms S. aureus and E. coli whereas
high concentrations induce the formation of GO aggregates shielding
their edges. When cluster size increases, bacterial deactivation through
T.G. Vladkova, et al.
wrapping is observed. Graphene-based materials differ in their
morphology (mono or multilayers) as well as in their surface
chemistry (graphene), GO, reduced graphene oxide (RGO). Lateral
size for instance is important for enhancing bacterial adhesion
whereas the sharp edges may act as nano-knifes. GO can enhance the
antimicrobial activity through oxidative stress with or without
production of reactive oxygen species [80–82]. When comparing the
antibacterial activity of graphite, graphite oxide, GO, and RGO towards
E. coli under similar conditions, GO shows the highest antibacterial
activity, followed by RGO, graphite, and graphite oxide [82].
Synergistic effects are reported for graphene-based nanocomposites
with silver and other antibacterial nanoparticles, as well as with
polymeric or enzymatic bactericides [83–87]. Decorated with silver
NPs, graphene nanolayers can be prepared by the methods of the
printed electronics using, for example, a spray-coating system [84].
These methods are not only economical, but also enable the printing of
layers of various thicknesses on different types of materials, including
flexible and nonplanar substrates. An improvement of the antibacterial
property of reduced graphene oxide was achieved by the preparation of
rGO-CuO nanocomposites via a simple hydrothermal method. Their
antibacterial mechanism is attributed to electron transfer from the
bacterial cells [85]. Microstructure and antibacterial efficacy of
graphene oxide nanocomposite fibers were just reported. Their
antibacterial potential was investigated using E. coli. Average
bacterial reduction was found ranging from 46 to 85% with results
favoring the strongest bioactivities of the nanocomposite containing
8 wt% of GO [86]. Carbon nanotubes (CNTs) are also studied as
antimicrobial material since they can be easily embedded into the
polymers. A variety of morphologies were studied, either single wall or
multi-wall, but it seems that their antimicrobial activity is lower than
that of GO-based materials [87]. It was demonstrated [88] that
germanium doped DLC film significantly reduces P. aeruginosa biofilm
formation and has no effect against Gram-positive S. aureus biofilm.
Three types of nanostructured coatings deposited on PDMS substrate:
DLC (by plasma enhanced-CVD), molybdenum disulfide (MoS2) and
Tungsten disulfide (WS2) (both through self-assembly) show good
adhesion to the substrate PDMS, WS2 coating being the most resistant
to encrustations after 4 weeks' immersion in artificial urine [89–91].
Results from evaluating the effects of pristine and chemically
functionalized CNTs incorporation into PDMS on the composite's
thermal, electrical, and surface properties on bacterial adhesion in
dynamic conditions were lately reported. Initial bacterial adhesion,
studied by a parallel-plate flow chamber assay under conditions similar
to those in the urinary tract devices (catheters and stents) using E. coli
as a model organism, in general was less on the composites with pristine
rather than functionalized CNTs [91]. Quantum dots (CDs) are
relatively new class of carbon materials which are useful for
identification of bacteria due to their tunable photoluminescence
properties [92]. When the CDs surface is decorated with Ag NPs,
their selective attachment to Gram-positive bacteria is possible and
inducing antimicrobial activity through the membrane-disrupting
mechanism [89].
Inhibition of the bacterial growth on urinary tract indwelling de­
vices by clay nanotubes–silicone composites was studied. PDMS was
doped with clay (halloysite) nanotubes (HNTs), and the PDMS-HNTs
composite surfaces were coated with PDMS-b-polyethylene oxide (PEO)
and antibacterial agents. The properties of the composite material were
examined using SEM, energy dispersive spectroscopy, water contact
angle measurements, tensile testing, UV–Vis spectroscopy, thermal
gravimetric analysis and fibrinogen adsorption studies. The anti­
bacterial potential of the PDMS/halloysite nanotubes composites ap­
pears to be better compared to the commercial urinary tract devices as
tested by E. coli and S. aureus [93].
3.2.1.3. Based on polymer–nanoparticle interaction. Polymer–nanoparticle
interaction is used as a design principle to develop durable ultrathin
6
Surface & Coatings Technology 404 (2020) 126424
universal binary anti-biofilm coatings. Mei et al. [94] utilized the
interaction of polydopamine (PDA) nanoaggregates/nanoparticles and
ultrahigh molecular weight hydrophilic polymers to generate stable
coatings with broad spectrum anti-biofilm activity useful for protection
of medical devices both with short- and long-term application. Wang et al.
[95] show that a silver-polytetrafluoroethylene (Ag-PTFE) nanocomposite
coating deposited onto silicone tubes, inhibits bacterial migration and
biofilm formation along the external tube surface and significantly resist
encrustation, as tested by two in vitro bladder models: against E. coli and
against Pr. mirabilis performances. Reduced bacterial adhesion to
polyurethane (PU) ureteral stents was reported by surface covalent
bonding of kanamycin-chitosan nanoparticles. A comparative testing of
surface-modified PU and unmodified PU stents shows significantly
increased antibacterial activity against E. coli and Pr. mirabilis of the
surface modified PU stent [96].
3.2.1.4. Polymer brushes-based. Polymer brushes are widely used in the
preparation of contact-active antimicrobial surfaces. Polyethylene
glycol (PEG), amphiphilic, zwitterionic, bioinspired bactericidal
polymers, and incorporating antimicrobial agent polymers are used
for preparation of functional antibacterial surfaces. Some engineered
surfaces have dual effect, for example anti-adhesion and contact killing
[97]. One contact-active strategy utilizes dynamic cationic
polyethyleneimine (PEI) brush-like structures to achieve permanent
bactericidal activity on PU ureteral stent. PEI chains are covalently
attached on the PU surface by “grafting to” approach [98]. The high
efficiency of PEI brushes grafted on PU stents was proved both in vitro
and in vivo (in a rat model). Incorporating of PEI brushes onto PU
surface reduces sharply the adhesion of P. mirabilis cells and inhabits
their encrustation both in dynamic bioreactor and in vivo due to the
dynamic motion of the brushes in liquid environment and the cationic
structure of PEI, disrupting the cell membrane, thus killing the bacteria
in the time of contact. According to Atomic Absorption Spectroscopy
(AAS), approximately 90% of encrustation is inhibited on in vivo rat
models. Decrease in encrustation is clearly observed on the stents
extracted from rat model, by Scanning Electron Microscopy (SEM).
Histological evaluations show that PEI brush grafting decreases host
tissue inflammation in close relation to a decrease in biofilm formation
and encrustation. A dual effect of contact-killing and anti-adhesive
antibacterial strategy show high efficiency on PEI brushes grafted PU
stents both in vitro and in vivo [99,100].
A swelling-assisted infusion and polymerization of dopamine was
used as a simple strategy significantly enhancing the antifouling per­
formance of covalently cross-linked PEG and physically cross-linked
agar hydrogels by incorporation of a fouling-resistant polymer zwit­
terion, poly(2-methacryloyloxyethyl phosphoryl choline). Both, func­
tionalized PEG and agar hydrogels reduce protein adsorption > 90%
and adherence of E. coli and S. aureus greater than an order of magni­
tude, compared to the control hydrogels [101].
3.2.1.5. Based on naturally occurring antimicrobials. A number of
naturally occurring antimicrobials were tested as alternatives to
antibiotics: antimicrobial polymers and peptides, bacteriophages,
bacterial cell wall hydrolases, zosteric acid, etc. [89]. Thiol-ol
reaction is presented as a facile technique to graft two natural
polymer derivatives: agarose and quaternized chitosan, as
antibacterial coatings on polymer and metal substrates, pre-treated
with oxygen plasma followed by UV-induced grafting under
atmospheric conditions. The dimer caprol, a FDA-approved drug, was
used as both, surface anchor and cross-linker of the polymer chains
during the grafting [102].
3.2.1.6. Based on antimicrobial peptides (AMPs). AMPs, proteins and
glycosaminoglycans were studied as a promising alternative to
conventional antibiotics. AMPs typically consist of short amino acid
chains with a net cationic charge (provided by arginine, lysine or, in
T.G. Vladkova, et al.
acidic environments, histidine) and a substantial portion of
hydrophobic residues (generally > 50%). The positive charge and
amphiphilic nature provide the ability of the AMPs to interact with
bacterial membranes non-specifically. They also translocate through
the membrane and target intracellular components. The AMPs have a
broad-spectrum activity against bacteria and fungi but they are costly to
produce and may cause toxicity at high doses at which are efficient
[103–105]. To overcome the short AMPs half-life in vivo, a covalent
immobilization onto biomaterial surface is usually applied. In addition,
a correct peptide orientation and exposure from the surface is essential
to maintain an antimicrobial activity. For example, chemo selective
covalent immobilization of Dhvar5 AMP was found to result in a higher
anti-adherence effect than simple physical adsorption, improved
antimicrobial properties and readiness to be functionalized [106]. An
antimicrobial biomaterial for urological tubes was produced by
incorporating of the AMP Bmap-28 in biodegradable hydrophilic
polyurethane, PEGU25. As compared to the control PEGU25, Bmap-
28-incorporated PEGU25 delays the encrustation, demonstrating a
significantly lower P. mirabilis load and antimicrobial effect
throughout the whole 7-day test in vitro [107].
Strong antibacterial polydopamine (PDA) coatings prepared by a
facile shaking-assisted method are reported for the first time during
2016. The replacement of the static solution condition with a me­
chanical shaking produces roughened polydopamine (rPDA) coatings
on different substrates, like glass, stainless steel and plastics. The rPDA
coatings exhibit remarkably enhanced antibacterial activity in the ab­
sence of any other antibacterial agents that is unimpaired by steam
sterilization treatments [108]. Chaparro et al. [109] found that the
antibacterial activity of a synthetic peptide, derived from bovine lac­
toferricin is affected by the polyvalence. The effect of multi copy ar­
rangements of the RRWQWR motif (linear and branched) on its anti­
bacterial activity against S. aureus and K. pneumoniae was examined.
The overall results demonstrate that, compared to linear analogues,
polyvalent presentation of the RRWQWR motif enhances its anti­
bacterial activity against both Gram-negative and Gram-positive bac­
teria even on resistant strains.
3.2.1.7. Polysaccharides based. A number of widely distributed in the
nature polysaccharides display anti-biofilm properties. Surface
treatment by natural or modified polysaccharides is accepted as a
promising means to fight against indwelling medical devices associated
biofilm infections. Nanomaterials based on mammalian hyaluronic
acid, chondroitin sulfate and heparin are a trend in the development
of new biomaterials with antimicrobial activity. Besides classical
hydrophilic hyaluronic acid and heparin based coatings, the
promising anti-adhesive properties of the algal polysaccharide ulvan
are underlined [110]. Besides classical hydrophilic coatings based on
hyaluronic acid and heparin, the promising anti-adhesive properties of
the algal polysaccharide ulvan are underlined. Surface
functionalization by antimicrobial chitosan and derivatives is
extensively surveyed, in particular chitosan association with other
polysaccharides in layer-by-layer assemblies to form both anti-
adhesive and bactericidal coatings [111] The great influence of the
conditioning film composition on the anti-biofouling properties of stent
materials was demonstrated by studying the encrustation of chondroitin
sulfate grafted polyurethane film in urine. It was found that the
composition of the conditioning films was more important than other
surface properties such as hydrophilicity, zeta potential and roughness
for inorganic salt deposition and bacterial adhesion. In addition, the
anti-encrustation properties of the surface were promoted by proteins
and inhibited by polysaccharides [112]. An antifouling polyurethane
film, modified by chondroitin sulfate (PU-CS) was prepared by chemical
grafting with N-Boc-1,3-propanediamine as a spacer. The different mass
fraction of N-Boc-1,3-propanediamine was investigated to obtain PU-CS
films with different CS grafting density. Proteins adsorption on
glycosaminoglycan films was evaluated. The results show that the
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Surface & Coatings Technology 404 (2020) 126424
increase of CS grafting density improves not only the hydrophilicity but
the antifouling performance of the films. Changes in inorganic salt
deposition after co-adsorption of proteins and glycosaminoglycans on
PU-CS suggests that the proteins promote the inorganic salt deposition,
while glycosaminoglycans inhibit the crystal growth. The negatively
charged polysaccharides might promote the generation of smaller
crystals which could be conducive to provide theoretical and practical
guide to develop novel urinary stents with significant anti-encrustation
properties [113].
3.2.1.8. Bacteriophages based. Bacteriophages are viruses infecting
bacteria. They are highly efficient in preventing bacterial
contamination and relatively cost-effective. Bacteriophages are host-
specific, but infecting several strains or species of bacteria, both Gram-
positive and Gram-negative, they can have broad host range.
Attachment of bacteriophages to a stent surface can be achieved
electrostatically, by physic-sorption or covalent bonding. Phages are
specifically sensitive to moisture and can be deactivated when dried.
However, re-activation upon wetting is feasible and addition of
polysaccharides improves their stability [114–116].
3.2.1.9. Enzymes based. Bacterial cell walls hydrolases have limitations
towards Gram-negative bacteria due to the presence of the outer
membrane, and some important Gram-positive pathogens such as S.
aureus are already resistant to lysozymes. Cellobiose dehydrogenase
functionalized urinary catheter [117] as well as enzyme multilayer
coatings inhibiting P. aeruginosa biofilm formation on urinary catheters
[118,119] were presented as anti-biofilm systems. It was found that the
covalently immobilized protease, α-chymotrypsin (α-CT) to a low-
density polyethylene (LDPE) provides a new non-leaching material
(LDPE-α-CT) able to preserve surfaces from biofilm growth over a long
time. Plate count viability assays, as well as confocal laser scanning
microscopy (CLSM) analysis, show that LDPE-α-CT significantly
impacts E. coli biofilm formation by (i) reducing the number of
adhered cells; (ii) affecting the biofilm thickness, roughness,
substratum coverage and (iii) decreasing the matrix polysaccharide
volume. CLSM images show also a destabilized biofilm with many cells
dispersing from it [120].
3.2.1.10. Others. Zosteric acid and salicylic acid bounded to LDPE
surface successfully control bacterial biofilm formation: reduce the
mass of E. coli biofilm, affect the morphology and make its more
susceptible to ampicillin and ethanol [121]. Reducing bacterial
adhesion, lysozyme immobilized polyvinylchloride catheters are
prepared by three-step procedure including: gamma-ray pre-
irradiation; grafting a mixture of N-vinylcaprolactam and 2-
hydroxyethylmethacrylate serving as binding points and finally
immobilization a lisozyme [122]. Antibacterial and anti-encrustation
biodegradable polymer coating for urinary tract devices is reported
based on a combination of the antibacterial effect of norfloxacin and
silver nanoparticles with the neutralization of alkali products of urea
hydrolysis by degradation products of polylactic acid in an aqueous
medium. The loaded polymer films with the two antibacterial agents
are deposited on commercial PU and silicon sheets, using bare ones as
controls. Artificial urine and an in vitro encrustation model were used to
show that the coatings resist the encrustation for at least 2 weeks [123].
3.2.2. Surfaces delivering antimicrobial agent
Controlled release of biologically active agents from the stents can
be utilized to enhance their antimicrobial activity and the healing of the
surrounding tissues. Stents eluting biologically active agents are
equipped with a specific coating system for production of drug on the
stent surface (Fig. 6).
It is usually achieved by preliminary chemical modification or not of
the material surface followed by wet chemistry or dry methods of de­
position a coating delivering drug or antimicrobial agent. The
T.G. Vladkova, et al.
Living
bacteria
Surface releasing
biologicaly active
substance
Fig. 6. Killing microbial cells by a surface releasing antimicrobial substance.
mechanism of their antimicrobial activity is still not fully understood. It
seems that in the most cases, the antimicrobial activity happens not
only by released biologically active substances but also by direct con­
tact killing [124–129]. Biologically active agents eluting material sur­
faces and coatings are discussed as a promising concept to prevent
stent-related symptoms without affecting the mechanical properties and
to render stents unfit for insertion. Drug-eluting ureteral stents, uti­
lizing technologies developed for cardiac stents, are a new area of stent
design. All of them however are still considered as experimental ap­
proaches although some of them were in vivo tested in animal models.
Variety of antimicrobial approaches under study employ chemical
modification with or without preliminary plasma treatment to create
functional antimicrobial coatings for delivering of new antibiotic sys­
tems, nanomaterials, polymer hydrogels, QS inhibitors, bacteriophages,
etc.
3.2.2.1. New antibiotic systems. Variety of biologically active agents
delivering stent coatings are based on new antibiotic systems, like nano-
penicillin [130] for eradiation of E. coli and P. aeruginosa biofilms;
cypofloxacine [131]; a combination of azithromycin and ceftazidime
for more effectively prevention of P. aeruginosa biofilm formation
[132]; triclosan-loaded water born polyurethane for inhibition of P.
mirabilis growth in artificial urine [133]; fluoxetine and thioridazine for
inhibition of efflux, reduction the P. mirabilis and E. coli biofilm
formation and increase the time to block catheters and stents. [134].
Quite different release profiles from long-term studies (105 days) were
observed for urinary tract antibiotics, mixed with bio-absorbable
polyester, poly(D,L-lactide-co-ε-caprolactone). An engineered and
implemented as a sustained drug delivery platform, bilayer swellable
drug-eluting ureteral stent enhanced localized drug delivery to the
highly impermeable urothelium [135].
McCoy et al. [136] developed an innovative anti-adhesive bioma­
terial (hydrogel copolymer) for urinary tract devices coatings with
complementary hydrophobic drug-carrying and eluting capacities. The
amphiphilic block copolymer, Poloxamer 188, was chemically deriva­
tized with methacryloyl moieties and copolymerized with the hydrogel
monomer, 2-hydroxyethyl methacrylate. Performance of the synthe­
sized copolymers was evaluated in terms of equilibrium swelling, sur­
face water wettability, and mechanical integrity, resistance to en­
crustation and bacterial adherence, and ability to control the release of
the loaded antibiotic, cyclofloxacin. The newly developed matrices are
able to reduce more than 90% in both adherence of the common ur­
inary pathogen E. coli and encrusting crystalline deposits as compared
to the commonly employed hydrogel, poly(hydroxyethyl methacrylate).
The release kinetics of a loaded hydrophobic drug could be adjusted by
optimization of the polymer composition [136].
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Surface & Coatings Technology 404 (2020) 126424
Dead
bacteria
biologicaly active
substance
3.2.2.2. Nano-materials based. Porous ZnO/2–Hydroxyethyl Methacrylate
(HEMA) bilayer coatings for drug eluting ureteral stents were prepared by
sputtering of mesoporous ZnO layers followed by coating with poly-
hydroxy-ethyl-metacrylate (HEMA) and poly-(HEMA-co-acrylic acid)
employing vacuum infiltration and drop-casting [137,138]. Wang et al.
[134] achieved controllable and sustained release of silver over several
weeks by immobilization of Ag NPs on PDA pre-treated silicone surface
followed by another PDA coating. The number of Ag NPs-PDA bilayers
controls the loaded silver amount. Grafted poly(sulfobetaine methacrylate-
co-acrylamide) provides an antifouling outer layer ensuring free diffusion
of Ag from the surface. The bilayer AgNPs-PDA coating reduces
colonization by uropathogens by approximately two orders of
magnitude [139]. The effect of Ag coatings adhesion on the
effectiveness and durability of antibacterial properties was studied and
the tailored adhesion was found to provide a choice for clinical
applications [73,140]. Highly active dual-function polymer‑silver
nanocomposites were reported consisting of an inherently antimicrobial
and biodegradable polymer in one-pot. Nanocomposite-coated surfaces
releasing active Ag+ over an extended period of time were reported to
effectively inhibit both bacterial and fungal biofilm formation [141].
Nissen et al. [142] report a-C:H:Cu composite coatings deposited by PVD-
CVD hybrid process onto Ti6Al4V substrates to study the release of Cu2+
ions and how it can be controlled. Drug loaded nanoparticles were
proposed that could overcome the limitations of conventional antibiotic
treatments associated with toxicity, improper delivery, or enzymatic
degradation. Hydroxyapatite, chitosan, collagen, silica, and titanium
dioxide are used as nano-matrices to incorporate antimicrobials [143].
3.2.2.3. Hydrogel coatings. Multi-functional hydrogel coatings are used
for attainment of targeted, site-specific delivered bioactive agents from
indwelling devices [144]. Multistep procedure was described to prepare
long-term preventing bacterial colonization of silicone, microscale two-
layer bi-functional coating, and sustained releasing 4-amide-piperidine
[145]. The pathogen-induced elevation of urine pH was used as a
trigger for “intelligent” antimicrobial release from novel hydrogel drug
delivery systems of 2-hydroxyethyl methacrylate and vinyl-
functionalized nalidixic acid derivatives [146]. Stimuli-responsive
polymers were reviewed that can be used for drug targeting, creation
of contact-killing surfaces and competitive release. Such polymers offer
novel tools for the design of macrophage-, bacteria- and/or biofilm-
targeted nano-carriers as well as of medical devices with switchable
anti-biofouling properties [147]. A promising “kill–release” approach
was proposed by Wei et al. [148] to construct “smart” antibacterial
surfaces, which can kill bacteria attached to the surface and then to
undergo on-demand release of the dead bacteria. Polyurethane/N-
halamine semi-interpenetrating polymer networks are proposed with
excellent antimicrobial activity towards both Gram-positive and Gram-
T.G. Vladkova, et al.
Avoid live Living bacteria
bacteria adhesion
Slipper film
coating
slipping
Fig. 7. A strategy for non-toxic biofouling control by low-/non-adhesive slip­
pery surfaces.
negative bacteria [149]. Natural products, such as honey and other
attract interest due to their high antimicrobial activity and lack of or
low toxicity. Honey demonstrates potency to inhibit antibiotic resistant
pathogens (S. aureus, Salmonella Typhimurium, E. coli, Bacillus subtilis
and P. aeruginosa) at low concentrations. Manuka honey at defined
dilutions significantly inhibits bacterial attachment to urinary tract
devices and reduces early biofilm development [150,151].
3.2.2.4. Quorum-sensing based. USAIs are caused by uropathogens with
QS-dependent biofilm formation. Therefore, the interruption of QS
system is an approach to combat drug resistance [152]. Rajasekharan
et al. [153] show that some phytotherapeutic agents, like Hyptis
suaveolens (HEHS) can be employed as QS inhibitors of biofilm
formation by E. coli, P. vulgaris, P. mirabilis, Klebsiella pneumoniae and
Serratia marcescens. HEHS reduces the QS-dependent virulence factors
(protease, hemolysin) production and promotes the loosening of biofilm
architecture. Anti-QS and anti-biofilm activity was found in other
phitocompounds like miquelianin and peltatoside from the root
extracts of Arctium lappa Linn, which can be a source for a
complementary medicine against three clinical isolates of E. coli, P.
mirabilis, and Serratia marcescens [154]. Controlled release coatings,
delivering QS inhibitors and antimicrobial species like ceragenin,
nitrofurantoin, gallium, zinc complexes, silver ions, nanoparticles,
selenium nanoparticles, etc. were reviewed [154,155].
3.2.2.5. Bacteriophages based. The interest to the bacteria infecting
viruses, bacteriophages, as an alternative of the conventional
antibiotics increases with the increase of the microbial pathogens
resistance. Bacteriophages offer several advantages over the
conventional antimicrobial treatment including replication at the site
of infection, specificity and, in some cases, biofilm degrading ability.
The host range of the bacteriophages can be broadened by use of phage
cocktails infecting several strains bacterial species, both Gram-positive
and Gram-negative. Immobilized with phages sample surfaces,
exhibiting antimicrobial activity, include gold, glass, polymers and
hydrogels [156–158]. Lehman et al. [157] found that hydrogel-coated
silicone urinary tract devices, pretreated with mixtures of P. aeruginosa
and P. mirabilis bacteriophages, significantly reduce mixed-species
biofilm formation, as tested in a multiday continuous-artificial urine
flow model. A limited number of phages for P. mirabilis have been
isolated and studied. Two virulent phages, podovirus vB_PmiP_5460
and myovirus vB_PmiM_5461 were found to prevent adherence to and
colonization of silicone surfaces. The efficacy of other three P. mirabilis
bacteriophages: vB_PmiS_NSM6, vB_PmiP_#3 and vB_PmiM_D3 was
proved by pre-treatment of urinary tract devices and testing in vitro.
The pre-treatment with phage cocktail increases additionally the time
to blockage compared to single phage treatment [158]. An infection-
responsive coating was developed that releases a bacteriophage in
response to elevated urinary pH, in order to delay encrustation and
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Surface & Coatings Technology 404 (2020) 126424
blockage tubes by P. mirabilis [159]. Polyvalent bacteriophages (total
number of 13) and phage cocktails were studied to control planktonic
forms and uro-pathogenic P. mirabilis strains biofilm formation. Three
bacteriophages: 39APmC32, 65APm2833 and 72APm5211 demonstrate
strong anti-biofilm activity, without blocking each other's activity in a
cocktail [160].
3.3. Low-adhesive surfaces creation
The creation of low adhesive surface is based on the idea of de­
creasing the bioadhesion down to levels not allowing attachment or
allowing easy detachment of microbial cells (Fig. 7). Non-toxicity is the
main advantage of this strategy together with some others.
In 1984, Ikada, Susuki and Tamada [161] theoretically predict and
experimentally prove that the work of adhesion in aqueous media,
W1,2w approaches zero when the water contact angle (WCA) or surface
tension, γc approaches zero. This is the starting point in the develop­
ment of strong hydrophilic or strong/super hydrophobic low-adhesive
protein repellent biomaterials and biofouling release coatings. Strongly
hydrated surfaces appeared to be very promising at the bioinert bio­
materials. Strong and super hydrophobic, low energy surfaces attract
interest because of their better stability in water media [40,161]. The
creation of low-adhesive surfaces inhibiting the attachment of micro­
bial cells is already accepted as a promising approach in the non-toxic
control of bioadhesion and biofouling. Within the anti-adhesive idea,
different approaches are used such as topographical modifications,
coating by diamond like carbon, hydrated, zwitterionic or supehy­
drophobic polymers, grafting of anti-adhesive peptides, etc. Quasi ir­
removable, “bottom up” or “top down” deposited, slippery films are
relatively new direction.
3.3.1. Topographical modifications
Topographical modifications at micrometer and nanometer scale,
usually inspired by nature (dolphin skin, lotus leaf, spiders, wings of
insects such as cicadas and dragonflies, etc.) are used to add anti-ad­
hesive properties of material surfaces. Their practical application is
limited by the difficult fabrication of desired nanostructures and their
insufficient stability. Metal-assisted chemical etching fabrication of bio-
inspired silicon nano-spikes is reported as a simple, fast, low-cost, and
scalable surface nanotechnology [162].
3.3.2. Strongly hydrated surfaces
Hydrogels of hydrophilic polymers have resistance to non-specific
protein adhesion. Rosman et al. [163] prepare a gel-based, resistant
towards biofilm formation ureteral stent, composed of a highly hy­
drated, partially hydrolyzed polyacrylonitrile. During 15-days test
period, it demonstrates 43–71% reduced pathogenic E. coli biofilm
formation as compared to conventional stents (Boston Scientific, Na­
tick, MA). Antifouling poly(N-vinylpyrrolidon) PVP brushes were suc­
cessfully grafted on PU films by surface-initiated atom transfer radical
polymerization (SI-ATRP). The effect of polymerization time on surface
properties and topography was studied. Hydrophilicity and protein
fouling resistance of PVP–PU films were greatly promoted [164]. In
vitro investigated by Pidhatika et al. [165] bacterial adhesion to a
surface-attached and cross-linked poly(N,N-dimethylacrylamide)
(PDMAA) hydrogel network, deposited on PU substrate demonstrated
fivefold reduced adherence of E. coli.
3.3.3. Strong/super hydrophobic surfaces
Strategies to prevent protein adsorption and bioadhesion include
not only strong hydrophilic (hydrated) but also strong- and super-hy­
drophobic (water contact angle > 150°) surfaces. The creation of na­
nostructures is important in the development of super hydrophobic
surfaces because the three-dimensional nanomorphology (nanopillars)
renders them superhydrophobic and slippery [166].
The reduction of the bacterial adhesion by exploration of super
T.G. Vladkova, et al.
hydrophobicity is relatively new not systematically studied topic. Some
novel findings about the early stage anti-bioadhesion behavior of four
types superhydrophobic, soot based coatings towards P. putida [167]
and a simple spray coating procedure for deposition of novel silver-
doped shoot coating with enhanced wear resistance and anti-microbial
performance were reported the last year [168].
3.3.4. Zwitterionic surfaces
Zwitterionic polymer brushes may also delay or even prevent mi­
crobial attachment to a surface, since the hydration layer surrounding
the ionic surface prevents non-specific protein adsorption. Zwitterionic
polymer brushes cannot inactivate bacterial cells. Liu et al. [169]
achieve a synergistic anti-adhesion and bacterial inactivation by
grafting of zwitterionic poly(sulfobetaine methacrylate) brushes with
embedded biocidal silver nanoparticles. Antifouling photograftable
zwitterionic coatings on PDMS substrates were reported by Leigh et al.
[170]. Poly(dimethylsiloxane) (PDMS) surfaces were coated with two
zwitterionic polymers, poly(sulfobetaine methacrylate) (pSBMA) and
poly(carboxybetaine methacrylate) (pCBMA), using a simultaneous
photografting/photo-cross-linking process to produce a robust grafted
zwitterionic hydrogel, reducing nonspecific protein adsorption, the first
step of the biofouling. The coating process uses benzophenone, as a
photografting agent and type II photoinitiator, to covalently link the
cross-linked zwitterionic thin film to the PDMS surface. The cross-
linked pSBMA and pCBMA hydrogels can be readily photografted to
PDMS substrates. Such hydrogels are promising as antibacterial ureteral
stents coatings [170].
3.3.5. Antiadhesive peptide coating
An anti-adhesive, brush type, peptide coating on PU surface was
reported that prevents urinary tract devices associated infection in vivo
in a mouse model. An optimized surface active AMP was used, labeled
with cysteine at the C-terminus. The coated PU tube reduces the bac­
terial adhesion in vivo more than 4 logs than the uncoated one and
inhibits planktonic bacteria growth in the urine by nearly 3 logs [171].
3.3.6. Antiadhesive DLC coatings
Anti-adhesive Si-and F-doped micro-nanostructured DLC coatings
for medical devices were prepared by a radio frequency plasma-en­
hanced CVD (rf-PECVD). Under water contact angle measurement was
used to characterize the surface properties of these DLC coatings, and
bacterial adhesion assess were performed by fluorescence microscopy
to evaluate their anti-bacterial ability. Quartz Crystal Microbalance
technology (QCM-D) for measuring bacterial adhesion and related as­
sesses, was used to measure and record the bacterial adhesion process
with the time. The frequency change curves and dissipation factor
change curves of bacterial adhesion onto the coatings were obtained. In
this way it was shown that the micro-nano-structured surfaces sig­
nificantly reduce or delay the encrustation in urine [172].
3.3.7. Anti-adhesive quasi irremovable liquid surface coatings
Anti-adhesive quasi irremovable liquid surface coatings can be
prepared by “bottom up” or “top down” approach. The “bottom up”
approach was used in the development of marine antimicrobial siloxane
composite coatings, containing silicone or fluorinated oil do not parti­
cipate in the formation of the vulcanization network. Thus, the oil
migrates on the surface (“bottom up”) and forms quasi irremovable top
layer because of a high difference in the surface tension of the oil and
the water medium. The oil migrating on the surface could be utilized as
a carrier for delivering biologically active substances, contributing to
the reduction of biofilm formation [173–181].
The deposition of infused liquid (IL) surface coatings, utilizing “top
down” approach is a relatively new approach. Easily deposited on
surfaces with complicated shape and different sizes, the IL surface
coatings are accepted as promising for the creation of anti-adhesive
medical devices surfaces. The common feature of this approach is that
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Surface & Coatings Technology 404 (2020) 126424
the surface is exposed to a lubricating liquid attracted to the underlying
material, repelling the biological fluid and/or cells as well as reducing
adhesion-mediated biological interactions, such as biofilm formation,
fibrosis, etc. [181]. The immobilized perfluorocarbon liquids on ex­
panded polytetrafluoroethylene (ePTFE), termed Slippery Liquid In­
fused Porous Surfaces (SLIPS) are the first reported by the Aizenberg
group in 2011 [182]. To display low adhesion to the contaminating
liquid or solid being repelled, the lubricating liquid should pre­
ferentially wet the solid substrate, forming a stable thin film. Therefore,
this system must have a lower total energy than a system in which the
substrate is wetted by the contaminating liquid and determines which
substrate–lubricant combinations will form a stable IL layer [183].
Various IL surfaces were shown to reduce adhesion and biofilm
formation of a range of pathogens. The clinically relevant P. aeruginosa,
E. coli and S. aureus pathogens are most often studied, because they are
the most frequently responsible for biofilm formation on medical de­
vices. The liquids (silicon oils or fluorinated substances) are not toxic to
the pathogens themselves but they repel pathogen adhesion and in this
way inhibit the growth and deposition of matrix that is necessary for
biofilm formation under static and dynamic conditions. Planar and
tubular geometry silicone substrates can be infused with non-toxic si­
licone oil to create a stable, extremely slippery interface that exhibits
exceptionally low bacterial adhesion and prevents biofilm formation.
Analysis of a flow culture of P. aeruginosa through untreated PDMS and
infused PDMS (iPDMS) tubing shows at least one order of magnitude
reduction of biofilm formation on iPDMS, and almost complete absence
of biofilm on iPDMS after a gentle water rinse. The iPDMS can be used
to coat a wide range of materials being also compatible with traditional
sterilization methods [184–187].
Nepenthes pitcher plant-inspired materials, called slippery liquid
infused porous surfaces (SLIPS) attract attention of scientists because of
the special surface wetting properties. Mimicking is achieved by in­
fusing rough micro/nanostructured substrates with a liquid film of lu­
bricating liquids, such as perfluoropolyethers, silicone oil or ionic li­
quid, creating smooth liquid-infused surfaces at the molecular-level.
SLIPS materials could have broad applications because of their omni­
phobicity and efficiency against bacterial biofilms [188]. Impregnation,
swelling and sol–gel method are the conventional technologies for
preparation of SLIPS. Such silicone oil-/fluorinated oil-infused surfaces
exhibit outstanding long-term slippery stability even under extreme
operating conditions such as high shear rate, elevated evaporation, and
immersion in flowing aqueous that makes them applicable under harsh
environmental conditions [189,190]. Some reports about in vivo testing
of the anti-biofilm ability of IL coating are found in the literature, for
example applied to the enamel of New Zealand white rabbit incisors
[191] or in a rat model [192], demonstrating a limited colonization in
both cases. But the clinical translation of IL surfaces requires con­
sideration of a number of factors like validation the technology and
others [193]. No reports were found about antimicrobial protection of
ureteral stents by IL surface coatings, although it holds promise for
efficient reduction of urology pathogens adhesion, biofilm formation
and encrustation.
3.3.8. Complementary approaches
Complementary approaches are currently under development since
the biofilm formation and encrustation are complementary phenom­
enon [194]. Novel biomaterials integrating naturally occurring anti-
adhesive polymers with specific metal ions or carbon NPs improve
chemical, physical and biological properties of the anti-adhesive sur­
faces. For example, Colberg et al. [195] demonstrated anti-Ps. aerugi­
nosa biofilm properties of alga-secreted polysaccharide and biomaterial
patches with metal complex films. It was found that chitosan coating
functionalized with the natural marine polymer, N-acetylcysteine re­
duces the bacterial adhesion [196]. IL coatings with included small-
molecule quorum-sensing inhibitors (bacterial antivirulence factors)
are also reported. They attenuate the production of P. aeruginosa
T.G. Vladkova, et al.
virulence factor, pyocyanin, by up to 80%, a level of inhibition
equivalent to that observed upon external administration [197]. Lu­
bricious ionic polymer brush functionalized silicone elastomer surfaces
are prepared to increase the lubricity of urinary tract devices and hence
to reduce ureteral trauma and infections caused by indwelling devices.
A simple three-step synthesis route was proposed, complemented by
surface analysis and tribological assessment of the surfaces. The surface
functionalization significantly reduces the hydrophobicity and reduces
the friction coefficient [198]. Porous, amine-reactive films, in­
corporating lubricant and silver nanoparticles are used in the devel­
opment of multimodal antibacterial surfaces. The benefit rises from the
combination of antiadhesion and bactericidal properties of these sur­
faces [199]. Film-based lubricant-infused Ag NPs-incorporated PDMS
surfaces demonstrate outstanding antibacterial effect towards both
waterborne and airborne E. coli [197]. Combination of anti-adhesive
properties with immobilization of antimicrobial core-shell nanospheres
[200] as well as of bacteria-responsive multilayer coatings containing
polycationic nanospheres [201] both hold promise to prevent bacterial
biofilm formation.
4. Concluding comments
Bacterial colonization, biofilm formation and encrustation of the
stent surface continue to be the most common causes of ureteral stent
associated infections and obstruction. One approach to mitigate the
problem remains the employment of new surface engineered bioma­
terials and stents.
There are literature reports about antimicrobial biomaterials and
ureteral stents reducing biofilm formation and encrustation to some
extent only and none about material or stent totally preventing crys­
talline biofilm development.
Despite the variety of antimicrobial surfaces developed so far such
as heparinized, or coated with cationic polymers, peptides, or nano­
particles, drug delivering surfaces and others, huge research remains
focused on the surface engineering of biomaterials and urinary stents.
The review of the progress during the last 5 years shows a con­
tinuing interest in surface modification and coating using three prin­
cipal anti-biofilm strategies: 1) mechanical detachment; 2) killing mi­
crobial cells and 3) creation of low-adhesive surfaces. Interest in the
utilization of complementary approaches and natural biologically ac­
tive substances is increasing.
New carbon and biodegradable materials; bacteriophages and phage
cocktails; combination of coating and flow dynamic; antiadhesive,
quasi irremovable coatings and other are under intensive study, almost
all of them in vitro, only few in vivo in animal models and no one in
human. Despite the insufficient antimicrobial activity and possible side
effects in vivo, silver continues to be one of the most studied anti­
microbial agents because of its good performance in vitro. Some of the
liquid infused coatings, already tested in animal models, seem to be the
closest to clinical application at other medical devices but so far no one
was applied at ureteral stents.
The control over material surface characteristics, influencing initial
interactions with microbial cells, such as surface chemistry, energy,
topography, roughness and elastic modulus could be a tool for reducing
the biofilm formation. The most important prerequisite of a non-toxic
“clean” surface is to be low adhesive. Its anti-biofilm performance could
be improved by including a bio-surfactant and/or an inhibitor of both,
QS and/or EPSs crosslinking.
The key to identification of “universal” surface that would repel/
release all microbial cells is probably hidden in the in-depth under­
standing the mechanism of the initial reversible adsorption of EPSs
secreted by microbial cells, since it initiates the biological cascade of
biofilm formation.
11
Surface & Coatings Technology 404 (2020) 126424
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ­
ence the work reported in this paper.
Acknowledgments
Bulgarian National Science Fund is gratefully acknowledged for its
financial support (grants No DCOST 01/4/2018; KP-06-COST/20; No
KP-06-H27/17/2018). The support from COST Action CA 16217
“European Network for Interdisciplinary Research to Improve Urinary
Stents” is also acknowledged.
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