Open Ceramics 14 (2023) 100347

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Open Ceramics
journal homepage: www.sciencedirect.com/journal/open-ceramics

Effect of strontium and iron on the structural integrity and drug delivery
of Whitlockite
Sadaf Batool *, Zakir Hussain, Mah Rukh Rehman, Muhammad Umair Idrees
School of Chemical and Materials Engineering (SCME), National University of Sciences & Technology (NUST), Sector H-12, 44000, Islamabad, Pakistan

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

Handling Editor: Dr P Colombo Localized drug delivery is a promising approach to treat bone infections. An ideal scaffold should provide a good
regeneration environment and must be able to treat possible infections during healing. In this work, Strontium
Keywords: (Sr) and Iron (Fe) co-substituted whitlockite (WH) is prepared and comprehensively evaluated for the localized
Whitlockite drug delivery application. Strontium and iron are added in varying ratios to study the effect of foreign metal
Drug delivery
concentration on crystallinity, phase purity, and drug delivery of WH. The prepared bioceramics were analyzed
Bone Tissue Regeneration
using x-ray diffraction (XRD), Fourier transforms infrared spectroscopy (FTIR), and Scanning electron micro­
Bone infections
scope (SEM/EDS). The XRD and FTIR analysis confirmed that the strontium and iron addition did not form
secondary CaP phases. The in-vitro release study of the prepared samples showed a sustained release for 25 days
in all samples. Results demonstrated in the present study confirm the potential of prepared bioceramics for drug
delivery and biomedical applications.

1. Introduction Bone is a complex composite of different metals and organic com­

Bone tissue regeneration is the best alternative to autologous grafts
in reconstructive surgery [1]. An ideal scaffold should imitate the nat­
ural environment for the growth and repair of damaged tissues. Calcium
phosphates (CaPs) like hydroxyapatite (HA), Whitlockite (WH), and
β-tricalcium phosphate (β-TCP) are the material of choice for bone tissue
regeneration. Hydroxyapatite ((Ca3(PO4)5OH) and Whitlockite
((Ca18Mg2(HPO4)2(PO4)12) are the major CaP phases of hard tissues,
however, both have different physicochemical properties. Hydroxyap­
atite and β-TCP have been explored widely for bone tissue regeneration
and drug delivery applications; however, their poor mechanical
strength, less stability in physiological fluids and bio-inertness have
restricted their use for clinical applications. Whitlockite has not been
explored earlier due to difficulty in its synthesis. WH phase is stable
under a narrow range of pH, temperature, and time because the crys­
talline structure of WH is complex that possess many substitution sites
[2]. Recent studies have shown that WH can be synthesized in bulk
while biological studies [3–5] suggested that it could be the best alter­
native to other CaPs because it has negative surface charge, soluble in
physiological fluids and stable under acidic pH. It has magnesium as its
structural integral part that delays osteoporosis during later stages of
life. It’s mechanical strength is better compared to HA and β-TCP [6].
pounds. Along with CaPs, hard tissues have trace amounts of magne­
sium, iron, zinc, and strontium. These metals are commonly known as
therapeutic metals and play a significant role in the growth and stability
of bone tissue [1]. For example, zinc (Zn) activates aminoacyl-tRNA
synthetase that stimulates the synthesis of osteoblast cellular protein.
It also takes part in calcium ion signaling, and its deficiency plays a
pathophysiological role in bone regeneration [7,8]. Strontium (Sr) acts
as a calcium-sensing receptor of bone growth and promotes the trans­
duction of mitogen-activated kinase signals. It restricts bone dissolution
by increasing osteoblast production while inhibiting osteoclast growth
and promoting vascularization during bone development [9]. Iron (Fe)
is biocompatible, antimicrobial, non-cytotoxic, and used to improve the
mechanical strength of the scaffolds [10]. Magnesium (Mg) plays a
critical role in bone metabolism, and its deficiency activates the para­
thyroid hormone that stimulates RANKL protein and decreases osteo­
protegerin production. It leads to a decrease in bone mass that results in
osteoporosis [11]. These therapeutic metals assist the natural regener­
ation system for fast healing [1]. These metals have been added to CaPs
to improve their physical and biological properties [1,8,9,12–15]. They
are economical compared with biomolecules added to scaffolds to
improve the regeneration and signaling process as special processing
conditions are required to avoid denaturation of biomolecules [1].

* Corresponding author.
E-mail addresses: sbatool.phdscme@student.nust.edu.pk (S. Batool), zakir.hussain@scme.nust.edu.pk (Z. Hussain).

https://doi.org/10.1016/j.oceram.2023.100347
Received 30 October 2022; Received in revised form 18 March 2023; Accepted 21 March 2023
Available online 22 March 2023
2666-5395/© 2023 The Authors. Published by Elsevier Ltd on behalf of European Ceramic Society. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Batool et al. Open Ceramics 14 (2023) 100347

Besides these attributes, such materials can be modified selectively to
create scaffolds for specific applications [15]. Hence, adding trace ele­
ments in CaPs based scaffolds is ideal for imitating natural bone
environments.
The other critical factor that constructive surgery needs to address is
bacterial infections. These are the major complications in critical size
defects. The biofilm can develop on the surface of scaffolds, at the
scaffold tissue interface, and at a defective site that could lead to failure
of the scaffold and is toxic to surrounding tissues [16]. The bacterial
pathogens S. aureus, S. epidermidis, P. aeruginosa, and P. mirabilis are
found in bone infections. Ciprofloxacin (CP) is currently the most used
fluoroquinolone to treat bone infections because it is highly effective
against bone pathogens, and its minimum inhibitory concertation is very
low i.e. 0.25–2 μg/ml [17]. Recent studies have shown that localized
treatment of the infected bone is more appropriate than a regular
administration system with severe disadvantages like low accessibility
to the infected zone, damaging healthy tissues, and inducing pathogenic
resistance [18]. The drug-containing scaffold treat infected bone and
provide a sustained drug release to prevent further infections during
regeneration [19]. Previous studies have shown that composite scaffolds
of hydroxyapatite containing CP have been used to treat infectious bone
[20–25].
Here, in this study, we aimed to explore the effect of the addition of
Sr and Fe on the phase purity, crystallinity of WH along with the
comparative effect of these metals on the drug delivery capability of
WH. Previous studies on the incorporation of strontium (Sr) and iron
(Fe) in HA have confirmed that Sr and Fe competes with calcium and
change the growth mechanics of HA at lab scale, leading to the forma­
tion of amorphous mixed phases of CaPs but its presence improves the
drug delivery ability of HA [7]. In native bone, during mineralization of
WH, magnesium (Mg) competes with calcium, blocks the growth of the
0001 facets, restricts the growth of HA and forms rhombohedral crystals
of bone WH [13,26]. Therefore, effect of Sr and Fe on phase purity,
growth mechanics, and drug delivery potential of WH on lab scale must
be studied and in this work we presented these results. To the best of our
knowledge, no such investigation on incorporating Fe and Sr in WH for
drug delivery of ciprofloxacin has been reported earlier.
added in varying concentrations (Table 1) following previously reported
work with HA [27].
3. Characterization
3.1. Physicochemical characterization
The prepared products were characterized using different tech­
niques. Phase analysis of pristine WH and Sr/Fe/WH bioceramics was
carried out using an X-ray diffraction machine (DRON-8 Bourevestnik,
Saint-Petersburg, Russia). Fourier Transform Infrared Spectroscopy
(FTIR) analysis was done using PerkinElmer, spectrumTM100 spectro­
photometer by employing KBr pellet method. To confirm the elemental
composition and morphology of the pristine WH and Sr/Fe/WH bio­
ceramics, scanning electron microscopy (SEM) and EDS analysis was
done using JEOL JSM-64900 machine. BWS 415-532S–I (Newark NJ,
USA) raman spectroscope was used to confirm the functional bonds of
bone WH.
3.2. In-vitro drug release study
The drug release potential of the prepared bioceramics was carried
out in phosphate-buffer saline (PBS) solution. Ciprofloxacin (CP) and
prepared bioceramics under investigation were mixed in 1:2. Pellets of
9.68 mm diameter and 2.43 mm thickness were made by applying a 2-
ton load for 1 min using a hydraulic press. Then the drug-loaded pel­
lets were immersed separately in 100 mL of PBS (pH 7.34 ± 0.06). All
drug-loaded samples were placed on an orbital shaker at 100 rpm for 25
days. An aliquot of 2 mL was taken from the dissolution medium at
different intervals, and in-vitro drug release was calculated by
measuring absorbance at λmax of CP using a UV–visible spectrometer
(Optima SP-3000DB). The concentrations of drug release were deter­
mined using the following formula.
Absorbance at time (t)
Drug Release(%) =
Absorbance of pure drug
x100

4. Results
2. Materials and methods

4.1. Whitlockite nanoparticles

2.1. Materials

The x-ray diffractogram (Fig. 1 (a)) shows the characteristic peaks of

Ferric chloride hexahydrate (FeCl3.6H2O) was purchased from Dae­
WH at 22.0 , 25.9 ,28.0 , 31.2 , 32.7 , and 34.6 with hkl (024), (1010),
◦ ◦ ◦ ◦ ◦ ◦

jung (South Korea), Strontium nitrate hexahydrate (Sr(NO3)2.6H2O)

(214), (2010), (128), (220) matched exactly with JCPDS (01-070-2064
from Sigma Aldrich (Germany), and Orthophosphoric acid from Hon­
and 00-042-0578) and literature [28,2,29] that confirms the formation
eywell (USA), Calcium hydroxide from GPR Rectapur, and Magnesium
of single-phase WH crystals. To further confirm phase purity, Raman and
hydroxide from Duksan (South Korea). The drug was gifted from the
FTIR analysis of the prepared pristine WH NPs were performed. In the
local pharmaceutical industry (A&K Pharmaceuticals, Sargodha
FTIR spectrum (Fig. 1 (b)), the peak at 872 cm− 1 is characteristic of the
Pakistan), and all the chemicals were used as received without any
HPO2−4 group, again confirming the formation of bone WH. The
further processing.
stretching vibrations at 1120 cm− 1, 1029 cm− 1, 963 cm− 1, and 606
2.2. Preparation of pristine whitlockite and Sr/Fe Co-substituted WH
nanoparticles (NPs) Table 1
Concentration of precursors for the preparation of various WH bioceramics.

Whitlockite was prepared using the wet precipitation method re­ Composition Molar Concentrations M* (Ca
+ Mg
ported in our previous work [2]. Briefly, 0.13 M solution of Mg (OH)2
Sr +
and 0.37 M Ca (OH)2 was prepared, mixed, and stirred for 20 min at Fe)
40 ◦ C followed by addition of 0.5 M H3PO4 at the rate of 10 ml/5min.
Ca Mg H3PO4 FeCl3.6H2O Sr M*/P
Under constant stirring, until the mixture attains pH 5. This mixture was
(OH)2 (OH)2 (NO3)2.
then heated at 100 C in an oil bath for 10 h with subsequent ageing and
◦
6H2O
without stirring at room temperature. The precipitates were filtered,
WH 0.37 0.13 0.5 – – 1.00
washed thrice with deionized water, and dried overnight at 50 ◦ C to Sr/Fe-1 0.27 0.13 0.5 – 0.100 1.00
obtain WH NPs. To prepare Sr/Fe/WH bioceramics, the same procedure Sr/Fe-2 0.27 0.13 0.5 0.025 0.075 1.00
was repeated by keeping the Ca + Mg + substituent/P ratio constant. Sr/Fe-3 0.27 0.13 0.5 0.050 0.050 1.00
The desired molar concentration of Fe and Sr were added at step two Sr/Fe-4 0.27 0.13 0.5 0.075 0.025 1.00
Sr/Fe-5 0.27 0.13 0.5 0.100 1.00
when the calcium and magnesium mixtures were mixed. Sr and Fe are
–

2
S. Batool et al. Open Ceramics 14 (2023) 100347

Fig. 1. (a) XRD of WH NPs (b) FTIR spectrum of WH NPs. (c) Raman spectrum of WH NPs (d SEM image of WH NPs).

cm− 1 are due to the PO3−4 group. The absence of a peak at 650 cm
− 1

confirms the phase purity of the synthesized WH since these are the
characteristic peaks of the secondary CaP phase i.e. HA [2,30]. The
Raman spectrum (Fig. 1 (c)) shows a broad peak at 962 cm− 1 which is
characteristic of ʋ1 vibration of a PO3−
4 , a group of bone apatite. The
broad peak confirms formation of the WH phase as HA and β-TCP show a
sharp peak at 962 cm− 1. The peak at 586 cm− 1and 432 cm− 1 is ʋ4 and ʋ2
vibrations of the PO3−
4 group. No significant difference is present in HA,
β-TCP and WH at ʋ4 and ʋ2 according to literature that could be because
it is of PO3−
4 group that is characteristic of all CaPs [2,31]. The SEM
images (Fig. 1 (d)) of WH exhibited a mixed rhombohedral and cubic
shape [2,4,32].

4.2. Sr/Fe substituted WH NPs

The XRD analysis of Sr and Fe substituted WH show no significant

change from pristine WH (Fig. 2). However, a slight change in peak
intensity is observed after adding iron to WH, leading to the formation of
amorphous mixed WH phases at maximum substituent concentration.
This confirms the substitution of Fe in the WH crystal lattice or on its
surface [9,14,27,33]. In the case of strontium, the x-ray diffractogram
Fig. 2. XRD of prepared Bioceramic containing Iron and Strontium.
matched exactly with the WH phase, confirming magnesium’s domi­
nance over strontium in forming a WH phase. However, peak broad­
minerals, bone are all different in chemical composition i.e. all contain
ening appeared at the highest concentration of iron and in the absence of
different mono, divalent ions along with calcium and phosphate [6].
strontium, i.e., Sr/Fe-5. It is assumed that iron could have competed
In Sr/Fe-5 bone WH is the dominant and magnesian Whitlockite
with magnesium to substitute in WH crystal lattice and led to the for­
[35–37] is a minor phase. The absence of characteristic peak for stron­
mation of mixed WH phases. In native bone, although all essential
tium (27.4 , 31.5 , 34.8 , 40.5 ,49.9 ) [9] and iron (36 , 41 , 49 , 54 ,
◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦

metals are present but precipitation of Mg-WH (bone WH) occurs only
59 , 66 ) [13] confirms the dominance of whitlockite single phase only.
◦ ◦

which could be due to the enzymatic factors that are involved in the
The FTIR analysis of prepared Sr/Fe WH (Fig. 3) bioceramics also
precipitation of bone minerals. Jensen et al. has reported that the
confirms that strontium has not replaced calcium in WH crystal lattice,
probability of formation of any whitlockite structure in a system con­
nor did any secondary iron and strontium phases are present in the
taining zinc, sodium, magnesium, iron is same [34]. However, Con­
system. The FTIR spectrum showed a characteristic peak at 1029 cm− 1
centration of ions in a reaction system favors the precipitation of desired
which is characteristic of ʋ3 vibration of a phosphate group (PO3−
4 ). The
whitlockite. Therefore, whitlockites exist in asteroids, earth crust,

3
S. Batool et al. Open Ceramics 14 (2023) 100347

vibration of the HPO2−4 group [38,39], confirming the formation of the

whitlockite crystal system only. The absence of peaks at 433, 543, and
613 cm− 1 confirms the absence of iron and strontium oxide phases. Also,
the absence of peaks 650 cm− 1 in all prepared bioceramics confirms the
absence of the HA phase [40]. Moreover, the absence of peak a of 725
cm− 1 also confirms the absence of the β-TCP phase in our prepared
system, forming only WH phase in all batches. However, some variations
in the FTIR spectrum could be due to the presence of Sr and Fe on the
surface of WH, which can be called as substitution effect [27,10].
In the SEM analysis, Fe and Sr doped WH (Fig. 4.) showed mixed
morphology [27,9]. Agglomeration in all samples could be due to the
absence of any stabilizing agent in the reaction media and adsorption of
Fe and Sr species on the WH crystal lattice. The EDS analysis of pristine
WH, Sr/Fe-1, and Sr/Fe-5 (Table 2) was also carried out to confirm the
substitution of iron and strontium in WH.

Table 2
EDS analysis of Pristine WH, Sr/Fe-1, and Sr/Fe-5 Bioceramic.
Compound Elements (wt %)
Fig. 3. FTIR spectrum of prepared Bioceramic. Mg Ca P O Sr Fe

WH 0.49 27.33 17.2 44.99 – –

peaks at 963 and 606 cm− 1 are associated with ʋ1 stretching and ʋ4 Sr/Fe-1 2.08 6.81 16.4 36.80 0.95 –
bending vibration of the O–P–O bond of the phosphate group. The Sr/Fe-5 1.45 2.46 15.8 33.73 – 0.20
characteristic peak of WH appeared at 872 cm− 1, which is the stretching

Fig. 4. SEM images of Fe and Sr doped WH.

4
S. Batool et al.
4.3. In-vitro drug release studies of WH systems
Role of Fe and Sr addition in the WH system for the release of CP was
carried out for all the compositions prepared (Fig. 5 a, b). Pristine WH
released 16% drug within the first 12 h of incubation and the percent
release increased with an increase in the substituent concentration.
Pristine WH exhibited the slowest release while Sr/Fe-5 the fastest
among all the bioceramics under investigation. The drug release study
was conducted for 25 days, the optimum healing time for damaged
bone, and all prepared scaffolds showed a sustained release for the
specified period [41]. After 25 days of immersion, pristine WH released
85.34%, Sr/Fe-1 92.435%, Sr/Fe-2 94.387%, Sr/Fe-3 90.325%, Sr/Fe-4
97.895%, Sr/Fe-5 98.974% of the drug. The drug release of Sr/Fe-4 and
Sr/Fe-5 was fast in the first ten days of immersion. However, the release
of a drug became slower and sustained later, leading to an almost
complete discharge from the bioceramic matrix after 25 days of im­
mersion. Sr/Fe-3 showed an optimum release speed among all the bio­
ceramics under investigation, not too fast like Sr/Fe-5 and not too slow
like pristine WH.
5. Discussion
Strontium and iron have inhibitory effects on the crystallization ki­
netics of calcium phosphates according to literature. The divalent and
trivalent metals compete with calcium during crystal growth of HA and
β-TCP to replace it [42,9,13]. Reported literature suggests that the
reduction in the number of peaks of HA after adding Fe and Sr confirms
that iron and strontium are loaded into the crystal system [10]. More­
over, the addition of these foreign metals results in a decrease in crys­
tallinity. This decrease in crystallinity is evident in the replacement of
calcium ions by strontium [33]. However, in our prepared bioceramics,
the absence of any other CaP phase in samples confirms the structural
integrity of WH phase among all other CaPs. However, the decrease in
peak intensity and increase in peak broadening in the presence of Fe
confirm that iron could have substituted at partial empty Ca(IV) position
in WH crystal lattice. However, the substitution was not dominant
enough to be observed in XRD analysis, even at the highest concentra­
tion. In the case of strontium, no significant change in x-ray diffracto­
gram appeared than pristine WH.
It is reported that WH crystal structure can be formed by incorpo­
rating sodium [43], iron [44], and zinc [12] in calcium phosphates
during crystal growth. Magnesium occupies an octahedral position in
WH, giving rhombohedral crystal lattice extra stability [45]. It sub­
stitutes calcium partially at Ca (IV) and completely at Ca (V). The other
divalent and trivalent metals can only substitute calcium partially at the
Ca (IV) position. The replacement at the Ca (IV) position distorts the WH
crystal structure and leads to the formation of mixed WH phases [46].
Also, the addition of foreign specie in WH crystal lattice and formation
of specific WH structures depends upon the size, charge density, and
Fig. 5. In-vitro drug release study of prepared bioceramics.
5
Open Ceramics 14 (2023) 100347
concentration of the foreign specie [47]. Watmough P. reported that a
system containing iron, sodium, magnesium, zinc, and any divalent
metal has equal ability to form a WH crystal system, but the metal
present in large fractions will dominate others. He also reported that the
XRD pattern of all WH containing iron, sodium, zinc, and magnesium is
the same; however, small peaks towards lower and higher angles can be
observed for differentiating. This peak shift depends upon the size and
density of the foreign specie replacing calcium at Ca (IV) and Ca (V)
positions [34]. In our prepared bioceramics, the peak shift towards a
lower or higher angle was not observed, confirming the incorporation of
magnesium only in the WH crystal lattice. There are very few reports on
the doping of WH compared with other CaPs. Recently, doping of cerium
[48] and Eu3+/Tb3+ [16] in WH has been done, and the XRD pattern
showed no significant change in the diffraction angle after the addition
of metals. Results confirmed WH crystal lattice’s stability because
magnesium dominates other metals in replacing calcium to form a stable
WH phase. As in a native bone, magnesium compete with calcium and
replaces it at Ca (IV) and Ca (V) positions to restrict HA phase formation
[49]. This observation can also be related here as magnesium is present
in large quantities, and native bone contains strontium and iron, but no
iron or strontium WH formed there [34]. Thus, magnesium dominates
other metals and forms bone WH in natural and synthetic systems.
However, iron has affected the crystal growth of WH to some extent.
This could be because of the size of strontium ion (132 p.m.), much
larger than that of magnesium (79 p.m.) and iron (78.5 p.m.). Therefore,
strontium ion might be just adsorbed on the surface of WH, the XRD
pattern of WH is the same in the case of strontium addition, and with the
addition of iron, no significant change is observed at lower concentra­
tions. However, at higher concentrations, the amorphous and broad
peaks appear that suggest some substitution of iron in WH crystal lattice
at Ca (IV) as both Mg and Fe have almost equal ionic radii. Therefore,
substitution chances are maximum. However, the characteristic peak of
WH that appeared at Sr/Fe-5 confirms the dominance of magnesium.
Iron partially replaced calcium at Ca (IV), resulting in the formation of
amorphous mixed WH phases in Sr/Fe-5. The FTIR results showed a
slight change in peak position for example the peak for WH appeared at
1029 cm− 1 while in case of substituted WH the peak shifted from 1029 to
1031, 1032 cm− 1. These slight changes in peak positions could be due to
adsorption of Sr and Fe ions on WH crystal surface that transmitted the
striking beam to a different angle. The EDS analysis of the highest Sr and
Fe concentration samples confirms the presence of iron and strontium.
The EDS analysis of Sr-1 and Sr-5 samples was done because they
contain the highest content of substituents. However, there is no
confirmed evidence that Fe has substituted in the WH crystal lattice.
However, a slight change in peak position in XRD and FTIR analysis
confirms that some adsorption of these substituents have occurred.
There is a possibility that strontium get absorbed on the surface of WH
only due to negative surface charge that appears in the Energy-
dispersive X-ray spectroscopy (EDS) analysis while it did not affect
S. Batool et al.
crystal growth significantly. However, a change in XRD peaks suggest
that iron might have substituted Ca (IV) position slightly. But the XRD
data did not confirm this hypothesis significantly therefore, it is a gen­
eral assumption that iron and strontium are adsorbed on the surface only
[10,14,50].
The drug release efficiency of the bioceramics understudy also sup­
ports the adsorption of Sr and Fe on the surface of WH. WH has a
negatively charged surface. CP has anionic carboxylate and cationic
amine groups with a strong affinity with the charged surfaces. The drug
could have made a non-covalent interaction with negatively charged
WH surface during compression molding that resulted in slow release of
drug from pristine WH scaffold. However, in the presence of Sr and Fe,
there is a gradual increase in the drug release with an increase in sub­
stituent concentration. The increase in drug release in the presence of Fe
and Sr could be due to the less availability of charged sites for the drug to
interact as metals are adsorbed on the WH surface. To confirm this
theory, we prepared strontium hexaferrite using the sol-gel auto-com­
bustion method (SI). Using the uniaxial hydraulic press method, an
equal amount of pristine WH, strontium ferrite, and the drug were taken
to form the pellet. The prepared scaffold was immersed in PBS for 25
days and the drug release potential was measured after regular intervals.
The comparative analysis of Sr/Fe substituted WH and ex-situ prepared
strontium ferrite/WH composite suggested that the ex-situ prepared
strontium ferrite has released the drug at a faster rate and more than
90% of the drug was released after 15 days of immersion (SI). Thus, the
highly magnetic strontium ferrite interacts with negatively charged WH
[51] during compression, leaving very few or no sites for the drug to
interact. This led to a fast and earlier release of the drug.
The drug released after 12 h of immersion in all bioceramics under
investigation is enough to treat infection at the infected site. The gradual
release over 25 days inhibits the growth of bone, infecting microbes
during healing. The onsite drug delivery system throughout the healing
period effectively avoids bacterial growth and prevents the toxic effects
of drugs on the healthy tissues as well. The oral administration damages
healthy tissues and the amount of drug that does not reach the infected
site, resulting in poor bone growth during the healing process. The drug
release speed was optimum in Sr/Fe-3 composite, where an equimolar
ratio of Sr and Fe is loaded in the WH system. Sr/Fe-4 and Sr/Fe-5
exhibited a fast release after ten days of immersion, following slow
release till 25 days. The initial fast release from the matrix could be due
to the drug’s presence on the pellet’s surface. All prepared bioceramics
and new WH are effective for sustained drug delivery to the infected site.
The slow and sustained release of the drug is a promising aspect of
prolonged antibiotic therapy for the treatment of osteomyelitis [52,53].
6. Conclusions
Reported data confirm WH’s structural stability and integrity
compared with other CaPs. It can be concluded that strontium did not
replace calcium in WH crystal lattice but only adsorbed on the surface.
However, iron in higher concentrations was slightly successful in
replacing calcium resulting in the formation of mixed WH phases. The
prepared composites showed a slow and sustained release of the drug for
25 days. The drug-released potential of prepared bioceramics increased
gradually with an increase in the Fe and Sr concentrations which com­
plements well with physicochemical analysis. The best drug release re­
sults were observed in Sr/Fe-3 composite, where the strontium and iron
are added to WH reaction media in equimolar concentrations. The drug
release in Sr/Fe-3 is optimum, not too fast, and nor too slow compared
with all the prepared scaffolds. Based on the obtained results, it is sug­
gested to perform a comparative analysis of the role of therapeutic
metals in bone development and on the physicochemical properties of
CaPs to better understand their addition to artificial scaffolds. Also, a
real-time study of divalent and trivalent metals’ addition in WH can give
a deeper insight into the role of magnesium in the crystal growth of WH
and its biological properties.
6
Open Ceramics 14 (2023) 100347
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgements
This research was conducted at the School of Chemical and Materials
Engineering (SCME), National University of Sciences and Technology,
Sector H-12, Islamabad. Authors acknowledge the financial and
administrative support from the SCME, NUST. Authors also acknowl­
edge support from Dr. Irshad Hussain, LUMS, Lahore for SEM analysis of
Whitlockite and Dr. M. Aftab Akram, SCME, NUST for Raman analysis of
the sample. The authors are also grateful to the JECS Trust for funding
(Contract no. 2022294).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.oceram.2023.100347.
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