Materials Science & Engineering C 83 (2018) 99–107

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Materials Science & Engineering C

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Review

Mesoporous silica-based bioactive glasses for antibiotic-free antibacterial T

applications
⁎
Seray Kayaa, Mark Cresswellb, Aldo R. Boccaccinia,
a
Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstrasse 6, 91058 Erlangen, Germany
b
Lucideon Ltd., Stoke-on-Trent, ST4 7LQ, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Bioactive glasses (BGs) are being used in several biomedical applications, one of them being as antibacterial
Mesoporous materials. BGs can be produced via melt-quenching technique or sol-gel method. Bactericidal silver-doped sol-
Antibacterial gel derived mesoporous silica-based bioactive glasses were reported for the first time in 2000, having the
Bioactive glass composition 76SiO2-19CaO-2P2O5-3Ag2O (wt%) and a mean pore diameter of 28 nm. This review paper dis-
Sol-gel technique
cusses studies carried out exploring the potential antibacterial applications of drug-free mesoporous silica-based
Antibiotic-free
BGs. Bioactive glasses doped with metallic elements such as silver, copper, zinc, cerium and gallium are the point
of interest of this review, in which SiO2, SiO2-CaO and SiO2-CaO-P2O5 systems are included as the parent glass
compositions. Key findings are that silica-based mesoporous BGs offer a potential alternative to the systemic
delivery of antibiotics for prevention against infections. The composition dependent dissolution rate and the
concentration of the doped elements affect the antibacterial efficacy of BGs. A balance between antibacterial
activity and biocompatibility is required, since a high dose of metallic ion addition can cause cytotoxicity.
Typical applications of mesoporous BGs doped with antibacterial ions include bone tissue regeneration, multi-
functional ceramic coatings for orthopedic devices and orbital implants, scaffolds with enhanced angiogenesis
potential, osteostimulation and antibacterial properties for the treatment of large bone defects as well as in
wound healing.

1. Introduction Various amounts of other oxides are incorporated in silicate, borate

The first bioactive glass (BG) was invented by Prof. Larry Hench at
the University of Florida in 1969 [1]. This bioactive glass has a com-
position of 46.1SiO2-24.4Na2O-26.9CaO-2.6P2O5 (mol%), it was later
termed 45S5 Bioglass®, and exhibits as a key property the formation of
a bond with bone [1,2]. From a compositional viewpoint, bioactive
glasses can be basically divided into three groups, depending on the
representative network former oxide present in the formulation, i.e.,
SiO2-based (silicate), B2O3-based (borate) and P2O5-based (phosphate)
systems. The first group comprises a wide range of glass formulations,
including 45S5 Bioglass® and other typical compositions such as 1393
BG (wt%: 53SiO2-6Na2O-12K2O-5MgO-20CaO-4P2O5) [3–5] and S53P4
BG (53%SiO2-23%Na2O-20%CaO-4%P2O5) [6–8] commercially named
as BonAlive® (BonAlive Biomaterials, Turku, Finland).
Borate glasses are characterized by their higher reactivity in com-
parison to silica-based glasses, which results in faster bioactive kinetics
[5,9]. Phosphate glasses are resorbable materials and their dissolution
rate can be tuned according to their oxide composition [10].
or phosphate BGs to impart particular properties to the material; for
instance, CaO, K2O, Na2O and MgO are useful to adjust the surface
reactivity in the biological environment; ZnO, CuO and Ag2O allow the
release of biologically active ions with antibacterial properties [11].
BGs can be produced by two different methods; namely the classic
oxide melting procedure and the sol-gel method. Since sol-gel BGs are
more bioactive and bioresorbable [12–14] than melt-quenched glasses,
in some applications the use of sol-gel BGs is preferred. The sol-gel
method has advantages of compositional purity and molecular mixing,
allowing control of the sample porosity by changing the processing
conditions and/or by adding suitable templates [15]. The use of tem-
plates during the sol-gel process generates products with an ordered
mesoporous structure which induces higher bioactivity with respect to
melt-quenched glasses [16] and makes them suitable for use in drug
delivery applications [17–20].
Bone reconstruction surgeries can be compromised by osteomyelitis
caused by bacteria infection and to treat these, systemic antibiotic ad-
ministration, surgical debridement, wound drainage and implant

⁎
Corresponding author.
E-mail address: aldo.boccaccini@ww.uni-erlangen.de (A.R. Boccaccini).

https://doi.org/10.1016/j.msec.2017.11.003
Received 31 May 2017; Received in revised form 23 August 2017; Accepted 9 November 2017
Available online 10 November 2017
0928-4931/ © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
S. Kaya et al.
removal are applied [21]. These methods are not always effective, so
the patients may require subsequent surgeries to combat bacterial in-
fections. Introduction of a local drug release system into the implant
site can be another approach to treat the problem [22]. This treatment
offers high drug delivery efficiency, continuous action, reduced toxicity
and convenience to the patient [21,23]. Mesoporous bioactive glasses
(MBGs) are highly attractive for such applications.
In 2004, for the first time, Yan et al. [20] developed MBGs with the
combination of sol-gel and surfactant templating methods. The ob-
tained MBG particles were around several tens of micrometers in dia-
meter, with highly ordered 5 nm mesopore channels. In comparison
with non-mesoporous bioactive glasses (NBGs), MBGs have enhanced
surface area, higher pore volume, better ability to induce in vitro
apatite mineralization in simulated body fluid (SBF) and excellent cy-
tocompatibility [24–27].
For the preparation of MBGs, the addition of structure-directing
agents (e.g. Pluronic P123, F127 and cetrimonium bromide, CTAB) is
essential to obtain well-ordered pore structures. Under appropriate
synthesis conditions, these agents self-organize into micelles. Micelles
link the hydrolysed silica precursors through the hydrophilic compo-
nent and self-assemble to form an ordered mesophase [18,28]. Then,
the mixture reaction system undergoes evaporation-induced self-as-
sembly (EISA) process. Once the mixture is dry and the surfactant has
been removed, a well-ordered mesoporous structure is obtained, having
high surface area and high porosity. The basic process to produce me-
soporous silica is illustrated in Fig. 1 [28].
In 2006 and 2008 MBG powders with 58S and 77S compositions
having excellent in vitro bioactivity were prepared by hydrothermal
treatment using P123 [19,29]. By using the same method, in 2008 Li
et al. [30] prepared Mg, Zn or Cu containing MBG particles. Later in
2010 CaO-SiO2 MBG particles were synthesized for hemostatic appli-
cations [31].
There is a general trend to upgrade the properties of MBGs with
some of the well-known therapeutic ions [11,32–34]. By substituting
small amounts of oxides, the osteogenesis, antibacterial capacity, an-
giogenesis or cementogenesis [34–36] effects of MBGs can be improved.
Fig. 2 (left) illustrates the year of discovery and the average time
required for the in vitro bioactive response of three different silicate
glass families, MPGs (melt-prepared glasses), SGGs (sol-gel bioactive
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Materials Science & Engineering C 83 (2018) 99–107
glasses) and MBGs (Mesoporous bioactive glasses). In addition, the
schematic diagram in Fig. 2 (right) gives information about the biolo-
gical function of some metallic ions that can be added to MBG com-
positions to enhance their biological functionalities [37].
Prevention against bacterial infection is an essential need in or-
thopedic surgery due to the significant medical complications to pa-
tients related to infections [38]. Although strict hygienic protocols and
preventive antibiotic prophylaxes have drastically reduced the per-
centage of postoperative infections, many bacterial species have de-
veloped selective resistance against antibiotics that can cause serious
infections, which are hard to recover from and usually lead to second
operations.
An alternative to the systemic delivery of antibiotics is the use of
orthopedic devices or prostheses made from synthetic materials with
intrinsic antibacterial properties [39–42]. In this context, silica-based
bioactive glasses offer a potential alternative to the systemic delivery of
antibiotics for prevention against bacterial infections. The antibacterial
properties of bioactive glasses have been investigated by Stoor et al.
[43–45] from the clinical point of view. According to their study on
S53P4 BG, in an aqueous environment, ions (Ca2 +, Na+, PO43 −, and
Si4 +) are released from the S53P4 BG which results in a rise in pH and
osmotic pressure in its vicinity. These factors potentially influence the
viability of oral microorganisms at the dentogingival margin indicating
potential for use in dental applications. The antibacterial effects of a
paste made of a bioactive glass (S53P4) on oral microorganisms were
examined [43]. It was found that Actinomyces naeslundii bacteria lost its
viability within 10 min when exposed to calcium, phosphorus, silicon
and sodium dissolution products. The loss of viability was 60 min for
Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and
Streptococcus mutans bacteria. Actinobacillus actinomycetemcomitans has
been suggested to play a role in juvenile periodontitis [46,47], Por-
phyromonas gingivalis has been associated with destructive periodontal
lesions in adults [48–50] and Streptococcus mutans is considered to play
a major role in caries [51].
Indeed the antibacterial effect of BGs is used in clinical settings to
combat osteomyelitis [52–55], an infection of bone and bone marrow.
Polymethyl methacrylate (PMMA) beads mixed with antibiotics have
been used in the treatment of osteomyelitis [56]. However, after two
weeks of insertion into the bone defect, these beads must be removed by
Fig. 1. Steps required to synthesize mesoporous silica from
a micellar solution, according to Arcos and Vallet-Regi [28].
(Reproduced with permission of Elsevier).
S. Kaya et al.
surgery [57], since beads release about 24% ( ± 11%) of their anti-
biotic content (mini-beads even up to 93 ± 1.4%) [58]. Besides the
antibiotic release issue, unexpected bone loss can occur when these
beads are used [59].
Having discovered that S53P4 bioactive glass has antimicrobial
properties [4,7,54], this glass took the place of polymer beads in the
treatment of chronic osteomyelitis [53,54,60]. Polymer beads are ef-
fective against osteomyelitis treatment when they are mixed with an-
tibiotics; however in this case they have to be removed by surgery due
to their release of antibiotics and bone loss issues [58,59]. Compared
with polymer beads, bioactive glasses are osteoconductive and bio-
compatible materials [60]. In addition to their potential use in bone and
tissue repair applications, BGs provide antibacterial and blood vessel
promoting properties [11,45].
A range of polymer based antibacterial carriers is available which
could be combined with BGs for achieving improved antibacterial ef-
fects. For example, cationic proteolytic-resistant polymers with poly-
amide backbones have been tested for their antimicrobial activities and
their cytotoxicity against primary human dermal fibroblasts [61]. These
polymers were demonstrated to elicit fast bactericidal activity against
A. baumanii, E. coli, K. pneumonia and P. aeruginosa and were non-toxic
to epithelial cells which made them safe and potentially useable as
broad spectrum ophthalmic antibiotics. Gelatin and antifungal drug-
loaded gelatin fiber mats have been produced via electrospinning
method [62]. Due to their cell compatibility and antifungal properties,
electrospun antimicrobial nanofibers can be used in several applica-
tions, as scaffolds in controlled drug delivery, wound dressings, tissue
engineering, stem cell regeneration and differentiation, and also in food
packaging [63–66]. In addition, gentamicin has been incorporated into
a layer by layer (LbL) coating with clay interlayer barrier to achieve a
controlled bactericidal effect [67–69]. However, the combination of
such polymeric substrates (antibiotic carriers) with BGs to exploit po-
tential synergistic effect of antibiotics and antibacterial ions has not
been investigated.
In general terms, three approaches have been used to investigate the
antibacterial activity of bioactive glasses. The first one is based on
bioactive glasses that change the local physiological conditions when
implanted in the body. The second one includes doping the bioactive
glasses with antibacterial metallic elements, so that the glass degrades
by releasing ions and induces the bactericidal effect. The last approach
investigates antibiotic added to bioactive glasses [17,34,35,70–72].
Moreover, mesoporous bioactive glasses, due to their ordered meso-
pores which can incorporate biomolecules and drugs, are suitable to
achieve the synergistic release of drugs and antibacterial metallic ions
to increase the effectiveness against bacteria and to impart other bio-
logical effects [73–75].
Considering the interest in combatting infections with minimal use
of antibiotics [33,38], however, it is important to investigate antibiotic-
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Materials Science & Engineering C 83 (2018) 99–107
Fig. 2. (Left): Discovery years of three bioactive silicate glass types
showing the average time required for achieving bioactivity, de-
termined by the formation of HA on the surface upon immersion in
SBF. (Right): Typical metallic ions added to these glasses and their
biological functions.
(Modified from ref. [37]).
free BGs which achieve antibacterial effects exclusively by the release
of metallic ions. Therefore the aim of this review is to summarize the
information available in the open literature on the antibacterial prop-
erties of mesoporous silica-based bioactive glasses with emphasis on the
specific antibacterial effects of therapeutic ionic dissolution products
without any drugs or antibiotics added.
The studies reviewed in this article consider thus the antibacterial
activity of sol-gel derived SiO2-CaO and SiO2-CaO-P2O5 mesoporous
bioactive glasses based on incorporation of antibacterial metallic ions
into the glass structure. The composition dependent dissolution rate
and the concentration of the doped elements affect the antibacterial
efficiency of bioactive glasses. Studies have shown that a balance be-
tween antibacterial activity and biocompatibility is required since a
high dose of metallic ion addition can lead to cytotoxicity [76,77],
these aspects are also addressed in this review.
2. Mesoporous silica-based bioactive glasses doped with
antibacterial elements
2.1. Silver doped-MBGs
Silver ion has been the most studied metal ion as a biocide (defined
in the European legislation as a chemical substance or microorganism
intended to destroy, deter, render harmless, or exert a controlling effect
on any harmful organism by chemical or biological means), as it pre-
sents a broad and strong antimicrobial behavior [78–80]. Ag has no
toxicity effect to human cells in suitably low concentrations, and it can
provide bioactive glasses with extra functionality in addition to their
inherent osteoconductivity and bone bonding ability [81–85]. As me-
tallic silver reacts with moisture on the skin surface or with wound
fluids, silver ions are released that damage bacterial RNA and DNA,
hence inhibiting replication. In the case of silver, inactivation of critical
enzymes of the respiratory chain (e.g. succinate dehydrogenase) by
metal binding to thiol groups and induction of hydroxyl radicals appear
to play a major role [86].
Silver is potentially cytotoxic if released in great amounts and thus,
strict control of the introduced Ag amount is necessary. It is well-known
that surface functionalization of glasses can occur by ion-exchange
treatments while enabling the bulk structure and main properties to
remain unaltered. In such a way silver can be introduced by ion ex-
change in the outer layers of glass surfaces, conferring to them anti-
bacterial properties while maintaining the intrinsic BG characteristics
[76,77,87].
A wide range of silver doped silica glasses (Ag-BG) have been de-
veloped by sol-gel methods [81,82,88–95] to create bioactive glasses
exhibiting inhibitory effects on bacterial growth.
Among these studies, BGs exhibiting mesoporous structure were
produced via sol-gel methods [81,82,92] and via a structure-directing
S. Kaya et al.
agent assisted sol-gel technique [94,96,97].
In this context, incorporation of Ag2O into sol-gel produced bioac-
tive glass compositions (45S5 BG: 46.1SiO2-24.4Na2O-26.9CaO-
2.6P2O5 (mol%)) has been reported to minimize the risk of microbial
contamination through the leaching of Ag+ ions [81,82].
In 2000, [81] the incorporation of 3 wt% Ag2O in 76SiO2-19CaO-
5P2O5 (wt%) sol-gel produced mesoporous bioactive glass was shown to
exhibit a bacteriostatic effect on Escherichia coli (E. coli) with 0.01%
reduced bacterial growth without compromising the glass bioactivity.
Sol-gel derived 3 wt% Ag2O incorporated mesoporous silica bioactive
glass in the SiO2-CaO-P2O5 system showed good antibacterial property
against E. coli, Pseudomonas aeruginosa (P. aeruginosa) and Staphylo-
coccus aureus (S. aureus). The effect was attributed to the leaching of
silver ions from the glass matrix [82]. It has been confirmed that Ag+
ions in concentrations of 0.05–0.20 mg/ml released from Ag-doped BGs
inhibited the growth of different bacterial strains (E. coli, P. aeruginosa
and S. aureus) [82].
In the study of Saravanapavan et al. [88], the introduction of Ag2O
into sol-gel derived bioactive glass compositions was aimed at mini-
mising the risk of microbial contamination through the potential anti-
microbial activity of the leaching Ag+ ions. It was shown that the
bioactive glass doped with Ag2O was bacteriostatic and elicited a rapid
bactericidal reaction.
Another study reported that 60SiO2-2Ag2O-34CaO-4P2O5 (mol%)
bioactive glass produced by sol-gel method was suitable to coat surgical
sutures. These sutures were shown to be bioactive, and had anti-
microbial and bactericidal properties against Staphylococcus epidermidis
(S. epidermidis) [89,90]. Moreover, 1 mol% Ag2O incorporated sol-gel
derived 70S30C (70SiO2-30CaO) (mol%) bioactive glass scaffold was
produced, which released 0.95 μg/ml of Ag+ ions in 23 h, giving a
bactericidal effect on E. coli, P. aeruginosa and S. aureus cultures [91].
A study comparing the antibacterial activity of a sol-gel derived
silver-doped 64SiO2-26CaO-10P2O5 (mol%) BG with its undoped
counterpart against E. coli species showed that the silver-free BG had
neither bacteriostatic nor bactericidal effects; however 5 mol% Ag2O
doped BG was found to have > 99% killing efficiency towards E. coli
[92]. In related studies, 4 and 8 wt% Ag2O were added to
62.3SiO2–28.9CaO-8.6P2O5 (wt%) sol-gel obtained bioactive glass to
investigate and to compare their antibacterial behavior with that of
undoped BG against E. coli DH5α ampicillin-resistant and Streptococcus
mutans (S. mutans) [95].
Both silver loadings demonstrated minimum bactericidal con-
centration (MBC), of 100–150 mg/ml for E. coli and 5–10 mg/ml for S.
mutans, whereas the MBC for the undoped BG was > 300 mg/ml.
3 wt% Ag2O was incorporated into structure-directing agent
(Pluronic P123) assisted sol-gel derived 73SiO2-13CaO-11P2O5 (wt%)
mesoporous bioactive glass system to investigate the antibacterial
properties of this glass [94]. Ag-MBG showed a very good anti-bacterial
effect against S. aureus strain, with strong evidence of bactericidal ac-
tivity at 0.5 mg/ml of glass concentration. MBC decreased from
2.2 × 109 to 2 × 104 CFU/ml from undoped to 3 wt% Ag2O doped
MBG (> 99.9% killing efficiency).
58S (60SiO2-36CaO-4P2O5) (mol%) mesoporous BGs produced via
structure directing agent (P123) assisted sol-gel method was doped with
1 mol% Ag2O and it was shown that this glass exhibited 100% killing
efficiency against E. coli and S. aureus [98].
Table 1 presents a summary of compositions, synthesis methods and
results obtained from the studies involving silver containing MBGs
discussed above.
2.2. Copper doped-MBGs
Copper is a naturally occurring element in the human body being
essential to numerous metabolic processes [99,100]. It is, in the right
quantities, non-toxic to human tissues, but is known to have a strong
effect on microorganisms. The antibacterial properties of CuO doped
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Materials Science & Engineering C 83 (2018) 99–107
mesoporous bioactive glasses have already been proven in many studies
[95,101,102]. Due to their controllable dissolution rate, soluble glasses
represent an attractive delivery system for antibacterial copper ions.
In one of these relevant investigations, 62.3SiO2–28.9CaO-8.6P2O5
(wt%) sol-gel produced bioactive glass was doped with 4.7 and 9 wt%
CuO to investigate its behavior against E. coli DH5α ampicillin-resistant
and S. mutans bacteria [95]. These Cu-doped glasses had MBC of
100–150 mg/ml for E. coli and 5–10 mg/ml for S. mutans bacteria. The
Cu release in SBF from 4.7 wt% CuO doped MBG was in the range
20–60 ppm and for 9 wt% doped ones, it was in the range 20–80 ppm.
A further study [101] was carried out to prepare structure directing
agent assisted sol-gel derived copper-doped (molar: 0, 1, 2 and 5%)
MBG scaffolds. These scaffolds were shown to possess good bio-
compatibility with no significant cytotoxic effect on human bone
marrow stromal cells (hBMSC) and in addition the incorporation of
5 mol% Cu induced a significant antibacterial effect against E. coli. The
released Cu2 + ions from MBG scaffolds significantly inhibited the
viability of Escherichia coli, as shown in Fig. 3 [101].
A glass system made by sol-gel method with the composition
75SiO2-(25-x)CaO-5P2O5-xCuO (x = 0, 2, 5 mol%) was incorporated
into a nanocoating to produce nanocomposite films for wound healing
applications [102]. 5 mol% CuO doped films had better antibacterial
activity than pure and 2 mol% CuO doped films against E. coli, due to
increased Cu ion release into DMEM medium after 7 days (0.0491 ppm
vs 0.0391 ppm, respectively).
For the development of wound dressings, prevention against bac-
terial infections and enhancement of angiogenesis are the key issues
which have to be taken into account. Wounds heal faster with the
transportation of nutrients and removal of waste products from the
tissues; therefore new blood vessel formation (angiogenesis) is very
important [103,104]. When a wound is infected by bacteria, the process
of healing will take longer [105]; which has to be prevented or treated
with appropriate biomaterials like BGs [102]. In terms of these re-
quirements, Cu-BG nanocomposite films are promising biomaterials for
wound dressing applications also providing antibacterial properties.
Composites of nanofibrillated cellulose (NFC) and Cu doped (2 and
5 mol%) MBG which have molar ratios of Si/Ca/P = 80/15/5 were
developed in aerogel form [106]. After successful production of these
composites, their dissolution behavior, mineralization, cytotoxicity,
angiogenic performance and the antibacterial properties were ex-
amined against E. coli.
Cu-MBGs were shown to have ordered and hexagonally packed
mesoporous structure, high surface area and large volume of pores.
These endow Cu-MBGs with high bioactivity when the material is im-
mersed in SBF.
When Cu-MBGs were added to NFC fibrils, they retained the ab-
sorption capability of NFC aerogels, therefore controlling the moisture
around the wounds, which is beneficial to support the wound healing
process.
These aerogels enhanced the gene expression of VEGF A, VEGF C,
PDGF B and FGF 2 in the culture of 3T3 fibroblasts. 5% Cu doped MBG-
NFC composite induced HUVEC sprouting and promoted ECM pro-
duction. Both the NFC-Cu-MBG composites and Cu-MBG (2 and 5 mol%
Cu) killed the E. coli strains, the effect of 5 mol% Cu being higher than
that of 2 mol% Cu MBG.
In a later study, MBGs with 2% molar percentage of Cu (molar ratio
Cu/Ca/Si = 2/13/85) and 5% molar percentage of Cu (molar ratio Cu/
Ca/Si = 5/10/85) were prepared by a one-pot ultrasound-assisted sol-
gel procedure and the final textural features, the in vitro bioactive re-
sponses and the antibacterial properties of the synthesized MBGs, were
tested against E. coli, S. aureus and S. epidermidis [107].
2% mol Cu-MBG had 550 m2 g− 1 surface area, 2.6 nm size of me-
sopores, showing in vitro bioactive behavior and a sustained release of
Cu2 + ions into SBF. When 2% mol Cu-MBG was exposed to 1 day of
incubation in the three bacteria, approximately 30 to 40% of inhibition
of bacteria growth was observed. For 3 days of incubation, E. coli and S.
S. Kaya et al. Materials Science & Engineering C 83 (2018) 99–107

Table 1
Summary of reviewed publications on silver containing MBGs used in antibacterial applications.

Reference Composition Synthesis method Antibacterial Results

Bellantone, Coleman, and Hench
2000 [81]
Bellantone, Williams, and Hench
2002 [82]
Balamurugan et al. 2008 [92]
Palza et al. 2013 [95]
Gargiulo et al. 2013 [94]
H. Zhu et al. 2014 [98]
76SiO2, 19CaO, 5P2O5, 3Ag2O (wt%)
76SiO2, 19CaO, 5P2O5, 3Ag2O (wt%)
64SiO2, 26CaO, 10P2O5, 5Ag2O (mol
%)
62.3SiO2, 28.9CaO, 8.6P2O5, 4 and
8Ag2O (wt%)
73SiO2, 13CaO, 11P2O5, 3Ag2O (wt
%)
60SiO2, 36CaO, 4P2O5, 1Ag2O (mol
%)
Sol-gel Bacteriostatic effect on E. coli MG1655 with 0.01% reduced
bacterial growth
Sol-gel MBCs (99.9% killing) for AgBG of 1, 0.5, and 0.5 mg/ml
For E. coli, P. aeruginosa, and S. aureus, respectively
Sol-gel MBC of Ag-BG: 1 mg/ml for E. coli (> 99% killing efficiency)
Sol-gel 4Ag2O and 8Ag2O: MBC 100–150 mg/ml for E. coli and 5–10 mg/
ml for S. mutans
Structure directing agent MBC decreased from 2.2 × 109 to 2 × 104 CFU/ml for 3Ag2O
assisted sol-gel doped BG (> 99.9% killing efficiency)
Structure directing agent 100% killing efficiency towards E. coli and S. aureus
assisted sol-gel

Fig. 3. Released Cu2 + ions from MBG scaffolds significantly inhibited the viability of
bacteria according to ref. [101]. ⁎0Cu-MBG group compared to blank control (p < 0.05).
⁎⁎
5Cu-MBG group compared to blank control and 0Cu-MBG group (p < 0.01). The Cu-
containing scaffolds significantly inhibited bacterial viability compared to scaffolds
without Cu.
(Modified from ref. [101]).
aureus were killed to an extent of 70 to 75% and S. epidermis was nearly
up to 50%.
According to the final properties, this Cu-MBG which has both ex-
cellent bioactivity and antimicrobial property can be considered a
suitable candidate to prevent infections and to treat bone defects.
development than the ones with 7 ZnO (mol%). This is likely due to the
amount of Zn2 + ions released from the 4 mol% ZnO scaffold being
more effective than the amount release from the 7 mol% ZnO scaffolds.
In addition, 4 mol% ZnO scaffolds provided better antibacterial prop-
erties against S. aureus, which can also be related with the more ef-
fective Zn ion release from 4 mol% ZnO doped MBG than the 7 mol%
doped one.
In a recent study [37], the inclusion of 4 ZnO (mol%) substituting
SiO2 in 80SiO2-15CaO-5P2O5 (mol%) BG scaffolds was reported to
drastically increase the amount of dead bacterial cells (S. aureus). Also,
this amount of added ZnO increased the osteoblast development when
zinc containing scaffolds were soaked in extracts of culture medium for
1, 3 and 6 days.
Atkinson et al. [117] prepared three MBGs having composition
70SiO2-(26-x)CaO-4P2O5-xZnO (x = 0, 3 and 5 mol%) by the combined
sol-gel process and polymer templating methods. Their antibacterial
properties were tested against Bacillus subtilis (B. subtilis) and Pseudo-
monas aeruginosa (P. aeruginosa). 3 mol% ZnO doped MBGs had 40%
inhibition for B. subtilis and up to 31–35% inhibition for P. aeruginosa
after 2 h of incubation. 5 ZnO (mol%) doped MBG showed the highest
antibacterial effect with 91.3% inhibition for B. subtilis after 2 h in-
cubation, as well as 89.4% inhibition for P. aeruginosa. The higher an-
tibacterial inhibition achieved by the 5 mol% ZnO doped MBGs in
comparison to the 3 mol% ones can be correlated with higher zinc
concentration determined in the SBF solution after the 14th day of
immersion. 2 ppm of zinc concentration was observed for 5 mol% ZnO
MBGs and 1.8 ppm for the 3 mol% doped ones. However, the 5 mol%
ZnO composition had a lower rate of hydroxyapatite precipitation,
which is a prominent marker of bioactivity for BGs [118]. The authors
suggested that the best performing material from this study for implant
applications was the 3 mol% ZnO added MBG, since it displayed
medium HA precipitation and antibacterial properties.

2.3. Zinc doped-MBGs 2.4. Cerium doped-MBGs

Zinc has important effects in the development, formation and me-
tabolism of bone cells [108–110], in the growth of blood vessels [111]
and as antibacterial agent [112]. It also improves wound healing
[113,114]. Zinc provides antibacterial activity by inhibiting glycolysis,
transmembrane proton translocation and acid tolerance in bacterial
cells [115]. Having high impact on bone formation and growth and
with its antibacterial properties, zinc ions are being increasingly con-
sidered in combination with BGs for bone regeneration applications
[110].
80SiO2-15CaO-5P2O5 (mol%) mesoporous bioactive glass (MBG)
scaffolds doped with 4 and 7 ZnO (mol%) were investigated for their
cytocompatibility and antibacterial properties against S. aureus [116]. 4
ZnO (mol%) substitution was shown to make the MBG a suitable can-
didate for bone regeneration applications [116] since scaffolds with this
composition led to better human osteoblast-like (HOS) cell
It has been reported that Ce3 + ions reduce enamel demineraliza-
tion, are neuroprotective [119] and promote antibacterial behavior
when added into biomaterials [120].
Goh et al. [120] added 1, 5 and 10 mol% CeO2 into 50SiO2-45CaO-
5P2O5 (mol%) mesoporous silicate glasses via quick alkali mediated sol-
gel method. The antibacterial properties were investigated using the
quantitative viable count method. It was found that 5 and 10 mol% Ce-
MBGs exhibited significant antibacterial properties compared to 1 mol
% Ce and undoped samples. The antibacterial mechanism of cerium
(III) ion was reported to be by binding rapidly to E. coli cells, inhibition
of endogenous respiration of cells as well as penetration into the cy-
toplasm of the cells and interfering with their metabolic functions
[121]. All samples were confirmed to have suitable bioactivity, with
induced formation of apatite particles upon immersion in simulated
body fluid (SBF). These Ce-MBGs were reported to have potential

103
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applications in the bone regeneration field.
2.5. Gallium doped-MBGs
The US Food and Drug Administration (FDA) has approved Ga3 + as
an effective agent for treating bone resorption, autoimmune disease, for
inhibition of biofilm formation, for bone, colon and prostate cancer
treatments [122] and also for fighting against both Gram-positive and
Gram-negative bacteria [37,123–128].
Salinas and Vallet-Regí [37] carried out a study on the production of
scaffolds made of mesoporous 3.5 Ga2O3 (mol%) substituted for SiO2 in
80SiO2-15CaO-5P2O5 (mol%) bioactive glasses. Ga3 + ions were hardly
released from the glass network; therefore it is unlikely that they im-
parted antibacterial property to the glasses.
A recent study done by Pourshahrestani et al. [126] investigated the
effects of 1–3 Ga2O3 (mol%) addition on the antibacterial properties of
80SiO2-15CaO-5P2O5 (mol%) ordered mesoporous bioactive glasses, in
which they found that 3 Ga2O3 (mol%) addition had the highest anti-
bacterial rate against S. aureus with 99% after 12 h of incubation. The
highest antibacterial rate can be related with the highest Ga ion con-
centration after the release into Tris–HCl solutions. After 150 h of in-
cubation, solutions of 1, 2 and 3 mol% Ga2O3 doped MBGs had around
0.1, 0.23 and 0.32 ppm of Ga ion concentrations, respectively.
Moreover, Sanchez-Salcedo et al. [127] synthesized mesoporous
glasses with the composition 80SiO2-15CaO-5P2O5 (mol%), containing
5 mol% of Ga2O3 via evaporation induced self-assembly method. It was
shown that the Ga3 + concentrations released from MBG into Dulbecco's
Modified Eagle Medium (DMEM) and Todd Hewitt Broth (THB) were in
the non-cytotoxic levels, also in the effective antibacterial range against
P. aeruginosa and not far from the effective range against S. aureus. In
DMEM, the maximum Ga3 + concentration obtained was 2.5 ppm,
which is below the toxicity limit of Ga3 + in blood plasma (14 ppm)
[38]. In THB the release of Ga3 + concentration was 9.8 ppm, which is
140 times higher than the IC90 (drug concentration inhibiting 90% of
parasite's activity) of P. aeruginosa and 2 times lower than that of S.
aureus [117]. Therefore, this MBG was considered a promising material
for bone regeneration applications.
3. Summary and outlook
BGs are being used in bone regeneration applications as fillers in
composites [129], as scaffolds for bone tissue engineering [72,77,130]
and as coatings of implants [131]. The failure of implants may happen
due to bacterial colonization or infections [38]. These failures are
mostly solved by the administration of systemic antibiotics to the pa-
tient. This solution can lead to allergic reactions, microbial flora de-
pletion and bacterial resistance.
Due to these limitations of antibiotics, the modification of bioma-
terials with alternative antibacterial agents [132] is being intensively
investigated. In this perspective, bioactive and soluble glasses are
capable of controlled and sustained release of antimicrobial ions (e.g.
Ag, Cu, Zn, Ce and Ga) and thus have the potential to allow localized
antimicrobial treatments which are advantageous compared to systemic
antibiotic delivery systems. Osteogenesis and angiogenesis properties
are also promoted with the release of some of the therapeutic ions, e.g.
Cu, Zn, Ce and Ga [11,37,102,116,120]. In low concentrations silver
has no toxicity effect to human cells, and it can also give antibacterial,
osteoconductivity and bone bonding properties to BGs [81–85].Copper
ion is widely used due to its vascularization/angiogenesis stimulation
properties [133]. Zinc is a cofactor in metabolic processes in bone,
articular tissues and immune system functions [110,134,135]. Bone
formation and mineralization are stimulated by activating aminoacyl-
tRNA synthetase in osteoblastic cells via the zinc doping of BGs [116].
Cerium has been shown to enhance the proliferation, differentiation
and mineralization of primary osteoblasts [136]. Besides promoting
osteogenesis, cerium incorporated materials have demonstrated
104
Materials Science & Engineering C 83 (2018) 99–107
promising antibacterial properties [120]. Gallium ions are effective
against bone desorption and for the treatment of osteoporosis and
cancer related hypercalcemias [137,138]. Ga is also effective against
organisms causing tuberculosis and malaria in human beings as well as
against Pseudomonas aeruginosa [139,140]. Moreover, besides limiting
bacteria attachment, these ions can inhibit bacteria replication by da-
maging bacteria RNA and DNA, i.e. silver ions, or decreasing bacterial
Fe uptake, i.e. gallium ions. Silver has been used more than the other
antibacterial ions (Cu, Zn, Ce and Ga) as it has a broad and strong
antimicrobial behavior and has no toxicity effect to human cells in
suitable concentrations, thus providing extra functions to BGs in addi-
tion to osteoconductivity and bone bonding ability.
Acknowledgement
The authors would like to acknowledge the European Union's
Horizon 2020 research and innovation programme under the Marie
Skłodowska-Curie grant agreement No 643050, project “HyMedPoly”.
Funding
This work was supported by the European Union's Horizon 2020
research and innovation programme under the Marie Skłodowska Curie
[grant number 643050] project “HyMedPoly”.
References
[1] L.L. Hench, R.J. Splinter, W.C. Allen, T.K. Greenlee, Bonding mechanisms at the
interface of ceramic prosthetic materials, J. Biomed. Mater. Res. 5 (1971)
117–141, http://dx.doi.org/10.1002/jbm.820050611.
[2] L.L. Hench, Opening paper 2015 — some comments on bioglass: four eras of
discovery and development, Biomed. Glass. 1 (2015) 1–11, http://dx.doi.org/10.
1515/bglass-2015-0001.
[3] A. Hoppe, B. Sarker, R. Detsch, N. Hild, D. Mohn, W.J. Stark, et al., In vitro re-
activity of Sr-containing bioactive glass (type 1393) nanoparticles, J. Non-Cryst.
Solids 387 (2014) 41–46, http://dx.doi.org/10.1016/j.jnoncrysol.2013.12.010.
[4] D. Zhang, O. Leppäranta, E. Munukka, H. Ylänen, M.K. Viljanen, E. Eerola, et al.,
Antibacterial effects and dissolution behavior of six bioactive glasses, J. Biomed.
Mater. Res. A 93 (2010) 475–483, http://dx.doi.org/10.1002/jbm.a.32564.
[5] M. Brink, T. Turunen, R.P. Happonen, A. Yli-Urpo, Compositional dependence of
bioactivity of glasses in the system Na2O-K2O-MgO-CaO-B2O3-P2O5-SiO2, J.
Biomed. Mater. Res. 37 (1997) 114–121, http://dx.doi.org/10.1002/(SICI)1097-
4636(199710)37:1<114::AID-JBM14>3.3.CO;2-7.
[6] O. Lepparanta, M. Vaahtio, T. Peltola, D. Zhang, L. Hupa, M. Hupa, et al.,
Antibacterial effect of bioactive glasses on clinically important anaerobic bacteria
in vitro, J. Mater. Sci. Mater. Med. 19 (2008) 547–551, http://dx.doi.org/10.
1007/s10856-007-3018-5.
[7] E. Munukka, O. Leppäranta, M. Korkeamäki, M. Vaahtio, T. Peltola, D. Zhang,
et al., Bactericidal effects of bioactive glasses on clinically important aerobic
bacteria, J. Mater. Sci. Mater. Med. 19 (2008) 27–32, http://dx.doi.org/10.1007/
s10856-007-3143-1.
[8] L. Hupa, Melt-derived bioactive glasses, Bioact. Glas. Mater. Prop. Appl. 2011, pp.
3–28, , http://dx.doi.org/10.1016/B978-1-84569-768-6.50001-6.
[9] R.F. Brown, M.N. Rahaman, A.B. Dwilewicz, W. Huang, D.E. Day, Y. Li, et al.,
Effect of borate glass composition on its conversion to hydroxyapatite and on the
proliferation of MC3T3-E1 cells, J. Biomed. Mater. Res. A 88 (2009) 392–400,
http://dx.doi.org/10.1002/jbm.a.31679.
[10] E.A. Abou Neel, D.M. Pickup, S.P. Valappil, R.J. Newport, J.C. Knowles, Bioactive
functional materials: a perspective on phosphate-based glasses, J. Mater. Chem. 19
(2009) 690–701, http://dx.doi.org/10.1039/b810675d.
[11] A. Hoppe, N.S. Guldal, A.R. Boccaccini, A review of the biological response to ionic
dissolution products from bioactive glasses and glass-ceramics, Biomaterials 32
(2011) 2757–2774, http://dx.doi.org/10.1016/j.biomaterials.2011.01.004.
[12] M. Cerruti, G. Magnacca, C. Morterra, Characterization of sol–gel bioglasses with
the use of simple model systems: a surface-chemistry approach, J. Mater. Chem.
(2003) 1279–1286, http://dx.doi.org/10.1039/b300961k.
[13] R. Li, A.E. Clark, L.L. Hench, An investigation of bioactive glass powders by sol-gel
processing, J. Appl. Biomater. 2 (1991) 231–239, http://dx.doi.org/10.1002/jab.
770020403.
[14] B. Lei, X. Chen, Y. Wang, N. Zhao, G. Miao, Z. Li, et al., Fabrication of porous
bioactive glass particles by one step sintering, Mater. Lett. 64 (2010) 2293–2295,
http://dx.doi.org/10.1016/j.matlet.2010.07.066.
[15] C. Brinker, G. Scherer, Sol-gel science: the physics and chemistry of sol-gel pro-
cessing, Adv. Mater. 3 (1990) 912, http://dx.doi.org/10.1186/1471-2105-8-444.
[16] I. Izquierdo-Barba, D. Arcos, Y. Sakamoto, O. Terasaki, A. Lopez-Noriega,
M. Vallet-Regi, High-performance mesoporous bioceramics mimicking bone mi-
neralization, Chem. Mater. 20 (2008) 3191–3198, http://dx.doi.org/10.1021/
S. Kaya et al.
cm800172x.
[17] C. Wu, J. Chang, Y. Xiao, Mesoporous bioactive glasses as drug delivery and bone
tissue regeneration platforms, Ther. Deliv. 2 (2011) 1189–1198, http://dx.doi.
org/10.4155/tde.11.84.
[18] D. Arcos, A. López-Noriega, E. Ruiz-Hernández, O. Terasaki, M. Vallet-Regí,
Ordered mesoporous microspheres for bone grafting and drug delivery, Chem.
Mater. 21 (2009) 1000–1009, http://dx.doi.org/10.1021/cm801649z.
[19] W. Xia, J. Chang, Well-ordered mesoporous bioactive glasses (MBG): a promising
bioactive drug delivery system, J. Control. Release 110 (2006) 522–530, http://
dx.doi.org/10.1016/j.jconrel.2005.11.002.
[20] X. Yan, C. Yu, X. Zhou, J. Tang, D. Zhao, Highly ordered mesoporous bioactive
glasses with superior in vitro bone-forming bioactivities, Angew. Chem. Int. Ed. 43
(2004) 5980–5984, http://dx.doi.org/10.1002/anie.200460598.
[21] L. Zhao, X. Yan, X. Zhou, L. Zhou, H. Wang, J. Tang, et al., Mesoporous bioactive
glasses for controlled drug release, Microporous Mesoporous Mater. 109 (2008)
210–215, http://dx.doi.org/10.1016/j.micromeso.2007.04.041.
[22] V. Mouriño, A.R. Boccaccini, Bone tissue engineering therapeutics: controlled drug
delivery in three-dimensional scaffolds, J. R. Soc. Interface 7 (2010) 209–227,
http://dx.doi.org/10.1098/rsif.2009.0379.
[23] Y. Zhu, Y. Zhang, C. Wu, Y. Fang, J. Yang, S. Wang, The effect of zirconium in-
corporation on the physiochemical and biological properties of mesoporous
bioactive glasses scaffolds, Microporous Mesoporous Mater. 143 (2011) 311–319,
http://dx.doi.org/10.1016/j.micromeso.2011.03.007.
[24] X. Yan, X. Huang, C. Yu, H. Deng, Y. Wang, Z. Zhang, et al., The in-vitro bioactivity
of mesoporous bioactive glasses, Biomaterials 27 (2006) 3396–3403, http://dx.
doi.org/10.1016/j.biomaterials.2006.01.043.
[25] E. Leonova, I. Izquierdo-Barba, D. Arcos, A. López-Noriega, N. Hedin, M. Vallet-
Regí, et al., Multinuclear solid-state NMR studies of ordered mesoporous bioactive
glasses, J. Phys. Chem. C 112 (2008) 5552–5562, http://dx.doi.org/10.1021/
jp7107973.
[26] A. García, M. Cicuéndez, I. Izquierdo-Barba, D. Arcos, M. Vallet-Regí, Essential
role of calcium phosphate heterogeneities in 2D-hexagonal and 3D-cubic
SiO2 − CaO − P2O5 mesoporous bioactive glasses, Chem. Mater. 21 (2009)
5474–5484, http://dx.doi.org/10.1021/cm9022776.
[27] M. Alcaide, P. Portoles, A. Lopez-Noriega, D. Arcos, M. Vallet-Regi, M.T. Portoles,
Interaction of an ordered mesoporous bioactive glass with osteoblasts, fibroblasts
and lymphocytes, demonstrating its biocompatibility as a potential bone graft
material, Acta Biomater. 6 (2010) 892–899, http://dx.doi.org/10.1016/j.actbio.
2009.09.008.
[28] D. Arcos, M. Vallet-Regi, Sol-gel silica-based biomaterials and bone tissue re-
generation, Acta Biomater. 6 (2010) 2874–2888, http://dx.doi.org/10.1016/j.
actbio.2010.02.012.
[29] W. Xia, J. Chang, Preparation, in vitro bioactivity and drug release property of
well-ordered mesoporous 58S bioactive glass, J. Non-Cryst. Solids 354 (2008)
1338–1341, http://dx.doi.org/10.1016/j.jnoncrysol.2006.10.084.
[30] X. Li, X. Wang, D. He, J. Shi, Synthesis and characterization of mesoporous
CaO–MO–SiO2–P2O5 (M = Mg, Zn, Cu) bioactive glasses/composites, J. Mater.
Chem. 18 (2008) 4103, http://dx.doi.org/10.1039/b805114c.
[31] X. Wu, J. Wei, X. Lu, Y. Lv, F. Chen, Y. Zhang, et al., Chemical characteristics and
hemostatic performances of ordered mesoporous calcium-doped silica xerogels,
Biomed. Mater. 5 (2010) 35006, http://dx.doi.org/10.1088/1748-6041/5/3/
035006.
[32] A. Hoppe, A.R. Boccaccini, Biological impact of bioactive glasses and their dis-
solution products, Front. Oral Biol. 17 (2015) 22–32, http://dx.doi.org/10.1159/
000381690.
[33] V. Mourino, J.P. Cattalini, A.R. Boccaccini, Metallic ions as therapeutic agents in
tissue engineering scaffolds: an overview of their biological applications and
strategies for new developments, J. R. Soc. Interface 9 (2012) 401–419, http://dx.
doi.org/10.1098/rsif.2011.0611.
[34] C. Wu, J. Chang, Mesoporous bioactive glasses: structure characteristics, drug/
growth factor delivery and bone regeneration application, Interface Focus 2
(2012) 292–306, http://dx.doi.org/10.1098/rsfs.2011.0121.
[35] C. Wu, J. Chang, Multifunctional mesoporous bioactive glasses for effective de-
livery of therapeutic ions and drug/growth factors, J. Control. Release 193 (2014)
282–295, http://dx.doi.org/10.1016/j.jconrel.2014.04.026.
[36] C. Wu, W. Fan, Y. Zhu, M. Gelinsky, J. Chang, G. Cuniberti, et al., Multifunctional
magnetic mesoporous bioactive glass scaffolds with a hierarchical pore structure,
Acta Biomater. 7 (2011) 3563–3572, http://dx.doi.org/10.1016/j.actbio.2011.06.
028.
[37] A.J. Salinas, M. Vallet-Regí, Glasses in bone regeneration: a multiscale issue, J.
Non-Cryst. Solids 432 (2016) 9–14, http://dx.doi.org/10.1016/j.jnoncrysol.2015.
03.025.
[38] D. Campoccia, L. Montanaro, C.R. Arciola, The significance of infection related to
orthopedic devices and issues of antibiotic resistance, Biomaterials 27 (2006)
2331–2339, http://dx.doi.org/10.1016/j.biomaterials.2005.11.044.
[39] A.M. Mulligan, M. Wilson, J.C. Knowles, The effect of increasing copper content in
phosphate-based glasses on biofilms of Streptococcus sanguis, Biomaterials 24
(2003) 1797–1807, http://dx.doi.org/10.1016/S0142-9612(02)00577-X.
[40] T.N. Kim, Q.L. Feng, J.O. Kim, J. Wu, H. Wang, G.C. Chen, et al., Antimicrobial
effects of metal ions (Ag+, Cu2 +, Zn2 +) in hydroxyapatite, J. Mater. Sci. Mater.
Med. 9 (1998) 129–134, http://dx.doi.org/10.1023/A:1008811501734.
[41] J.C. Wataha, P.E. Lockwood, A. Schedle, Effect of silver, copper, mercury, and
nickel ions on cellular proliferation during extended, low-dose exposures, J.
Biomed. Mater. Res. 52 (2000) 360–364, http://dx.doi.org/10.1002/1097-
4636(200011)52:2<360::AID-JBM16>3.0.CO;2-B.
[42] O. Yamamoto, J. Sawai, T. Sasamoto, Change in antibacterial characteristics with
105
Materials Science & Engineering C 83 (2018) 99–107
doping amount of ZnO in MgO-ZnO solid solution, Int. J. Inorg. Mater. 2 (2000)
451–454, http://dx.doi.org/10.1016/S1466-6049(00)00045-3.
[43] P. Stoor, E. Söderling, J.I. Salonen, Antibacterial effects of a bioactive glass paste
on oral microorganisms, Acta Odontol. Scand. 56 (1998) 161–165, http://dx.doi.
org/10.1080/000163598422901.
[44] P. Stoor, E. Söderling, R. Grénman, Bioactive glass S53P4 in repair of septal per-
forations and its interactions with the respiratory infection-associated micro-
organisms Heamophilus influenzae and Streptococcus pneumoniae, J. Biomed. Mater.
Res. 58 (2001) 113–120, http://dx.doi.org/10.1002/1097-4636(2001)
58:1<113::AID-JBM170>3.0.CO;2-V.
[45] P. Stoor, E. Söderling, R. Grenman, Interactions between the bioactive glass S53P4
and the atrophic rhinitis-associated microorganism Klebsiella ozaenae, J. Biomed.
Mater. Res. 48 (1999) 869–874, http://dx.doi.org/10.1002/(SICI)1097-
4636(1999)48:6<869::AID-JBM16>3.0.CO;2-6.
[46] M.G. Newman, S.S. Socransky, E.D. Savitt, D.A. Propas, A. Crawford, Studies of the
microbiology of periodontosis, J. Periodontol. 47 (1976) 373–379, http://dx.doi.
org/10.1902/jop.1976.47.7.373.
[47] J. Slots, The predominant cultivable organisms in juvenile periodontitis, Scand. J.
Dent. Res. 84 (1976) 1–10.
[48] J. Slots, The predominant cultivable microflora of advanced periodontitis, Scand.
J. Dent. Res. 4 (1977) 114–121, http://dx.doi.org/10.1111/j.1600-0722.1977.
tb00541.x.
[49] C.A. Spiegel, S.E. Hayduk, G.E. Minah, G.N. Krywolap, Black-pigmented
Bacteroides from clinically characterized periodontal sites, J. Periodontal Res. 14
(1979) 376–382, http://dx.doi.org/10.1111/j.1600-0765.1979.tb00234.x.
[50] A.C.R. Tanner, C. Haffer, G.T. Bratthall, R.A. Visconti, S.S. Socransky, A study of
the bacteria associated with advancing periodontitis in man, J. Clin. Periodontol. 6
(1979) 278–307, http://dx.doi.org/10.1111/j.1600-051X.1979.tb01931.x.
[51] J.M. Tanzer, J. Livingston, A.M. Thompson, The microbiology of primary dental
caries in humans, J. Dent. Educ. 65 (2001) 1028–1037.
[52] L. Drago, D. Romano, E. De Vecchi, C. Vassena, N. Logoluso, R. Mattina, et al.,
Bioactive glass BAG-S53P4 for the adjunctive treatment of chronic osteomyelitis of
the long bones: an in vitro and prospective clinical study, BMC Infect. Dis. 13
(2013) 584, http://dx.doi.org/10.1186/1471-2334-13-584.
[53] J. McAndrew, C. Efrimescu, E. Sheehan, D. Niall, Through the looking glass;
bioactive glass S53P4 (BonAlive®) in the treatment of chronic osteomyelitis, Ir. J.
Med. Sci. 182 (2013) 509–511, http://dx.doi.org/10.1007/s11845-012-0895-5.
[54] C.L. Romano, N. Logoluso, E. Meani, D. Romano, E. De Vecchi, C. Vassena, et al., A
comparative study of the use of bioactive glass S53P4 and antibiotic-loaded cal-
cium-based bone substitutes in the treatment of chronic osteomyelitis: a retro-
spective comparative study, Bone Jt J 96 (B) (2014) 845–850, http://dx.doi.org/
10.1302/0301-620X.96B6.33014.
[55] N.A.P. Van Gestel, J. Geurts, D.J.W. Hulsen, B. Van Rietbergen, S. Hofmann,
J.J. Arts, Clinical applications of S53P4 bioactive glass in bone healing and os-
teomyelitic treatment: a literature review, Biomed. Res. Int. 2015 (2015), http://
dx.doi.org/10.1155/2015/684826.
[56] J.H. Calhoun, M.M. Manring, M. Shirtliff, Osteomyelitis of the long bones, Semin.
Plast. Surg. 23 (2009) 59–72, http://dx.doi.org/10.1055/s-0029-1214158.
[57] J. Geurts, J.J. Chris Arts, G.H.I.M. Walenkamp, Bone graft substitutes in active or
suspected infection. Contra-indicated or not? Injury 42 (2011), http://dx.doi.org/
10.1016/j.injury.2011.06.189.
[58] G. Walenkamp, Small PMMA beads improve gentamicin release, Acta Orthop.
Scand. 60 (1989) 668–669, http://dx.doi.org/10.3109/17453678909149599.
[59] T.F. Calton, T.K. Fehring, W.L. Griffin, Bone loss associated with the use of spacer
blocks in infected total knee arthroplasty, Clin. Orthop. Relat. Res. (1997)
148–154.
[60] N.C. Lindfors, Bioactive glass S53P4 as a bone graft substitute in the treatment of
osteomyelitis, Bioact. Glas. Mater. Prop. Appl. 2011, pp. 209–216, , http://dx.doi.
org/10.1016/B978-1-84569-768-6.50009-0.
[61] R. Lakshminarayanan, V.A. Barathi, M. Venkatesh, N.K. Verma, S. Liu, X.J. Loh,
R.W. Beuerman, Membrane selectivity of cationic polyamides and rational design
of proteolyticresistant antimicrobial peptides, Invest. Ophthalmol. Vis. Sci. 57
(2016) 333.
[62] R. Lakshminarayanan, R. Sridhar, X.J. Loh, M. Nandhakumar, V.A. Barathi,
M. Kalaipriya, et al., Interaction of gelatin with polyenes modulates antifungal
activity and biocompatibility of electrospun fiber mats, Int. J. Nanomedicine 9
(2014) 2439–2458, http://dx.doi.org/10.2147/IJN.S58487.
[63] M. Ignatova, I. Rashkov, N. Manolova, М. Ignatova, I. Rashkov, N. Manolova,
Drug-loaded electrospun materials in wound-dressing applications and in local
cancer treatment, Expert Opin. Drug Deliv. 10 (2013) 469–483, http://dx.doi.org/
10.1517/17425247.2013.758103.
[64] S. Puttipipatkhachorn, J. Nunthanid, K. Yamamoto, G.E. Peck, Drug physical state
and drug-polymer interaction on drug release from chitosan matrix films, J.
Control. Release 75 (2001) 143–153, http://dx.doi.org/10.1016/S0168-3659(01)
00389-3.
[65] D. Kai, G. Jin, M.P. Prabhakaran, S. Ramakrishna, Electrospun synthetic and
natural nanofibers for regenerative medicine and stem cells, Biotechnol. J. 8
(2013) 59–72, http://dx.doi.org/10.1002/biot.201200249.
[66] C. Dhand, M. Venkatesh, V.A. Barathi, S. Harini, S. Bairagi, E. Goh Tze Leng, et al.,
Bio-inspired crosslinking and matrix-drug interactions for advanced wound dres-
sings with long-term antimicrobial activity, Biomaterials 138 (2017) 153–168,
http://dx.doi.org/10.1016/j.biomaterials.2017.05.043.
[67] J. Min, R.D. Braatz, P.T. Hammond, Tunable staged release of therapeutics from
layer-by-layer coatings with clay interlayer barrier, Biomaterials 35 (2014)
2507–2517, http://dx.doi.org/10.1016/j.biomaterials.2013.12.009.
[68] X. Zhu, Loh X. Jun, Layer-by-layer assemblies for antibacterial applications,
S. Kaya et al.
Biomater. Sci. 3 (2015) 1505–1518, http://dx.doi.org/10.1039/C5BM00307E.
[69] P. Gentile, M.E. Frongia, M. Cardellach, C.A. Miller, G.P. Stafford, G.J. Leggett,
et al., Functionalised nanoscale coatings using layer-by-layer assembly for im-
parting antibacterial properties to polylactide-co-glycolide surfaces, Acta
Biomater. 21 (2015) 35–43, http://dx.doi.org/10.1016/j.actbio.2015.04.009.
[70] M.N. Rahaman, D.E. Day, B. Sonny Bal, Q. Fu, S.B. Jung, L.F. Bonewald, et al.,
Bioactive glass in tissue engineering, Acta Biomater. 7 (2011) 2355–2373, http://
dx.doi.org/10.1016/j.actbio.2011.03.016.
[71] V. Mouriño, A.R. Boccaccini, Bone tissue engineering therapeutics: controlled drug
delivery in three-dimensional scaffolds, J. R. Soc. Interface 7 (2010) 209–227,
http://dx.doi.org/10.1098/rsif.2009.0379.
[72] J. Hum, A.R. Boccaccini, Bioactive glasses as carriers for bioactive molecules and
therapeutic drugs: a review, J. Mater. Sci. Mater. Med. 23 (2012) 2317–2333,
http://dx.doi.org/10.1007/s10856-012-4580-z.
[73] J. Ye, J. He, C. Wang, K. Yao, Z. Gou, Copper-containing mesoporous bioactive
glass coatings on orbital implants for improving drug delivery capacity and anti-
bacterial activity, Biotechnol. Lett. 36 (2014) 961–968, http://dx.doi.org/10.
1007/s10529-014-1465-x.
[74] C. Wu, Y. Zhou, W. Fan, P. Han, J. Chang, J. Yuen, et al., Hypoxia-mimicking
mesoporous bioactive glass scaffolds with controllable cobalt ion release for bone
tissue engineering, Biomaterials 33 (2012) 2076–2085, http://dx.doi.org/10.
1016/j.biomaterials.2011.11.042.
[75] J.-H. Lee, A. El-Fiqi, N. Mandakhbayar, H.-H. Lee, H.-W. Kim, Drug/ion co-de-
livery multi-functional nanocarrier to regenerate infected tissue defect,
Biomaterials 142 (2017) 62–76, http://dx.doi.org/10.1016/j.biomaterials.2017.
07.014.
[76] S. Di Nunzio, C. Vitale Brovarone, S. Spriano, D. Milanese, E. Verné, V. Bergo,
et al., Silver containing bioactive glasses prepared by molten salt ion-exchange, J.
Eur. Ceram. Soc. 24 (2004) 2935–2942, http://dx.doi.org/10.1016/j.
jeurceramsoc.2003.11.010.
[77] P.J. Newby, R. El-Gendy, J. Kirkham, X.B. Yang, I.D. Thompson, A.R. Boccaccini,
Ag-doped 45S5 Bioglass®-based bone scaffolds by molten salt ion exchange: pro-
cessing and characterisation, J. Mater. Sci. Mater. Med. 22 (2011) 557–569,
http://dx.doi.org/10.1007/s10856-011-4240-8.
[78] A.B.G. Lansdown, Silver in health care: antimicrobial effects and safety in use,
Curr. Probl. Dermatol. 33 (2006) 17–34, http://dx.doi.org/10.1159/000093928.
[79] W.K. Jung, H.C. Koo, K.W. Kim, S. Shin, S.H. Kim, Y.H. Park, Antibacterial activity
and mechanism of action of the silver ion in Staphylococcus aureus and Escherichia
coli, Appl. Environ. Microbiol. 74 (2008) 2171–2178, http://dx.doi.org/10.1128/
AEM.02001-07.
[80] S. Pal, Y.K. Tak, J.M. Song, Does the antibacterial activity of silver nanoparticles
depend on the shape of the nanoparticle? A study of the Gram-negative bacterium
Escherichia coli, J. Biol. Chem. 290 (2015) 1712–1720, http://dx.doi.org/10.1128/
AEM.02218-06.
[81] M. Bellantone, N.J. Coleman, L.L. Hench, Bacteriostatic action of a novel four-
component bioactive glass, J. Biomed. Mater. Res. 51 (2000) 484–490, http://dx.
doi.org/10.1002/1097-4636(20000905)51:3<484::AID-JBM24>3.0.CO;2-4.
[82] M. Bellantone, H.D. Williams, L.L. Hench, Broad-spectrum bactericidal activity of
Ag2O-doped bioactive glass, Antimicrob. Agents Chemother. 46 (2002)
1940–1945, http://dx.doi.org/10.1128/AAC.46.6.1940-1945.2002.
[83] T.J. Berger, J.A. Spadaro, S.E. Chapin, R.O. Becker, Electrically generated silver
ions: quantitative effects on bacterial and mammalian cells, Antimicrob. Agents
Chemother. 9 (1976) 357–358, http://dx.doi.org/10.1128/AAC.9.2.357.
[84] M.A. Hollinger, Toxicological aspects of topical silver pharmaceuticals, Crit. Rev.
Toxicol. 26 (1996) 255–260, http://dx.doi.org/10.3109/10408449609012524.
[85] J.L. Clement, P.S. Jarrett, Antibacterial silver, Metal-Based Drugs 1 (1994)
467–482, http://dx.doi.org/10.1155/MBD.1994.467.
[86] O. Gordon, T.V. Slenters, P.S. Brunetto, A.E. Villaruz, D.E. Sturdevant, M. Otto,
et al., Silver coordination polymers for prevention of implant infection: thiol in-
teraction, impact on respiratory chain enzymes, and hydroxyl radical induction,
Antimicrob. Agents Chemother. 54 (2010) 4208–4218, http://dx.doi.org/10.
1128/AAC.01830-09.
[87] E. Vernè, S. Di Nunzio, M. Bosetti, P. Appendino, C. Vitale Brovarone, G. Maina,
et al., Surface characterization of silver-doped bioactive glass, Biomaterials 26
(2005) 5111–5119, http://dx.doi.org/10.1016/j.biomaterials.2005.01.038.
[88] P. Saravanapavan, J.E. Gough, J.R. Jones, L.L. Hench, Antimicrobial macroporous
gel-glasses: dissolution and cytotoxicity, Annu. Meet. Int. Soc. Ceram. Med.
254–256 2004, pp. 1087–1090, , http://dx.doi.org/10.4028/www.scientific.net/
KEM.254-256.1087.
[89] J.J. Blaker, S.N. Nazhat, A.R. Boccaccini, Development and characterisation of
silver-doped bioactive glass-coated sutures for tissue engineering and wound
healing applications, Biomaterials 25 (2004) 1319–1329, http://dx.doi.org/10.
1016/j.biomaterials.2003.08.007.
[90] J. Pratten, S.N. Nazhat, J.J. Blaker, A.R. Boccaccini, In vitro attachment of
Staphylococcus epidermidis to surgical sutures with and without Ag-containing
bioactive glass coating, J. Biomater. Appl. 19 (2004) 47–57, http://dx.doi.org/10.
1177/0885328204043200.
[91] J.R. Jones, L.M. Ehrenfried, P. Saravanapavan, L.L. Hench, Controlling ion release
from bioactive glass foam scaffolds with antibacterial properties, J. Mater. Sci.
Mater. Med. 17 (2006) 989–996, http://dx.doi.org/10.1007/s10856-006-0434-x.
[92] A. Balamurugan, G. Balossier, D. Laurent-Maquin, S. Pina, A.H.S. Rebelo, J. Faure,
et al., An in vitro biological and anti-bacterial study on a sol–gel derived silver-
incorporated bioglass system, Dent. Mater. 24 (2008) 1343–1351, http://dx.doi.
org/10.1016/j.dental.2008.02.015.
[93] N. Nezafati, F. Moztarzadeh, S. Hesaraki, Surface reactivity and in vitro biological
evaluation of sol gel derived silver/calcium silicophosphate bioactive glass,
106
Materials Science & Engineering C 83 (2018) 99–107
Biotechnol. Bioprocess Eng. 17 (2012) 746–754, http://dx.doi.org/10.1007/
s12257-012-0046-x.
[94] N. Gargiulo, A.M. Cusano, F. Causa, D. Caputo, P.A. Netti, Silver-containing me-
soporous bioactive glass with improved antibacterial properties, J. Mater. Sci.
Mater. Med. 24 (2013) 2129–2135, http://dx.doi.org/10.1007/s10856-013-
4968-4.
[95] H. Palza, B. Escobar, J. Bejarano, D. Bravo, M. Diaz-Dosque, J. Perez, Designing
antimicrobial bioactive glass materials with embedded metal ions synthesized by
the sol-gel method, Mater. Sci. Eng. C 33 (2013) 3795–3801, http://dx.doi.org/10.
1016/j.msec.2013.05.012.
[96] F. Baino, S. Fiorilli, R. Mortera, B. Onida, E. Saino, L. Visai, et al., Mesoporous
bioactive glass as a multifunctional system for bone regeneration and controlled
drug release, J. Appl. Biomater. Biomech. 10 (2012) 12–21, http://dx.doi.org/10.
5301/JABB.2012.9036.
[97] R. Phetnin, S.T. Rattanachan, Preparation and antibacterial property on silver
incorporated mesoporous bioactive glass microspheres, J. Sol-Gel Sci. Technol. 75
(2015) 279–290, http://dx.doi.org/10.1007/s10971-015-3697-1.
[98] H. Zhu, C. Hu, F. Zhang, X. Feng, J. Li, T. Liu, et al., Preparation and antibacterial
property of silver-containing mesoporous 58S bioactive glass, Mater. Sci. Eng. C 42
(2014) 22–30, http://dx.doi.org/10.1016/j.msec.2014.05.004.
[99] M.L. Turski, D.J. Thiele, New roles for copper metabolism in cell proliferation,
signaling, and disease, J. Biol. Chem. 284 (2009) 717–721, http://dx.doi.org/10.
1074/jbc.R800055200.
[100] J.F. Collins, J.R. Prohaska, M.D. Knutson, Metabolic crossroads of iron and copper,
Nutr. Rev. 68 (2010) 133–147, http://dx.doi.org/10.1111/j.1753-4887.2010.
00271.x.
[101] C. Wu, Y. Zhou, M. Xu, P. Han, L. Chen, J. Chang, et al., Copper-containing me-
soporous bioactive glass scaffolds with multifunctional properties of angiogenesis
capacity, osteostimulation and antibacterial activity, Biomaterials 34 (2013)
422–433, http://dx.doi.org/10.1016/j.biomaterials.2012.09.066.
[102] J. Li, D. Zhai, F. Lv, Q. Yu, H. Ma, J. Yin, et al., Preparation of copper-containing
bioactive glass/eggshell membrane nanocomposites for improving angiogenesis,
antibacterial activity and wound healing, Acta Biomater. 36 (2016) 254–266,
http://dx.doi.org/10.1016/j.actbio.2016.03.011.
[103] A.A. Gorustovich, J.A. Roether, A.R. Boccaccini, Effect of bioactive glasses on
angiogenesis: a review of in vitro and in vivo evidences, Tissue Eng. B Rev. 16
(2010) 199–207, http://dx.doi.org/10.1089/ten.teb.2009.0416.
[104] A. Aguirre, A. González, M. Navarro, Ó. Castaño, J.A. Planell, E. Engel, Control of
microenvironmental cues with a smart biomaterial composite promotes en-
dothelial progenitor cell angiogenesis, Eur. Cell. Mater. 24 (2012) 90–106 (doi:-
vol024a07 [pii]).
[105] J. Grzybowski, M.K. Janiak, E. Oidak, K. Lasocki, J. Wrembel-Wargocka, A. Cheda,
et al., New cytokine dressings. II. Stimulation of oxidative burst in leucocytes in
vitro and reduction of viable bacteria within an infected wound, Int. J. Pharm. 184
(1999) 179–187, http://dx.doi.org/10.1016/S0378-5173(99)00064-2.
[106] X. Wang, F. Cheng, J. Liu, J.-H. Smått, D. Gepperth, M. Lastusaari, et al.,
Biocomposites of copper-containing mesoporous bioactive glass and nanofi-
brillated cellulose: biocompatibility and angiogenic promotion in chronic wound
healing application, Acta Biomater. 46 (2016) 286–298, http://dx.doi.org/10.
1016/j.actbio.2016.09.021.
[107] A. Bari, N. Bloise, S. Fiorilli, G. Novajra, M. Vallet-Regí, G. Bruni, et al., Copper-
containing mesoporous bioactive glass nanoparticles as multifunctional agent for
bone regeneration, Acta Biomater. (2017) 1–12, http://dx.doi.org/10.1016/j.
actbio.2017.04.012.
[108] L. Fong, K. Tan, C. Tran, J. Cool, M.A. Scherer, R. Elovaris, et al., Interaction of
dietary zinc and intracellular binding protein metallothionein in postnatal bone
growth, Bone 44 (2009) 1151–1162, http://dx.doi.org/10.1016/j.bone.2009.02.
011.
[109] A. Grandjean-Laquerriere, P. Laquerriere, E. Jallot, J.M. Nedelec, M. Guenounou,
D. Laurent-Maquin, et al., Influence of the zinc concentration of sol-gel derived
zinc substituted hydroxyapatite on cytokine production by human monocytes in
vitro, Biomaterials 27 (2006) 3195–3200, http://dx.doi.org/10.1016/j.
biomaterials.2006.01.024.
[110] P. Balasubramanian, L.A. Strobel, U. Kneser, A.R. Boccaccini, Zinc-containing
bioactive glasses for bone regeneration, dental and orthopedic applications,
Biomed. Glass. 1 (2015) 51–69, http://dx.doi.org/10.1515/bglass-2015-0006.
[111] R. Pasqualini, C.F. Barbas, W. Arap, Vessel maneuvers: zinc fingers promote an-
giogenesis, Nat. Med. 8 (2002) 1353–1354, http://dx.doi.org/10.1038/nm1202-
1353.
[112] C. Lang, C. Murgia, M. Leong, L.-W. Tan, G. Perozzi, D. Knight, et al., Anti-in-
flammatory effects of zinc and alterations in zinc transporter mRNA in mouse
models of allergic inflammation, Am. J. Phys. Lung Cell. Mol. Phys. 292 (2007)
L577–84, http://dx.doi.org/10.1152/ajplung.00280.2006.
[113] Y.H. Cho, S.J. Lee, J.Y. Lee, S.W. Kim, C.B. Lee, W.Y. Lee, et al., Antibacterial
effect of intraprostatic zinc injection in a rat model of chronic bacterial prostatitis,
Int. J. Antimicrob. Agents 19 (2002) 576–582, http://dx.doi.org/10.1016/S0924-
8579(02)00115-2.
[114] A.B.G. Lansdown, U. Mirastschijski, N. Stubbs, E. Scanlon, M.S. Agren, Zinc in
wound healing: theoretical, experimental, and clinical aspects, Wound Repair
Regen. 15 (2007) 2–16, http://dx.doi.org/10.1111/j.1524-475X.2006.00179.x.
[115] T.N. Phan, T. Buckner, J. Sheng, J.D. Baldeck, R.E. Marquis, Physiologic actions of
zinc related to inhibition of acid and alkali production by oral streptococci in
suspensions and biofilms, Oral Microbiol. Immunol. 19 (2004) 31–38, http://dx.
doi.org/10.1046/j.0902-0055.2003.00109.x.
[116] S. Sanchez-Salcedo, S. Shruti, A.J. Salinas, G. Malavasi, L. Menabue, M. Vallet-
Regi, In vitro antibacterial capacity and cytocompatibility of SiO2-CaO-P2O5 meso-
S. Kaya et al.
macroporous glass scaffolds enriched with ZnO, J. Mater. Chem. B 2 (2014)
4836–4847, http://dx.doi.org/10.1039/c4tb00403e.
[117] I. Atkinson, E.M. Anghel, L. Predoana, O.C. Mocioiu, L. Jecu, I. Raut, et al.,
Influence of ZnO addition on the structural, in vitro behavior and antimicrobial
activity of sol–gel derived CaO–P2O5–SiO2 bioactive glasses, Ceram. Int. 42 (2016)
3033–3045, http://dx.doi.org/10.1016/j.ceramint.2015.10.090.
[118] T. Kokubo, H. Takadama, How useful is SBF in predicting in vivo bone bioactivity?
Biomaterials 27 (15) (2006) 2907, http://dx.doi.org/10.1016/j.biomaterials.
2006.01.017.
[119] C. Leonelli, G. Lusvardi, G. Malavasi, L. Menabue, M. Tonelli, Synthesis and
characterization of cerium-doped glasses and in vitro evaluation of bioactivity, J.
Non-Cryst. Solids 316 (2003) 198–216, http://dx.doi.org/10.1016/S0022-
3093(02)01628-9.
[120] Y.F. Goh, A.Z. Alshemary, M. Akram, M.R. Abdul Kadir, R. Hussain, In-vitro
characterization of antibacterial bioactive glass containing ceria, Ceram. Int. 40
(2014) 729–737, http://dx.doi.org/10.1016/j.ceramint.2013.06.062.
[121] J.M. Sobek, D.E. Talburt, Effects of the rare earth cerium on Escherichia coli, Am
Soc Microbiol 95 (1968) 47–51.
[122] P. Collery, B. Keppler, C. Madoulet, B. Desoize, Gallium in cancer treatment, Crit.
Rev. Oncol. Hematol. 42 (2002) 283–296, http://dx.doi.org/10.1016/S1040-
8428(01)00225-6.
[123] E. Zeimaran, S. Pourshahrestani, B. Pingguan-Murphy, N.A. Kadri, H.A. Rothan,
R. Yusof, et al., Fabrication and characterization of poly(octanediol citrate)/gal-
lium-containing bioglass microcomposite scaffolds, J. Mater. Sci. 50 (2015)
2189–2201, http://dx.doi.org/10.1007/s10853-014-8782-2.
[124] L.R. Bernstein, Mechanisms of therapeutic activity for gallium, Pharmacol. Rev. 50
(1998) 665–682.
[125] Y. Kaneko, M. Thoendel, O. Olakanmi, B.E. Britigan, P.K. Singh, The transition
metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has anti-
microbial and antibiofilm activity, J. Clin. Invest. 117 (2007) 877–888, http://dx.
doi.org/10.1172/JCI30783.
[126] S. Pourshahrestani, E. Zeimaran, N. Adib Kadri, N. Gargiulo, S. Samuel,
S.V. Naveen, et al., Gallium-containing mesoporous bioactive glass with potent
hemostatic activity and antibacterial efficacy, J. Mater. Chem. B 4 (2016) 71–86,
http://dx.doi.org/10.1039/C5TB02062J.
[127] S. Sanchez-salcedo, A. Salinas, M. Vallet-Regi, Development of mesoporous
bioactive glasses able to release antibacterial Ga3 + ions, Conf. Abstr. 10th World
Biomater. Congr., Front. Bioeng. Biotechnol. 2016, pp. 5–7, , http://dx.doi.org/10.
3389/conf.FBIOE.2016.01.01476.
[128] F. Minandri, C. Bonchi, E. Frangipani, F. Imperi, P. Visca, Promises and failures of
gallium as an antibacterial agent, Future Microbiol. 9 (2014) 379–397, http://dx.
doi.org/10.2217/fmb.14.3.
107
Materials Science & Engineering C 83 (2018) 99–107
[129] G. Chouzouri, M. Xanthos, In vitro bioactivity and degradation of poly-
caprolactone composites containing silicate fillers, Acta Biomater. 3 (2007)
745–756, http://dx.doi.org/10.1016/j.actbio.2007.01.005.
[130] Q. Fu, E. Saiz, M.N. Rahaman, A.P. Tomsia, Bioactive glass scaffolds for bone
tissue engineering: state of the art and future perspectives, Mater. Sci. Eng. C
Mater. Biol. Appl. 31 (2012) 1245–1256, http://dx.doi.org/10.1016/j.msec.2011.
04.022.Bioactive.
[131] M. Mehdipour, A. Afshar, M. Mohebali, Electrophoretic deposition of bioactive
glass coating on 316L stainless steel and electrochemical behavior study, Appl.
Surf. Sci. 258 (2012) 9832–9839, http://dx.doi.org/10.1016/j.apsusc.2012.06.
038.
[132] T.N. Kim, Q.L. Feng, J.O. Kim, J. Wu, H. Wang, G.C. Chen, et al., Antimicrobial
effects of metal ions (Ag+, Cu2 +, Zn2 +) in hydroxyapatite, J. Mater. Sci. Mater.
Med. 9 (1998) 129–134, http://dx.doi.org/10.1023/A:1008811501734.
[133] N. Kong, K. Lin, H. Li, J. Chang, Synergy effects of copper and silicon ions on
stimulation of vascularization by copper-doped calcium silicate, J. Mater. Chem. B
2 (2014) 1100, http://dx.doi.org/10.1039/c3tb21529f.
[134] P.D. Saltman, L.G. Strause, The role of trace minerals in osteoporosis, J. Am. Coll.
Nutr. 12 (1993) 384–389, http://dx.doi.org/10.1080/07315724.1993.10718327.
[135] M. Yazar, S. Sarban, A. Kocyigit, U.E. Isikan, Synovial fluid and plasma selenium,
copper, zinc, and iron concentrations in patients with rheumatoid arthritis and
osteoarthritis, Biol. Trace Elem. Res. 106 (2005) 123–132, http://dx.doi.org/10.
1385/BTER:106:2:123.
[136] G. Zhou, G. Gu, Y. Li, Q. Zhang, W. Wang, S. Wang, et al., Effects of cerium oxide
nanoparticles on the proliferation, differentiation, and mineralization function of
primary osteoblasts in vitro, Biol. Trace Elem. Res. 153 (2013) 411–418, http://
dx.doi.org/10.1007/s12011-013-9655-2.
[137] R.P. Warrell, R.S. Bockman, C.J. Coonley, M. Isaacs, H. Staszewski, Gallium nitrate
inhibits calcium resorption from bone and is effective treatment for cancer-related
hypercalcemia, J. Clin. Invest. 73 (1984) 1487–1490, http://dx.doi.org/10.1172/
JCI111353.
[138] P. Melnikov, A.R. Teixeira, A. Malzac, B. Coelho M de, Gallium-containing hy-
droxyapatite for potential use in orthopedics, Mater. Chem. Phys. 117 (2009)
86–90, http://dx.doi.org/10.1016/j.matchemphys.2009.05.046.
[139] D.M. Pickup, R.M. Moss, D. Qiu, R.J. Newport, S.P. Valappil, J.C. Knowles, et al.,
Structural characterization by X-ray methods of novel antimicrobial gallium-
doped phosphate-based glasses, J. Chem. Phys. 130 (2009), http://dx.doi.org/10.
1063/1.3076057.
[140] R.J. Martens, N.A. Miller, N.D. Cohen, J.R. Harrington, L.R. Bernstein,
Chemoprophylactic antimicrobial activity of gallium maltolate against in-
tracellular Rhodococcus equi, J. Equine. Vet. Sci. 27 (2007) 341–345, http://dx.doi.
org/10.1016/j.jevs.2007.06.007.