Ceramics International 46 (2020) 17149–17175

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Ceramics International
journal homepage: www.elsevier.com/locate/ceramint

Review article

Hydroxyapatite derived from food industry bio-wastes: Syntheses, properties T

and its potential multifunctional applications
Soo-Ling Bee∗, Z.A.Abdul Hamid∗∗
School of Materials and Mineral Resources Engineering, Engineering Campus, Universiti Sains Malaysia, 14300, Nibong Tebal, Penang, Malaysia

ARTICLE INFO ABSTRACTS

Keywords: Food industry's wastes such as eggshell, bones and seafood shells that are usually piled up in landfill can indeed
Hydroxyapatite serve as an excellent precursor to form bioceramic materials such as hydroxyapatite owing to its high calcium
Food industrial wastes content. The present manuscript is aimed to provide a comprehensive overview on the utilization of various food
Biomedical application industry's bio-waste in producing hydroxyapatite. Properties of hydroxyapatite prepared using different bio-
Bone tissue engineering
waste sources will be thoroughly discussed with respect to different preparation methods used. In addition, this
Drug delivery
review also explores the potential employment of different biowaste-derived hydroxyapatite in multidisciplinary
Adsorbent
fields, including biomedical (bone tissue engineering, metallic implant coating, drug delivery) and environ-
mental pollution remediation applications. The concept of transforming bio-waste into hydroxyapatite is not
only promising in addressing the environmental issues caused by waste disposal but also creating an economic
opportunity to manufacture products required for pharmaceutical and environmental-related industries.

1. Introduction
Rapid development in animal agriculture and food industry have led
to the large-scale production of wastes all over the world. The inedible
by-products deriving from slaughterhouse, catering, baking and food
processing industries which are of no economic value, such as bones,
seafood shells and eggshells will be usually regarded as wastes and
discarded in landfill without fully utilizing it. Improper management of
these food wastes will lead to numerous undesirable environmental
consequences such as the spreading of risk pathogen, emission of nox-
ious odours and tendency to leach pollutants into the environment
[1,2]. Driven by environmental and economic consideration, a vast
number of research attentions have been devoted to the proper man-
agement and recycle of these by-products in order to reduce their waste
output. In many cases, these by-products can serve as potential pre-
cursor to be converted into value-added products, for instance, as an
inexpensive source of calcium to form calcium phosphate materials
[3,4].
Among various members of calcium phosphate family, hydro-
xyapatite (HAp) is considered as one of the most potent bioceramics
used in biomedical applications particularly for dental and orthopaedic
fields owing to its biocompatibility, non-toxicity, osteointegration and
osteoconductivity [5,6]. Due to its structural and chemical composition
that resemble the mineral phase of natural bone, HAp can promote
rapid bone regeneration and direct strong bonding to host tissue
without the need of intermediate connective tissues [7]. Furthermore,
HAp also serves as a source of Ca2+ and PO43− ions upon dissolution in
biological fluid, therefore useful to mediate multiple cellular responses
such as cell proliferation, osteogenesis and bone metabolism [8,9]. Over
the years, many researchers attempt to tailor the biological perfor-
mance (bioactivity, cellular activity and antimicrobial properties) of
synthetic HAp by incorporating different kinds of anions and cations
such as Ag+, Cl−, F−, Mg2+, Sr2+ and Zn2+ into its crystal structure to
form ions substituted HAp [10–14]. Till now, synthetic HAp has been
widely applied as a biomaterial to fabricate artificial bone substitute or
scaffold for orthopaedic, periodontal reconstruction and alveolar ridge
augmentation [15–17]; as a biocompatible coating for metallic implants
[18]; or as a drug vehicle of antibiotics and chemotherapeutics to treat
bone-associated disease [19,20].
On the other hand, its inherent chemical characteristics such as
thermal and chemical stability, acid-base properties, low solubility,
great adsorption capability and ion-exchange ability make it pertinent
not only for biomedical application, but also serve as an effective ad-
sorption and stabilization medium for the removal of harmful con-
taminants in the field of water and wastewater treatment [21,22].
Generally, HAp can be fabricated in crystalline or amorphous, dense or

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: sooling0427@gmail.com (S.-L. Bee), srzuratulain@usm.my (Z.A.A. Hamid).

https://doi.org/10.1016/j.ceramint.2020.04.103
Received 15 February 2020; Received in revised form 3 April 2020; Accepted 9 April 2020
Available online 15 April 2020
0272-8842/ © 2020 Elsevier Ltd and Techna Group S.r.l. All rights reserved.
S.-L. Bee and Z.A.A. Hamid
porous forms and used in the form of blocks or scaffolds, fibers, ce-
ments, coatings and nano- or micro-particles [23–25].
Depending on the application, there is often a need to tailor the
physicochemical properties of HAp [26]. This is because the properties
of HAp such as particle size, Ca/P molar ratio, phase composition,
porosity and surface area will have a direct influence on its adsorption
efficiency and biological properties. For instance, nanocrystalline HAp
with higher surface area and smaller particle size can offer better
sorption capacity and cell compatibility to be applied as adsorbent and
biomaterial [27,28].
While most of the commercial synthetic HAp used today involves
chemical methods that requires expensive reagent graded chemicals, it
can also be derived from natural bio-resources [29]. In recent years,
various bio-wastes produced from food industry including bovine bone
[30], pig bone [31], chicken bone [32], fish bone [29], fish scale [33],
eggshell [34], mussel shell [35], clam shell [36], snail shell [37], oyster
shell [38], abalone shell [39] and etc. have been extensively used to
form HAp. The conversion of these bio-wastes into HAp is desirable not
only as a waste management strategy to reduce the environmental
impact but also economically feasible to reduce the cost of HAp pro-
duction [29].
In the past few years, there are several interesting literatures re-
viewing the synthesis of HAp from myriad natural resources, where
most of them focused on the sole natural bio-wastes such as fish bone or
eggshell [40–42]. Despite this, to date, there is lack of comprehensive
and critical reviews on the formation of HAp derived from all types of
bio-wastes as well as detailing its future potential applications in var-
ious material fields.
Herein, we are going to explore into the recent studies related to
HAp derived from food industry bio-wastes. As in the first part of the
review, we are going to provide an insight into the structural properties
of HAp in order to possess a better understanding for its subsequent
application. Thereafter, classification of HAp based on its preparation
from different types of bio-wastes source will be discussed. Particularly,
the effect of bio-waste sources and processing methods on the proper-
ties of the resulting HAp such as Ca/P molar ratio, crystallinity, particle
size, morphology and phase composition will be highlighted and ad-
dressed extensively. Finally, the potential functionality of bio-wastes-
derived HAp in various fields, including biomedical (bone tissue en-
gineering, implant coating and drug delivery) and environmental re-
mediation applications will be discussed in this review.
2. Structure of HAp
In general, the crystal structure of stoichiometric HAp
[Ca10(PO4)6(OH)2] encompasses a compact assemblage of phosphate
(PO43−) tetrahedra held together by Ca2+ ions interspersed among
them, where the Ca2+ cations can be located in two possible sites, i.e.
Ca(I) and Ca(II) sites. In Ca(I) site, the Ca2+ ions are coordinated by
nine oxygens belonging to six PO43− tetrahedra in a columnar ar-
rangement parallel to c-axis. Meanwhile, Ca2+ ions at Ca(II) site are
coordinated by seven oxygen atoms (six belonged to the PO43− tetra-
hedra and one to hydroxide ion (OH−)), which then form alternate
equilateral triangles and staggered along the c-axis. The large size of Ca
(II) triangle in the crystal lattice endow the mobility of OH− anion
along the column axis [29,43]. Typically, stoichiometric HAp which
contains Ca/P molar ratio of 1.67, is belonged to hexagonal crystal
system and displays two principal crystal planes: a- and c-plane as de-
picted in Fig. 1. It is noted that a-planes is mainly composed of Ca2+
ions and thus positively charged, whereas c-planes is negatively
charged as it is rich in PO43− ions. As a result, HAp surfaces show
anisotropic properties such as anisotropic adsorption profiles toward
biomolecules [44].
Due to the intriguing structure of HAp, it enables a great number of
cationic and anionic substitutions to transpire within its lattice that
leads to the existence of non-stoichiometric HAp, forming either Ca-
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deficient (Ca/P < 1.67) or Ca-rich (Ca/P > 1.67) HAp. Indeed,
natural HAp is non-stoichiometric in nature as it is often associated
with trace amount of elements such as Mg2+, K+, Na+, Zn2+, Sr2+, F−
and CO32− multi-substituted in its crystal lattice. Hence, it can be ex-
pressed in the following general formula: (Ca,M)10(PO4,Y)6(OH,Z)2,
wherein M represents monovalent (Na+, K+ ions) or divalent (Mg2+,
Zn2+, Sr2+ ions) cations that can substitute Ca2+ ions in the lattice, Y
represents anionic elements such as CO32− that can substitute for
PO43− ions and Z can be monovalent (F−, Cl− ions) or divalent (CO32−
ions) anions that substitute for OH− site [45].
Usually, the CO32− content in biological apatite of bone mineral
varies according to age and its constitution ranges from 2 to 8 wt%
[46,47]. Considering the structure of HAp, the CO32− ion can substitute
and accommodate at two possible anionic sites in the apatite lattice: (i)
at the OH− location to form A-type carbonated HAp and (b) at the
PO43− position to form B-type carbonated HAp [48]. Simultaneous
substitution of CO32− ions at both OH− and PO43− position is termed
as AB-type carbonated HAp [49]. Ion substitution phenomenon can
profoundly influence the resulting crystal changes (e.g. alteration of
lattice parameters, charge imbalance, vacancies formation and crys-
tallinity), solubility and bioactivity of HAp, leading to major changes in
biological activity which will affect its usage in biomedical application
[50,51].
3. Fabrication of HAp from food bio-wastes
Generally, HAp can be obtained from natural bio-waste resources
which will either act as calcium phosphate (CaP) or mere calcium (Ca)
sources. The bio-waste that serves as CaP source often involves the
complete extraction of HAp from bio-waste without the necessity of
further reaction. Meanwhile, the latter involves extraction of Ca source
(e.g. CaCO3) from the bio-wastes where additional reaction step with
phosphorous precursors is requisite to form HAp. It is worthwhile to
mention that the bio-wastes nature, age, the presence of trace elements,
extraction method and processing condition used will affect the final
properties of HAp [52,53]. The Ca/P ratio of HAp formed from bio-
wastes usually deviates from stoichiometric HAp (1.67) depending on
the availability of trace elements, which varies from different types of
natural resources [54]. Fig. 2 delineates two different groups of bio-
waste sources that can be employed to form HAp.
3.1. Bio-wastes that serve as CaP source
This type of bio-waste source includes animal bone (e.g. bovine,
porcine, caprine, galline and fish bones) and fish scale. Since bone and
fish scale are primarily made up of inorganic material (CaP) and or-
ganic components (collagen, proteins, lipids and polysaccharides), they
have been widely employed as a source of CaP to form HAp [55,56].
Formation of HAp based on this class of bio-waste sources usually in-
volves approaches that eliminate organic matter from the mineral
matrix in order to directly obtain HAp. Among common techniques that
can be employed to extract HAp from this class of bio-wastes include
thermal calcination, subcritical water, alkaline heat hydrolysis and
combination of these methods.
3.1.1. Animal bones waste
Mammalian (such as bovine, porcine and caprine) and galline bones
are two kind of widely available by-products from meat production
which can be used as precursor to form HAp. Among numerous bone
wastes, bovine bone remains the most well-established natural source
used to extract HAp due to the consideration of practical aspect in term
of its size, abundancy and structural resemblance to human bone
[57,58]. Usually, the diaphysis of animal femur bone is used for HAp
formation, where the spongy bone will be removed to acquire only
cortical segment. Prior to the extraction process, all collected bones are
often subjected to a series of preliminary cleaning procedures including
S.-L. Bee and Z.A.A. Hamid
Fig. 1. Hexagonal crystal structure of stoichiometric HAp, where a-plane is Ca site (positive charge) and c-plane is PO43− site (negative charge) [44].
boiling and chemical washing (using chemicals such as acetone, al-
cohol, chloroform, hydrogen peroxide, salt or alkaline solution) for the
following reasons: (1) degreasing purpose, (2) to soften the bone for the
ease of cutting, (3) to allow easy removal of adhered soft tissues and
bone marrow from the bone samples and (4) bone deproteinization
[59,60]. Alternatively, organic residues from the bone samples can be
further removed by burning the bones sample under direct fire or gas
torch flame as reported in some literatures [61,62].
Thermal calcination is one of the most frequently used approaches
for extracting HAp from bone sample. Basically, calcination process
involves heating the bone samples in furnace at high temperature in
order to burn off the organic residues from the bone samples, therefore
leaving inorganic product, i.e. HAp behind. Since these waste materials
already contain large numbers of microbes, calcination method is thus
highly advantageous not only to remove organic phase but also useful
to destroy the pathogens that might present. This is especially crucial to
prevent the risk of disease spreading such as bovine spongiform
Fig. 2. Classification of bio-waste sources based on their precursor content to form HAp.
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encephalopathy (BSE), foot-and-mouth disease (FMD) and creutzfeldt
jakob disease [29,56,63]. In many cases, hydrothermal treatment which
involves the process of autoclaving bones at temperature above 100 °C
is often combined with thermal calcination technique for further de-
proteinization purpose. This step can help to reduce collagen in the
form of gelatine which is useful to avoid the formation of black charred
matter in the product at the end of calcination process [64].
Based on the past literatures, thermal calcination usually is per-
formed at various temperature ranging from 600 to 1400 °C to form
HAp; with 2.5–10.0 °C/min of heating rate and soaking time which
varies greatly from 1 to 50 h. Calcination parameters including calci-
nation temperature, soaking time, heating and cooling rate as well as
the atmospheres used during thermal process play a crucial role in in-
fluencing the physicochemical properties of HAp, such as crystallinity,
composition, morphology, size, surface area, porosity, phase impurity
and Ca/P ratio [42]. Notably, calcination parameters should be care-
fully selected to avert thermal decomposition of HAp into secondary
S.-L. Bee and Z.A.A. Hamid
phase while at the same time remain effective in eliminating organic
component without causing unnecessary energy wastage during calci-
nation process that will increase the production cost. For the extraction
of HAp intended for biomedical applications, calcination condition
should also be wisely tailored as high temperature can lead to the de-
composition of biogenic composition (e.g. CO32− content) from the
HAp lattice and further causing crystallite growth which can affect the
biological properties of the resulting HAp [55,65].
Ooi and co-workers [55] investigated the properties of biogenic
HAp prepared by calcination of bovine bone obtained for temperatures
between 400 and 1200 °C under 2 h of heating time. It was revealed
that thermal treatment above 600 °C would successfully eliminate or-
ganic component from the bone sample, where their crystallinity would
become enhanced when calcination temperature increased. However, it
was reported that calcination of bovine bone above 1000 °C has led to
partial decomposition (dehydroxylation) of HAp phase into β-tri-
calcium phosphate (β-TCP) as well as complete dissociation of CO32−
from the HAp structure. Haberko et al. [66] also demonstrated that the
CO32− content found in the animal bone-derived HAp would decrease
with increasing calcination temperature. Similarly, [67] also showed
that calcination of bovine bone at temperature exceeding 1000 °C can
lead to the partial dehydroxylation of HAp phase into β-TCP.
In another study, the effect of calcination temperature on the
composition and porosity of naturally-derived HAp was scrutinized.
HAp powders from different origins (bovine and porcine) were obtained
by calcination in air at 600, 900 and 1200 °C for 18 h. It was found that
the porosity of HAp derived from different animal origin (bovine and
porcine) decreased with increasing heating temperature, while their
CO32− content were no longer detected after calcination at 900 °C. Both
bone samples calcined at 600 °C displayed the highest porosity (~50%)
and microporosity which is promising for bone formation [59]. It is
worthwhile to mention that the complete CO32− dissociation occurred
at relatively lower temperature (i.e. 900 °C) as compared to the result
reported by Ooi et al. [55] (i.e. 1000 °C), probably due to the much
longer sintering time employed in this research. Meanwhile, a research
conducted by Kusrini and Sontang [67] further revealed that the den-
sity and fracture toughness of bovine bone-derived HAp material in-
creased upon increasing of sintering temperature. This is ascribed to the
elimination of porosity from the microstructure of HAp phase that has
increased its fracture strength.
In a work of Ramirez-Gutierrez et al. [53], thermogravimetric
analysis (TGA) was used as preliminary tool to perceive the decom-
position event of pig bone powder during calcination process. As de-
picted in Fig. 3 (a), it is revealed that the thermal decomposition event
below 670 °C corresponds to combustion of organic constituents from
the bone sample while the subsequent thermal changes above 670 °C
could be related to the structural transformation of HAp. The authors
then further evaluated the impact of heating time and temperature on
the properties of HAp: HAp powders were obtained by heating the bone
samples under atmospheric air at two different temperatures (600 and
1000 °C) for 1, 2, 3, 7, 20 and 50 h accordingly. For all samples calcined
at 600 °C, the colour of the bone powders changed from light yellow
(due to the presence of organic phase) to gray (due to the presence of
organic ash residue) and finally white (complete removal of organic
phase) when heating time increased from 1 to 50 h (Fig. 3(b)). How-
ever, no significant morphological transformation was observed (as
demonstrated in Fig. 4) when prolong sintering time was employed
under the same temperature. This dictates the effectiveness of longer
sintering time at 600 °C in eliminating the organic composition without
imparting structural transformation to the resulting HAp. Meanwhile,
the grain particles for all samples calcined at 1000 °C displayed a dis-
cernible hexagonal growing pattern when sintering time rose from 1 to
50 h (Fig. 5) due to coalescence phenomenon.
Research conducted by Londono-Restrepo et al. [68] showed that
different heating rate used during calcination process have a direct
effect on the crystallite growth and phase composition of bovine bone-
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derived HAp; higher heating rate can promote crystallite growth and
lead to the formation of secondary phase. All these can be elucidated by
the higher thermal energy given to the system that will eliminate the
substituted ions from the HAp lattice and improved its crystalline
quality.
The influence of calcination atmosphere on the morphology of the
HAp was also studied by Janus et al. [69] by sintering cleaned pig bone
under O2 and CO2 environments. It was shown that thermal calcination
at different atmospheres produce HAp with different morphologies.
HAp formed under CO2 atmosphere was found to display comparatively
lesser pores and bigger crystallite size when relative to samples calcined
under O2 environment.
In order to study about the impact of cooling rate on the micro-
structural properties of HAp, Ramirez-Gutierrez and colleagues [60]
allowed the bovine bone samples that were calcined at 940 °C to cool
under four different conditions, i.e. under air, water, liquid nitrogen or
furnace air. According to this study, higher cooling rate which are at-
tained for samples cooled in air, water and liquid nitrogen produce HAp
with polycrystalline structure, while sample air cooled inside furnace
yields single crystal HAp with better crystalline quality. The authors
attributed this outcome to the fast cooling process (for samples cooled
in air, water and liquid nitrogen) that generates thermal stress within
the lattice which subsequently affecting the crystalline quality of the
resulting HAp.
Comparative study of HAp derived from different animal bone bio-
wastes, namely bovine, caprine and galline bones were also performed
in order to evaluate their thermal stability and microstructure at dif-
ferent heating temperatures (600–1000 °C). It was revealed that bovine
bone-derived HAp was thermally stable across the range of tempera-
tures investigated while the others displayed phase instability with the
formation of β-TCP when the calcination temperature exceed 700 °C.
On the other hand, calcined galline bone showed significantly higher
porosity with lower hardness while bovine and caprine derived HAp
exhibited lower porosity structure with hardness values that are com-
parable to human cortical bone [70].
Apart from the thermal calcination approach, HAp can also be ex-
tracted from bone sample by heat treating them with alkaline solution
(usually NaOH) via hydrolysis method in order to remove organic
phase. Noted that the properties of HAp extracted using this method can
be largely affected by alkaline concentration and period of hydrolysis
treatment. Brzezińska-Miecznik et al. [71] extracted HAp from bovine
bone waste by treating them in both NaOH and KOH solution with
concentration varies from 0.5 to 4 M from 1 to 14 days. HAp produced
from higher concentration and prolonged treatment period had shown a
relatively smaller specific surface area (SSA) and larger crystallite size.
This can be ascribed to the dissolution of smaller HAp particles at
higher alkali concentration and prolonged time of treatment that fur-
ther lead to their crystallization on larger particles surface. Ad-
ditionally, the CO32− content also decreased due to its partial sub-
stitution by hydroxyl groups. All HAp produced from this method are
organic-free.
Barakat and co-workers [72] employed three different techniques
(i.e. calcination, subcritical water and alkaline hydrothermal hydrolysis
methods) to extract HAp from bovine bone wastes. They found that the
composition, morphology and shape of HAp were directly influenced by
the extraction methods used. It was reported that the amount of CO32−
content found in HAp extracted using different approaches varied ac-
cording to the following order: subcritical water process > alkaline
hydrothermal hydrolysis > calcination. Meanwhile, HAp obtained
from thermal calcination exhibited better crystallinity with irregular
shape, while subcritical water and alkaline hydrothermal hydrolysis
techniques produced lower crystallinity products with nanoflakes and
nanorod shapes respectively (Fig. 6). Another research conducted by
Sun et al. [73] also corroborate that HAp extracted from alkaline
treatment exhibited much lower crystallinity compared to calcined
HAp.
S.-L. Bee and Z.A.A. Hamid
3.1.2. Fish bones and scales waste
Rapid growing of fish processing industries around the world has
contributed to massive amount of solid fish waste production every
year. Annually, more than 91 million tons of fish are caught worldwide.
Out of the total fish catch, accounting about 50–60% is used for human
consumption, while the remaining by-products are rejected as wastes
during the processing, thus leading to numerous waste management
and environmental related issues [42,74]. In fact, research studies re-
lated to the valorization of fish waste have been largely explored in
recent years [75–78]. One of the research directions that has gained
considerable attention is the transformation of fish bio-wastes, specifi-
cally bones and scales into HAp [79]. Indeed, preparation of natural
HAp based on fish bio-wastes is more preferred over coral and mam-
malian-based sources due to its sustainability and safeness which pre-
sent low risks of transmitting disease to human [29]. Moreover, unlike
bovine and porcine origin, fish source-derived HAp is not subjected to
controversy related to cultural or religious belief [80].
Many different protocols of pre-treatment and extraction methods
have been proposed in the literatures to prepare HAp from fish sources.
Generally, macroscopic impurities from the bone or scale samples such
as remnant flesh or unwanted debris will be firstly cleaned by running
water and boiling procedure. Further, the bone can be chemically
treated with acid, alkaline or acid-alkaline solution for deproteinization
purpose [81]. It should be noticed that utilization of different pre-
treatments approach can affect the final properties of HAp. In a re-
search conducted by Deb and co-workers [82], it was observed that
acid-treated fish scale displayed relatively smaller crystallite size with
much uniform interconnected porous network and highest yield com-
pared to the alkaline and acid-alkaline pre-treatment procedures.
Depending on the species, mineral matrix of fish bones and scale
might vary in chemical composition. Past studies have shown that
bones and scales from various fish species contain Al, Cl, Cu, F, Fe, Mg,
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Fig. 3. (a) TGA curve of pig bone powder and its first
derivative as a function of temperature with a
heating rate of 5 °C/min, (b) Colour changes as a
function of increasing heating time for samples cal-
cined at 600 °C [53]. (For interpretation of the re-
ferences to colour in this figure legend, the reader is
referred to the Web version of this article.)
K, Na, Si, Sr and Zn existed as minor or trace elements, where their
composition variation can greatly affect the properties of the HAp
formed [54]. Over the years, bone and scale wastes from various fish
species such as anchovy, barramundi, carp, catfish, cattle, croaker, cod,
conger eel, flat fish, flying fowl, greater amberjack, mackerel, salmon,
sardine, seabass, seabream, sheelavati, sword fish, tilefish, trigger fish,
trout, tuna and yellowtail have been successfully utilized as low-cost
source to extract HAp [42].
Goto and colleagues [83] reported the effect of trace elements
composition on the thermal stability of HAp derived from different fish
bones, i.e. tuna, yellowtail, greater amberjack and hoarse mackerel
fishes using calcination approach. In the research, it was disclosed that
calcination temperature of 600 °C was adequate to produce single-
phase B-type carbonated HAp for all fish bone samples except for hoarse
mackerel sample which showed the presence of β-TCP as minor phase
with the least crystallinity. This phenomenon is correlated to the
amount of Mg element found in the bone samples, as higher Mg sub-
stituting for Ca in hoarse mackerel bone tends to distort crystal lattice
of HAp and accelerates the partial decomposition of HAp into β-TCP.
The amount of Mg for all samples was in the order: hoarse mackerel
(0.21 mmolg−1) > greater amberjack (0.15
mmolg−1) > tuna = yellowtail (0.13 mmolg−1). In another study,
different calcium phosphate products, i.e. HAp, β-TCP and biphasic
HAp/β-TCP had been obtained by heat treating different type of fish
bone under the same calcination parameter (600 °C, 3h), with varying
Ca/P ratio formed in the range of 1.20–1.68 [84].
In another study, natural HAp isolated from different fish bones, i.e.
rainbow trout (Onchorynchus mkiss), cod (Gadus) and salmon
(Oncorhynchus keta) bones by annealing at 650 °C were compared in
term of their composition. Except for HAp derived from cod fish bone,
other bone-derived HAp have shown the present of CO32−. Meanwhile,
both Mg and Na elements were found in all samples, with cod fish-
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Fig. 4. SEM micrographs of (a) un-calcined sample and (b)–(g) samples calcined at 600 °C with heating time of 1, 2, 3, 7, 20 and 50 h [53].

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Fig. 5. SEM micrographs showing the morphological transformation for samples calcined at 1000 °C for 1, 2, 3, 7, 20 and 50 h [53].

Fig. 6. SEM images of HAps obtained from (A) calcination, (B) subcritical water process and (C) alkaline hydrothermal hydrolysis methods [72].

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derived sample possessing the least amount of Mg (0.33 wt%) and
larger crystallite size compared to rainbow trout (0.71 wt%) and
salmon (0.66 wt%) [85].
As previously mentioned, calcination temperature is effective to
prompt the conversion of phases in HAp. A research conducted by Paul
and co-workers [56] demonstrated that calcined powder derived from
catla catla fish scale showed the formation of β-TCP as secondary phase
when calcination temperature used is > 800 °C. In another research,
Zhu et al. [65] examined the phase composition of HAp extracted from
salmo salar, anoplopoma fimbria and sardine fish bone when calcined at
temperature ranging from 600 to 1000 °C. Except for 600 °C sample, all
calcined products composed of biphasic HAp/β-TCP mixture, where β-
TCP content increased proportionally with increasing calcination tem-
perature. Their relatively low thermal decomposition temperature
could be accredited to the mineral composition of the fish bone used in
this study that was made of Ca-deficient HAp, as evidenced by their
lower Ca/P ratio value. On the contrary, it was reported that natural
HAp derived from sheelavati (roho labio) fish bones were thermally
stable up to 1000 °C without the formation of secondary phase [86].
Similarly, single-phase HAp was formed by annealing of Japanese
seabream bones at temperature ranging from 800 to 1200 °C, where its
phase transformation was only observed at 1300 °C [87]. On the other
hand, calcination of Labeo rohita fish scale at temperature ≥1000 °C
produced β-TCP as secondary phase, while trace of tetracalcium phos-
phate (TTCP) was further observed when calcined at 1400 °C [88]. This
can be thus deduced that the thermal behavior of bone and scale
samples varies with different fish species.
In a work of Piccirillo and co-workers [89], it was reported that
thermal calcination of Atlantic cod fish (Gadus morhua) bone at tem-
perature from 900 to 1200 °C would result in the formation of biphasic
HAp/β-TCP mixture with 75:25 ratio. Interestingly, the authors further
revealed that single phase HAp, chloroapatite and fluroapatite could be
formed by pre-treating un-calcined bone sample in calcium chloride
dehydrate (CaCl2·2H2O) and sodium fluoride (NaF) solution respec-
tively before submitted for calcination process. Moreover, the phase
composition of HAp in HAp/β-TCP mixture could also be tailored by
adjusting their treatment time. In case of treatment in Ca-containing
solution, it was reported that the percentage content of HAp in HAp/β-
TCP mixture would increase when treatment time increased, where
single phase HAp could be produced when treatment time was pro-
longed to 16 h at 75 °C. This could be explained by the ion exchange
phenomenon between Ca ions from the solution with the Na ions sub-
stituted in the bone apatite lattice that would increase the Ca content
and thus the Ca/P ratio of the calcined product. Meanwhile, excess
concentration of CaCl2·2H2O solution also enable substitution of Cl ions
onto the OH− site of the bone apatite, thus forming chloroapatite.
Compared to chloroapatite, fluoroapatite could be formed at a rela-
tively shorter treatment time and lower NaF concentration due to the
smaller dimensions of F ions that could easily replace both OH− and
PO43− site of apatite lattice.
Properties of calcium phosphate products which are deriving from
bone and scale waste of same fish origin, namely European sardine
(Sardina pilchardus) was also scrutinized by Piccirillo et al. [90]. It was
reported that annealing of these bio-wastes resulted in the formation of
different products: a mixture of HAp/β-TCP (for bone) and HAp or
chloroapatite (for scale). Meanwhile, the properties of HAp extracted
from different part of tilapia by-products, i.e. bone (head, body and fin
bones) and scale were also compared. Except for scale and fin bone
samples, all calcined samples showed a trace of β-TCP when calcined at
900 °C. The average Ca/P ratio of all calcined products were deviated
from the stoichiometric value: scale (1.95), body bone (1.90), head
bone (1.83) and fin bone (1.52) [91].
In order to obtain nanostructured HAp, thermal calcination can be
coupled with milling process under appropriate calcination parameter
and milling time. Coelho et al. [92,93] prepared nanocrystalline HAp
from Brazilian fish bones by thermally treating them at 900 °C followed
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by milling process, and their structural properties were further in-
vestigated as a function of different milling time (2, 4, 8 and 16 h). It
was revealed that the particle size of HAp decreased with increased
milling time. Moreover, low milling time had the tendency to form ir-
regular HAp particles while prolonged milling time up to 16 h resulted
in HAp particles with much regular and spherical shape. In their sub-
sequent study, it was also disclosed that the crystallite size of the ex-
tracted HAp decreased drastically from 80 to 22 nm when milling time
increased up to 16 h.
Alternatively, nano-HAp can also be directly isolated from fish bio-
waste (bone and scale) via alkaline hydrolysis approach without the
necessity of milling process. Pon-On and colleagues [81] prepared
natural nano-HAp from Probarbus jullieni fish scale by alkaline hydro-
lysis. The result showed that fish scale-derived HAp was of Ca-rich type
(Ca/P ratio: 2.01) which composed of flat-plate like nanocrystal with
15–20 nm of width size and range of 100 nm in length. Extraction of
nanostructured HAp in the size range of 15–20 nm and 30–50 nm from
tilapia nilotica [94] and cirrhinus mrigala [95] fish scale, respectively
using alkaline heat hydrolysis method had also been reported. A com-
parative research conducted by Venkatesan et al. [96] also demon-
strated that alkaline hydrolysis approach was capable of preserving the
nanorod-like shape (5–10 nm width and 17–71 nm length) of HAp from
raw tuna (Thunnus obesus) fish bone, while thermally calcined bone
showed relatively good crystallinity with irregular shape and micron-
size dimension that ranged from 0.3 to 1.0 μm due to the particle ag-
gregation during calcination process. Hence, despite both techniques
that can be used to extract HAp from wastes source, alkaline hydrolysis
method is more preferred in order to obtain nanostructured HAp, as
thermal calcination approach can be penalize in terms of causing
crystal growth.
Nevertheless, common hydrolysis approach is rather time-con-
suming and requires a long completion period to extract HAp. In this
context, Sricharoen et al. [97] has successfully adopted a relatively
simple and green approach to accelerate the alkaline extraction of HAp
from Nile tilapia fish scale using ultrasonic technology. In order to form
HAp, the acid-treated scale was subjected to 40 kHz ultrasonic bath
under 0.4 kw of ultrasonic power for 45 min at 60 °C and further treated
with NaOH until the pH value = 12. Owing to the synergistic impact of
ultrasound, vibration as well as heating process, the extraction effi-
ciency and sample throughput was greatly improved, thus resulting to a
faster extraction process.
Other than conventional extraction methodologies using thermal or
alkaline treatment, alternative approaches using novel procedures have
also been proposed to isolate natural HAp from fish bio-wastes.
Muhammad et al. [98] extracted HAp using ionic liquid treatment by
heating the grounded carp fish (Cyprinidae) scale in 1-butyl-3-methy-
limidazolium acetate at 100 °C for 12 h. Primarily, the concept un-
derlying this approach is to cause dissolution of organic phase (col-
lagen) from the mineral matrix by using ionic liquid with high
hydrogen bond basicity to disrupt the hydrogen interaction within the
organic composition. The mineral phase (HAp) of the scale sample will
thus remain un-dissolved and can be collected as precipitate through
filtration process. HAp formed from this method is slightly larger
(1870 nm) in size. Unlike other techniques that will irreversibly elim-
inate the collagen component from mineral matrix, collagen constituent
that was produced as side-product (as supernatant) in this study can be
collected and further extracted to achieve fully utilization of waste
materials without wastage [99].
Liu et al. [100] reported the novel extraction of HAp from bighead
carp (Aristichthys nobilis) scales using deep eutectic solvent. Being a
mixture constitutes of a hydrogen bond donor and a hydrogen acceptor,
deep eutectic solvent (choline chloride/glycerol: 1/2) can help to dis-
solve collagen phase from fish scale sample via hydrogen bonding in-
teraction to isolate HAp as precipitate. The results showed that HAp
that was extracted under optimized parameters (70 °C, a solid/liquid
ratio of 1/15 g/g and a 2.5 h extraction time) displayed irregular
S.-L. Bee and Z.A.A. Hamid
Fig. 7. SEM images of HAp hydrothermally synthesized from tuna fish bone at different urea concentrations: (a) HAp-1 M, (b) HAp-0.5 M, (c) HAp-0.25 M, and (d–f)
HAp-0.1 M [102].
morphology, higher Ca/P ratio (1.73) and good hemocompatibility.
Additionally, natural HAp can also be extracted from fish scale by
enzymatic hydrolysis method. In a work reported by Huang et al. [101],
tilapia (Oreochromis sp.) scales were treated using 1% protease N for
2.5 h which followed by 0.5% flavourzyme for another 0.5 h under an
optimum pH and temperature. Upon the completion of hydrolysis,
hydrolysates were boiled to deactivate the enzyme. HAp formed possess
slightly higher Ca/P ratio of 1.76 as compared to the stoichiometric
value, which could be due to the presence of CO32−.
In another research, needle- and sponge-shaped HAps were pre-
pared from calcined tuna fish bone using urea-assisted hydrothermal
treatment at varying urea concentration. In this study, tuna fish bone
which was initially calcined at 1000 °C was then hydrothermally
treated using 0.1–1.0 M urea solutions at 160 °C for 3 h. It was found
that 0.1–0.5 M urea concentration would result in needle-shaped HAp
crystals (Fig. 7(b)-(f)), where the length of the needle-shaped crystal
decreased further with increasing urea concentration. Apart from
needle-shaped crystals, rhombohedral and dumbbell-shaped HAp
crystals were also observed when the urea concentration was as low as
0.1 M (Fig. 7(e) and (f)). Meanwhile, sponge-shaped crystals with size
ranging from 2 to 3 μm were observed at high urea concentration
(1.0 M) (Fig. 7(a)). Additionally, SSA of the hydrothermally-treated
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HAp also increased proportionally with increasing urea concentration,
which increased profoundly from 2.2 to 86.6 m2/g when urea con-
centration increased from 0.1 to 1.0 M [102].
3.2. Bio-wastes that serve as Ca source
This class of bio-waste sources, which includes eggshell and various
mollusk shells (such as abalone, cuttlebone, clam, mussel, oyster and
snail shells), are mainly composed of calcium carbonate (CaCO3), a
mineral with great value that can be used or converted into other form
of Ca precursor to synthesize HAp [103]. Depending on the bio-waste
source, CaCO3 can be existed in various polymorphic form (usually
calcite or aragonite) [104]. For the synthesis of HAp using these
sources, reaction with phosphorus precursor is necessary. Examples of
phosphorus precursor that can be used include ammonium dihydrogen
phosphate (NH4H2PO4), diammonium hydrogen phosphate
((NH4)2HPO4), dicalcium phosphate anhydrous (DCPA, CaHPO4), di-
calcium phosphate dehydrate (DCPD, CaHPO4·2H2O), disodium phos-
phate (Na2HPO4), dipotassium phosphate (K2HPO4), potassium dihy-
drogen phosphate (KH2PO4), triethyl phosphate (C6H15O4P) and
phosphoric acid (H3PO4). For this class of bio-wastes, two research
directions can be considered to synthesis HAp:
S.-L. Bee and Z.A.A. Hamid
(i) Direct synthesis, which involves direct treatment of as-received
precursor (CaCO3) with phosphorus-based reagents to form HAp
[105,106].
(ii) Indirect synthesis, which requires the conversion of as-received
precursor (CaCO3) into intermediate Ca-based products such as
calcium oxide (CaO), calcium chloride (CaCl2), calcium hydroxide
(Ca(OH)2) and calcium nitrate (Ca(NO3) before subjected for further
treatment with phosphorus-based reagent. These intermediate spe-
cies can be obtained via the following possible routes: (a) thermal
decomposition of as-received sample under high temperature
[107,108], (b) dissolving the as-received sample in concentrated
acid (HCl or HNO3) [109,110] and (c) forming Ca complex [111].
Over the years, numerous methods including chemical precipitation
[107], hydrothermal [108,109], hydrolysis [112], microwave irradia-
tion [3,111], solid-state [38] and sol-gel [113] techniques have been
adopted to synthesis HAp from these class of bio-waste source. It is
worth to emphasize that the type of Ca precursors and synthetic
methodologies employed can influence the ensuing properties of the
synthesized HAp.
3.2.1. Eggshell waste
Eggshells waste generated from restaurants, bakeries, kitchen,
poultries and food manufacturing industries as a result from egg
breakage have becoming a source of pollution to our environment.
According to EC regulations, industrial eggshell is considered as ha-
zardous waste and requires proper waste management in order to avoid
the spreading of risk pathogens (e.g. Salmonella) into environment and
human health. Basically, eggshell constitutes approximately 94% of
CaCO3 (calcite polymorph) as major composition, along with minor
amount of other components including magnesium carbonate (~1%),
calcium phosphate (~1%) and organic materials (~4%) [111,112].
Furthermore, traces of Na, K, Cu, Fe, Mn and Sr are also present in the
eggshell [114]. Due to its calcium-rich constitution, abundancy and
sustainability, eggshell waste can serve as a valuable source for the
synthesis of HAp.
Generally, chicken eggshell is a ceramic material with a multi-
layered structure, namely the outermost cuticle layer, middle calcite
layer (spongy and mammillary layer) and innermost shell membrane
Fig. 8. (a) Schematic illustration of eggshell structure; SEM microstructure of chicken eggshell: (b) inner surface showing fiber-like morphology and (c) outermost
surface showing intrinsic pore [104].
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(Fig. 8 (a)). Both spongy and mammillary layers form a matrix consists
of protein fiber which is affixed to calcite crystals in a porous micro-
structure [115,116]. Meanwhile, eggshell membrane is constituting
mostly protein fibers and other organic components such as glucosa-
mine, hyaluronic acid and chondroitin [114]. In order to synthesis HAp,
inner protein membrane adhered to the eggshell will be discarded, and
the remaining eggshell will be cleaned and crushed into powder to be
used as precursor [109,111,117].
In general, HAp nanostructures with different morphologies have
been synthesized using eggshell wastes, such as spherical- [118], pro-
late spheroidal- [113], rod- [109], needle- [112] and flower-like [3]
shapes. The diversified microstructure of the synthesized HAp is very
much depending on the processing method used.
Solid-state reaction is a relatively simple method that has been
prevalently employed for the large-scale production of HAp from egg-
shell waste. In general, solid-state reaction involves milling of both
calcium and phosphorus precursors into homogenous mixture and
further undergoing sintering procedure at an elevated temperature
(≥900 °C) to yield HAp [119]. As a consequence of high thermal
temperature treatment, HAp with a well-crystallized structure is
formed. One major issues often associated with HAp synthesized by this
approach is its heterogeneity in term of phase composition that caused
by the appearance of secondary phases such as β-TCP or starting ma-
terials [120,121]. Importantly, the phase purity of the final product is
largely dependent upon the processing variables, which include the
type of reagents used, reagents mixing ratio, duration of milling, rota-
tional speed and calcination temperature. Therefore, it is always ad-
visable to have a precise control over these processing parameters in
order to prepare single-phase HAp with high phase purity.
Lee at al [122] successfully synthesized both pure HAp and β-TCP
ceramics by using eggshell waste and H3PO4 as precursors via solid
state approach. In this research, cleaned eggshell was initially calcined
at 900 °C to allow the conversion of CaCO3 into CaO. Thereafter, the
CaO powder was ball milled with H3PO4 under different mixing ratio
(wt.% of eggshell: H3PO4) from 1: 1.0 to 1: 1.7 which then followed by
calcination process at 900 °C for 1 h. It was showed that the phase
composition of the final products is depended on CaO: H3PO4 mixing
ratio: HAp was formed when a lower mixing ratio (1: 1.1) was em-
ployed, whereas higher ratios (1: 1.3 to 1: 1.5) will yield β-TCP. The
S.-L. Bee and Z.A.A. Hamid
chemical reactions involved can be represented in Eqs. (1)–(3).
CaCO3 → CaO + CO2 (1)
2 CaO + H3PO4 → CaHPO4 + Ca(OH)2 (2)
5 CaHPO4 + 5 Ca(OH)2 + H3PO4 →Ca10(PO4)6(OH)2 + 8H2O (3)
In a research conducted by Wu and co-workers [123], it has been
demonstrated that the final products made up of either entirely HAp
phase or biphasic HAp/β-TCP mixture can be easily prepared by tai-
loring the milling time. In their work, DCPD and eggshell powder were
employed as starting materials to prepare HAp. In this case, eggshell
powder was directly mixed with DCPD in 4: 3 mol ratio by wet-milling
for 1, 5 and 10 h and further heated at 1000 °C for 1 h. At lower milling
time, the traces of Ca2P2O7 (pyrophosphate derived from DCPD after
heating) and CaO along with both phases of HAp and β-TCP were de-
tected after heat treatment. Upon milling for 5 h and subsequent heat
treatment, biphasic HAp/β-TCP mixture with predominantly HAp
phase was formed without any traces of Ca2P2O7 and CaO. Meanwhile,
pure HAp could be formed upon heat treating 10 h milled sample at
1000 °C. Additionally, the prepared HAp also showed the presence of
CO32− content which belong to both A- and B-type carbonated HAp,
along with the existence of Mg (0.648 wt%) and Sr (0.031 wt%) ele-
ments.
The effect of heat treatment's temperature and time on the phase
composition of the products were further scrutinized by the same re-
search groups [106]. Briefly, ball milled mixture of eggshell powder
and DCPD was sintered at various temperatures (900, 1000, 1100 and
1200 °C) for 1, 3, 5 and 10 h. It was found that increasing calcination
temperature and time will gradually decrease the amount of starting
materials (CaO and Ca2P2O7) and β-TCP formed. Higher calcination
temperature (1200 °C) and prolonged heating time (5 or 10 h) are fa-
vourable to form single-phase HAp. It was disclosed that greater
amount of HAp would be produced at higher temperature and longer
heating time as HAp is thermodynamically more stable than β-TCP.
This finding is in agreement with the researches performed by Refs.
[124,125].
Ho et al. [124] compared the effects of different Ca precursors,
namely, un-calcined eggshell (denoted as A), calcined eggshell at 450 °C
(organic-free CaCO3, denoted as B) and calcined eggshell at 900 °C
(CaO, denoted as C) on the phase composition of the final products. The
synthetic route involved conventional ball milling of these Ca pre-
cursors and DCPD with distilled water and further sintered at 1000 °C
for 3 h. For powder A and B, dual phase comprised of HAp and β-TCP
with trace of starting materials (CaO and DCPD) were obtained upon
their calcination with DCPD. Calcination of powder C with DCPD re-
sulted in formation of HAp/β-TCP mixture (mostly HAp phase) without
the presence of any starting materials. This study dictates the conver-
sion of eggshell into CaO is useful to allow the complete reaction with
DCPD.
On the other hand, it was further proposed that conventional mixing
of precursors as adapted by previously discussed study was not effective
to allow the complete reaction between CaCO3 and DCPD. Ramesh et al.
[126] suggested that homogenous mixing of the starting materials with
a proper heat treatment of eggshells (to burn off organic matter) is
indispensable to allow the direct conversion of CaCO3 into single phase
HAp. In their work, pure HAp with crystallite size of 54.6 nm was
successfully synthesized based on the following procedure: The eggshell
powder was initially calcined at 700 °C for 2 h to completely eliminate
the organic composition (without converting CaCO3 into CaO). The
calcined eggshell powder was then mixed with DCPD by wet attrition
milling for 2 h and further calcined at 800 °C. The proposed reactions
can be deciphered in Eq. (4).
6 CaHPO4·2H2O + 4 CaCO3 → Ca10(PO4)6(OH)2 + 4 CO2 +4H2O
(4)
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Gergely and colleagues [127] compared the effects of attrition and
planetary ball milling on the morphology of the powders. It was showed
that attrition milling could produce finer powder with nanosized grains
whist ball milling resulted in agglomerated grains in micron-size. The
finer nanostructured characteristics of powder milled by attritor was
visible even after sintering at 900 °C.
A research carried out by Hamidi et al. [128] showed that the ro-
tational speed used during mechanochemical activation process could
be a crucial factor in affecting the phase composition of HAp. Even
before calcination, the presence of HAp phase (along with starting
materials) was detected during higher speed of milling (600 rpm),
which was not observed in lower milling speed (200 rpm) process. This
is due to the heat generated during high speed milling process that
cause the partial conversion of precursor into HAp. After calcination,
single phase HAp with relatively higher degree of crystallinity was
formed at higher speed milled sample (600 rpm). Trace of starting
materials are found in calcined sample which was milled at lower ro-
tational speed (200 rpm).
Hydrothermal technique is also widely used for the synthesis of HAp
from natural resources. To synthesis HAp nanoparticles, hydrothermal
approach can be accomplished by chemical reaction between calcium
and phosphorus precursors in an aqueous solution under elevated
pressure and temperature. Through the effect of condensation and an
increase in reactivity under high temperature and pressure condition,
hydrothermal method can effectively increase the crystallinity of the
products and favourably lead to the formation of HAp as main phase
[41,43,129]. Nevertheless, the control of morphology and particles size
distribution using this approach is rather poor [109]. In recent years,
alternative routes known as template-mediated hydrothermal method
have been widely exploited for the synthesis of HAp with controlled
morphology. In this technique, auxiliary additives such as cetyl-
trimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS)
surfactants will serve as “soft” template to govern the nucleation and
crystal growth of HAp [130,131]. For most of the times, this method is
used to synthesis 1-D nanostructured materials such as nanorod-like
shaped HAp [119].
The mechanism behind the synthesis of rod-shaped HAp can be
elucidated by the role of extraneous surfactant as shape-controlling
agent. Taking the most famous surfactant, i.e. CTAB as an example,
CTAB molecules will ionize completely in an aqueous system, thus
forming cationic species (CTAB+) with tetrahedral structure. As soon as
their concentration exceeds the critical micelle concentration (CMC),
these cationic species will self-organize into rod-like micelles, forming a
stern layer of cationic moieties which will further interact with PO43−
ions electrostatically to form CTAB+— PO43− complexes micelles. This
will decrease the total charge and freedom of the PO43− ions in the
aqueous system. Upon the addition of Ca containing solution, these
complex micelles will attract Ca2+ ions to form CTAB+— PO4 3-—
Ca2+ complex micelles with rod-like shape. These complex micelles
will subsequently serve as nucleating points for the growth of rod-like
HAp nanocrystals during crystallization process as schematized in Fig. 9
[131,132].
Recently, Nga et al. [109] synthesized rod-like shaped HAp (52 nm
in mean diameter and 161 nm in mean length) using eggshell and
Na2HPO4 as starting materials in the presence of CTAB as regulator. In
this method, the crushed eggshell powder was dissolved in HCl solution
to convert CaCO3 into CaCl2. Thereafter, mixture containing 0.1 M
Na2HPO4 and 0.64 g of CTAB was stirred with prepared CaCl2 solution
and hydrothermally treated at 180 °C for 12 h, and finally calcined at
500 °C for 1 h to produce HAp. Carbonated HAp showing both A- and B-
type CO32− substitutions was formed in this study, where the
CO32−content of 2.14 ± 1.36 wt% was found. Moreover, Mg, Na and
K elements were also present in the synthesized HAp.
In another research conducted by Prabakaran and Rajeswari [108],
the effect of surfactant concentration and hydrothermal duration on the
HAp nanoparticles formed using CTAB-assisted hydrothermal method
S.-L. Bee and Z.A.A. Hamid
Fig. 9. Scheme of the formation process of crystalline HAp nanorods in the presence of CTAB.
were investigated elaborately. It was found that the samples hydro-
thermally treated at shorter ageing period (1 and 5 h) formed larger
agglomerated HAp while longer ageing time (10 and 15 h) produce
uniform nano-sized HAp. At lower CTAB concentration (below critical
micelle concentration (CMC)), reduced crystallization of HAp was ob-
served. Meanwhile, when the addition of CTAB reach CMC (i.e. CTAB:
PO43− ratio = 1: 1), CTAB-forming micelles will act as a nucleating
point for crystal growth, thus improving the crystallinity of HAp. The
protocol to synthesis HAp in this study was summarized as following:
CaCO3 → CaO + CO2 (5)
CaO + H2O → Ca(OH)2 (6)
10 Ca(OH)2 + 6H3PO4 →Ca10(PO4)6(OH)2 + 18H2O (7)
In a recent study, nanorod-like HAp was synthesized in Na2HPO4
solution by hydrothermal method using eggshell-derived vaterite
CaCO3 as the sacrificial template. Vaterite CaCO3, which is the least
stable form of CaCO3 polymorph, was used as template because ionic
substitution of CO32− by PO43− can take place facilely under hydro-
thermal condition to form HAp. In this study, vaterite CaCO3 template
was produced from eggshell using polyelectrolyte-templated route in
the presence of poly (styrene sulfonic acid) sodium salt (PSS) as crystal
growth regulator according to the following protocols: (i) calcination
(900 °C for 2 h) and hydration to form Ca(OH)2, (ii) reaction of Ca(OH)2
with HCl to form CaCl2, (iii) mixing of CaCl2 solution with PSS and
Na2CO3 to form vaterite CaCO3. To form rod-like HAp, Na2HPO4 so-
lution was added into eggshell-derived CaCO3 and hydrothermally
treated at 121 °C for 45 min [133].
A facile and green hydrothermal route for the synthesis of HAp
nanoparticles using fruit peel waste extract as a template was proposed
by Wu and co-workers [134]. In the green synthesis of HAp, three fruit
peels, i.e. grape, sweet potato and pomelo were initially boiled in
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distilled water and filtered to obtain fruit peel extract. Subsequently,
each fruit extract along with precursors were hydrothermally treated at
150 °C for 72 h in independent experiment to form HAp. The
morphologies of HAp crystals were found to vary depending on the
types of fruit peel extract used. HAps produced from both grape and
pomelo peel extract showed rod-like nanostructure while irregular ag-
gregates of nanoparticles that resembled rice shape was observed for
sweet potatoes peel extract sample. Noted that these fruit peel extracts
contain exclusive phytochemical compounds which can act as nuclea-
tion site for HAp crystal growth. The grape peel extract contains
polyphenolic compound and β-carotene; polyphenols and carotenoids
are found in sweet potato peel extract and pomelo peel consists of
mainly limonene. It seems that the phytochemical compounds present
in grape and pomelo peel played a good role in regulating the shape of
the HAp nanoparticles. However, the mechanism for the HAp nano-
particles formation using green-mediated hydrothermal treatment was
not discussed in this study.
Being the straightforward and simple synthetic method, wet che-
mical precipitation is among the most frequently employed approach
for the synthesis of HAp. Usually, precipitation procedure comprised of
the reaction between alkaline Ca source and phosphorus-based reagent,
where the Ca/P molar ratio is fixed as stoichiometry corresponding to
its ratio in HAp (1.67). It usually proceeds with the precipitation, aging
and filtration, drying and eventually calcination steps, respectively.
This reaction is often conducted at pH values ranging from 3 to 12, with
reaction temperatures ranging from room temperature to temperature
below 100 °C [43]. Processing parameters including the reactants type
and concentration, reaction temperature, reactant addition rate, pH
value, duration of aging and calcination temperature play a decisive
role on the final properties of synthesized HAp. Sometimes, wet che-
mical precipitation technique proceeds in the presence of templates to
control the morphology of synthesized HAp [119].
S.-L. Bee and Z.A.A. Hamid
In a work performed by Kamalanathan et al. [135], phase pure
nanocrystalline HAp with needle-like morphology was successfully
prepared via wet chemical precipitation using eggshell and H3PO4 as
starting materials. Eggshell was first converted into CaO by calcination
which then followed by hydration to form Ca(OH)2. H3PO4 was then
added dropwise into Ca(OH)2 solution at a rate of 10–20 drops/min,
where NH4OH was used to maintain the pH value of the suspension
at > 10.5. Finally, the reaction was allowed to age for 24 h to form
HAp. It was found that the HAp formed using this method exhibited B-
type carbonated substitution. For it sinterability, it was revealed that
the as-synthesized HAp showed phase stability up to 1250 °C, while
beyond this temperature will result in secondary phases such as α-TCP
and TTCP.
On the other hand, nanorod-shaped HAp was formed from the re-
action between Ca(NO3)2 and (NH4)3PO4 solution at pH 11–12. Noted
that Ca(NO3)2 was formed from the reaction between calcined eggshell
(CaO) and HNO3 solution. The overall procedure as proposed by this
research can be depicted in Eqs. (8) and (9) [136]:
CaO + 2 HNO3 → Ca(NO3)2 + H2O (8)
10 Ca(NO3)2 + 6 (NH4)3PO4 + 2 NH4OH → Ca10(PO4)6(OH)2
+ 20 NH4NO3 (9)
In another study, K2HPO4 has been used as phosphorus precursor
instead of sodium- or ammonium-based reagent to form HAp. The se-
lection of this precursor is due to the spontaneous formation of HAp
using potassium salt. In this study, K2HPO4 was mixed with calcined
eggshell (CaO) for 15 min and the pH was kept at ~ 12. Maturation
period ranging from 1 to 7 days under 37 °C was employed to allow the
completion of reaction. The result stated that HAp crystal size had very
little dependent on the aging time in K2HPO4 solution, where its grain
size exhibited almost uniform shape. The chemical reaction for the HAp
formation based on the proposed study can be expressed in Eq. (10)
[107].
10 CaO +6 K2HPO4 + 4H2O → Ca10(PO4)6(OH)2 + 12 KOH (10)
Goloshchapov et. al. [137] used a combination of calcination and
wet chemical precipitation to form HAp from eggshell and H3PO4. In
brief, Ca(OH)2 which was deriving from eggshell waste was titrated
with 0.6 M of H3PO4 at room condition. The pH of the reaction was kept
within the range from 7 to 9 (with an increment 0.5). The precipitates
formed were further calcined at 400, 700 and 900 °C for 1 h. Results
showed that the phase composition and Ca/P ratio of resultant HAp
were dependent on the pH of the reaction. When the precipitate formed
was calcined at 700 °C, whitlockite was observed as secondary phase for
samples prepared under lower pH (7 and 7.5), while higher pH (≥8)
yield single-phase HAp. Moreover, Ca/P ratio of the synthesized HAp
also decreases from 2.1 to 1.7 when the reaction pH decreases from 9 to
7.
Conversion of eggshell waste to mesoporous HAp nanoparticles
(< 10 nm) with high surface area (212.4 m2/g) was accomplished using
precipitation method at room temperature. Cleaned eggshell was dis-
solved in HNO3 solution to form Ca(NO3)2, and followed by addition of
H3PO4 solution using a syringe pump. The key factor in improving the
surface area or pore size of such biogenic HAp is attributed to the use of
syringe pump to control the addition of H3PO4, thus permitting the
effective control of the reaction pH due to the consistency and precision
of H3PO4 inclusion rate. Pivotally, this will allow effective dissolution
of reactants, precipitation and maturation of HAp nanoparticles over
the aging period, thus forming HAp with high SSA with small particle
size [138].
Sol-gel approach has also been used to synthesize HAp from eggshell
waste. For instance, single-phase nanosized HAp was prepared through
sol-gel reaction between Ca(NO3)2 derived from eggshells and KH2PO4.
The reaction mixture was maintained at constant pH of 10 and kept
overnight at room temperature for ageing process, which followed by
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thermal calcination at 700 °C for 30 min. Result showed that the syn-
thesized HAp exhibited prolate spheroidal morphology with average
particle size of 35–50 nm, where the HAp formed was belonged to B-
type carbonated substitution [113].
On the other hand, HAp can also be prepared by microwave irra-
diation method. In general, this approach uses a high-frequency mi-
crowave to rapidly heat the starting materials to a high temperature.
The underlying heating mechanism of microwave processing can be
deciphered by the dipole polarization and ionic conduction occurring
within the starting materials as a result of microwave irradiation [43].
Compared to traditional methods, microwave processing offers the
benefits of high reproducibility, energy saving, high homogeneity, non-
polluting, fast heating rate and shorter processing time [139–141].
Microwave irradiation method is often combined with other conven-
tional techniques to provide synergistic outcome from different ap-
proaches in order to achieve higher yield in an expeditious fashion
[142].
Krishna and co-workers [143] prepared HAp from calcined eggshell
and (NH4)2HPO4 using microwave irradiation method and compared its
properties to synthetic HAp synthesized from commercial Ca precursor.
The merits of using eggshells as starting materials and microwave
processing were highlighted in this study. It was found that the mi-
crowave processed HAp displayed higher SSA than commercially
available HAp. Moreover, eggshell-derived HAp also exhibited better
sinterability in term of hardness and density compared to synthetically
derived sample. The HAp formed from eggshell waste belonged to B-
type carbonated HAp, which showed mostly agglomerated platelets
structure with dimension of 33–50 nm in length and 8–14 nm in width.
It is worthwhile to mention that the microwave parameters such as
microwave power and the duration of exposure play a prominent role in
the synthesis of final HAp nanostructures. In a study performed by
Sajahan and Ibrahim [140], it was found that increasing microwave
irradiation time had a significant effect on the shape and size of the
HAp formed from eggshell wastes and (NH4)2HPO4. At low irradiation
time, single-phase HAp with irregular circular nanosized was success-
fully synthesized. As the irradiation time increased from 15 to 45 min,
the HAp particle size increased and the shape become more uniformly
distributed. Meanwhile, varying irradiation time from 15 to 45 min did
not cause any significant impact on the phase composition of HAp.
Rahman et al. [144] performed microwave-assisted wet precipita-
tion approach to form HAp using eggshell waste and (NH4)2HPO4 as
starting materials. Briefly, aqueous (NH4)2HPO4 was dropwise added
into Ca(NO3)2 suspension (formed from treating eggshell with HNO3)
and the final pH was adjusted to 11 using NH4OH before further sub-
jected to microwave irradiation for 15 min under isothermal condition
at 80 °C. The results showed that this approach favoured the HAp
crystal growth along c-axis, which resulted in an irregular needle-like
morphology with SSA of 100.6 m2/g. The chemical reaction of HAp
formation can be presented in Eqs. (11) and (12).
CaCO3 + 2 HNO3 → Ca(NO3)2 + CO2 + H2O (11)
10 Ca(NO3)2 + 6 (NH4)2HPO4 + 8 NH4OH → Ca10(PO4)6OH2
+ 10 NH4NO3 (12)
In addition, organic modifiers such as CTAB, citric acid, ethylene-
diaminetetraacetic acid (EDTA), ethylene glycol and SDS are often used
as template for the morphology and size-controlled synthesis of HAp by
microwave-assisted method. In particular, EDTA has been well de-
monstrated as an efficient crystal growth modifier for the synthesis of
flower-like HAp nanostructure. Kumar et al. [111] synthesized flower-
like HAp from eggshell powder and Na2HPO4 using EDTA-mediated
microwave irradiation using a reaction pathway as described in Fig. 10.
According to the result, the obtained flower-like nanostructure was
composed of radially oriented leaf-like flakes with 100–200 nm width
and 0.5–1 μm length. In addition, the prepared sample was B-type
carbonated HAp and composed of Mg as trace element.
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Fig. 10. Microwave conversion of eggshells into a flower-like HAp nanostructure in the presence of EDTA as chelating agent [111].

In this case, EDTA acts as a hexadentate ligand by strongly chelate
the free Ca2+ions using four oxygens and two nitrogens to form five
member chelate ring complex. Under this circumstances, these complex
will serve as nucleus for HAp crystals and further growth into crystallite
upon reacting with phosphorus precursor under microwave irradiation.
Noted that the further growth of HAp crystallite will be controlled by
the stability of Ca-EDTA complex and the hindrance effect imposed by
OH− ions associated on the facets of the crystallite. Under highly basic
condition (pH 13), all facets of the crystallite have equal probability to
adsorb OH− ions which create limited active sites for its further growth.
At the meantime, Ca2+ ions will be integrated into the active sites in the
form of complex because of its higher stability. Owning to rapid heating
by microwave irradiation, Ca-EDTA complexes will undergo decom-
position and a reaction between Ca2+ and PO43− ions will take place
rapidly. As a result, HAp crystals will grow anisotropically along the c-
axis to form flower-like architecture.
A novel combination of liquid-assisted milling and rapid microwave
irradiation approach has been successfully employed to synthesize HAp
with needle-liked morphology. The key for the synthesis of needle-
shaped nanostructured as proposed by this study is attributed to the
role of spindle-shaped CaCO3 precursor (Fig. 11 (a)) as template to
direct the growth of HAp into needle-liked shape (Fig. 11 (b)) during
microwave irradiation. To form spindle-shaped template, a combina-
tion of different milling ball sizes (with 12 of 3 mm and 6 of 6 mm
stainless steel balls) is used to mill the eggshell precursor under wet
condition. The formation of this unique shaped precursor can be ac-
credited to the special arrangement of these different size balls in re-
lation to the eggshells (as illustrated in Fig. 11 (c)) in the mill sample
holder during wet milling process. Upon acid etching and subsequent
reaction with (NH4)2HPO4 under microwave irradiation, spindle-
shaped CaCO3 will act as consumable templates for the formation of
needle-shaped HAp [145]. Unlike surfactant-templated technique that
involves the usage of organic modifiers and excess organic solvent, this
approach is said to be promising due to its environmental benign route
in directing the precursor crystal growth and thus the morphology of
the HAp.
Sonochemical method, which is based on the reaction initiated by
powerful ultrasonication radiation, has been recognized as a promising
strategy to synthesis HAp owning to its ability to shorten the synthesis
time and yield nanosized products with minimal agglomeration [43].
Sonochemistry-assisted microwave irradiation approach, a unique
combination of traditional sonochemistry and microwave process, has
been applied to synthesize nano-scaled powders. In a research carried
out by Derkus and colleagues [118], nanosized HAp with spherical
morphology was synthesized via sonochemistry-assisted microwave ir-
radiation approach. The protocol involved the reaction between 0.3 M
of Ca(OH)2 suspension (formed by sintering of eggshell followed by
hydration process) with 0.5 M of (NH4)2HPO4 followed by

Fig. 11. Morphologies of (a) eggshell milled with 12 of 3 mm and 6 of 6 mm stainless steel ball, (b) as-synthesized HAp and (c) schematic illustration depicting the
milling of eggshells into spindle shape particles using a combination of balls [145].

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ultrasonication for 45 min under 750 W power and 20 kHz frequency
condition. Finally, the mixed reagents were irradiated in microwave
oven to form HAp. Sample without ultrasonication showed aggregated
rod-like structure while homogenously distributed spherical mor-
phology with diameter of 60–80 nm was formed for sonochemical-as-
sisted microwave method.
HAp can also be prepared from other CaP phases (such as TCP,
DCPA and etc.) and eggshell waste through hydrolysis process. Usually,
aqueous hydrolysis of CaP into HAp crystallites comprised of two
stages: dissolution and precipitation. For instance, Patel et al. [112]
studied the conversion of TCP into HAp via its reaction with calcined
eggshell (CaO) by hydrolysis followed by calcination process. Needle-
like morphology HAp was formed using this approach. The chemical
reaction adopted for the hydrolysis synthesis of HAp using eggshell and
TCP as precursors can be depicted in the following Eqs. (13) and (14):
CaCO3 → CaO + CO2 (13)
CaO + 3 Ca3(PO4)2 + H2O → Ca10(PO4)6(OH)2 (14)
3.2.2. Mollusk shells waste
Generally, mollusk shells are microlaminate organic-inorganic
composites which are composed of an outer prismatic calcite layer and
an inner nacreous aragonite layer that surrounded by organic matrix. It
typically consists of 95–99% CaCO3 by weight, and the remainder being
organic composition (proteins, glycoproteins, chitin, and poly-
saccharides) [146–148]. They are by-products from the food industry
and have been advocated as valuable CaCO3 sources to synthesize HAp.
B-type carbonated HAp with 1-D nanostructure were prepared from
clam shells (Venerupis philippinarum) powder and triethyl phosphate
using hydrothermal routes at 140 °C for 2–12 h. Increasing hydro-
thermal time from 2 to 12 h resulted in the transformation of the HAp
morphology from nanorods to nanowires shape. HAp nanowires formed
exhibited a narrowly distributed diameter ranging from 40 to 130 nm,
with aspect ratio in the order of 102 and SSA of 40 m2/g [36].
HAp with dense structure was formed from conch (Strombus gigas)
and clam (Tridacna gigas) shells via hydrothermal reaction with
(NH4)2HPO4 solution at 180–240 °C for 2–20 days. It was revealed that
the conversion process was facilitated at higher temperature, and the
thickness of the HAp deposition layer increased with increasing con-
version time. The original layered aragonite was completely converted
into HAp at 200 °C after 10 days of hydrothermal reaction [149].
Sr-doped HAp obtained from Mercenaria clam shell was also re-
ported by Pal and colleagues [150]. Mixtures of CaO powder (derived
from clam shells), (NH4)2HPO4 and strontium chloride (SrCl2, 10, 30,
50, 70%) solutions were autoclaved at 130 °C for 8 h. Result showed
that the aspect ratio of rod-like HAp decreases with increasing Sr in-
corporation into HAp. The sintered density of HAp progressively in-
creases with increasing Sr content, which increases from 3.04 g/cc for
undoped HAp to 3.50 g/cc when 70% of Sr substitution was introduced.
The abalone shell which consists of both inner aragonite sheets and
outer prismatic calcite (Fig. 12 (a)), was pulverized and hydrothermally
heated with (NH4)2HPO4 at 150 °C for 6, 18, and 72 h to form HAp.
Morphology of HAp changed from non-uniform flake- or rod-like shape
into uniformly rod-like structure when hydrothermal time increased
from 6 to 72 h. The authors explained that the HAp sheets nanos-
tructure was arisen from the aragonite sheets, while the prismatic cal-
cite would produce nanorods HAp when hydrothermally reacted with
phosphorus precursor. Nonetheless, monocrystalline HAp would pre-
ferentially grow along the c-axis of HAp structure upon prolonged hy-
drothermal period [39].
Biogenic CaCO3 microsphere derived from nacre of Corbicula flu-
minea has been converted to mesoporous B-type carbonated HAp mi-
crospheres through hydrothermal treatment with Na2HPO4 at 140 °C
for 12 h. The spherical HAp microspheres with the diameter of ~5 μm
are composed of many carbonated HAp nanoparticles which are
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oriented perpendicular to its surfaces and distributed within the whole
microsphere. This agglomerated nanoparticles on the microspheres
surface give rise to the mesoporous structure with pore size of
4.5–14.0 nm among them [151].
Conversion of aragonitic mussel shell into flower-like HAp archi-
tecture using rapid microwave irradiation in the presence of EDTA as
chelating agent was reported by Kumar et al. [152]. Na2HPO4 was
dropwise added into mussel shell/EDTA solution and the pH of reaction
mixture was maintained at 13 using NaOH solution, which was fol-
lowed by microwave irradiation for 15 min. The synthesized HAp
possesses high Ca/P ratio (1.79) due to the presence of B-type CO32−
groups in the lattice. On the other hand, nanorod-like HAp has been
successfully synthesized from Ca(OH)2 (derived from decomposition
and hydration of green mussel shell) and Na2HPO4 using a similar ap-
proach [153].
Ca-deficient HAp with various morphologies were prepared from
Chinese mystery snail (Cipangopaludina chinensis gray) shell wastes
using different condensed phosphate precursors (i.e. Na2HPO4,
Na4P2O7, Na5P3O10 and Na6P6O18) via hydrothermal route. Ca/P molar
ratio of all synthesized HAp were in the range of 1.26–1.33. A typical
nanorod-like morphology was observed for HAp prepared using
Na2HPO4. In contrast, agglomerates of spherical-like particles were
formed for HAp prepared from Na4P2O7 and Na5P3O10. For Na6P6O18
sample, the HAp formed composed of both spherical and irregular
particles. Regardless of the phosphate precursors used, all HAps formed
contain Mg, Na and CO32− in their structure [37].
Anjaneyulu et al. [154] prepared pure HAp and biphasic HAp/β-
TCP from triethyl phosphate and triethyl phosphite precursors, re-
spectively using sol-gel synthetic approach. It was revealed the HAp
derived from triethyl phosphate and snail shell displayed rod shaped
morphology (30–80 nm) with Ca/P ratio of 2.14. On the contrary, ir-
regular spherical shaped particles in the size ranged from 60 to 100 nm
and Ca/P ratio of 1.59 was formed from triethyl phosphite precursor.
AB mixed-type carbonated HAp was successfully derived from oy-
ster shell (Crassostrea angulate) powder via hydrothermal treatment
with (NH4)2HPO4 at 220 °C for 6 h. The results showed that plate-like
morphology with relatively lower crystallinity was observed for oyster
shell-derived HAp, as compared to synthetic HAp which possess na-
norod-like structure with significantly higher crystallinity [155].
Nanorod-shaped HAp were facilely synthesized from oyster shells
(Crassostrea gigas) and (NH4)2HPO4 via hydrothermal approach in the
presence of exogenous surfactants (CTAB and SDS). It was revealed that
addition of surfactant might facilitate disparate phases conversion
during reaction between starting materials under hydrothermal condi-
tion. It was also revealed that HAp nanorods formed with CTAB pos-
sessed much thinner width compared to SDS-mediated sample [130].
Solid state reactions between oyster shell powders (Crassostrea gigas,
calcite polymorph of CaCO3) and Ca2P2O7 or DCPD were conducted
using a combination methods of ball milling and calcination treatment
to form HAp. Oyster shell powder which had been ball milled with
DCPD for 5 h followed by heat treatment at 1000 °C for 1 h yielded
single-phase HAp. Meanwhile, ball milling and calcination of oyster
shell powder and Ca2P2O7 resulted in mainly HAp with small amount of
β-TCP as a secondary phase [105].
3.2.3. Cuttlebone waste
Cuttlebone, which is the internal shell of cuttlefish, is the by-pro-
duct formed from seafood processing that usually end up discarded as
waste product. It is composed of mostly CaCO3 (aragonite polymorph),
organic composition (3–4.5 wt%), chitin and protein [104,156]. Basi-
cally, the microstructure of cuttlebone consists of two regions: an ex-
ternal wall (known as dorsal shield) (Fig. 13(a)) and internal calcareous
(lamellae) region (Fig. 13(b)). The inorganic calcareous matrix of cut-
tlebone is made up of many horizontal aragonite lamellar sheets which
are supported by transverse pillars that form chambers sealed from each
other [157].
S.-L. Bee and Z.A.A. Hamid Ceramics International 46 (2020) 17149–17175

Fig. 12. SEM images of the cross-section of abalone

shell (A) and the samples exposed to different hy-
drothermal times: (B) 6 h, (C) 18 h, and (D) 72 h; The
inset (E) is a magnified view of the selected red area.
(F) Schematic diagram of the HAp hexagonal crys-
tallites [39]. (For interpretation of the references to
colour in this figure legend, the reader is referred to
the Web version of this article.)

Fig. 13. Schematic view of cross-section through the cuttlebone: SEM micrographs of (a) dorsal shield and (b) lamellae spacing [159].

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Whether in powder or cut piece form, cuttlebone can be susceptibly
transformed into HAp via reaction with phosphorus reagents. In cut
piece form, its highly porous structure enables the diffusion of the re-
actant solution towards CaCO3 and thus resulted in fast conversion into
HAp. Prior to the conversion process into HAp, cuttlebone will be
treated with an aqueous solution of sodium hypochlorite (NaOCl) in
order to remove the organic composition [157]. Most of the times, the
external wall of cuttlebone will be removed, thereby leaving only the
lamellar part to be used as starting material for HAp formation
[158,159].
Recently, preparation of HAp using aragonitic cuttlebone as pre-
cursor has been extensively explored in several literatures. For ex-
amples, Ivankovic et al. [159] successfully prepared a highly porous
HAp from cuttlebone (Sepia officinalis L.) and NH4H2PO4 using hydro-
thermal approach at temperatures ranging from 140 to 220 °C for
20 min to 48 h. It was revealed that both poorly crystallized HAp and
brushite (CaHPO4·2H2O) phases were observed in samples treated at
lower hydrothermal temperatures (i.e. 140-180 °C). Complete conver-
sion of aragonite into HAp was attained when hydrothermally treated
at 200 °C for 24 h. Meanwhile, treatment time exceeding 24 h will result
in the formation of both phases of HAp and anhydrous monetite
(CaHPO4). On the other hand, the HAp morphology on the surface of
lamellae changed from dandelion-like spheres (3–8 μm diameter) into
radially oriented nanoplates and nanorods (with average length of
8–10 μm and average diameter of 200–300 nm) upon longer hydro-
thermal treatment period (Fig. 14). B-type carbonated HAp was formed
from this study.
Fig. 14. SEM micrograph depicting the nanostructure of HAp derived from cuttlebone: (a)–(b) dandelion-like shaped, (c)–(d) nanoplate-like shaped and (e)–(f)
nanorod-like shaped [159].
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In another similar study, Rocha and co-workers [160] showed that
aragonite transformation into HAp was completed after hydrothermally
treated for 9 h at 200 °C. Furthermore, it was revealed that the as-
synthesized HAp was thermally stable on calcination up to 1350 °C,
while calcination beyond 1400 °C can lead to the decomposition of HAp
into β-TCP. It is worth stressing that the original porous channelled
microstructure of cuttlebone preserves even after hydrothermal treat-
ment and calcination at 1250 °C, which is promising for supporting
bone tissue growth and vascularization for bone tissue engineering
application.
HAp rods, with a small amount of β-TCP as by-product, were syn-
thesized by Zhang et al. [161] using different CaCO3 polymorph pre-
cursors, i.e. aragonite cuttlebone and calcite CaCO3 chemical. In their
study, hydrothermal-assisted hydrolysis reaction between CaCO3 (ara-
gonite and calcite) powder and DCPA was achieved inside sealed au-
toclaves at 140 °C for 1–24 h. It was showed that formation of HAp from
aragonite precursor (begin at 1 h) was much faster relative to calcite
(start at 2 h), in which a much smaller amount of β-TCP was found in
the aragonite reaction. The proposed reaction for the formation of HAp
and β-TCP are shown in Eqs. (15) and (16):
6 CaHPO4 + 4 CaCO3 + 2H2O → Ca10(PO4)6(OH)2 + 4H2CO3 (15)
2 CaHPO4 + CaCO3 →β-Ca3(PO4)2 + H2CO3 (16)
Ferro and Guedes [104] also studied the possibility of synthesizing
HAp via mechanochemical approach using biogenic CaCO3 sources
(cuttlebone and eggshell) and H3PO4 as starting materials. The Ca
S.-L. Bee and Z.A.A. Hamid Ceramics International 46 (2020) 17149–17175

precursor and H3PO4 in ratio complying with Ca/P ratio of stoichio-
metric HAp were subjected to high-energy ball milling with transferred
energy values ranging from 1.6 to 123.0 kWh/g to assess the formation
kinetic of HAp. In case of cuttlebone, it was showed that increasing
transferred milling energy results in CaCO3 DCPD HAp reaction se-
quence, while the use of eggshell precursor involves Ca-
CO3 DCPD DCPA HAp reaction sequence. Depending on the CaCO3
polymorph used, single-phase HAp could be obtained from mechan-
ochemical process when above its transferred energy value. The
minimum energy needed for HAp formation starting from cuttlebone
(aragonite) was only 6.2 kWh/g, while 52.5 kWh/g was required for
HAp deriving from eggshell precursor. In both cases, crystalline HAps
were formed.
Additionally, many attempts have been carried out to substitute or
dope ions such as F, Mg, Si, Sr and Zn into HAp lattice in order to
optimize their functionality in various applications. Kannan et al. [162]
and Tkalčec et al. [158] demonstrated the conversion of aragonitic
cuttlebones into fluorinated HAp (partially or completely F-substituted
HAp) via hydrothermal treatment with (NH4)2HPO4/NH4H2PO4 and
NH4F as a source of phosphate and fluorine. Additional thermal treat-
ment could be used to tailor the chemical composition of resulting
calcium phosphate product: partially F-substituted HAp was obtained
when heat-treated at temperature below 1100 °C while calcination at
1300 °C yield fluorapatite. In another study, Si-substituted HAp was
prepared by hydrothermally treating cuttlebone with (NH4)2HPO4 and
silicon acetate (Si(CH3COO)4) [163]. Multi-ions (Sr2+, Mg2+ and Zn2+)
doping of cuttlebone-derived HAp was also successfully demonstrated
by Neto and co-workers [164] by using nitrate salts of cationic (Sr2+,
Mg2+ and Zn2+) solutions as dopants.
4. Potential applications of bio-waste derived-HAp
4.1. HAp for biomedical applications
4.1.1. As bone tissue engineering (BTE) scaffolds and bone grafts
Large bone defects and fractures ensued from trauma, resection of
tumours or bone related infections often necessitates external treatment
such as bone grafting surgery (autograft/allograft/xenograft/synthetic
bone graft) to allow the reconstruction of damaged tissues [165]. Al-
ternatively, BTE which involves appropriately designed scaffolds also
emerged as a promising approach for bone regeneration. In BTE, scaf-
folds will serve as a temporary extracellular matrix (ECM) to facilitate
progenitor cell migration, proliferation and differentiation that induce
the natural process of tissue regeneration [166,167]. Ideally, BTE
scaffold should possess the characteristics that resemblance natural
bones, which including biocompatibility, high porosity with inter-
connected structures, suitable biodegradable rate and mechanical
properties, as well as the capabilities to induce osteoinduction, osteo-
conduction and osteointegration [168–171].
HAp has been extensively applied in BTE application to treat bone,
alveolar ridge and periodontal defects owning to its exceptional
biocompatibility, bioactivity, osteoconductivity and osteoinductivity
[172]. Indeed, various in vitro cellular studies (as listed in Table 1) have
shown that HAp deriving from different bio-waste sources displays
good cell compatibility toward various cell lines. Additionally, in vitro
bioactivity evaluation in simulated body fluid (SBF) and hank's ba-
lanced salt solution (HBSS) as reported by numerous researches re-
vealed that HAp formed from natural resources including bovine [173],
porcine [174], caprine [175], fish bone [176], fish scale [81,82], egg-
shell [109,177], snail shell [178] and cuttlebone [160] wastes were
capable of inducing bone-like apatite formation on its surface, which
indicates their bioactivity and bone-bonding tendency.
In recent years, bio-waste derived HAp has gained much attention in
BTE as compared to synthetic stoichiometric HAp. This is due to their
structural and chemical resemblance to the natural bone that possess
additional ions (e.g. CO32−, Na+, K+, Mg2+, Sr2+, Zn2+ and etc)
multi-substituted in their crystal lattice. The presence of these ions
tends to distort the crystal lattice of HAp, which will reduce the crys-
tallinity and thus increase the solubility, resorbability and bioactivity of
the resulting HAp [51,179]. Furthermore, the existence of bioactive
trace elements in the HAp structure, once released as dissolution pro-
duct, can elicit a positive therapeutic effect that can direct biochemical
process related to bone metabolism or angiogenesis [180]. For example,
it has been demonstrated that tuna bone-derived HAp scaffolds showed
better cellular attachment and proliferation as compared to synthetic
HAp scaffold which was formed from chemical precursor. The enhanced
bioactive properties can be ascribed to the presence of trace elements
(i.e. Na, Mg, Cr, Co, Cu and Sr) in the crystal lattice of tuna-derived HAp
scaffold [181]. Yang et al. [155] also found that MC3T3-E1 cells on the
oyster shell-derived HAp scaffold showed better adhesion and
spreading behaviour than that on the synthetic HAp scaffold.
Mondal et al. [182] also evaluated the bone regenerative capability
of the fish scale-derived HAp scaffold by in vivo implantation study
using albino rabbit model. The histological study showed that the
fabricated scaffold was well-integrated with the surrounding host bone
and able to facilitate new bone cells formation on its surfaces. In par-
ticular, it was found that fish scale derived HAp scaffold possessed
superior osteointegration with formation of more healthy new bone
cells at the traumatized region (Fig. 15 (a)) in comparison to synthetic
HAp scaffold synthesized from chemical precursor (Fig. 15 (b)). This
study showed the potential of fish bone-derived HAp scaffold to be used
for traumatized hard tissue regeneration. Similarly, eggshell-derived
HAp also displayed a greater bone formation after 8 weeks of im-
plantation in a rabbit calvarial defects when relative to the synthetic
HAp [183].
It is worth noticing that the biological properties of naturally-de-
rived HAp are greatly affected by its physicochemical properties (in-
cluding crystallinity, particle size, composition and etc.), which is much
dependent on the preparation parameter and its source. An interesting
research related to the relationship between calcination temperature
and the osteoconductivity of the bovine bone-derived HAp were carried
out by Rhee et al. [184]. They found that the biogenic HAp derived at

Table 1
HAp deriving from different sources which showed non-cytotoxicity toward its respective cell lines as reported by past literatures.
Source Cell type/lines References

Bovine bone Human bone marrow derived mesenchymal stromal cell (hBM-MSCs), human fetal [173,187]
osteoblastic (hFOB) cell
Chicken bone (Gallus domesticus) Human gingival fibroblast (HGF), osteoblastic cell [192]
Fish bone (sword, tuna cod, Salmo salar, Anoplopomafimbria and Mouse osteoblast MC3T3-E1, human osteoblast-like MG-63, human osteosarcoma (Saos-2) [29,65,176,181]
Sardine) cell, mesenchymal stem cell (MSC)
Fish scale (Catla catla P.Jullieni, Cirrhinus mrigala) Osteoblast-like MG-63, mouse osteoblast MC3T3-E1, rat osteoblast-like UMR-106 cells, [56,81,95]
human osteosarcoma MG-63 cell
Eggshell Mouse fibroblast 3T3-L1 cell [177]
Oyster shell (Crassostrea angulate, Crassostrea gigas) Mouse osteoblast MC3T3‐E1 cell [130,155]
Snail shell NIH-3T3 fibroblast cell [154]
Cuttlebone Mouse osteoblast MC3T3-E1 cell [188]

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Fig. 15. Biological in vivo implantation study of the developed HAp scaffolds [182].
600 °C displayed better osteoconductivity than the one derived at
1000 °C. The authors attributed this outcome to the negative impact of
higher calcination temperature that led to CO32− depletion and in-
creased crystallinity which in turn decreased the osteoconductivity of
the resulting HAp. This explanation is coherent with the studies re-
ported by Shi et al. [185] and Stanislavov et al. [186] that highlighted
the prominent role of substituted CO32− and particle size in promoting
the activity of osteoblast.
Niakan et al. [187] further examined the in vitro response of human
bone marrow mesenchymal stromal cells (hBM-MSCs) and its osseoin-
tegration potential on bovine bone-derived HAp calcined at varying
temperature (600–1000 °C). Bovine bone-derived HAp scaffold sintered
at 750 °C showed a significant increase in osteogenic markers indicating
its superior osteoinductivity than others, though other sintered tem-
perature samples were biocompatible and displayed high cells coloni-
zation and proliferation activity.
A comparative study of the biological properties for HAp derived
from different fish bones, i.e. rainbow trout, salmon and cod fish have
been reported recently. It was revealed that HAp originated from
rainbow trout and salmon bones displayed better biological osteoblastic
compatibility (with higher cell viability and alkaline phosphatase (ALP)
activity) compared to cod bone-extracted HAp and synthetic HAp. This
outcome is related to the different composition and crystallite size ex-
hibited by HAp formed, since cod fish bone derived HAp showed no
trace of CO32− and possessed the least amount of Mg (0.33 wt%) and
larger crystallite size compared to rainbow trout (0.71 wt%) and
salmon bones (0.66 wt%) which both belonged to carbonated HAp
[85].
The potential of the bio-waste-derived HAp as BTE scaffold or bone
substitute has been widely scrutinized and reported in the literatures.
Krishnamurithy and co-workers [167] prepared a 3D-porous scaffold
based on bovine bone bio-wastes and examined its feasibility in sup-
porting osteogenic differentiation of human bone marrow derived
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mesenchymal stem cells (hBMSCs). To prepare 3D-porous scaffold, the
HAp powder which was deriving from calcination of bovine cortical
bone was mixed with sugar and uniaxially compacted into green bodies,
followed by sintering in air atmosphere at 900 °C. The sintered scaffold
possessed desirable porous architecture with porosity of
~76.7 ± 0.6% and pore size in the range of 0.04–0.25 mm. Moreover,
the developed scaffold demonstrated improved proliferation and dif-
ferentiation of hBMSCs under osteogenic condition, which showed cell
penetration into the pores and formed continuous layer of fusiform over
the surface of the scaffold after 14 days of cell seeding. The osteogenic
potential of the developed scaffold was further confirmed by the up-
regulation of osteogenic related genes like osteocalcin and ALP as evi-
denced by the quantitative real-time polymerase chain reaction (qPCR)
data.
Cuttlebone bio-waste which contain high porosity (~90%), ideal
pore size (200–600 μm) and interconnectivity has been widely studied
as bone substitute material for BTE application. As mentioned in pre-
vious section, hydrothermal transformation of aragonite cuttlebone
granule into HAp is able of preserving the interconnected porous fea-
ture of cuttlebone. Notwithstanding, the mechanical properties of cut-
tlebone-derived HAp scaffold can be greatly debilitated during hydro-
thermal treatment, which in turn affecting their practical uses in
clinical stage. In order to overcome this shortcoming, coating of scaffold
with biodegradable polymers has been explored to augment its me-
chanical properties. Milovac et al. [157] demonstrated that coating
procedure using poly (ϵ-caprolactone) (PCL) was able to improve the
mechanical properties of cuttlebone-derived HAp scaffold, which
showed higher compressive strength (0.88 MPa) and elastic modulus
(15.5 MPa) compared to raw cuttlebone (0.46 MPa; 6.2 MPa) and the
hydrothermally synthesized HAp scaffold (0.15 MPa; 0.7 MPa). More-
over, the open interconnected porous structure of scaffold was main-
tained without causing any pores blockage even after PCL coating. The
preservation of the overall microstructure of the cuttlebone is pivotal
S.-L. Bee and Z.A.A. Hamid
for cells penetration into the scaffold and enable the sufficient exchange
of nutrients and wastes during bone formation process. Biological as-
sessment of preosteoblastic cell line MC3T3-E1 such as proliferation,
differentiation and expression of bone ECM components for the fabri-
cated PCL-coated HAp scaffold were further evaluated. A positive im-
pact of PCL coating on the cell spreading, proliferation, differentiation
and ECM deposition were observed with respect to the un-coated HAp
scaffold. After 21 days of experimental period, infiltration of cells
through the entire depth of scaffold was observed [188]. These results
demonstrated the potential of PCL coating in improving the mechanical
and biological properties of cuttlebone-derived HAp scaffolds to be used
for BTE application.
In addition, bio-waste-derived HAp had also been used as reinfor-
cing filler for polymer composites to improve their biofunctionality and
mechanical properties necessary for bone regeneration. According to
the study conducted by Rakmae et al. [189], it was revealed that the
incorporation of HAp into polylactic acid (PLA) matrix is capable of
inducing bone-like apatite formation that indicates the improvement of
material's bioactivity. Addition of fish scale-derived HAp also found to
improve the hydrophilicity of PLA biofilms, which subsequently en-
hance its biocompatibility [190]. In another study, it was found that the
incorporation of needle-shaped HAp derived from eggshell waste has
improved the strength and modulus of the electrospun PLA fiber scaf-
fold [191].
HAp, alone or combined with guided bone regeneration (GBR)
barrier membrane, can also be used in dentistry and maxillofacial
surgery to support periodontal or alveolar bone regeneration. Luna-
Domínguez et al. [192] reported the in vivo assessment of chicken bone-
derived bioceramic as bone filling graft substitute in combination with
a chitosan dental barrier membrane in regenerating rabbit calvarial
bone defects. The immunocytochemistry results after 6 and 8 weeks
postoperative demonstrated a significant enhancement of osteogenic
activity as evidenced by an increased expression of the biomarker os-
teonectin. In comparison to the control group defects, early formation
of mineralized ECM and fully developed cortical bones was also ob-
served in bone defect filled with chicken bone-derived bone graft and
chitosan membrane implant. This dictated the potential uses of chicken
bone-derived bone graft in conjunction with dental barrier membrane
in facilitating new bone formation for GBR application.
Kattimani et al. [193] reported the clinical evaluation of eggshell-
derived HAp as bone substitute for the regeneration of human maxillary
cystic bone defects. A total of eight patients with maxillary bone defects
were treated using eggshell-derived HAp bone substitute after cystic
enucleation and/or apicoectomy. After 8 weeks of postoperative sur-
gery, defects grafted with eggshell-derived HAp had attained the bone
density of that as neighbouring normal bone or more in all cases, in-
dicating the complete bone regeneration after bone grafting procedure.
In a recent study, the feasibility of eggshell-derived HAp for the en-
hancement of bone regeneration after surgical removal of the bilateral
mandibular impacted wisdom teeth was further scrutinized by the same
research group [194]. The complete bone recovery with increased
density and reduced probing depth with insignificant bone loss as
compared to control sites implying the effectiveness of eggshell-derived
bone graft for early bone reconstruction. No undue complications were
observed during study protocol demonstrating the safeness of eggshell-
derived HAp as a synthetic bone graft material. Therefore, eggshell-
derived HAp may serve as an inexpensive bone graft substitute to be
used for maxillofacial bone reconstruction in dentistry application.
Benlidayi et al. [195] employed bovine bone-derived HAp as bone
graft substitute for secondary alveolar bone grafting surgery (SABG) in
patients with cleft lip and palate and compared its clinical outcome
with an autogenous iliac bone graft. They reported that the bovine-
derived HAp bone graft was comparable to that of the autogenous iliac
bone graft in the SABG procedure. The bovine-derived bone graft can be
thus served as an alternative candidate for the SABG surgery to de-
crease the postoperative complications that might possibly associated
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with conventional autogenous graft harvesting procedure such as pa-
tient morbidity.
4.1.2. As bioactive coating for metallic implant
Metallic implants which are mostly made of stainless steel (316L),
cobalt alloys, titanium (Ti) or titanium-based alloys are widely used in
orthopaedic and dental implantology due to their high mechanical
strength, endurance and chemical stability under in vivo biological en-
vironment [170,196]. Nevertheless, pristine metallic implants often
encounter implantation failure in the host body due to their poor bio-
compatibility and osseointegration with the surrounding host tissues
[197]. Owning to the biocompatibility, chemical stability and osteo-
conductivity characteristics of HAp, it can be used as a coating material
to promote better osseointegration of the metal implants via apatite
formation at the implant-tissue interfaces [198]. Moreover, such
coating can be useful to enhance corrosion resistance of metallic im-
plants when in contact with body fluid or blood plasma under physio-
logical environments [199].
In recent years, surface coating of metallic implants using HAp de-
riving from natural bio-wastes have been successfully performed using
various methodologies such as micro-arc oxidation [200], electro-
phoretic [201], electrochemical [202], pulsed laser [197,203], plasma
spray and high-velocity oxygen fuel deposition [204]. For example,
Qaid and co-workers [200] demonstrated that the deposition of HAp
coatings prepared from 1.5 g/L eggshell-derived HAp on Ti6Al4V alloy
substrate surface using micro-arc oxidation approach exhibited a well-
formed coating layer with enhanced adhesive strength and corrosion
resistance properties as compared to un-coated substrate. Comparative
study related to the properties of bovine bone-derived HAp coatings
formed from high-velocity oxygen fuel (HVOF) and atmospheric plasma
spray (APS) approaches were also conducted by Clavijo-Mejía et al.
[204]. It was disclosed that the HVOF technique will lead to the for-
mation of a secondary phase (dolomite) in HAp coatings, which will
detrimentally decrease the coating stability as evidenced by its dela-
mination after 5 days of SBF immersion. Meanwhile, single phase HAp
coating with high bioactivity, proper thickness and surface roughness
was formed from APS method.
In order to enhance the mechanical and biological performance of
HAp coating, some efforts have been devoted to the synthesis of ionic-
substituted HAp for its deposition on metallic substrate. Popescu et al.
[197] synthesized lithium (Li)-substituted HAp coating on substrate
surface via pulsed laser deposition method. It was shown that the Li
substitution of HAp coatings can impart surface roughness and hydro-
philicity which are favourable for subsequent cellular activities and
thus bone regeneration process. In vitro cell viability tests also showed
that the substitution of Li into HAp lattice can facilitate the hMSC cell
growth on the film surfaces. Meanwhile, some studies also attempted to
develop HAp-based composite coating with improved biological and
mechanical performance by including reinforcing component into the
coating formulation. For example, nanocomposites coating composed of
bovine-derived HAp and diopside are shown to display favourable
bioactivity, wettability and enhanced hardness property as compared to
mere HAp coating [201]. Mihailescu et al. [203] also showed that the
inclusion of MgF2 and MgO to the bovine bone-derived HAp did not
only improve the adhesion of the coatings obtained by the pulsed laser
techniques on the metal substrate, but also concomitantly increased the
microbicidal activity against dental pathogen, as compared to bovine
HAp-coated sample. Nirmala et al. [205] also reported that the de-
position of silver nanoparticle onto bovine bone-derived HAp showed
good bactericidal action against Staphylococcus aureus, making them
promising candidate as implant coating material. Similarly, zinc-HAp
composites originated from Labeo rohita fish bone also demonstrated
potent antibacterial and antibiofilm ability against Escherichia coli and
Staphylococcus aureus [206].
S.-L. Bee and Z.A.A. Hamid
4.1.3. As drug delivery carrier
The use of bioceramic material as controlled drug delivery vehicle
to treat bone-related diseases (e.g. bone tumour and osteomyelitis) has
been extensively explored over the past decades due to their increased
drug bioavailability and reduced systemic side effects as compared to
traditional drug administration regimen [207,208]. The local and sus-
tained release of drugs allows shortening of the prolonged therapies and
can accelerate the bone healing process, as well minimize the extent of
surgical removal of the affected bone. Among numerous bioceramic
materials, HAp (both synthetic and natural origin-derived types) has
emerged as a promising candidate to be used as a sustained release drug
carrier due to its ability to adsorb a broad range of therapeutic species
as well as its non-toxic degradation products that can be absorbed by
the body [209,210]. The utilization of HAp materials as drug delivery
system for the treatment of bone-associated diseases can be beneficial
for carrying dual functionality: the capability to chemically bond with
host bone tissues while concomitantly improving drug efficiency by
sustained release of drugs at the specific site [211].
To date, bio-waste-derived HAp with different morphologies in-
cluding rod-like [133], flower-like architecture [177], hollow micro-
sphere and mesoporous [212] structure have been used as drug carriers
to be utilized in traumatized or post-operative bone tissues site. For
example, Kumar et al. [177] reported the potential of eggshell derived-
HAp with flower-like structure to be used as drug vehicle for the de-
livery of doxycycline hydrochloride. In another research, nanorod-like
HAp which was synthesized from eggshell waste exhibited excellent
loading of curcumin drug (82.50 ± 0.02%) and showed controlled
release fashion in the physiological buffer solution [133]. Guo et al.
[212] synthesized a hollow carbonated HAp microspheres with meso-
porous structure from nacre of Corbicula fluminea for the delivery of
vancomycin hydrochloride. The high drug loading capacity (about
85 wt%) and sustained drug release property suggesting its potential
use for bone-implantable drug-delivery applications.
4.2. HAp as adsorbent for environmental pollution remediation applications
Pollution caused by inorganic and organic contaminants as a result
of anthropogenic activities represents a serious threat to living organ-
isms and environment. Adsorption technology is one of the most com-
monly employed mitigation approach for the removal of these con-
taminants due to its simplicity, inexpensive, availability of a wide range
of adsorbents and easy application [139,213,214]. At present, low cost
and environmentally friendly adsorbent originating from agricultural
and food industry wastes has garnered much attention over traditional
adsorbents [215–217]. Among them, HAp which can be derived from
various bio-waste sources has been widely studied as adsorbent mate-
rial for the removal of hazardous pollutant (such as heavy metals,
radionuclides, inorganic and organic pollutants) particularly in water
and wastewater treatment applications. This is attributed to the unique
characteristics of HAp such as high adsorption capacity, ion-exchange
capability and low water solubility [102,218]. In addition, the em-
ployment of bio-waste-derived HAp does not only offer economic
benefits in terms of reducing the cost of adsorbent production, but also
contributes in attaining a sustainable development as a part of waste
management approach to reduce waste output.
It is worth stressing that the physicochemical properties of HAp
such as Ca/P molar ratio, phase composition, presence of substituted
ions, particle size, porosity and surface area have direct influence on its
efficiency to be used as adsorbent in environmental remediation ap-
plications. In other words, identification of the optimum preparation
methods and synthetic conditions for different types of bio-waste
sources is said to be crucial for an effective adsorption process since
these factors have significant impact on the physicochemical properties
of HAp. For example, a variation of Ca/P molar ratio can either aug-
ment or exacerbate the adsorption efficiency of HAp, which will be
contingent on the acido-basicity nature of the pollutant. In case of
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acidic-based pollutant, an increase of the Ca/P molar ratio would be
expected to be advantageous for its adsorption, which on the other
hand can be unfavourable for the adsorption of a basic pollutant.
Similarly, the acido-basicity nature of HAp can also be affected by the
presence of substituted ions, e.g. CO32− substitution can increase the
acidity while basicity nature of HAp can be enhanced by the substitu-
tion of Na+ [218]. Additionally, HAp with larger surface area offers
more accessible adsorption sites that can facilitate the removal of more
pollutants [219,220].
4.2.1. As adsorbent for heavy metals
Tremendous amount of heavy metals discharged into the environ-
ment from various natural and industrial activities are known to be one
of the major factors leading to water pollution. Due to their bioaccu-
mulation, non-biodegradable and toxicity nature even at low con-
centration, the removal of even trace amount of heavy metals from
water source is becoming extremely crucial [221]. Up to date, both
synthetic and natural resources-derived HAp have been reported in
numerous literatures to be used as adsorbent material for removing
heavy metals. The utilization of HAp which is deriving from bio-waste
source including fish bone and scale [97,222–224], mammalian bone
[225], clam shell [226], snail shell [139], mussel shell [227] and
eggshell [228,229] have been widely documented as low-cost ad-
sorbent for the removal of Cd, Co, Cu, Cr, Hg, Ni, Pb and Zn heavy
metals.
It is noteworthy that HAp exhibits preferential adsorption of some
cations over others, because of its greater ability toward the particular
cations. Recently, Núñez et al. [226] used clam shell-derived HAp to
study its removal efficiency of divalent cations (i.e. Pb2+, Cu2+ and
Cd2+) at acidic pH range of 3–5. The authors showed that the ad-
sorption efficiency of HAp decreases with decreasing of pH for both
Cu2+ and Cd2+, while adsorption of Pb2+ showed more than 99% re-
moval efficiency over all range of tested pH. The selectivity of metals
removal using a multicomponent solution containing Cu2+, Cd2+ and
Pb2+ were further investigated. It was found that the adsorption of
Pb2+ from the multicomponent solution showed nearly complete re-
moval. Nevertheless, its adsorption capacity toward Cu2+ and Cd2+
were adversely debilitated in the presence of other metal ions due to the
competitive effect among divalent ions. The high adsorption selectivity
of HAp toward Pb2+ in multicomponent solution can be ascribed to the
high electronegativity of Pb2+ as well as its ionic radius which is in the
range of Ca2+ ionic radius that favour its adsorption process.
Imam et al. [230] studied the sorption behaviour of some metals (Co
(II), Cd(II), Mo and Tc) from aqueous waste solutions using eggshell-
derived HAps prepared using ultrasonic-assisted precipitation method
with (CEHAp) and without (EHAp) calcination process. The results re-
vealed that none of the adsorbents showed affinity to adsorb Mo and Tc,
where EHAp displayed much higher sorption characteristic than CEHAp
materials towards Co and Cd from aqueous solution. This research
showed the potential of eggshell-derived HAp for selective removal of
metal ions from contaminated sites.
A very recent literature reported by Sricharoen et al. [97] showed
that fish scale-derived HAp could be an effective sorbent for the re-
moval of Hg2+ under the assistant of ultrasonic action. The maximum
removal of Hg2+ was attained when 0.02 g adsorbent dosage, 0.4 kW
ultrasonic power, pH 8 and 30 °C of adsorption temperature was em-
ployed. The sorption mechanism of the prepared HAp towards Hg2+
could be attributed to the cationic exchange of Hg2+ to Ca2+ in crystal
structure of HAp as well as the electrostatic interactions between
electronegative sorbent surface with the positively charged Hg2+.
Moreover, the prepared HAp also found to be stable during sorption-
desorption recovery studies without showing significant loss of ad-
sorption efficiency, thus proving its reusability for Hg2+ removal.
Combining HAp with other adsorbent materials via surface im-
mobilization can be an effective approach to optimize its metal removal
capacity. Piccirillo et al. [224] reported the immobilization of metal-
S.-L. Bee and Z.A.A. Hamid
resistant bacterial strains onto the surface of HAp of natural origin (fish
bone) to prepare heavy metal adsorbent. The prepared composites
showed synergistic effect for removing Zn2+ and Cd2+ from aqueous
solution, which exhibited maximum absorption capacities of up to 4
and 3 times higher for Zn2+ and Cd2+ in comparison for the un-
modified HAp.
4.2.2. As adsorbent for radionuclides
Extensive activities associated with nuclear technologies and in-
dustrial mining have undisputedly increased the discharge of nuclear
wastes containing radionuclides into the environment. Owing to their
chemical and radiological toxicity, the presence of radionuclides can
impose a long-term threat to the human health and bio-ecosystem
[231,232]. Permeable reactive barriers (PRBs), which involves the use
of adsorbent materials to separate and immobilize the contaminants, is
one of the emerging technologies for the remediation of radionuclides
in groundwater [233,234]. Amidst various available sorbent materials,
HAp appears as an attractive PRB material and has been reported to be
useful for the removal of problematic radionuclides such as U
[231,235,236], Sr [102,233] and Pu [237].
Han et al. [236] evaluated the ability of fish bone derived HAp as a
remediating agent for removing U(VI) radionuclides from aqueous so-
lutions in a laboratory batch mode. Experimental results showed that
fish bone derived HAp formed by calcination at 600 °C had high U(VI)
sorption capacity of 384.56 mg/g, which was comparable to the com-
mercially available HAp. The sorption mechanism of U(VI) was attrib-
uted to its chemical reaction with HAp to form autinite (Ca
(UO2)2(PO4)2(H2O)6), thus contributing to the U(VI) immobilization.
Sequestration of U(VI) to form autinite can provide long term stability
which can effectively hinder its desorption that can cause secondary
pollution. In another study, Lammers et al. [235] further demonstrated
the efficacy of fish bone-derived HAp in the immobilization of U(VI)
from natural groundwater. In-field testing involving the reaction of fish
bone-derived HAp adsorbent with depleted U(VI) contaminated
groundwater was performed under both ambient flow in-situ, and
under accelerated flow ex-situ. The result showed that the U(VI) se-
questered under both ambient and accelerated flow environments were
strongly bound to the HAp material, with exceeding 99% of U(VI) being
removed from groundwater. Meanwhile, a stable U(VI) uptake with
greater than 50 g U/kg solid was attained via the precipitation of U(VI)-
phosphate phase in the form of chernikovite. These result confirmed the
feasibility of fish bone waste-derived HAp for the treatment of U(VI)
contaminated sites.
A study by Sasaki and Goto [233] investigated the ion-exchange
efficiency of Sr2+ ions in aqueous solution using HAp deriving from
different fish bone wastes. The presence of impurity content and phase
composition were found to be the principal factors in controlling the
removal of Sr2+ ions from aqueous solution using HAp formed from
heat treatment of fish bone wastes. It was revealed that the natural fish
bone with high Mg content will undergo thermal decomposition to form
secondary phase, i.e. β-TCP upon calcination treatment, which can
worsen its Sr2+ sorption efficiency. Meanwhile, natural HAp with high
CO32− content showed better Sr2+ adsorption due to the increased
solution pH that can facilitate the ion-exchange process. Moreover, the
Sr2+ sorption capacity and ion-exchange rate of fish bone-derived HAp
were found to be higher than those of chemically fabricated HAp.
4.2.3. As adsorbent for inorganic elements
Contamination of inorganic elements in water and soil system can
be equally hazardous to human health and living organisms just like
heavy metals. These inorganic elements, usually qualified by the term
of “trace elements”, can be both beneficial and poisonous to living or-
ganisms depending on their concentration. Fluoride (F−), which is a
typical trace element that is beneficial in preventing dental caries at low
dosage, will become detrimental to mankind when its concentration in
drinking water exceeds 1.5 mg/L [238,239]. Elevated F− concentration
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in drinking water system as a result of geological and industrial con-
tamination can lead to diseases such as dental/skeletal fluorosis,
thyroid disorders and liver disease [240,241]. Hence, the scrutiny of
appropriate adsorbents for water defluoridation treatment is becoming
vital. Since HAp can be easily produced from various food industry
wastes, its economically practical and source abundancy making them a
viable option as absorbent for water defluoridation.
Bio-waste-derived HAp has been proved to be promising for water
defluoridation according to several F− adsorption studies in aqueous
solutions [242]. In a work performed by Asimeng et al. [243], it was
observed that the optimize HAp sample prepared from snail shell waste
could effectively reduce the F− concentration from 20.00 to
1.59 ± 0.06 mg/L in aqueous solution. In another adsorption study
using HAp synthesized from eggshell waste, it was shown that the de-
fluoridation efficiency was pH dependent, where 98.8% of F− was re-
moved at pH 3.0 while 85% of F− was removed when aqueous pH is
~7.0. This is ascribed to the presence of more H+ ions at lower pH
condition that will cause neutralization of the OH− ions from the ad-
sorbed surface, thus reducing the hindrance for the F− diffusion. In
addition, the biowaste-derived HAp was further tested under real F−
contaminated groundwater water samples obtained from Bofo and
Serenity sites and found to exhibit about 81% of F− removal efficiency.
Most importantly, it exhibited comparable defluoridation efficiency to
commercially available HAp, thus supporting the prospect of using bio-
waste-derived HAp for F− decontamination in water treatment appli-
cation [244].
Selenium (Se) is another example of inorganic trace element where
its consumption can be both essential and toxic depending on its con-
centration [245]. At low concentration, it plays a pivotal role in me-
tabolism as well as protecting the body from the external damaging
effects but can adversely cause bioaccumulation and toxicity at elevated
dosage intake. Over the years, synthetic HAp has been proven to be
efficient in removing Se (IV) (selenite, SeO32−) from aqueous system
attributed to its ability to ion-exchange/substituted with SeO32− anions
by using its PO43− groups in the lattice [246,247]. In fact, HAp deriving
from natural fish scale waste was found to possess a higher absorption
capacity and faster adsorption kinetics towards Se (IV) than those of
other sorbents (including commercial HAp, chitosan and fish scale).
The adsorption capacities of fish scale derived-HAp, fish scale, com-
mercial HAp and chitosan absorbent were in the order:
5.51 > 2.12 > 1.42 > 1.35 (mg g−1) (L mg−1)1/n [94].
4.2.4. As adsorbent for organic contaminants
The research upon the remediation of organic contaminated was-
tewater has been exclusively associated to the removal of organic dis-
perse dyes which is primarily discharged from textile industry. The
release of dyes-containing effluent into the water system can bring
adverse effect to living organisms due to their toxicity, non-biode-
gradability and mutagenicity [248]. In an effort for the mitigation of
organic dye polluted wastewater, HAp which can be prepared from
agriculture and food industry bio-wastes can serve as a promising ad-
sorbent material to remove organic dye. A research carried out by
Adegun and co-worker [249] employed poultry eggshell waste-derived
HAp to remove Reactive Yellow 4 (RY4) dye from aqueous solution.
The results demonstrate the effectiveness of inexpensive eggshell-de-
rived HAp for the adsorption of RY4 pollutants which exhibited sig-
nificantly higher adsorption capacity in comparison to other adsorbents
(i.e. synthetic HAp, chitosan coated magnetite nanoparticles, octo-
calcium phosphate and TCP) [249].
5. Conclusion
Food industry by-products, such as animal bones, seafood shells and
eggshells are often regarded as wastes and discarded, despite the fact
that they have multidisciplinary applications. Aspired by the concept
from waste to wealth, they can act as valuable precursors to form HAp
S.-L. Bee and Z.A.A. Hamid
owing to their calcium-rich constitution. Herein, formation of HAp from
various food industry bio-wastes of natural origin have been extensively
discussed in this review. In general, HAp can be produced from two
types of bio-waste sources: bio-wastes that serves as CaP (animal bones
and fish scale) or mere Ca sources (eggshells and mollusk shells). The
first class of bio-waste source often involves direct extraction procedure
from waste source by eliminating organic phase from mineral matrix to
obtain HAp. On the contrary, the latter involves multi-step procedure
that consists of extraction of CaCO3 from the waste source, where its
subsequent reaction with phosphorus precursor is required to furnish
HAp. Properties of bio-wastes-derived HAp such as morphology, Ca/P
ratio, particle size, crystallinity, porosity, surface area, composition and
phase purity are being extensively discussed with respect to the bio-
waste sources and preparation methods employed.
Moreover, this review also provides an insight into the potential
uses of bio-wastes-derived HAp in biomedical (BTE, implant coating
and drug delivery) and environmental pollution remediation applica-
tions by thoroughly discussing the relevant literatures that have been
reported over the years. In overall, it has been demonstrated that these
bio-wastes can be a promising alternative for chemical-based precursor
to produce HAp. Indeed, HAp that is deriving from natural bio-waste
can be more preferred to the commercial ones due to the presence of
beneficial substituted composition that resemblance the natural bone
structure. This is especially favourable to be used in biomedical-related
fields. The valorization of natural bio-wastes to extract HAp does not
only offer economic benefit in terms of reducing the cost of HAp pro-
duction, but also serves as an effective waste management strategy to
address the environmental issues that might associated with their dis-
posal.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
Soo-Ling Bee would like to acknowledge USM Global Fellowship for
her postgraduate scholarship sponsorship.
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