Journal of the Australian Ceramic Society

https://doi.org/10.1007/s41779-023-00912-9

RESEARCH

The synthesis of calcium doped zinc oxide ceramic nanoparticles

via sol–gel effective against the emerging multidrug‑resistant Candida
auris
A. E. Reda1   · B. Fayed2

Received: 1 February 2023 / Revised: 19 May 2023 / Accepted: 14 June 2023

© The Author(s) 2023

Abstract
This work aimed to prepare calcium-doped zinc oxide (ZC) ceramic nanoparticles in this formula (1-x)ZnO–xCaO with
(x = 0, 0.10 and 0.90 mol.%) which are effective against the emerging multidrug-resistant Candida auris for the first time to
our knowledge using the sol–gel method. Three different calcination temperatures (Tc) (500, 550 and 600 °C) were employed
here. The prepared samples were characterized by XRD, SEM, and Zeta sizer. Also, their antimicrobial activity was assessed.
All the prepared samples that were calcined at 600 °C showed particle size at nanometer range. All ZC ceramic samples
showed negative zeta potential with higher magnitude indicating the stability of the produced nanoparticles. On increasing,
calcium oxide doped in ZC10 and ZC90 ceramic samples, the particle size was decreased with regular hexagonal shape in
SEM images. Finally, the prepared ZC ceramic nanoparticles exhibited excellent inhibitory activity against the emerging
multidrug-resistant C. auris. Additionally, the prepared nanoparticles were active against both gram-positive Staphylococ-
cus auris (ATCC 25923) and gram-negative E. coli (ATCC 25922). Collectively, ZC ceramic nanoparticles can be used to
combat the emerged drug-resistant C. auris instead of applying the current antifungal drugs that exhibited minimum activity.

Keywords  Zinc-calcium oxide · Yeast · X-ray diffraction · Antimicrobial activity

Introduction commodities for industries [3, 4]. According to many lit-

Nowadays, nanocrystalline material has wide attention due
to their unique properties and their widespread application
in various aspects such as catalysis, optoelectronic materials
to sensors, remediation, and biomedicine [1].
Ceramic oxides in nanometer particle size range like
Magnesiumoxide (MgO), Calcium oxide (CaO), Titanium
oxide ­(TiO2), and Zinc Oxide (ZnO) were found to have anti-
bacterial activity [2]. Particularly, the usage of ZnO ceram-
ics has attracted attention due to their distinct properties and
characteristics. ZnO can be used in various applications like
photocatalysis and as an antibacterial substance, in addi-
tion to its wide safety profile thus making them exciting
* A. E. Reda
ae.reda@nrc.sci.eg
1
Refractories, Ceramics and Building Materials Dept.,
National Research Centre, Dokki, Cairo 12622, Egypt
2
Chemistry of Natural and Microbial Product Dept., National
Research Centre, Dokki, Cairo 12622, Egypt
eratures, the fabrication of ZnO and CaO in nanoparticles
(NPs) is very attractive as it is antibacterial and safe, inex-
pensive, and an environment friendly material. Also, zinc
and calcium are necessary elements to our health [3–5].
Additionally, the nanostructure of zinc oxide is character-
ized by massive catalytic activity and powerful adsorption
capability [6]. Many methods were recorded to prepare ZnO
nanoparticles like sol–gel method, thermal decomposition,
chemical vapor decomposition (CVD), and alloy evapora-
tion-deposition [7–11].
The sol–gel method is an attractive preparation method
that can control the product purity, with a high surface area
and the products can be prepared at a low crystallization
temperature, which implies low cost [12, 13]. Sol–gel tech-
nique makes molecular precursor transformation onto a sta-
ble condensed oxide network that is explained by several
stages, hydrolysis, and polymerization for the formation of
the sol precursor followed by condensation, dehydration,
nucleation, and growth, which is achieved through anneal-
ing [14, 15].

13
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Doping with calcium in zinc oxide has a great interest
in optical [16], sensing [17], and biological applications
[4, 18]. Despite the studies made on Z ­ n1−xCaxO system
being scarce, the aforementioned system is very interesting
because the calcium element has a higher ionic size than the
zinc element and consequently calcium oxide doping is very
effective for lattice stabilization and can increase the ionicity
of chemical bonds in ZnO system [19]. On the other hand,
the studies made on ceramic oxides like ZnO-CaO system
and measuring the antimicrobial activity are very rare so
our study focus on usage of this composition with different
concentrations and studying the availability in biological
application.
On the other hand, following the Covid-19 pandemic,
antimicrobial resistance was raised by 15% according to the
Centers for Disease Control and Prevention (CDC) [20].
Candida auris is an emerging multidrug resistant microor-
ganism that was first isolated in Japan in 2009 [21]. Accord-
ing to the CDC, C. auris cases were raised by 60% during the
Covid-19 pandemic between 2019 and 2020 [22]. Recently,
C. auris showed great ability to acquire resistance to sev-
eral classes of antifungal drugs once they were exposed to
the antifungal drug at sub-MIC level [4]. Combating anti-
microbial resistance requires the constant need for novel
antimicrobials. Metal nanoparticles have been considered a
new approach in combating antimicrobial resistance due to
their unique mechanisms, as they can disrupt the membrane
of the microbial cell and generate reactive oxygen species
(ROS) in-addition to the ability to inhibit biofilm formation
[4, 23]. Several types of metal nanoparticles have shown
antimicrobial activity against Candida such as silver nano-
particles (AgNPs), iron nanoparticles (IONPs), ZnONPs,
CaONPs, Copper nanoparticles (CuONPs), and titanium
dioxide nanoparticles ­(TiO2NPs) [4, 24]. For instance,
AgNPs showed potent synergistic activity with fluconazole
against Candida albicans as shown by Jia and Sun study
[25]. IONPs were functionalized with chitosan and the pro-
duced nanoparticles showed eightfold reduction in C. albi-
cans growth compared to the antifungal drug miconazole
[26]. On the other hand, CuNPs completely managed to
inhibit C. albicans growth at a concentration of 150 µg/mL
[27]. ­TiO2NPs with diameter of 26 nm managed to prevent
C. albicans adhesion on the polymethylmethacrylate denture
base [28]. Finally, ZnO NPs enhanced caspofungin activity
against C. auris [4]. Despite several reports that highlighted
the application of metal nanoparticles against C. albicans,
limited study evaluated the bioactivity of metal nanoparti-
cles against C. auris.
Hence, in the presented study, calcium-doped zinc oxide
samples in this formula (1-x)ZnO–xCaO (x = 0, 0.10 and
0.90 mol.%) were fabricated in nanoparticle size by sol–gel
method for the first time to our knowledge, and the possible
application of this composition as an antimicrobial against
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Journal of the Australian Ceramic Society
the emergent multidrug-resistant C. auris was evaluated. The
prepared samples were characterized by X-ray diffraction
(XRD), scanning electron microscope (SEM), and Zetasizer.
The antimicrobial activity was also evaluated on other bac-
terial strains such as E. coli and Staphylococcus aureus for
validation. The produced nanoparticles can be used to com-
bat the emerged drug-resistant C. auris instead of applying
the current antifungal drugs that exhibited minimum activity.
Material and methods
Materials
The starting materials used in this study were zinc acetate
dehydrate (Aldrich, USA) and calcium chloride (anhydrous)
(Alpha Chemicka, India). Polyethylene glycol and citric
acid were supplied by (Merk-Schuchardt, Germany), and
(Aldrich, USA).
Nanoparticles preparation by sol–gel (citrate route)
method
Three compositions of (1-x)ZnO–xCaO system (x = 0,
0.10 and 0.90 mol.% Ca) were stoichiometrically pre-
pared by sol–gel method. The samples were designed
as ZC0, ZC10, and ZC90, as shown in Table 1 where
the last two digits indicate the ratio of calcium oxide.
The gel was prepared using citric acid C ­ 6 H 8 O 7 •H 2 O/
polyethylene glycol 60:40 mass% as a crosslinking
agent. Starting, the citric acid was dissolved in deion-
ized water for 30  min. Then, stoichiometric batches
were weighed as required for compositions of (1-x)
ZnO–xCaO (x = 0, 0.10 and 0.90  mol.%) by mixing
of Zn(CH 3 COO) 2 .2H 2 O and ­C aCl 2 stoichiometrically
(mathematically calculated proportions) in deionized
water with continuous stirring. After mixing the salts
with complete dissolution in citric acid, the polyeth-
ylene glycol was added to the solution. The reaction
mixture was heated at 110 °C for 1 h with continuous
stirring to evaporate most water in the gel phase until
gel formation. After that, this solution was dried at 60℃
for 24 h to obtain nanoparticle ZC0, ZC10, and ZC90
Table 1  The composition of Sample name Batch
(1-x)ZnO–xCaO with (x = 0,
0.10 and 0.90 mol.%) prepared
composition
(mol.%)
by sol–gel method
ZnO CaO
ZC0 100 0
ZC10 90 10
ZC90 10 90
Journal of the Australian Ceramic Society
Fig. 1  Experimental scheme for
synthesis of zinc-calcium oxide
nanoparticles
samples as seen in Fig. 1. The dried gel were calcined
at different calcination temperature (Tc) (500, 550 and
600 °C) for 1 h under air [29].
Characterization of the samples
The prepared dried samples of ZC0, ZC10, and ZC90 were
characterized via different techniques to study the formed
phases and their morphologies as follows:
Zeta potential and particle size measurement
The zeta potential and the particle size of the prepared NPs
were measured by a Zetasizer (Malvern, Cambridge, UK).
Initially, particles were diluted with distilled water then the
particle size was assessed by the Dynamic Light Scattering
(DLS) mode at 25 °C, while the Zeta potential (mV) was
evaluated by applying Laser Doppler Velocimetry (LDV)
mode [30].
X‑ray diffraction analysis (XRD)
The X-ray diffraction analysis was used to study the formed
phases of the prepared calcined ZC sample at 600 °C for 1 h
using D8 advance diffractometer (Bruker, Germany) with
secondary monochromatic beam CuKα radiation at 40 kV
and 40 mA to identify the crystalline phases of formed sam-
ples in nanoparticle range at 600 °C temperature. Intensity
data were collected over the range of 2θ from 10 to 60°.
Scanning electron microscopy analysis (SEM)
The surface morphology and the particle size were explored
by applying SEM as follows, the calcined ZC samples at
600 °C for 1 h were sputter-coated with gold then they were
scanned and photomicrographed using the Philips XL30 scan-
ning electron microscopy (SEM) model, with an accelerating
voltage of 30 kV and magnification of up to 400,000 × .
Determination of the antimicrobial activity
The antimicrobial activities of the prepared nanoparticles
against C. auris (CDC-CAU9), C. auris (CDC-B11903), E.
coli (ATCC 25922) and S. auris (ATCC 25923) were evalu-
ated by liquid broth media according to modified Clinical
and Laboratory Standards Institute (CLSI) and as described
before [4]. Initially, several concentrations of the prepared
nanoparticles were prepared and suspended in growth broth
media for the tested microbes. For C. auris, Sabaroud dextrose
broth media was used while Miller Hinton broth media was
employed for E. coli (ATCC 25922), and S. aureus (ATCC
25923). The microbial culture was prepared ­(104 CFU/mL)
and incubated with the tested nanoparticles into 96-well micro-
plates at 37 °C for 48 h. The microbial growth was evaluated
by measuring the turbidity at OD600 with a microplate reader
(LT-4500, Labtech, Pocklington, York, UK). Colisitin (Cat#
C4461, Sigma-Aldrich) and Amphotricin-B (Cat#46,006,
Sigma-Aldrich) were used as positive controls while cultures
broth media only were employed as negative controls and each
test was performed in triplicate. Approval for exempt from
ethical review No.: EX0030052023.
Statistical analysis
The data was collected and graphed using GraphPad Prism
8.02 for windows (GraphPad Inc., La Jolla, CA, USA).
One-way analysis of variance (ANOVA) using Tukey’s
Multiple Comparison Test was used to analyze the data. A
P-value < 0.05 was considered as significant.
Results and discussion
Particle size of synthesized samples
Particle size can be affected in several ways: sonifica-
tion, adding a stabilizer, and dispersant [31]. Initially, we
13

measured the particle size for all zinc calcium oxide compo-
sitions fired at 500 °C, 550 °C and 600 °C for 1 h. Our data
showed that the particle size for all zinc calcium oxide com-
positions fired at 500 °C and 550 °C were in the micrometer
range while the zinc calcium oxide composition that was
fired at 600 °C showed particle size in the desired nanom-
eter range. Hence, the zinc calcium oxide ceramic samples
fired at 600 °C were selected for further characterization.
The decrease in particle size with raising the calcination
temperature like another report by Ramadan et al. [32] and
can be attributed to the ability of temperature to eliminate
the ZnO-CaO NPs traces reaction with completely removing
the moisture from the internal network of the produced ZC
NPs crystal. The calcined ZC ceramic samples at 600 °C as
illustrated in Fig. 2 showed that the particle size of ZC sam-
ples were 367 ± 50.99, 226.9 ± 29.18, and 137.3 ± 8.16 nm
for ZC0, ZC10, and ZC90, respectively. The particle size
reduced by increasing the doping of calcium oxide in ZC10
and ZC90 samples may be due to the saturation occurred
by calcium doping and this explanation agreed with those
recorded by various authors [33, 34].
Zeta potential of nano‑sized samples
The prepared zinc calcium oxide ceramic samples in
nanometer range were further characterized by measuring
the zeta potential. The obtained data showed that all the
measured samples have negative zeta potential with values
equal to − 12 ± 5.63, − 14.4 ± 4.95, and − 16.8 ± 4.22 mV,
for ZC0, ZC10, and ZC90, respectively as shown in Fig. 3.
Zeta potential reflects the surface charge of the developed
nanoparticles. The stability of ZnO-NPs is mainly affected
by the zeta potential of the prepared nanoparticles. The low-
est stability of ZnO NPs is observed at the isoelectric point
when the zeta potential is equal to zero, as the particles tend
Fig. 2  Particle size of zinc calcium oxide ceramic nanoparticles samples: ZC0 (A), (B) ZC10 and (C) ZC90
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Journal of the Australian Ceramic Society
to coagulate [6]. In contrast, the greater magnitude of zeta
potential will result in higher repulsion forces and more sta-
ble particle suspension will be produced [35]. On the other
hand, negatively charged nanoparticles have several bio-
medical applications as highlighted in several studies [30,
36–38]. For instance, Smeets et al. showed that nanoparti-
cles with negative Zeta potential were favorable over the
other charges for osseointegration of dental implants and
bone regeneration [37]. Additionally, the negative charged
nanoparticles can establish hydrophobic interactions with
bacteria as indicated by the recent study of Mahmud and his
colleagues [39]. Our fabricated ZC ceramic nanoparticles
showed negative zeta potential with higher magnitude, indi-
cating the stability of the produced nanoparticles ceramic
samples and their potential biomedical application.
Phase compositions (XRD)
Figure 4 represents the XRD pattern of calcined zinc cal-
cium oxide ceramic nanoparticles samples at 600 °C for
1 h. Generally, the XRD pattern for all ZC samples shows
strong and sharp peaks that confirm the presence of hex-
agonal wurtzite structure of ZnO as the main phase with
good crystallinity [32]. The pure zinc oxide sample for
ZC0 was composed of pure zincite ZnO phase without
any other phases according to ICDD card (01–089-1397)
which revealed the ZnO synthesized in nanocrystal size
with high purity as shown in Fig.  4. Interestingly, the
doping with calcium oxide in ZC10 and ZC90 ceramic
samples increases the intensity of peaks and indicates the
presence of pure zincite ZnO as the main phase with zinc
hydroxyl ­Z n 5(OH) 8Cl 2H 2O as secondary phase accord-
ing to ICDD card (01–074-3156) which is formed from
a chemical reaction between zinc and calcium chloride
during synthesis as seen in Fig. 4. This result is like that
Journal of the Australian Ceramic Society

Fig. 3  Zeta potential of zinc calcium oxide ceramic nanoparticles samples: ZC0 (A), ZC10 (B), and ZC90 (C)

Zn5(OH)8Cl2H2O Z Zincite Calcite Microstructure (SEM)

Z
ZC90
Z
Z
Figure  5 shows the SEM image of zinc calcium oxide
Z Z ceramic nanoparticles samples calcined at 600 °C for 1 h.
Z The SEM image was taken at × 12,000 and × 24,000 mag-
ZC10 Z Z nification. Figure 5(A–B) represents pure zinc oxide ZC0
Intensity(a.u)

Z Z
sample which appears as nanoflake-like structures in shape
Z and the size of the particles around ≈300 nm. On increasing
calcium oxide doped in ZC10 and ZC90 ceramic samples
Z occurs a decrease in particle size in grain with regular hex-
Z agonal shape. These particles have a size 226 nm, 148 nm;
ZC0 Z respectively, as seen in Fig. 5(C–F). This reduction in parti-
Z
cles size may be attributed to the distortion in the host ZnO
lattice by incorporating with ­Ca2+ in ZnO NPs surface area
10 20 30 40 50 60 that occurred in the reduction in nucleation process result-
2 ing in a decrease in particle size as shown in Fig. 5(E–F).
This behavior is in agreement with that reported by Hameed
Fig. 4  The XRD patterns of zinc calcium oxide ceramic nanoparticles et al. [18].
samples
Antimicrobial activity
recorded by Rosset et al. [9] that detects the same phase in
XRD observation by using ­CaCl2 as precursor in prepara- The antimicrobial activity of ZC ceramic samples was evalu-
tion for Ca-alloyed ZnO nanoparticles by sol–gel method. ated against two strains of the multi-drug resistant yeast C.
Also, traces amount of calcium carbonate as the calcite auris. The data exhibited in Fig. 6 showed that the 3 for-
phase appeared with increasing calcium oxide content in mula has potent activity against the two tested strains. For C.
ZC10 and ZC90 samples. A slight shift of the XRD peaks auris (CDC-B11903), the ­MIC50 for ZC0, ZC10, ZC90 were
can be noted, which may be due to the difference in ion 40.93, 77.51, and 44.76 µg/ml respectively. ­MIC50 is referred
size between zinc (1.42 Å) and calcium (1.94 Å). Fur- to the lowest concentration of the nanoparticles that inhibit
thermore, the increasing of calcium oxide doping in ZC 50% of the growing microorganism [4]. Additionally, ZC0,
samples is more effective for the stabilization of lattice ZC10, ZC90 were effective against C. auris (CDC-CAU9)
systems which increases the chemical bonds ionicity in with ­MIC50 equal 110.8, 167.6, and 101.9 µg/ml respec-
ZnO system [40]. tively. Furthermore, the prepared nanoparticles exhibited

13

Fig. 5  SEM photo zinc calcium
oxide ceramic nanoparticles
samples: (A–B) for ZC0, (C–D)
for ZC10, and (E–F) for ZC90
(A)
0.9ZnO-0.1CaO
(C)
0.1ZnO-0.9CaO
(E)
antibacterial activity against E. coli (ATCC 25922), and S.
aureus (ATCC 25923) as shown in Fig. 7. ZC0 showed bet-
ter activity against the two strains with ­MIC50 87.97 and
87.11 µg/ml against E. coli (ATCC 25922), and S. aureus
(ATCC 25923) respectively, while ZC10, ZC90 showed
comparable activity against the two strains with M ­ IC50
144.6, 116.7 µg/ml and 132.2, 139.9 µg/ml against E. coli
(ATCC 25922), and S. aureus (ATCC 25923) respectively.
The antimicrobial activity is considered the main biologi-
cal application of metallic nanoparticles. The most favorable
metallic nanoparticles for pharmaceutical application are the
ZnO-NPs for being safe, cheap, and FDA-approved to be used
as pharmaceutical excipients [41, 42]. Our antimicrobial data
showed that the prepared nanoparticles produced a potent effect
against the multidrug-resistant strain C. auris. The aforemen-
tioned strain is causing a major thread in the healthcare setting
[43]. It was observed that once C. auris is exposed to antifungal
13
Journal of the Australian Ceramic Society
ZnO ZnO
(B)
0.9ZnO-0.1CaO
(D)
0.1ZnO-0.9CaO
(F)
drugs, it can develop several resistance mechanisms to over-
come the antifungal pressure [4, 44]. The developed resistance
mechanism is mainly dependent on the upregulation/mutation
in the antifungal target genes [4]. To combat the aforementioned
resistance mechanism, it is advisable to use an antifungal agent
that targets multiple biomolecules to hinder the ability of C.
auris to develop acquired resistance [45]. Based on that, the
prepared nanoparticles in the current study would be the opti-
mal solution to overcome the acquired resistance mechanism
developed b C. auris. This is because ZnO in the nano range
is passively internalized within the microbial cells and releases
­Zn2+. The release of ­Zn2+ generates reactive oxygen species
and will induce disequilibrium in the zinc-mediated protein
­ n2+ can interact with cellular protein and lipids
activity. Also, Z
and induce metabolic pathway disruption [23]. Altogether, it
will induce oxidative stress and harmfully affect cellular DNA
replication that eventually kills the target microbe [46, 47]. The
Journal of the Australian Ceramic Society

ability of ZnO NPs to act on multi-biomolecules within C. auris

cells, makes it an ideal potential treatment for C. auris infection.

Conclusion

In the presented study, novel zinc calcium oxide (ZC)

ceramic nanoparticles in formula (1-x)ZnO–xCaO with
(x = 0, 0.10 and 0.90 mol.%) were produced by the sol–gel
method. Calcination temperatures (Tc) of 600 °C produced
particles at nano size unlike calcination at 500, and 550 °C.
Particles were negative in charge indicating the stability
of the produced nanoparticles. Also, XRD confirmed the
presence of pure zincite ZnO as the main phase with good
crystallinity. On increasing, calcium oxide doped in ZC10
and ZC90 ceramic samples, the particle size was decreased
with regular hexagonal shape in SEM images. The produced
ZC ceramic nanoparticles samples inhibited the growth of
the emergent multidrug-resistant Candida auris with ­MIC50
around 40 µg/ml. The bioactivity of the ZC ceramic nano-
particles was also confirmed against E. coli and Staphylococ-
cus aureus and also ZC0 showed better activity against the
two strains with ­MIC50 87.97 and 87.11 µg/ml against E. coli
Fig. 6  Antimicrobial activity of the prepared ZC nanoparticles against
Candida auris  (ATCC 25922), and S. aureus (ATCC 25923) respectively as
compared with ZC10 and ZC90. The produced nanoparticles
could replace the current antifungal drugs to combat the
emerging multidrug resistant C. auris instead of applying
the current antifungal drugs that exhibited minimum activity.

Acknowledgements  This work was supported by the National Research

Centre, Giza, Egypt.

Author contribution  A.E. Reda contributed to the study conception

and design. Material preparation, data collection and analysis were per-
formed by A.E. Reda. B. Fayed contributed to study the antimicrobial
activity. The first draft of the manuscript was written by A.E. Reda.
The final draft of the manuscript was written by B. Fayed. All authors
read and approved the final manuscript.

Funding  Open access funding provided by The Science, Technology &

Innovation Funding Authority (STDF) in cooperation with The Egyp-
tian Knowledge Bank (EKB).

Declarations 
Ethics approval  Not applicable: the research did not involve human
participants and/or animals. Approval for exempt from ethical review
No.: EX0030052023.

Consent to participate  All authors have agreed to participate in this

research.

Consent for publication  The article was written by the named authors,
who are all aware of its content and have given their permission for it
to be published.
Fig. 7  Antimicrobial activity of the prepared ZC nanoparticles against
Competing interests  The authors declare no competing interests.
E. coli and Staphylococcus aureus 

13

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