DOI: 10.1002/ejic.

201800709 Microreview

Antibacterial Surfaces
Self-Assembled Monolayers of Silver Nanoparticles: From
Intrinsic to Switchable Inorganic Antibacterial Surfaces
Piersandro Pallavicini,*[a] Giacomo Dacarro,[a] and Angelo Taglietti*[a]

Abstract: The layer-by-layer technique allows to graft molec- sity, and of the molecular overcoating. While these surfaces dis-
ular monolayers on bulk surfaces that, in turn, allow to graft play an intrinsic antibacterial action, a further evolution will also
monolayers of metal nanoparticles. This microreview focuses on be reviewed, in which additional photothermal antibacterial ac-
the preparation of such materials featuring a monolayer of sil- tion can be switched on demand, using near-IR radiation and
ver nanoparticles (AgNP) and their use as antimicrobial surfaces non-spherical AgNP or a combination of AgNP with non-spheri-
against both planktonic bacteria and biofilms. The role of Ag+ cal AuNP. The intrinsic and switchable photothermal action of
release and of direct cell/AgNP contact in the antibacterial ac- these surfaces will be unraveled, and their synergistic effect
tion will be stressed as a function of the adhesive molecular stressed.
layer, of the AgNP dimension and shape, of their surface den-

1. Introduction tained with the silane-SiO2 surface chemistry, that after Au/S is
the most popular grafting function/material couple.[9,10] In this
The formation of molecular monolayers on bulk surfaces is an
case, R-Si(OR)3 trialkoxysilanes or R-SiCl3 trichlorosilanes react
important branch of nanochemistry, as the surfaces bearing
with the Si-OH groups on the surface of silica, glass or quartz
such monolayers are dimensionally modified on the nanoscale.
to form covalent R–Si–O–Si(surface) bonds. Once formed these
Implications are enormous, because a simple molecular mono-
bonds are not reversible, as a consequence the obtained mono-
layer allows the modification of the overall properties of the
layer is less ordered (and vertical polymerization is possible),
bulk material interfacing with a medium, e.g. hydrophilicity, hy-
but these materials profit from a much more stable grafting of
drophobicity, solvophobicity, fouling, fogging, conducibility.
the R-Si unit, allowing to prepare mechanically and chemically
Last but not least, molecular monolayers deeply influence the
resistant materials. After that the concept of (self )assembled
behavior of a bulk object in a biologically environment, chang-
monolayers was established, the idea of the layer-by-layer tech-
ing its interactions with cells and tissues, including adhesion,
nique came as an almost obvious consequence. In a seminal
biocompatibility, cytotoxicity, scaffolding and cell growth stimu-
paper in 1997, G. Decher[11] introduced the idea of grafting first
lation.[1] An arsenal of materials and of molecules populate the
a (mono)layer of a given molecule M on a bulk surface [S] and
literature in this area. The rationale (Scheme 1A) is to use a
then to lay a series of further different (mono)layers one after
molecule featuring a function X capable of specific, stable bind-
the other, by successive dipping processes in a solution contain-
ing with the atoms of a given surface. The largest number of
ing the molecule (or polymer) to be grafted, e.g. N, Scheme 1B.
examples regards gold as a surface and S as the binding group.
The driving force is the preferential interaction between the
In the late 80s and early 90s it has been shown by the many
moieties of the molecular layer exposed to the solvent and a
papers of scientist like Whitesides,[2,3] Nuzzo[4] and Allara[5] that
moiety (or the whole) of the molecule or polymer in solution.
the gold–sulfur interaction is coordinative (homolytic bond
The obtained surface can be made in a [S]–M–N–M–N.. replicat-
strength = 40 kJ/mol[6,7]) forming reversible, labile R–S––AuI
ing fashion (Scheme 1C), or in a [S]–M–N–P–Q.. fashion
bonds. In this case one can properly talk of self-assembled
(Scheme 1D), in principle continuing ad libitum the layering
monolayers of R-SH molecules on Au (flat) surfaces, as ordinate,
process.
2D-crystalline structures are obtained in a typical self-assem-
bling process, that allows self-correction of architectural mis- Modification of a bulk surface with a monolayer or with mul-
takes, as defined by the principles of supramolecular chemis- tiple molecular or nanoparticles layers can be an answer to the
try.[8] Less properly defined self-assembled monolayers are ob- problem of microbial infections spread by surfaces of common
use (e.g. touch screens in hospitals) or the problem of the for-
[a] Department of Chemistry, University of Pavia, mation of bacterial biofilms on the surface of internalized medi-
viale Taramelli, 12 - 27100 Pavia, Italy cal devices like prostheses and catheters.[12–15] Biofilms are
E-mail: piersandro.pallavicini@unipv.it sessile microbial communities with a strong mechanical and
angelo.taglietti@unipv.it
http://www-5.unipv.it/inlab/
biological resistance due mainly to their self-produced extracel-
ORCID(s) from the author(s) for this article is/are available on the WWW lular polymeric matrix[16–18] made of polysaccharides and pro-
under https://doi.org/10.1002/ejic.201800709. teins. Biofilms form after adhesion of planktonic bacteria to a

Eur. J. Inorg. Chem. 2018, 4846–4855 4846 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Microreview

Scheme 1. Sketch of the layer-by-layer approaches described in this paper.

surface in a biological environment, e.g. on an indwelling de- bacterial agents have been proposed to avoid bacterial adhe-
vice.[19,20] A short post-implantation period (6 h) seems neces- sion and biofilm formation.[26,27] The use of an inorganic anti-
sary to the formation of a stable adhering colony, that then bacterial agent such as Ag+ and, even more frequently, silver
evolves into a biofilm in 24 h.[19–21] When a biofilm is formed nanoparticles (AgNP), is extremely popular in antimicrobial ma-
with its full extracellular matrix, it cannot be removed with a terials, also thanks to the low resistance towards silver ex-
pharmaceutical antibiotic treatment.[22,23] When it is mature, pressed by most bacterial strains,[28] escaping the increasing
the release of planktonic bacterial cells leads to infections problem of bacterial antibiotic resistance.[29] Literature shows
spread in the whole patient body.[24] At this stage, surgical re- countless examples of impregnated materials, hybrid materials
moval of the biofilm-infected device (or prosthesis) is the only and composite materials based on silver cations or on AgNP,
possible solution.[25] A plethora of surfaces modified with anti- that have been extensively reviewed.[30–35] In all cases, the ac-

Piersandro Pallavicini (PhD in 1991 at the Scuola Normale Superiore, Pisa) is Full Professor since 2017 at the Department of Chemistry of
the University of Pavia. His research interests were first oriented towards supramolecular chemistry, controlled molecular movements and ion
translocation, for which he received in 2001 the Medaglia Nasini Prize from the Inorganic Chemistry division of SCI - Società Chimica Italiana.
Since 2007 his interests turned towards inorganic nanochemistry and its biomedical applications.

Giacomo Dacarro took is PhD in chemistry at the University of Pavia in 2008, under the supervision of prof. P. Pallavicini. From 2016 he is
a tenure-track researcher at the Department of Chemistry of the University of Pavia. His research is focused on the modification of surfaces
with coordination compounds and metallic and inorganic nanoparticles for the preparation of antibacterial materials, and on the use of
metal nanoparticles as theranostic devices.

Angelo Taglietti earned a Ph.D in Chemistry in 1995 from the University of Pavia, under the supervision of prof. Luigi Fabbrizzi, and now is
Associate Professor in Inorganic Chemistry in Pavia. His research interests focus on supramolecular systems based on transition metal ions,
synthesis and functionalization of nano-objects for sensing and theranostic applications, use of nano-objects and transition metal complexes
for antibacterial purposes

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 Microreview

tion is claimed to be exclusively due to the release of the Ag+

antibacterial cation, that may be contained as such in the mate-
rial or produced by oxidation of silver nanoparticles.
As it will be reviewed in this paper, the LbL technique allows
to prepare a molecular monolayer on a given surface, whose
moiety exposed to the solvent is able to further bind AgNP,
forming a monolayer of the latter by simple dipping the surface
in a colloidal AgNP solution(Scheme 1E). The fine tuning offered
by such approach implies the use of extremely low quantities
of silver to prepare efficient antibacterial and antibiofilm surfa-
ces, with a control over Ag+ release kinetics and the exploitation
of the additional disruptive effect played by the contact be-
Scheme 2. Reaction scheme for a trialkoxysilane reacting with a silica surface.
tween the bacterial membrane and the high-energy surface of Sketch A represent an activated surface (maximum of Si–OH bonds).
environment-exposed AgNP. Moreover, the LbL technique al-
lows also the implementation of layers of NP that are not intrin- (MPTS, X = SH, R′ = CH3).[39,40] The thiol groups firmly bind
sically antimicrobial but capable of exerting a photothermal ef- Ag,[6,7,41,42] thus appearing as an ideal grafting function to ob-
fect, i.e. to convert radiation into heat like gold nanostars (GNS) tain AgNP monolayers (type E surfaces in Scheme 1). The proce-
in Scheme 1F. This leads to antibacterial and antibiofilm materi- dure of choice consisted in dipping pre-activated glass slides in
als in which the hyperthermal disruption of a biofilm or of 5 % v/v solution of MPTS in anhydrous toluene, incubating at
planktonic bacteria can be switched on by laser irradiation. Us- 40 °C for 4 h, then rinsing with toluene, toluene/ethanol 1:1
ing suitable absorbing photothermal NP and laser sources in and ethanol, generating a surface density (ns) of 1.34 × 1014
the so-called Near-IR “biotransparent window” (750–900 nm), MPTS molecules/cm2. The complete reaction of grafted silanol
devices featuring photothermal surfaces can be activated by groups (B→C, Scheme 2) takes place by ageing (18 h, r.t.). Ther-
through-tissues irradiation when implanted. In principle, such a mal curing in an oven (air) at 100 °C for 16 h led to the forma-
medical device is capable to be switched on and to disrupt a tion of intermolecular disulfide bonds between surface-
biofilm on its surface with no need of surgical removal. In addi- grafted –SH moieties, that greatly reduced the number of avail-
tion, we will also review the most recent innovations attained able thiol groups (ns = 0.072 × 1014 cm–2). Preparations with
with the LbL approach in this area, i.e. antibacterial surfaces 2 % v/v of MPTS in acetone (followed by washing with acetone,
both featuring AgNP monolayers and capable of switchable acetone/ethanol and ethanol) or under the same conditions but
photothermal action. SiO2 will be the material considered as with water and then acetone washing for 30 s every 3 min (total
the bulk surface: beside the wide use of glass and materials silanization time 45 min) also lead to less efficient coatings (ns =
with comparable surface chemistry for surfaces for shared use 0.116 × 1014 cm–2 and 0.382 × 1014 cm–2, respectively). It has to
(e.g. ITO) or implants (e.g. Ti/TiO2), polydimethyl siloxane be noted that the highest theoretical number of Si-OH groups
(PDMS) has become a popular material for medical devices, and on an amorphous silica surface was calculated to be
the SiO2-silane chemistry studied on glass or silica surfaces can 4.9 × 1014 cm–2.[43] Considering that a X(CH2)3-Si(OR′)3 molecule
be easily transferred to pretreated PDMS materials.[36] has three potential functions to bind to surface Si-OH groups,
the 1.34 × 1014/cm2 ns value for MPTS represents a fully coated
surface. Similar dipping techniques can be used to graft an ar-
2. Molecular Monolayers for Grafting AgNP senal of silanes[44] including X(CH2)3-Si(OR′)3 where X is a moi-
ety capable of interactions with AgNP, although less strong then
Obtaining a molecular monolayer on SiO2 with a terminal X in the case of -SH. APTES (X = -NH2, R′ = -CH2CH3) forms dense
moiety is an easy task by reacting one of the many commercial monolayers on glass from a solution in acetone (plus water
propyltrialkoxy silanes X(CH2)3-Si(OR′)3 (R′ = -CH3 or -CH2CH3) treatment)[45] in toluene[46] or in ethanol.[47] As a further alter-
with the surface silanol groups. As sketched in Scheme 2, pre- native (see next section) PEI (polyethyleneimine) bearing an av-
hydrolysis of the alkoxysilane is required. Non aqueous solvents erage of 4 propyltrimethoxysilane functions per polymer unit
like absolute ethanol or toluene are used for these reactions, (mw = 2000–4000) was grafted on glass from an ethanol solu-
with a SiO2 bulk fragment (e.g. a glass slide for microscopy) tion at room temp.[48] or on an ITO surface.[49] Also the Cu2+
dipped in a solvent containing X(CH2)3-Si(OR′)3. complex of a tetraaza macrocyclic ligand was bound to iso-
The trace quantity of water needed for the alkoxysilane hy- cyanatopropyl trimethoxy silane via the coupling reaction of a
drolysis is adsorbed on the SiO2 surface during its pretreatment. dangling –NH2 arm with the –NCO group and grafted on glass
The maximum surface Si-OH groups is expressed by first clean- or quartz from an ethanol solution,[50] with the inert Cu2+ com-
ing glass with NH3 33 %/H2O2 35 %/water (1:1:5 in volume) and plex acting as a grafting centre by electrostatic interaction with
then treating the surface with a mixture of HCl 37 %/H2O2 negatively charged AgNP.
35 %/water (1:1:5 in volume) at 85 °C.[37] Alternatively, piranha
solution at room temperature gives similar results[38] (piranha
solution = 3:1 v/v H2SO4/H2O2 30 %). Reaction leading to B
3. Intrinsic Antibacterial Monolayers of AgNP
and C in Scheme 2 was studied in detail[37] by comparing litera- Although proposals have been advanced,[51] a standard nomen-
ture grafting methods for (3-mercaptopropyl)trimethoxysilane clature for nanoparticles is still missing. As it is common use to

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 Microreview

call “nanoparticles” (NP) nano-objects with a spherical shape, layer on glass, that firmly grafts the NP thanks to the strong
while giving to less symmetric objects trivial names like nano- Ag-thiolate interactions: the AgNP were not released when the
rods, nanostars, nanocubes, we will also adopt this use. As surfaces were exposed to water or in pseudo-physiological con-
sketched in Scheme 1E, grafting AgNP on a surface can be at- ditions (PBS, phosphate saline buffer).[54] A surface concentra-
tained with the LbL technique by dipping a surface bearing a tion of 0.357 μg Ag/cm2 was obtained, corresponding to ca.
first molecular monolayer in an AgNP solution. As mentioned 1.9 × 1011 AgNP/cm2. Slow and sustained oxidation to Ag+ was
in the previous section, the monolayer must have exposed observed, with about 15 % silver release in 15 d when the surfa-
functions capable of interacting with AgNP. Typically, AgNP are ces were exposed to water, with an ascending/plateau trend vs.
in an aqueous solution and negatively charged, due to the ex- time (Figure 1A, black up triangles). Ag+ release corresponded
tensively used citrate coating, from their typical synthesis with to a decrease in the absorbance of the grafted monolayer (a
Ag+ and citrate[52,53] or citrate/BH4–[54] Thus, most of the many band at ca. 400 nm due to the localized surface plasmon reso-
published examples of surface|monolayer|AgNP LbL materials nance phenomenon, LSPR), with a decrease/plateau trend both
rely on the electrostatic interaction between a surface bearing in H2O and in PBS (Figure 1), that was attributed to the slow
protonated amines and the negative AgNP. These are preva- formation of a Ag2O shell around the AgNP, influencing the
lently in the dimensional range 4 nm < d < 60 nm.[55] Glass has LSPR absorption. A test was introduced to evaluate the micro-
been frequently used as the bulk material,[53,56,57] but examples bicidal effect (ME) of functionalized surfaces, as a modification
can be found also with materials displaying a chemistry similar of a standard procedure.[62] ME = log (NR/NF), where NF is the
to SiO2 such as ITO,[58] TiO2,[59] mica.[60] Approaches describing number of colony forming unit (CFU) in a volume containing
the in-situ growth of AgNP from an Ag+ solution on a bulk planktonic bacterial after a given contact time (5 h or 24 h)
surface bearing molecular monolayer of (poly)amines have also with a functionalized glass surface, while NR is the number of
been reported for ITO[58] and silicon/SiO2.[61] Interestingly, in CFU for the same colony and same contact time but with
this mentioned literature based on amino-monolayers, pub- a plain glass surface. With glass|MPTS|AgNP the ME found for
lished earlier than 2010, the use of the top monolayer of AgNP the reference strains used for antibacterial materials, the
as antibacterial surface is not reported. In 2010 we prepared Gram- Escherichia coli (E. coli) and the Gram+ Staphilococcus
antibacterial glass|MPTS|AgNP surfaces, with citrate-coated aureus (S. aureus) is larger for the former (Table 1). This is typi-
AgNP (d = 7 nm) but in this case adhering on a MPTS mono- cally found for antibacterial agents, as Gram+ bacteria have a

Figure 1. A: % absorbance (with respect to the value read after preparation) of a SiO2|MPTS|AgNP surface dipped in water (pink triangles) and in PBS (red
circles), vs. time, left vertical axis. Black triangles refer to Ag+ released in water from the surfaces, vs. time. Dotted curves are not fitting functions, but
graphically drawn to guide the eye. B: absorption spectrum of a SiO2|MPTS|AgNP surface at t = 0 (blue) and t = 19 d (green). Figure is a graphical elaboration
of data from ref.[54]

Table 1. ME, microbicidal effect.

μg % Ag rel. S. aureus[a] E. coli[b]

Ag/cm2 (24 h) 5h 24 h 5h 24 h
[c]
Glass|MPTS|AgNP 0.357 15.4 1.37 5.54 4.93 5.90
Glass|CuN4|AgNP[d] 0.16 n.a. 2.33 6.60 5.29 7.06
Glass|PEI|AgNP[e] 0.76 7.2 0.03 0.86 2.57 6.16
Glass|MPTS|AgNP|GSH [f ] 0.35 12 0.24 0.96 0.42 1.38
Glass|PEI|AgNPLT[g] 6.2 2.1 0.8 >5 0.9 >5
Glass|PEI|AgNTR[h] 1.87 4[i] 0.9 2.5 3.2 3.6
Glass⏐APTES⏐GNS⏐SiO2⏐APTES⏐AgNP[l] 0.6 30 0.7 1.6 1.7 5.4
[a] ATCC 6538. [b] ATCC 10356. [c] Ref.[54]. [d] Ref.[50]. [e] Ref.[48]. [f] Ref.[71]. [g] Ref.[92]. [h] Ref.[100]. [i] After 48h; [l] ref.[101].

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 Microreview

thick continuous peptidoglycane cell wall (20–80 nm) while 180 and 15 μg/mL for S. aureus and E. coli, respectively (MIC =
Gram- bacteria have a thinner peptidoglycane layer (5–10 nm) minimum inhibitory concentration). This is mostly due to the
surrounded by a phospholipidic membrane. Large ME values disrupting and penetrating ability of such GSH-coated AgNP
showing almost 6 order of magnitude decrease of the CFU are towards E. coli and S. aureus,[68] an effect observed also for pec-
found for both strains at 24 h contact, allowing to candidate tin-embedded AgNP[69] and for biosynthesized AgNP (bearing
these surfaces as efficient antibiofilm coatings. Interestingly, the the cell free protein of Rhizopus oryzae as coating), in the latter
glass|MPTS|AgNP surface leaves a 66 % fraction of AgNP surface case displaying antibacterial action against E. coli (Gram-) and
exposed to the solvent[54] and prone to further LbL coating Pseudomonas aeruginosa.[70] The same citrate-coated AgNP
e.g. with a thiol-bearing molecule. Although no interaction with were grafted on glass|MPTS and further overcoated with GSH
bacteria was studied, we also demonstrated the possibility of on their available surface, in a typical LbL approach.[71] Despite
controlling the overcoating of the anchored AgNP with two dif- an identical total Ag surface concentration and a comparable
ferent, competing R-SH molecules, paving the way to antibacte- Ag+ release in 24h (15.7 % and 12 % for glass|MPTS|AgNP and
rial surfaces with tunable hydrophilicity or release ability.[63] Re- glass|MPTS|AgNP|GSH, respectively) the glass-immobilized GSH-
cently, MPTS has also been used to prepare antimicrobial mate- coated AgNP exerted a dramatically decreased ME (Table 1),
rials by grafting on flat glass AgNP prepared from ascorbic acid due to the complete cancellation both of their mobility and of
reduction of Ag+[64] and to graft AgNP on glass beads.[65] In the the contact effect. The membrane disruptive effect exerted by
latter case, a nanocomposite with silicone nanofilaments was the direct contact with non-overcoated AgNP was also shown
obtained, capable of efficient water disinfection, with a 6-order by AFM imaging, comparing E. coli shapes observed after con-
of magnitude CFU reduction on E. coli strains. tact with plain glass (Figure 2a–c), with glass|MPTS|AgNP|GSH
(Figure 2d–f ) and with glass|MPTS|AgNP (Figure 2g–i).
Lower Ag surface concentration but larger ME are found for
citrate-coated AgNP adhering to a monolayer of a Cu2+ tetraaza
macrocyclic complex grafted on glass, i.e. glass|CuN4|AgNP,[50]
Table 1. Differently from MPTS, the monolayer of the CuN4 com-
plex has a not negligible ME (1.65 and 2.46 for S. aureus and
E. coli, respectively, with 24h contact time), but displays an inde-
pendent effect, due to the antibacterial action of the Cu2+ cat-
ion. The increased ME found for the glass|CuN4|AgNP surface is
supposedly due to the simultaneous action of Cu2+ and AgNP,
and to the promoted release of Ag+, that in this case is 30.3 %
in 9 days. The role of the adhesive layer under AgNP is stressed
on the glass|PEI|AgNP surfaces. These are obtained forming first
a layer of PEI-silane.[48] This is of course not a proper monolayer,
due to the polymeric and reticulated nature of PEI, that on the
glass slides adopts a flat conformation (0.25–0.45 nm thickness,
determined by ellipsometry), promoted also by –NH···O(Si) in-
teractions, that are found in some silica-grafted amines.[66,67]
Citrate-coated AgNP with d = 7 nm where adsorbed on grafted
PEI after short dipping times (15 min). Despite an apparent
lower surface density of AgNP with respect to glass|MPTS|AgNP
suggested by AFM imaging, the found Ag amount in
Figure 2. AFM images of E. coli cells after 5h contact with plain glass slides
glass|PEI|AgNP was larger (Table 1), leading to the hypothesis
(a,b,c); glass|MPTS|AgNP|GSH (d,e,f); glass|MPTS|AgNP (g,h,i) (Figure repro-
of a multilayer of AgNP embedded in the PEI layer, with most duced by permission from ref.[71]. Copyright 2012 American Chemical Soci-
of the nanoparticles buried in the extended polymer. A smaller ety).
ME was observed for the more resistant S. aureus when in con-
tact with glass|PEI|AgNP, despite the release of 7.2 % Ag+ (with We reported also citrate-coated AgNP (d = 9 nm) grafted
respect to total silver) in water in 24h, corresponding to a quan- on an APTES (aminopropyltriethoxy silane) monolayer on glass,
tity of released Ag+ identical to that found for glass|MPTS|AgNP giving glass|APTES|AgNP surfaces with 0.73 μg Ag/cm2 surface
in 24h. This is a strong indication that not only released Ag+ concentration,[47] see Figure 3 for imaging. As in the
exerts an antibacterial action, but also a contact effect holds, glass|MPTS|AgNP case, the AgNP were not released in water
due to the disrupting role played by the high-energy AgNP even after long dipping times (19 days). However 0.12 μg Ag/
surface when interacting with bacterial membranes. This effect cm2 were released as Ag+ in the same time, observing the larger
was observed also with AgNP coated with the biomimetic Ag+ release in the first 24h [0.096 μg Ag/cm2 corresponding to
glutathione (GSH) molecule. These and analogous AgNP coated 80 % of the total (19 days) release]. These surfaces proved to
with cysteine (Cys) can be prepared from 7 nm citrate-coated have an unprecedented antibiofilm activity, as observed by us-
AgNP by addition of the thiolated Cys or GSH.[63] Such AgNP ing S. epidermidis RP62A, a strain capable of forming biofilms.
revealed a fair antimicrobial effect as colloidal solutions, despite Biofilms grown on glass and on glass|APTES|AgNP showed
their low Ag+ release, with a MICs for the GSH-capped AgNP of at 37 °C a 105 reduction in the CFU/cm2 in the latter case, after

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 Microreview

ammonium salts. This resulted in a first strong bactericidal ac-

tion thanks to Ag+ released, followed (after Ag depletion) by a
sustained antibacterial activity due to the immobilized quater-
nary ammonium functions.[75] Also flexible materials can be sur-
face-coated with an AgNP SAM to impart antibacterial proper-
ties, using a polyamine grafing layer: membranes of poly(vinyl-
idene fluoride) and poly(styrene co-maleic anhydride), over-
coated with a layer of polydopamine, allow the formation of
monolayers of AgNP, that are active against S. aureus and
E. coli.[76]

4. Switchable Antibacterial Surfaces

Nanomaterials are used in light-switched photodynamic anti-
bacterial therapy and photothermal bacterial lysis, although at
a limited extent and with nanoparticles as colloidal solu-
Figure 3. Antibiofilm activity of glass/APTES/AgNP. A: CFU/cm2 for S. epidermi- tions.[77,78] We recently introduced the use of the LbL technique
dis RP62A biofilm grown for 24 h at 37 °C on glass or on glass|APTES|AgNP to allow an additional switchable hyperthermal antibacterial ac-
(data averaged on 3 experiments, error bars are standard errors of the tion for modified surfaces by forming monolayers of photother-
means). B and C: CLSM images of S. epidermidis RP62A biofilm grown on
mally responsive nanoparticles (Scheme 1F). These are typically
glass (B) and on glass|APTES|AgNP (C) (sagittal sections of the biofilms are
below and at the right side of each panel. Scale bar = 100 μm). D, E: AFM noble metal nanoparticles (Au, Ag), that feature LSPR absorp-
imaging of the pristine glass|APTES|AgNP surface (D) and after 19 days expo- tion bands.[79] Depending on the shape of the nanoparticles,
sure to water (E). Reproduced with permission from ref.[47], Copyright 2014 such intense absorptions can be positioned in the visible or in
Elsevier. the NIR range, eg λmax ca. 400 nm for spherical AgNP, λmax ca.
520 nm for spherical AuNP, and λmax > 700 nm for Au nano-
24 h (Figure 3A). CLSM (confocal laser scanning microscopy) stars.[80–82] Independently on their shape and LSPR λmax posi-
images of S. epidermidis RP62A biofilm after staining with tion, when irradiated near the maximum of their LSPR absorp-
BacLight Live/Dead viability kit showed that bacteria on tion (usually with a laser source), all noble metal nanoparticles
glass|APTES|AgNP (Figure 3C) were mostly red fluorescent relax thermally. The T increase depends on the irradiance of the
(dead) with only a few green viable cells, and considerably more source, on the nanoparticles concentration in the irradiated
dispersed than those on the plain control glass (all green, via- area, and on their absorbance at the chosen wavelength.[83,84]
ble, Figure 3B). Staphylococcal cells closer to the surface of the LSPR bands falling in the NIR are found for larger non-spherical
AgNPs-coated glass were all dead, indicating that the antibio- nanoparticles (e.g. rods, stars, cages), and have higher extinc-
film effect was exerted both by released Ag+ and by contact tion coefficients than in small spherical nanoparticles. This,
with the AgNP surface. added to the lower energy of NIR radiations and to the already
Silanization with APTES and successive adhesion of citrate- mentioned biotransparency in the 750–900 nm window, has
coated AgNP layering was used also on Ti/TiO2 bulk disks, yield- pushed towards the use of non-spherical noble metal nanopar-
ing Ti/TiO2|APTES|AgNP surfaces.[72] These exerted a weak ticles when localized hyperthermal biomedical applications are
microbicidal effect, with ME = 1.26 and 1.34 for S. aureus (ATCC foreseen.[85–87] We first used the LbL technique to prepare
6538) and E. coli (ATCC 8099) respectively, in 24 h contact time, monolayers of GNS on glass slides bearing monolayers of
most probably due to the low surface coverage with AgNP. The MPTS[88] and of PEI-silane,[38] as pictorially sketched in
versatile LbL approach has been used also to obtain multilay- Scheme 1F. Kinetic control of the GNS surface density is possi-
ered materials, in which one or more AgNP layers are embed- ble with this approach. Pushing the coating to its maximum
ded in polyelectrolytes. Mono and multilayers of positively surface density, glass|MPTS|GNS slides were prepared with sur-
charged PEI and negatively charged, citrate-coated AgNP, were face concentration in the 2.0–3.0 μg Au/cm2 range, with LSPR
formed on silicon chips, intercalated by PSS (polystyrene sulfon- λmax at ca. 800 nm. The photothermal response ΔT linearly in-
ate) negative layers,[73] showing efficient anti-adhesion proper- creased from +2 to +20 °C (with respect to starting tempera-
ties against strongly adhesive Gram – bacterial strains such as ture) with a 808 nm laser source and irradiance increasing from
E. coli, Aeromonas hydrophila and Asaia lannenesis. AgNP were 0.08 to 0.80 W/cm2. In this context it must be mentioned that
in-situ generated in multilayers of negatively charged the maximum permitted exposure for skin is 0.32 W/cm2 at 800
Poly(acrylic acid) (PAA)/polyacrylamide (PAAm) and positively nm, as established by the American National Standards Institute
charged Poly(allylamine hydrochloride) (PAH), adhering to glass (ANSI) Laser Safety Standards[89–91] A methicillin-resistant
coverslides. These exerted an inhibitory effect towards E. coli S. aureus LP strain was used to grow a biofilm both on glass
and S. epidermidis on agar plates.[74] A development of this and on glass|MPTS|GNS slides. No biofilm viability decrease was
work brought to glass surfaces with a dual chemical antibacte- observed on such surfaces without laser irradiation, as well as
rial action, thanks to a layer of polymer-embedded AgNP sur- when biofilms were grown on plain glass and irradiated. Using
mounted by a SiO2 NP layer, decorated with quaternary a 808 nm laser source with 0.090 W/cm2 irradiance led instead

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 Microreview

to 90 % reduction of the CFU after 10 min irradiation and 95 % duced by laser irradiation (identical quantities of Ag+ were
reduction after 30 min irradiation.[88] found in water after 20 min contact time with or without irradi-
More recently, we coupled intrinsic (chemical) and switch- ation) but points towards a synergistic effect between Ag+ re-
able photothermal antibacterial action by preparing surfaces lease, nanomechanical contact of bacteria with surfaces, and
bearing monolayers of non-spherical Ag nanoparticles, with in- local hyperthermia. In this context, colloidal suspensions of pal-
tense absorptions in the NIR range.[92] Ag nanoplates (AgNPLT) ladium nanoplates coated with an Ag film revealed bactericidal
were grown on glass slides bearing a PEI-silane layer by means properties under irradiation larger than those of pure irradiation
of a seed-growth procedure, first forming an already described of the uncoated palladium nanoplates or the simple Ag+ ac-
monolayer of citrate-coated AgNP as seeds,[48] then dipping tion.[94] A similar result was found for colloidal suspensions of
these surfaces in a Ag+/citrate/ascorbic acid solution. Kinetically AuNP with an Ag shell, and overcoated with aspartame,[95] and
controlled growth of an AgNPLT monolayers was completed in for colloidal solutions of Au nanorods bearing a shell of Ag and
2h, Figure 4A–C, with the expected[93] enlargement of the LSPR further conjugated with antibacterial antibodies and stabilizing
absorption band and red shift to the NIR, Figure 4D. The Ag polymers[96] although in this case augmented Ag+ release un-
concentration in the nanoplates monolayer in glass|PEI|AgNPLT der irradiation was invocated.
slides was 6.2 μg/cm2, a 10-fold larger value with respect to The modified LbL approach, with the formation of a seed-
what found in the starting seed-slides (glass|PEI|AgNP, Table 1). surface on a bulk material bearing an adhesive molecular
The released Ag+ in water after 24 h was 0.13 μg/cm2, a larger monolayer, followed by the growth of Ag nanoobjects, has
value then in all the cases listed in Table 1, even if the % value been used to obtain other surfaces with monolayers of non-
was lower (2.1 %) due to the high overall Ag mass. Pure chemi- spherical nanoparticles i.e. triangles (AgNTR), although not for
cal (Ag+ release plus contact) ME effect of these surfaces was antibacterial purposes.[61,97] AgNTR have additional interest to
large (>> 5, no surviving bacteria) at 24 h contact on both S. the microbiological community as their colloidal solutions[98]
aureus and E. coli. Laser irradiation of glass|PEI|AgNPLT slides at showed increased intrinsic antibacterial action with respect to
808 nm gave intense photothermal response (ΔT = 28 °C). TME spherical and rod-like Ag nanoparticles.[99] We used the stan-
(thermal ME) was measured after 20 min contact time under dard LbL approach to graft large AgNTR (size ca. 170 nm) on a
irradiation. TME = log (NR/INF), where INF and NR are the num- glass surface bearing a PEI-silane layer, dipping the surfaces in
ber of CFU found for planktonic bacteria in contact with the a AgNTR colloidal solution.[100] Surface Ag concentration was
functionalized surface with and without irradiation, respec- 1.87 μg Ag/cm2, a value between those found for AgNP and
tively. TME was >>5 and 3.7 for E. coli and S. aureus, respectively, AgNPLT surfaces (Table 1) and Ag+ release (48 h) was significant
with a dramatic increase with respect to ME with no irradiation on an absolute scale (0.075 μg Ag/cm2) although low with re-
measured even at much longer contact times (5h) (Table 1). The spect to total Ag (4 %). The glass|PEI|AgNTR surfaces were
observed effect was not due to an increased Ag+ release in- poorly dense, when referring to the number of NP, due to the
large and thick nature of AgNTR, lying flat on glass|PEI. This
gave a relatively low overall Ag surface available for interaction
with the environment. The observed intrinsic ME effect (Table 1)
was inferior to that of surfaces with lower Ag/cm2 overall con-
centration but bearing monolayers of smaller size spherical NP.
This stresses the importance of the nanomechanical contact ef-
fect exerted by an higher number of AgNP with a smaller radius
of curvature (and an higher surface energy) with respect to that
exerted by few large and flat AgNTR. Irradiation of the sharp
LSPR absorption of glass|PEI|AgNTR (λmax = 820 nm) gave ΔT =
12 °C with irradiance 0.26 W/cm2 (laser source 808 nm). The
number of CFU for planktonic strains laser irradiated for 15 min
in contact with glass|PEI|AgNTR was significantly decreased,
with TME = 2.5 and 1.5 for E. coli and S. aureus, respectively,
also in this case evidencing a synergy between irradiation and
intrinsic effect.
The contribution of intrinsic and photothermal antibacterial
action was recently separated and unravelled in multilayered
materials built with the LbL approach.[101] A GNS monolayer
was grafted on glass slides bearing an APTES monolayer and
then sealed with a 4 nm SiO2 layer to give glass|APTES|GNS|SiO2
slides, presenting an an inert glass-like surface to the environ-
ment. These surfaces gave ME = 0 when in contact with plank-
Figure 4. a–c: SEM images of glass|PEI|AgNPLT slides after different times of
seed mediated growth: (a) 15 minutes, (b) 30 minutes, (c) 2 hours. D: absorp-
tonic E. coli and S. aureus. Laser irradiation at 808 nm, matching
tion spectra of the same slides (growth times in the graph). Reproduced with GNS LSPR absorption (λmax = 810 nm) gave ΔT = +5 °C with
permission from ref.[92], Copyright 2016 The Royal Society of Chemistry. irradiance 0.20 W/cm2 and a TME = 1.6 and 1.2 for E. coli and

Eur. J. Inorg. Chem. 2018, 4846–4855 www.eurjic.org 4852 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Microreview

S. aureus, respectively, with 30 min irradiation. This is a purely first grafted on the bulk material and then used to attach a
thermal effect, as no Ag+ can be released by these surfaces. further monolayer of AgNP. The foreseen use of such modified
Further layers where grafted over the surfaces obtaining surfaces in implants (prostheses, catheters) or on surfaces for
glass|APTES|GNS|SiO2|APTES|AgNP, i.e. surfaces bearing a segre- common use implies that safety issues about nanomaterials
gated photothermal heating layer and a monolayer of AgNP must be considered. Any nanomaterial considered, these are
(d = 9 nm, citrate coated) exposed to the environment, with an connected to body penetration and accumulation of nanoparti-
Ag concentration in the top layer of 0.6 μg/cm2. cles and to the intrinsic toxiciy of the material constituting the
These surfaces had the same photothermal response as the nanoparticles. As an example, small noble metal nanoparticles
parent glass|APTES|GNS|SiO2 and released 0.21 μg Ag+/cm2 in (15 nm) can permeate the skin and intestine,[102] intermediate
24h. The intrinsic ME of the AgNP-terminated surfaces was simi- dimensions nanoparticles (50 nm) may cross the blood brain
lar to what found for comparable materials (Table 1). TME was barrier,[103] and larger nanoparticles (250 nm) may accumulate
measured for 30 min irradiation at 0.25 W/cm2 (released Ag+ in in the blood, liver, and spleen.[104] In addition, ionic silver (Ag+,
30 min = 0.04 and 0.05 μg/cm2 without and with irradiation, delivered by the slow oxidation of AgNP) is weakly toxic, with
respectively). The dramatically increased values of TME (>> 6.0 a safety threshold established by the WHO for drinking water
for both strains, i.e. no remaining CFU) sharply indicates a syner- of 0.1 ppm.[105] The presented LbL approach may overcome or
gistic effect between the intrinsic (chemical and contact) micro- at least narrow such issues. First, it is reassuring that the surface
bicidal effect and local hyperthermia. An analogous trend was concentration of silver is maintained typically in the very low
demonstrated on bacteria adhering to the modified surfaces, 0.2–0.6 μg Ag/cm2 range. Second, by choosing an appropriate
investigated by SEM imaging, Figure 5. Enhanced cell disruption molecular monolayer for grafting AgNP, robust modified surfa-
emerged from the combination of photothermal GNS and Ag+ ces are obtained that do not release nanoparticles, as in the
release/contact with AgNP. The enhancement is remarkable case of MPTS.[51,60,65] or in avery recent example of AgNP deco-
considering that the temperature increase at the surface is rating melamine sponges.[106] Third, the versatily and modular
identical, irrespectively of the presence/absence of AgNP. nature of the LbL approach allows to freely choose among the
plethora of literature papers the safest dimensions and shape
of the AgNP to be grafted on a surface. At this stage, it must
be mentioned that very recent literature has also proposed
methods for surface decoration of bulk materials with sparse
AgNP and of formation of AgNP self-assembled monolayers on
bulk materials that skip the step of the formation of a first adhe-
sive molecular monolayer.[107,108] or use molecular monolayers
different from the traditional (poly)amines or thiols[109] This may
be of great interest on the technological point of view (due to
the simplified synthetic procedure), although mechanical and
chemical stability of the surface-AgNP assembly are still to be
fully assessed.
Of course this review does not cover and exhaust the whole
area of surface modification of bulk materials for antibacterial
and antibiofilm use. Surfaces releasing quaternary ammonium
salts,[110] peptides,[111;112], antibiotics,[113] materials coated with
graphene,[114] with Zinc oxide NP,[115] and with superhydropho-
Figure 5. SEM images showing the effect of laser irradiation on E. coli bic polymers,[116] are some of the most frequently encountered
cells attached to: (a,d, g) plain glass; (b,e,h) glass|GNS|SiO2; (c,f,i)
glass|GNS|SiO2|AgNP. Increasing power density by row: (a,b,c) = non irradi-
examples in recent literature. However, in this wide context self-
ated samples; (d,e,f) = samples irradiated with 5× power; (g,h,i) = 20 × power. assembled monolayers of AgNP prepared with the LbL tech-
All scale bars are 500 nm (adapted with permission from ref.[101], Copyright nique are a subset with some unique advantages. First, the al-
2017, Springer Nature). ready mentioned synthetic easiness and versatility is joined by
the double antibacterial action (Ag+ and nanomechanical) that
is strongly active towards the largest spectrum of bacterial
strains.[28] In addition, differently from the case of molecular
5. Conclusions and Outlook antibiotics, bacterial strains do not develop resistance towards
Bulk materials bearing an AgNP monolayer on the surface have inorganic agents such as Ag+ and AgNP.[29,30] This allows to ob-
been reviewed, stressing their antibacterial and antibiofilm tain potentially universal antibacterial materials, that could be
properties that are due both to the slow, sustained release of used for antimicrobial surfaces of common use, or to prevent
the Ag+ cation and to the direct nanomechanical action of the biofilm formation in indwelling medical devices. Then, the evo-
high energy AgNP surface, that promote the disruption of bac- lution featuring an additional switchable photothermal action
terial membranes and lead to cell death. These materials can must be considered, opening the way to more sophisticated
be prepared with simple dipping techniques, following the materials. These fit well in the very recent trend of smart, re-
layer by layer approach with a variety of molecular monolayers sponsive antibacterial surfaces.[117] While LbL-prepared photo-

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 Microreview

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