10.1007@978 3 030 10834 24

Hydroxyapatite for Biomedicine
and Drug Delivery
Behrad Ghiasi, Yahya Sefidbakht and Maryam Rezaei
1 Introduction
Hydroxyapatite (HA) is a member of the calcium phosphates family (Table 1) and

like the other ones is known as a bioceramic with specific advantages raise from
chemical similarity to the mammalian inorganic structure. In comparison to other
CaPs, HA has highest thermodynamic stability and solubility (after Fluorapatite) in
physiological conditions. Besides this, HA has the highest similarity with the struc-
ture and function to the biominerals like bone and teeth which makes it considerable
particle for researchers to treat bone and dental defects. However, there are also some
differences between biological HA and synthetic HA such as the substitution of ion
in biological HA’ network. HA’ crystal orientation also has a difference and exact
axle growth have not achieved in the laboratory. HA is a major constitution of bone as
Bone contains 65–70% HA in addition to 5–8% water and 20–25% organic materials
(Batchelar et al. 2006; Sato 2007; Malmberg and Nygren 2008).
HA nanoparticles have also used for other applications, such as remediation of
the environment, removal of metals and absorbance of organic molecules on the
surface (Piccirillo and L Castro 2017). Hydroxyapatite has the capability to adsorb
oxytetracycline from the aqueous medium (Harja and Ciobanu 2018).
The 1960’s was an initiative time to start the study about the potentiality of ceram-
ics as a bone substitute and other biomedical applications. The potency of this material
B. Ghiasi · Y. Sefidbakht (B)

Protein Research Center, Shahid Beheshti University, G.C, Tehran, Iran
e-mail: y_sefidbakht@sbu.ac.ir
Y. Sefidbakht
Nanobiotechnology Laboratory, The Faculty of New Technologies Engineering (NTE),
Shahid Beheshti University, G.C, Tehran, Iran
M. Rezaei
Institute of Biochemistry and Biophysics (IBB), Tehran University, Tehran, Iran
© Springer Nature Switzerland AG 2019 85

M. Rahmandoust and M. R. Ayatollahi (eds.), Nanomaterials for Advanced
Biological Applications, Advanced Structured Materials 104,
https://doi.org/10.1007/978-3-030-10834-2_4
86
Table 1 Characteristics of CaP family

Name Symbol Ca/P Formulas pKs at pH Solubility at Space group Density Application
25 °C stability 25 °C, g/L g/cm3
range in
aqueous
Hydroxyapatite HA 1.67 Ca10 (PO4)6 (OH)2 116.8 9.5–12 ~0.0003 Monoclinic P21/b or 3.16
hexagonal P63/m
Amorphous calcium ACP 1.2–2.2 Cax (PO4 )y nH2 O ~5–12 Dentistry (Zhao et al.
phosphate 2011)
β-Tricalcium (β-TCP) 1.5 Ca3 (PO4 )2 28.9 ~0.0005 Rhombohedral R3cH 3.08 Repair bone defects
phosphate (Agarwalla et al. 2018)
α-tricalcium (α-TCP) 1.5 Ca3 (PO4 )2 25.5 ~0.0025 Monoclinic P21/a 2.86 Orthopedic and dentistry
phosphate (Carrodeguas and De Aza
2011)
Octacalcium OCP 1.33 Ca8 (HPO4 )2 (PO4 )4 · 5H2 O 96.6 5.5–7.0 ~0.0081 Triclinic p 1 2.61 Bone defect (Tadashi et al.
phosphate 2014)
Dicalcium phosphate DCPA 1.0 CaHPO4 6.90 ~0.048 Triclinic p 1 2.89 Bone regeneration (Torres
anhydrous (monetite) et al. 2015)
Dicalcium phosphate DCPD 1.0 CaHPO4 · 2H2 O 6.59 2.0–6.0 ~0.088 Monoclinic la 2.32 Orthopedic (Zhang et al.
dehydrate (Brushite) 2017)
Monocalcium MCPA 0.5 Ca(H2 PO4)2 1.14 ~17 Triclinic p 1 2.58
phosphate anhydrous
Monocalcium MCPM 0.5 Ca(H2 PO4 )2 , H2 O 1.14 0.0–2.0 ~18 Triclinic p 1 2.23 Soluble phosphate
phosphate fertilizer (Nasri et al. 2015)
monohydrate
B. Ghiasi et al.
Hydroxyapatite for Biomedicine and Drug Delivery 87
Fig. 1 The growing number of published papers per year with specific subjects
makes it interesting so that many studies have been indexed by PubMed in recent
decades (Fig. 1). As it is shown in the number of publications related to this subject,
tissue engineering and implants are the most related topics, however, the applications
in drug delivery and combination with antibacterial agents are also growing fields.
Bioactivity, biocompatibility, osteoconductivity and absence of immune response
are predictable and tested features of HA due to the chemical similarity to biological
form. Facile fabrication methods and proper cost alongside intrinsic feature of HA
makes it as an appropriate agent for implants, scaffolds and also targeted drug carrier
for a verity of bone disease.
Indeed, constructing a suitable scaffold which is able to form bone, needs exact
porosity and special morphology to provide cell connectivity, cell attachment, cell
migration, and finally osteoformation. Several investigations indicate that morphol-
ogy and porosity are tuneable in HA nanoparticles that help to induce vascularization
and bone formation. In addition, there are studies which confirm the improvement
of implants by HA either as filler or coat (Kim et al. 2004a, b).
Same as other nanoparticles HA has a high surface to volume ratio and can be
loaded by a wide variety of drugs like antibiotics, hormones, growth factors, RNA
and DNA to enhance treatment efficiency and decrease duration.
For example, studies have shown Combination of HA with other polymers like
chitosan and collagen to improve bone mineralization (Li et al. 2002; Chen et al.
2012). Targeted drug delivery is approachable and significantly for reducing the
duration of treatment.
88 B. Ghiasi et al.
2 Different Synthesis Methods
Variety of methods are published to synthesise HA or extract it from natural resources

(Hu et al. 2001; Akram et al. 2014) generally, preparation methods are divided into
three groups and twelve subgroups:
(a) Dry methods: (1) solid-state and (2) mechanochemical.
(b) Wet methods: (1) chemical precipitation, (2) hydrolysis, (3) sol-gel (4)
hydrothermal, (5) emulsion and 6) sonochemical.
(c) High-temperature processes: (1) combustion, (2) pyrolysis, (3) synthesis from
biogenic sources and (4) combination procedures.
Other methods have also been reported, such as sol-gel, chemical methods, extract
from biosource (Fig. 2), and synthesis by alkoxides. The coating on other substrates
is also desirable and are achievable by utilizing plasma spray and electrochemical
deposition.
Dry methods are mostly used to produce a large amount of product; due to the
simplicity in controlling processing conditions and smooth influence of processing
parameters on the achieved product. In the solid-state synthesis, typical precursors
such as chemicals that contain calcium and phosphate or prepared CaP salts are
first milled and then gone under high temperature (e.g. 1000 C) to be calcined.
Hydroxyapatite with good crystallinity is achieved by this method because of being
calcined under high temperature. Calcination under high temperature provides a
well-crystallized structure of HA. The size is large and the shapes are irregular in
the HA production by solid state method.
Unlike dry methods, in the wet methods, the solvent is used (an organic sol-
vent is also possible). Many efforts have been applied to prepare HA particles with
nanosized structure besides regular morphology under wet methods. From the fun-
damental point of view, growing HA crystals in the aqueous phase can clarify the
biomineralization pathway which occurs in vivo. These options turn wet methods
to the promising method. For Instance, until 2013, 60% of articles discussed this
method (Sadat-Shojai et al. 2013). The low preparation temperature leads to low
crystallinity and production of other CaP phases moreover the impurity in the HA
crystals increase when other ions Present in aqueous solution.
Chemical precipitation is the simplest pathway to synthesize nanoHA among wet
chemistry methods. The reaction temperature is a range from room temperature to
the boiling point of the solvent, and the pH of the reaction should be higher than 4.2.
Calcium and phosphate salt are procedures of synthesis, (Tripathi and Basu 2012)
such as calcium nitrate, calcium hydroxide and diammonium hydrogen phosphate
or orthophosphoric acid (Dhand et al. 2014). The typical procedures are shown in
Fig. 3.
Hydrothermal method is another common process to prepare HA, the reaction
applied inside a chamber which is called pressure vessel or autoclave, which provide
high pressure to conduct ageing step at a higher temperature than the boiling point.
The product is highly crystalline with homogeneous composition and good stoi-
chiometric, also phase purity improved in this method due to the high temperature.
Fig. 2 Co-precipitation process, and schematic setup
Hydrolysis also occurs under aqueous phase, for example, hydrolysis of brushite and
TCP at a temperature ranged from 40 to 60 and pH 8.
3 Applications
HA has been under attention for decades due to the excellent biocompatibility
(Rabiei et al. 2007; Liang et al. 2011), affinity to biopolymers (Chen et al. 2007;
Pelin et al. 2009), and high osteogenic potency (Gu et al. 2004; O’Hare et al. 2010).
Several investigations have demonstrated the promoting effect of HA on bone
growth through osteoconduction mechanism without local or systematic toxicity,
inflammation, or immune response to the HA particles (Fig. 4) (Marini et al. 2004;
Kokubo and Takadama 2006; Habibovic et al. 2008). These properties make HA
a suitable candidate for orthopaedic and orthodontic applications including regen-
eration, replacement, and reconstruction. The main achievement of the material
containing HA or coated by HA, is providing an appropriate surface for cell adhesion
which remains for a long time.
90
Fig. 3 The typical procedures of HA synthesis

B. Ghiasi et al.
Advantages Disadvantages
Bioactive(hydration shell) Strong hydration shell, Ionic
surface, Fragile
Well attachment to Surface corona formation,
polymers aggregation
Ease of modification and Precipitation and turbid
surface functionalization solution
Ease of composite dispersity in chemical
formulation composition , size and
shape polymorphism,
Biodegradable High pH sensitivity and
Biocompatible solubility,
low stability
Self-assembly
Biomedical Applications
Tissue engineering
drug delivery
implants
Fig. 4 HA advantages and disadvantages and biomedical applications
Furthermore, investigators suggest that HA or HA Derivatives can be considered

as a model to study mineralization in the human body (Vallet-Regí and González-
Calbet 2004; Jee et al. 2011)
Lately, research has shown HA particles can inhibit the growth of a wide Variety
of cancer cells (Li et al. 2008b; Hou et al. 2009).
Hydroxyapatite is an accepted material for medical applications, especially in
hard tissue treatment, for example, improving and eliminating bone and tooth defects
(Furukawa et al. 2000; Trombelli et al. 2010); Lateral alveolar ridge augmentation
(Strietzel et al. 2007), middle ear implants (Ye et al. 2001), tissue engineering systems
(Lv et al. 2009; Seol et al. 2009), drug delivery agent (Itokazu et al. 1998b), teeth
material, and bioactive coat on metallic bone implants.
HA and its derivatives have led to a number of industrial and technological
applications such as chemical reactions catalyser, for example methane oxidation
(Sugiyama et al. 1996), host material for leaser and fluorescent materials (Li et al.
2008c), ion conductivity and gas sensor (Mahabole et al. 2005). Deploying HA to
chromatography columns provide simple and fast separation of biomolecules such
as nucleic acid and proteins (Jungbauer et al. 2004). Moreover, it has been shown
92 B. Ghiasi et al.
that HA might increase quality of water (Lin et al. 2009) refiner and also purification
of soil from heavy metals (Hashimoto et al. 2009).
Nowadays, compatible implant and substitution are needed. Biocompatibility,
bioactivity, mechanical properties and lack of immune response are great challenges
for scientists. In the individual treatment, implants must require flexibility to achieve
controlling details in micrometry level, similarity, non-toxicity, and biocompatibility
to provide a suitable implant for the patient.
Targeted drug delivery system with the authorization of controlling rate and dura-
tion of drug release is a popular field of research. Due to the high amount of hydroxyl
on the surface and polar charge, hydroxyapatite has appropriate properties to attract
and preserve DNA and peptides in along of HA osteoconductivity feature, make it a
suitable drug carrier (Sadat-Shojai et al. 2010).
The Biohydroxyapatite which is found in the hard biologic organ is plate or cone
shape like nanocrystals that have few thicknesses but a length equal to 10 nm. There is
a belief that due to the similarity of hydroxyapatite with natural mineral in mammals,
HA is one of the best material for substitution and bone regeneration (Cai et al. 2007).
HA nanocrystal demonstrates enhanced densification and improved sinterability due
to the higher surface to volume ratio which might increase fracture toughness.
The comparison with micro hydroxyapatite has shown that Nano hydroxyapatite
has higher reabsorbance capability and bioactivity (Dong et al. 2009; Wang et al.
2010). Moreover, calcium phosphate clusters can Couse forming and catalysed syn-
thesis path (Dorozhkin 2010).
Release calcium ion from biological hydroxyapatite is more similar to what
Happened to nanohydroxyapatite in comparison with micro apatite. Furthermore,
demineralization stops when the particle size reaches the critical point of nanoscale
(Wang and Nancollas 2009).
Nanohydroxyapatite shows higher density (Eriksson et al. 2011) and improved
sinterability (Bianco et al. 2009; Bose et al. 2009, 2010), due to high surface energy. In
general, nanostructured HA has enhanced mechanical properties because of reduction
in flaw sizes (Ahn et al. 2001), the ability of HA in decreasing apoptotic death,
improving cell activity and division reported in studied (Li et al. 2008a).
In hydroxilation process, calcium and phosphate preserve DNA until the appropri-
ate time. Cell proliferation and cellular differentiation can come from the excellent
functional surface of nanoHA, which has more surface and rigidity, that leads to
better cell attachment and better interaction in cellular matrix.
HA nanoparticles are under attentions in dentistry and oral care issues due to the
statistical data that demonstrate the ability of HA to decline hypersensitivity and
inhibit early lesions. So in the last decade, bioceramics and biocomposite base on
Nanohydroxyapatite (nHA) turned to promising material for the different medical
application.
In one hand many advantages come with HA particles which makes HA a promis-
ing agent for biomedical applications. On the other hand, there are also disadvantages
such as low mechanical strength and slow release of the drug. So more research is
provided to enhance HA properties and fit features to applications.
4 Tissue Engineering
Likely, more bone defects are consequences of Accident, osteoporosis, neoplasms,

osteoarthritis, tissue infection or bone tumours. Bone defects might lead to bone
loss or surgical removal in some cases. To regenerate these defects and bring the
functionality of the injured parts back, bone substitution is required. In general, bone
substitute origin is divided to three groups involving autologous (the most desirable),
allograft and bone graft.
Bone tissue engineering is an effective and risk-free alternative offer to auto-
grafts and allografts treatment (replacement). Bone graft has more advantages over
other substitute, merits such as low cost, availability, lack of probability of pathogen
transmission (like HIV and hepatitis virus) and also immune rejection are reported.
The bioengineered biomaterials are typically in the form of prostheses, scaffolds
and hydrogels.
In fact, slow resorption of an implant which is used in bone healing is desirable
in certain circumstances, while resorption rate has to be set to tissue regeneration
rate. If the solubility rate of implants is higher than the tissue regeneration rate, the
application will be limited to use in the bone cavity and defect filling (Best et al. 2008).
HA usually used as a bone substitute in granular structure and pore form (with
tuneability), this structure and form is an ideal for attachment of cell and their migra-
tion until bone formation.
Since 1981 HA has known as an ideal bone substitute for bone regeneration
due to its advantages like the superior biocompatibility, similarity and bioactivity,
affinity to host hard and soft tissues, slow biodegradability in situ, osteoconductivity,
osteoinductivity, osteoblastic differentiation and growth-promoting function are also
recognized as advantages.
HA applications in the tissue engineering is a broad territory from acting as a filler
for bone scaffolds (Khanna et al. 2017; Antony et al. 2018; Raucci et al. 2018) to
metallic implants coating (Chakraborty et al. 2017; Ke et al. 2017; Yan et al. 2017;
Furko et al. 2018) and self-setting bone cements (Sato et al. 2017; Dorozhkin 2018).
Physically, HA is accessible in many forms like particles, dense blocks, porous
scaffolds, granules, powders, implanting coating and composite component in the
specific shapes mostly for the orthopaedic applications. HA is prepared both from
natural sources and synthetic methods. Tissue engineering is going to develop bone
substitute with biocomposites’ help which has the power to restore and improve
tissue functions. To achieve this goal there are several requirements such as porous
scaffold which has enough space for cell growth and mimics the biological function
beside the specific structure of the host extracellular matrix. Not only in the phys-
ical structure but also in the chemical composition, also bioactive surface for cell
adhesion, proliferation and differentiation of osteoblast cell have to be provided to
achieve an efficient treatment.
As far as bone tissue engineering develop, weaknesses and defects of HA parti-
cles be more obvious such as slow degradation rate, low mechanical strength, weak
intensity, brittleness, fatigue failure and disability to induce vascularization.
94 B. Ghiasi et al.
However, the insufficient mechanical strength of pure HA restricts its application

to those which only require low-bearing applications, researchers suggest to fabricate
composition to solve this problem and match all needs in a system, so there are chal-
lenges to match mechanical properties to biological features. Therefore, toughness,
poor tensile strength and weak wear resistance become major obstacles for poten-
tial clinical applications. Exploiting graphene and its derivative as reinforcement to
hydroxyapatite composites has been studied recently (Li et al. 2018).
nHA/polymer composite is a promising agent for overcome these shortages. Poly-
mers are high elastic modulus and able to fill lack of stress shielding in ceramic
biomaterials that are easy to fabricate and control on mechanical properties and
degradation rate is possible so the characteristics properties are tailor-made. Facility
of fabricating polymers made researchers able to construct materials in the exact
shape and size.
Natural polymers which commonly use in bone healing regeneration are included
polysaccharides, proteins and polynucleotides and lots of investigations have pro-
ceeded to examine their combination in the multiplex system consists of polymers
and bioceramics like HA to developed bone substitute (Fig. 5). For decades, syn-
thetic polymers have attracted much attention as they longevity in term of shelf life
although the synthetic polymer biocompatibility has to be under attention.
There is a well cellular affinity for the natural polymer, on the other hand, syn-
thetic polymer exhibit better mechanical strength (Sanjay et al. 2018) and tuneable
degradation rate. Although in the many cases natural polymers exhibit admissible
biocompatibility and bioactivity, the probability of being denatured under scaffold
preparation is always there and necessary care must be kept as well.
The porous structure is required to provide enough space to promote bone
ingrowth, mesoporous structure facilitate mineralization and osteoid formation by
expansion osteoprogenitors and osteoblast migration inside the scaffolds, enhance-
Fig. 5 Schematic of HA application in bone regeneration

ment of nutrient diffusion and vascularization can be obtained by interconnected

microporous and it has been shown that porosity is adjustable by polymers.
The pure form of HA has a brittle nature and makes desirable fabrication in the
size and shapes hard.
HA-chitosan combination is well studied, chitosan obtained from chitin under
alkaline conditions. Chitosan like the other derivates of chitin has inherent antibac-
terial activity in addition to biocompatibility and biodegradability. Chitosan uses in
many applications such as tissue regeneration and wound healing. It’s known as an
excellent composition for bone tissue engineering because of having pivotal factors
in bone regeneration applications. HA conjugate to chitosan through the interaction
of calcium ions and the amine group of CS residue which, provide nucleate sites for
HA crystals that initiate growth and make mechanical fixation. HA-chitosan exhibits
more biocompatibility than pure chitosan.
Collagen is the major constituent of the bone and is familiar to have degradation
characteristics, cells attachment, and excellent biocompatibility. col-HA composite
matches the HA’s inherent bioactivity with cell migration and binding feature of
collagen to elevate osteogenic differentiation. By adding collagen to porous HA
mechanical properties can enhance due to a reduction in porosity. Fracture energy is
increased through the formation of H-bond between HA and collagen.
Hyaluronic acid is suggested to be added to HA composition, to provoke cell
differentiation and proliferation since hyaluronic acid has a significant role in the
cell signalling pathway in addition of properties such as elasticity and antimicrobial
activity. HA-hyaluronic acid interaction has studied for years.
Polylactic acid (PLL) is a synthetic polymer and generally exhibits high Young’s
modulus and tensile strength. There is 4 form of PLAs base on the chirality of lactic
acid and each one has a different amount of tensile strength and degradation rate
which application can be determined by these properties.
For example, poly L-lactic acid (PLLA) used in an orthopaedic fixation device,
4.8 GPa tensile strength and degradation rate up to 5 years in vivo. On the other
hand, poly D, L-lactic acid (PDLLA) has lower tensile stress (1.9 GPa), but a faster
degradation rate which makes them suitable for drug delivery applications.
PLA/HA nanocomposites have been used for both scaffold material and
drug carrier to deliver drug and protein to target that mainly is hard tissue in
bone regeneration. Furthermore, PLA/HA rate in this composition can moderate
mechanical properties. The degradation rate significantly depends on the process
temperature. For example, Young’s modulus of composites would gradually decrease
when the process developed at 220c for 5 min. The composite which consists of
70% HA shows more similar bending strength and fracture toughness to the bone
than composite with 80–85% HA.
Biocompatibility of PLA/HA has been confirmed via different cell lines such
as MG-63 osteosarcoma cells, MC3T3-E1 and L929 fibroblasts. Cell adhesion,
cell numbers, osteocalcin expression and osteoblast differentiation increased sig-
nificantly in each line.
Collagen also examined as a promising addition to enhance biomaterial properties
as it can act as a template that HA form on it. Collagen negative charge that came
96 B. Ghiasi et al.
from carboxylate group play an important role and has a high effect on the nucleation
of HA crystals on the membrane of collagen.
Collagen-HA interaction can promote the mechanical properties like elasticity.
Gelatine which is derived from collagen and has many usages in pharmaceutical,
cosmetic and food applications. HA-gelatine composite also has been well studied.
Polylactic acid (PLA), polyglycolic acid (PGA) and poly (lactic-co-glycolic) acid
(PLGA) are aliphatic polyesters with biodegradability feature which have been sev-
erally studied as a member of bone substitute composite. In addition of biodegrad-
ability PLA has shown thermal plasticity and in combination to HA would possess
mechanical strength.
Adding a second phase as a reinforcement suggest as a solution to proper adequate
fracture toughness and wear resistance. Carbon nano-tubes were introduced as an
effective reinforcement. Several methods are reported to coat HA and HA composite
on implant surface like electrophoretic deposition, plasma spraying, spark plasma sin-
tering (sps), hot isostatic pressing, and aerosol deposition and laser surface alloying
Biocompatibility of HA also can be enhanced by the use of some reinforcement
like carbon nano-tube, gelatine, carboxymethyl cellulose, pectin, hyaluronic acid
graphene oxide and montmorillonite which indicate an important role to improve
bioactivity.
HA coating on the other implants is an alternative solution to provide tough
biocompatible implants by coating metal implants with HA to improve bioactivity
and biocompatibility. Plasma sprayed HA coatings have known as major innovations
in the last decades. The results show HA coatings enhanced lifetime implantation
device in compare to uncoated this advantage is durable due to the expanse of lifetime
and high demand in a young patient.
De Groot et al., Furlong and Osborn are the very first developer of plasma sprayed
HA coating, who published their work about 20 years ago (De Groot et al. 1987;
Furlong and Osborn 1991). Osteosarcoma is a highly aggressive and lethal cancer.
Osteosarcoma cells are sustainable in the presence of nano-HA due to the activation
of caspase-9- pathway and suppression, and apoptosis is depending on nanoparticles’
sizes, where larger ones are more effective.
The scaffolds also can be loaded with a wide range of drugs to boost functionality
of biomaterials, since the bonding time in relatively long (Oonishi et al. 1999),
biomolecule entities were suggested to shortage bonding time, for example, loading
of vancomycin with a short release rate has studied by Martinez-Vazquez and exhibit
inhibiting of bacterial growth around scaffold. Controlled release of growth factored
also checked out in several investigations.
There are many regulating factors, which control bone regeneration process like
vascular endothelial growth factor (VEGF), bone morphogenetic proteins (BMP),
fibroblast growth factor (FGF), insulin-like growth factor (IGF-1) and platelet-
derived growth factor (PDFG-BB) and all are well studied in the bone regeneration
process.
Addition of growth factors like VEGF and BMPs to induce vascularization but
they are high cost and has low stability. Deepak Kumar Khajuria et al. synthesized
a nitrogen doped carbon dots (NCDs) conjugated with HA, and demonstrated the
osteogenic potential of NCDs-HA by a zebrafish jaw bone regeneration model and

MC3T3-E1. The nanoparticles significantly indicate an enhancement in alkaline
phosphatase activity, and the expression of genes that are involved in osteogenic
formation, in addition, bone regeneration in zebrafish enhanced (Khajuria et al. 2018).
5 Antibacterial Activity
As Stamm et al. reported, implant surgery is associated with about 50% of infec-
tions that occur in the hospital (Stamm 1978). The use of implant increase daily and
adding an antibacterial feature to them is a desirable approach because Materials
and tissues integration have to start without any bacterial adhesion or biofilms for-
mation (Zimmerli et al. 1984). On the other hand, antibacterial resistance made it
more complicated to remove infections so there are few alternatives to overwhelm
antibacterial resistance. A comparative study is brought in Table 2.
Incorporating of metal ions are known as a preventive method, for example, silver
ions which inhibited the enzymatic uptake of phosphate that lead to the structural
changes of DNA (Schreurs and Rosenberg 1982; Yang et al. 2009) or releasing
reactive oxygen species (Kim et al. 2007).
Placing an implant into the body can raise the oxidative stress in the environment of
implants, the oxidative stress causing delayed healing, apoptosis, and implant failure
that the last one leads to the bacterial infection. Panday et al. investigated a matrix
based on HA that contains ceria (IV) and Ag NPs and reported the matrix effect on
reducing ROS levels, and antibacterial efficiency. ROS scavenging is provided by
Ce3+ , and the Ag NPs provide antibacterial properties (Pandey et al. 2018).
BS Gholizadeh et al. fabricated a nanocomposite that contains HA and sodium
alginate with different amount of HA (1 up to 5%). they examined the HA effect
on physical and mechanical properties and antibacterial activity. Nanocomposite
consist 5% HA demonstrated the highest antibacterial activity in counter to the food-
borne pathogen (3 CFU/mg reduction). Addition of HA improved tensile strength
and elongation but also reduced water solubility and vapour permeability by 50%
(Gholizadeh et al. 2018).
D. Nancy et al. modified pure titanium with two layers that first contains TiO2-
SrHA (TH) and second contains Chitosan/Gelatine with the incorporation of van-
comycin (THV). THV samples showed enhancement in cell attachment and decrease
in bacterial adhesion. The nanocomposite indicates higher antibacterial activity than
free drug, in the concentration of 2.74 μg vancomycin (Nancy and Rajendran 2018).
Vuk Uskoković et al. construct a Hydroxyapatite-Gelatine-Silica nanocomposite
to overwhelm defects such as the speedy release of drug and inappropriate pore size
that are not large enough to provide space for cell growth. The gelatine and silica
causing more pore formation on the surface in the physiological fluid that leads to
a sustained release of the drug. The composite has promoted antibacterial activity
without harmful effect on the host cell (Uskokovic et al. 2017).
Mónica Cicuéndez et al. prepare a three-dimensional scaffold with a
multifunctional-therapeutic feature that is able to eradicate biofilm while enhancing
98 B. Ghiasi et al.
Table 2 Antibacterial loaded HA, drug and purpose

HA system used Drug Bacteria Reason/advantage References
(Antibacterial
agent)
Hydroxyapatite Silver Escherichia High flexibility, Xiong et al.
nanowires nanoparticles coli., Staphy- high drug (2017)
and lococcus loading capacity
ciprofloxacin aureus (447.4 mg/g)
(CIP) sustained and
pH-responsive
drug release
Silver-doped Silver doped Staphylococcus Addition of Riaz et al.
hydroxyapatite aureus silver increased (2018)
the antibacterial
activity
Antioxidant ceria Silver (Ag) Escherichia Combat Post- Pandey
(CeO2 ) and reinforced coli., Staphy- implantation et al. (2018)
antibacterial silver hydroxyapatite lococcus oxidative stress
(Ag) reinforced (HA) composite aureus and bacterial
hydroxyapatite (HA) infections
composite
Antibacterial ion Zinc, silver, and Staphylococcus Nanoparticles of Sampath
substituted calcium strontium aureus and length Kumar et al.
deficient doxycycline Escherichia 40–50 nm and (2015)
hydroxyapatite coli. width of 5–6 nm
(CDHA) The release of
nanoparticles antibacterial
ions was studied
over a period of
21 days
A long-term
antibacterial
activity
Calcium-deficient Tetracycline and Biocompatible Madhumathi
hydroxyapatite ibuprofen with significant et al. (2018)
(CDHA, Ca/P antibacterial and
1.61) and tricalcium anti-
phosphate inflammatory
(beta-TCP) activity
Nano- Antibacterial Pseudomonas Enhance Kurtjak
gallium/hydroxyapatite nanospheres of aeruginosa biocompatibility et al. (2016)
nanocomposite elemental and alternative
gallium for cytotoxic
Dense circular HA (HA)-binding Streptococcus Improved Huang et al.
disks antimicrobial sanguinis retention and (2016)
peptide Actinomyces antibacterial
(HBAMP) viscosus efficacy for oral
Streptococcus pathogen
mutants control
(continued)
Table 2 (continued)
HA system used Drug Bacteria Reason/advantage References
(Antibacterial
agent)
HA, nanorods Monocyclic N- Staphylococcus Strongly Giacomini
thio-substituted aureus inhibited the et al. (2017)
β-lactams Escherichia bacterial growth
(monocyclic N- coli. of both
thio-substituted methicillin
β-lactams) resistant and
methicillin
susceptible
clinical isolates
of S. aureus
from surgical
bone biopsies
nHA with a diameter Tetracycline E. coli. and B. Higher surface Hassan and
of 200–700 nm hydrochloride cereus roughness and Sultana
nHA/PCL (TCH) lower (2017)
(electrospun mechanical
polycaprolactone) properties than
PCL nanofibers
TCH/nHA/PCL
membrane
exhibited
increased drug
release
behaviour than
TCH/PCL
membrane
bone regeneration. HA embedded into the scaffold and mesoporous loaded with
levofloxacin as an antibiotic. The drug release significantly increases under pH
infection (6.7 and 5.5) which demonstrate pH sensitive reaction.
6 Ions Substitutions
There are several methods to incorporate metal ions into HA such as precipitation (Ma
et al. 1994; Kim et al. 1998; Stanić et al. 2010), coating methods (Zhang et al. 2018),
and spraying (Ke et al. 2017). Different methods have different effects on metal ion
distribution so the biological response and antibacterial properties are different.
Pure HA particles consist calcium (Ca2+ ), phosphate (PO4 3− ) and hydroxyl (OH− )
groups, the ions can be substituted by other ions which have affected crystallinity,
solubility, thermal stability, lattice parameters and crystal morphology. Chlorapatite
(Fahami et al. 2013; Nasiri-Tabrizi and Fahami 2014) and fluorapatite (Wei et al.
100 B. Ghiasi et al.
2003; Jarlbring et al. 2006; Shanmugam and Gopal 2014) are well-studied examples
of ions substitution.
Despite providing structural support and biocompatible material for healing bone,
the presence of therapeutic agents in scaffolds are necessary to control local infections
or post-implantation treatment for improved bone regeneration and inhibit systemic
infection are required.
Due to the insufficiency of systemic drug delivery to deliver planned concentra-
tions of drugs, local drug delivery introduced as an alternative by having advantages
like the limited risk of overdose, and high efficiency and control release rate and
period.
Covalent attachment and self-assembly are conventional methods to immobilize
drugs on scaffolds, whereas the capacity of loading drug is related to the surface
volume ratio and pore size. Immobilization of drugs can limit the drug activity. Berit
Mueller et al. examine an open-porous Hydroxyapatite/lysozyme scaffold, scaffold
obtained by a one-pot freeze gelation and different amounts of loaded lysozyme were
tested. One-pot freeze gelation method is reported as a one-step method to produce
protein loaded scaffold without deploying damage to biomolecules. Their composi-
tion implanted into domestic pigs without inflammation, resorption of material was
over 50% and new bone formation of 21% after eight weeks.
7 Dental Treatment
The alveolar bone loss is a consequence of the severe form of periodontitis which is a
kind of oral disease (Mombelli 2003). In general treatment, high dosage of antibiotic
administers systematically for a long duration (Slots and Ting 2002). To treat kinds of
infections which cause vascular damage, finding a suitable alternative for delivering
the antibiotic is necessary and the novel drug-delivery system has to be able to
transmit intended dosage of the antibiotic because the parenteral administration of
the effective concentration of antibiotics locally is difficult (Etienne 2003; Hanes and
Purvis 2003; Sundararaj et al. 2013; Bansal et al. 2018).
The similarity in the chemical composition of HA and biological hard tissue such
as bone and tooth causing the bio-conduction of HA particles to hard tissues for
remineralization (Otsuka et al. 1994; Krishnan et al. 2015; Wu et al. 2015; Kolanthai
et al. 2016). Coupling the drug loading capability with controlled release rate and
the possibility of inducing osteointegration, is desirable for treating bone defects and
periodontal disease.
The particle size of HA is a determining parameter for cell activity and injectability
(Gauthier et al. 1999). The proper hydroxyapatite for biomedical applications has to
have features like the uniformity in particle size at the nano range, slow agglomerated
rate, and phase homogeneity.
The pathogen that is supposed to be eliminate in the periodontal disease, is the
Indicating factor for choosing appropriate antibiotic (Durgesh et al. 2015) Since there
is a wide range of microorganisms in oral microflora, about 400 different species,

and only a few of them are the pathogen that has to be eliminated (Ferraz et al. 2007).
M.P. Ferraz et al. report the release kinetics and antimicrobial activity of antibiotic-
loaded HA with different porosity. The HA particle which has higher porosity also
has more stable release rate than the particle with lower porosity (Ferraz et al. 2007).
The control data in this paper indicate that pure HA microparticle has no antibiotic
activity.
Preventing dental decay and surgical free treatment of incipient lesion enamel
caries are a novel approach in contemporary dental research. So many efforts have
done to introduce an agent that has an ability to remineralize subsurface enamel
lesion, but additional investigations are required to achieve the agent (Azarpazhooh
and Limeback 2008). A vast number of investigation suggest delivery of bioavailable
calcium and phosphate ions into the lesion to induce remineralization (Huang et al.
2011; Elkassas and Arafa 2014; Cai et al. 2018).
An obstacle to deliver remineralizing ions to the subsurface of the lesion is the
presence of a dense mineral layer on the top of the carious lesion that blocks trans-
portation of incoming ions to the core of the lesion (Larsen and Fejerkov 1989).
A significant number of the investigation evaluated the effect of HA particle on
remineralization and reconstruction (Mahdi et al. 2018; Roveri et al. 2008; Jayasree
et al. 2017) and also HA potential to act as an preventing agent in dentistry (Hannig
et al. 2013). HA particles were used as an additive to toothpaste and mouthwash
(Tschoppe et al. 2011; Hiller et al. 2018; Vano et al. 2018).
Andrej M. Kielbassa et al. studied showed the similar remineralization capacities
for different HA contained toothpaste (Tschoppe et al. 2011).
S. Huang et al. by cross-sectional microhardness (CSMH) tests and polarized light
microscopy (PLM) indicate that nano-HA has higher remineralizing potential than
micro-HA and mineral deposition occur mostly on the top layer of the lesion and has
a low potency to decrease lesion depth. A detailed investigation using pH cycling
conditions demonstrate that remineralization effect gets higher when pH is less than
7.0 (Huang et al. 2011). Nano-HA properties have a relation to environmental pH
change (Olsson et al. 2000).
Bacterial adhesion on tooth surface and acid associated demineralization are two
of major reason for dental problems and decay, an alternative strategies to prevent
adhesion suggested to affect the thermodynamic, physical, and electrostatic inter-
actions that provoke microbial adhesion to interrupt their interaction (Besinis et al.
2015; Kensche et al. 2016).
Kensch A et al. investigated antibiofilm activity and anti bioadhesion effect of HA
in situ on bovine enamel and bacterial adhesion was measured by DAPI staining.
Result show significant reduction of adhesion in presence of HA but no observable
effect on streptococcus mutants viability (Kensche et al. 2017).
Shahmoradi M et al. design a method to achieve stable HA nanosuspensions for
remineralization of enamel caries. HA prepared by wet chemistry than transfer to a
high-pressure homogenizer. The obtained HA particles size were about 20–40 nm.
The nanosuspensions indicate higher remineralizing efficiency than the control group
(Shahmoradi et al. 2018).
The remineralizing of enamel depends on physiochemical mechanism since there

is no cellular mechanism to repair enamel caries. For years, fluoride has known as a
beneficial agent to repair early lesions. Kulkarni VK et al. examined the efficiency
of nano-HA as an alternative to fluoride. The result demonstrates that 10% of nano-
HA has a remineralization effect similar to 1000 ppm fluoride, so nano-HA can be
considered as an alternative to fluoride.
Fluoride has used for widely for remineralizing of early carious lesion, Vyavhare
et al. design an experiment to study (remineralizing enamel and make artificial lesion,
and treat with HA solution at pH cycle) the effect of HA as an alternative for fluoride,
the experiment shows the effect of HA on remineralizing but they conclude that it
has to use as an additive to enhance the fluoride therapy (Vyavhare et al. 2015).
In another study, Juntavee et al. examined the potency of HA gel on remineralizing
of enamel cementum by computer-aided design and manufacturing. Analysing of
surface micro-hardness (SMH) date indicate an increase in the demineralized enamel
after treating with HA gel (Juntavee et al. 2018). Vicker test is a common test for
asses SMH.
Ali Nozari et al. compared the ability of three remineralizing agents include NaF
varnish, Nano Silver fluoride (NSF) and n-HA on remineralize enamel. The results
show a significant superiority for NSF effect, and a similarity in the effect of n-HA
and NaF. A protective layer was formed in all cases as AFM images showed (Nozari
et al. 2017).
8 Implant
Hydroxyapatite implants made from sea coral are treated so that their structure and
the chemical composition becomes nearly identical to natural bone which is used in
plastic surgery. The advantage of these implants is osteoconduction, osteointegration,
and porous nature that allow tissue integration. In addition, these implants are usually
intensely heated and therefore are no immunogenic reactions.
There are several methods to coat HA on metallic implants to improve biofea-
tures include laser pulse deposition, electrochemical and electrophoretic deposition,
etching associated with sandblasting by aluminium dioxide or titanium dioxide,
and plasma spraying. The mentioned methods are complex and expensive so more
research is needed to introduce modification on these methods or develop new facile
and cheap methods which be universal.
Coating by phytic acid-metal complex multilayer was developed by Wang Q et al.,
the formed crystal by this group improved the osteogenic ability and biocompati-
bility of MG63 cells, they suggest this method for bone implants and orthopaedic
applications (Predoi et al. 2016).
In the other hand, Joo L.ong and Daniel C.N Chan discussed the important issues
for in vivo, and their clinical development is briefly summarized. Although there are
benefits in using HA, disadvantages are also seen, for example, risk of dissolution
might increase while HA used as coating and the susceptibility of bacterial infection
in HA coating increase in the camper to titanium implants, beside this fracture can
occur on the surface. To provide proper HA for clinical usage attention have to payed
on some properties such as chemical composition, coating thickness, the effect of
crystallinity or crystallite size and porosity, adjusting these properties lead to the HA
which is optimum in biological and physical properties (Ong and Chan 2000).
Biological performance of chemical hydroxyapatite coating associated with
implant surface modification by a laser beam (Faeda et al. 2009).
To overwhelm deficiencies of pure HA coatings, investigators suggested substitu-
tion of a dopant into the HA structure. Sahar Vahabzadeh et al. doped strontium (Sr)
into plasma sprayed HA to and checked out the changes on the protein release kinet-
ics (new generation of HA coating are supposed to deliver biomolecules), dissolution
behaviour and crystallinity. The Sr-HA has a lower crystallinity and higher dissolu-
tion rate than pure HA, this result illustrate that the HA properties are able to be tailor
through ion substitution and ion dopant (Vahabzadeh et al. 2015). Zhou-Shan et al.
prepared four groups of Sr-HA with different amount of Sr (0, 5, 10, 20%), 20% Sr
coating displayed best osseointegration property (Tao et al. 2016). Sr-substituted HA
also exhibits higher osseointegration in compare to zinc and magnesium substitute
(Tao et al. 2016).
Apart from ions substitution, drug and biomolecule have loaded on HA coating
to explore the effect on healing, for example, parathyroid hormone was loaded on
Sr-HA coating and significantly increased the osteointegration ability on rat samples
(Tao et al. 2016).
As were mentioned on preparation part HA particles can be achieved both with
chemical synthesis and extraction from biosources. A comparative study is done by
Karthik Alagarsmy and revealed the differences. HA nanoparticles which provided
from co-precipitation had higher crystallinity than goat femur bone extracted HA(c-
HA) and control of morphology was available in n-HA. Both particles were active
in vivo but n-HA showed better performance (Karthik et al. 2018).
β-tricalcium phosphate is another member of CaP family that is used for bone
repair, it shows interfacial compatibility and osteoinductive characteristic, but
osteointegration have to be added to its features. Chen Q et al. suggest a coating
of HA on it, the collected data demonstrate improvement in the osteointegration
and Osteogenesis (Chen et al. 2018). HA is also used to stabilize β-TCP blocks in
the defected part and make β-TCP blocks able to be used in reconstructing surgery
(Sakamoto et al. 2018).
9 Drug Delivery
Among several components of calcium-based bioceramics, hydroxyapatite (HA) is

recognized as a proper analogue to apatite which exists in the natural bone structure.
In term of the advantages of HA (reaching third generation of drug carriers Fig. 6 and
Table 3), it can target the damaged area of bone and deliver intended drug such as
stem cell containing biomaterials (Suchanek and Yoshimura 1998; Son et al. 2011;
Kang et al. 2013). This bioceramic can associate the drug molecules physically and
chemically and release them under control in a favourite time scale (Yunoki et al.
2011; Uskoković and Desai 2014).
Since numerous elderlies all over the world suffer from a variety of bone injuries,
therefore, bone tissue engineering is applied tremendously to help the patients to
improve the quality of life (Wei and Ma 2004; Wahl and Czernuszka 2006; Sadat-
Shojai et al. 2013; Dorozhkin 2015). There are numerous drugs which are not proper
clinically because of insolubility, separation of phases and toxicity (Yih and Al-Fandi
2006; Sun et al. 2018).
Several kinds of biodegradable Nanocarriers have been reported for drug deliv-
ery. For instance, organic silica, hydroxyapatite (HA) nanoparticles and polymeric
nanoparticles. Among them, HA has been recognized as the most favourite material
to design drug carriers (Kong et al. 2016; Xiong et al. 2016). HA with a hexagonal
structure (Cui et al. 2014), can be extracted easily in animal bones, eggshells and
codfish bones (Ha et al. 2015; Hamdy et al. 2016).
Indeed, a pure HA surface bioactivity causes the lack of biofunctionality of HA
which is considered as a disadvantage in HA-mediated drug delivery.
To combat this negative function, the loading of the anticancer drug into hydrox-
yapatite structure may intensify the interaction force between drug and HA in order
to reduce the drug leakage and several composites such as chitosan (Zhao et al. 2002),
agarose (Khanarian et al. 2012), collagen (Meagher et al. 2016), polyesters (Zhang
Fig. 6 Three generations of nanoparticles engineered for biomedical applications
Table 3 Different types of HA used for drug delivery

Porous HA types Anti-cancer drug carriers
Nanoparticles Dietylenediamineplatinum medronate (Palazzo et al. 2007)
Biphosphonate alendronate (Palazzo et al. 2007)
Paclitaxel (Venkatasubbu et al. 2013)
Block Cis—diamminedichloreplatinum (II) (Uchida et al. 1992; Netz et al.
2001)
Methotrexate (Itokazu et al. 1998b)
et al. 2009b; Hu et al. 2014), cellulose and its derivatives (Kong et al. 2005; Kwak
et al. 2014; Lukasheva and Tolmachev 2015), has been developed. A new version of
porous HA scaffold containing PLGA microsphere accompanied with Dexametha-
sone to deliver inorganic calcium phosphate in order to generate bone tissue in vivo.
This model has excellently affected the efficiency in Dexamethasone delivery.
Most studied have shown that hydroxyapatite could result in drug leakage during
blood circulation (Kundu et al. 2013). Penetration of drug into the blood can cause
severe side effects and also reduce its bioavailability. To overcome this problem,
hydroxyapatite Nanocarriers with drug loading inside the materials had been applied
(Sun et al. 2018). Doxorubicin (Dox)-loaded hydroxyapatite Nanorods consisting of
folic acid (FA) modification (DOX@HA-FA) were recognized as a powerful anti-
cancer treatment. This modified drug Nanocarriers, DOX@HA-FA Nanorods, were
developed to suggest a new template to load drug in hydroxyapatite materials. In
fact, in the microenvironment with folate receptors, endocytosis happened and the
nanorods exhibited an increase in cellular uptake (Fig. 7), more degradation. So, the
proliferation of targeted cells was inhibited. DOX@HAFA illustrated good stability
in neutral solution, but release under low pH conditions with no apparent side effects
(Sun et al. 2018).
Cancer is categorized in the group of disease which medical world deals with as the
second cause of the death that is a really big challenge (Almeida et al. 1998; Barakat
et al. 2009; Bian et al. 2010). Recently, using Nano-sized particles to attack cancer
cells attracted the attention (Yoo and Park 2004; Sumer and Gao 2008; Bamrungsap
et al. 2012; Elsabahy and Wooley 2012; Chan et al. 2017).
To enhance the tumour accumulation, Nanocarriers can be activated with a tumour-
targeting group which enable them to target cancer cells (Wei et al. 2013; Park et al.
2015; Wei et al. 2015).
In an experiment, Macroporous HA block was able to release the drug slowly,
which was up to 42 and 18 days only (Liu 1996; Itokazu et al. 1998a). On the other
hand, the specific properties of the drugs and the morphology of the HA nanopar-
ticles affected the uptake and release kinetics of the drugs. The negatively charged
alendronate was strongly adsorbed, while the neutral DPM complex showed a lower
affinity towards the negative surface of the HA nanoparticles (Fig. 8). Different
mechanisms of drug loading have applied on HA nanoparticles (Fig. 9).
Among them, porous HA nanoparticles are appropriate options for anticancer
drugs. Comparison between needle-shaped and plat shaped porous HA nanoparticles
show that drugs desorb faster from the needle-shaped HA. In fact, the surface charge
of drugs and the morphology of the HA nanoparticles play a key role in the association
and dissociation kinetics which is a pH-sensitive process.
HA sensitivity to pH acts as a factor degradation into calcium and phosphorous
elements under weak acidic condition (Xie et al. 2014, 2016; Munir et al. 2018).
In recent years, MgO has been applied as a microcarrier to facilitate the delivery
of HA toward the HepG2 cancer cells (Awwad et al. 2017). In a typical experiment,
the ability of ZnO–MgO (bimetal) as a powerful drug carrier for cancer cells was
observed (Sun et al. 2018).
Fig. 7 Schematic showing of HA nanoparticles loaded with DOX (drug) delivery process into the
tumour cells
Fig. 8 Schematic representation of negative charged drug molecules association with the positive
site of the HA and positive charged drug molecules association with the negative site of the HA
Hydroxyapatite for Biomedicine and Drug Delivery
Fig. 9 Different loaded agent on HA delivery agents. a Gold dotted Hydroxyapatite for therapeutic and diagnostic application. b The multilayer coated HA,
conjugated with alendronate for bone regeneration. c Schematic figure of lactoferrin absorbance on HA, the interaction at pH 9 is not so strong since the
electrostatic charge is mix on HA surface so Lf removes more easily after washing
107
Fig. 10 Schematic diagram of the porous HA scaffold containing Dex-loaded PLGA
Cellulose/HA-nanocomposites have good cytocompatibility and relatively high

protein adsorption ability toward haemoglobin. These data indicate that the cellulose/
HA nanocomposites are promising for using in different biomedical fields such as
tissue engineering and protein/drug delivery (Fu et al. 2018).
It was believed that in vivo bone regeneration could be jumped with HA scaffolds
containing DEX-loaded PLGA poly (lactic-co-glycolic acid) microspheres compared
to the use of HA scaffolds alone. With modification in form of PEI coated on PLGA
microsphere surfaces, resulting in a net positive charged surface. Of this microsphere
surfaces, DEX-loaded PLGA were immobilized on the negatively charged HA scaf-
fold surfaces (Fig. 10). Data illustrated enhanced volume and quality of new bone
formation when compared to defects drug with HA scaffolds alone (Son et al. 2011).
These days, HA is recognizing a favourite molecule for gene therapy. Activated
hydroxyapatite Nanorods with polyethylene mine (PEI) with Varying amounts of
EGFP encoding DNA Which were added applied in order to dispersion and the
dispersion stability was monitored by dynamic light scattering. In HeLa and MG-63
cells, the surface zeta potential of the cationic HA-PEI delivery system was reduced.
The Nanorods accompanied with small amounts of DNA illustrated higher positive
zeta potential and better cellular uptake by the negatively charged cell membrane
(Klesing et al. 2012).
Since the cell membrane is negatively charged, therefore, positively charged
nanoparticles lead to the higher degree of attraction due to the ionic interactions
between positively charged particles and cell membranes (Gratton et al. 2008;
Wang et al. 2015). In addition, an investigation reported that the positively charged
nanoparticles might escape from lysosomes and show perinuclear localization,
while the negatively and neutrally charged nanoparticles experience fusion with
lysosomes (Rabinovich-Guilatt et al. 2004; Vasir and Labhasetwar 2008). As a result,
conjugating the nanoparticles with special functional groups can increase the cellular
uptake and thus the transfection efficiency of the delivery system (Wang et al. 2015).
In an investigation, hydroxyapatite nanoparticles (HANP) which was synthesized
by hydrothermal method (Zhang et al. 2009a; Guo et al. 2011; Maia et al. 2016),
zeta potential is altered in pH lower than 3.45 which can be defined as the isoelectric
point of these nanostructures.
The high specific surface area plays a key role in HANP application as bioactive
molecules for drug delivery. In this specific study, the high surface area present
Table 4 Averages obtained water used for sample dilution and VCR incorporation into HANP
after modification of pH value (pH 3.4 and 5.0)
pH of the purified water Mean concentration VCR incorporated Incorporation
used for dilution (μg/ml) ± SD mean concentration efficiency (%) ± SD
(μg/ml) ± SD
3.4 25.70 ± 0.92 5.96 ± 3.93 5.92 ± 3.92
5.0 24.25 ± 0.95 1.24 ± 0.95 1.88 ± 5.27
7.4 25.23 ± 0.61 2.61 ± 6.31 3.06 ± 0.36
by HANP may favour the incorporation of VCR (vincristine) high concentration

(Table 4).
VCR-loaded HANP displayed inhibitory role both tubulin polymerization and
mitotic spindle formation in cancer cells. However, anticancer drugs efficacy in a
bone metastasis can be studied so as to prove the capacity of VCR-loaded HANP as
a drug delivery system (Maia 2018).
In another study, well-designed NHA (amine-functionalized hydroxyapatite)
nanoparticles were properly prepared for the delivery of p53 and candesartan
(CD) (p53/CD/NHA) nanoparticles to treat the breast cancer. The obtained NHA
nanoparticles with suitable amine groups supported effective condensation, and the
p53/CD/NHA nanoparticles with small particle size, positive charges illustrated the
excellent loading of drug and gene in vitro. Also, NHA nanoparticles had almost no
cytotoxicity (Zhao et al. 2017).
In conclusion, desirable drug delivery systems are expected to open new windows
to overcome the challenge of incurable disease. HA can amuse researchers from
several fields which is proved that necessity of these kinds of solutions in the medical
world. This review contributes to such multidisciplinary aspect to elucidate the HA
functions in the field of degradable and compatible biomaterial systems.
10 Conclusion
Nanohydroxyapatite is one of the well-studied members of CaP ceramics due to

the good characteristics that are appropriate for biomedical applications, such as
biocompatibility, nontoxicity, bioactivity and osteoinduction feature. On the other
hand, low mechanical strength has limited it’s utilization in bone regenerating to low
loaded organs an investigating is provided to achieve HA particles that would be able
to tolerate the high load of force to expand HA applications to the sites like backbone
and femur.
There are several methods to synthesise HA nanoparticle such as dry method and
wet method and each method has its own advantages, for example, some methods are
simple and are doable with different sources but it is hard to achieve well dispersity.
On the other hand, some methods are durable to achieve HA with high homogene-
ity and narrow dispersity but require high temperature and expensive instruments.
To fabricate a desirable HA particle, many investigators suggest a combination of

methods.
Porosity of HA particles is also an important property in both tissue engineering
and drug delivery applications, in tissue engineering porous have to proper enough
space for cell growth and the pore should be connected to provide cell-cell interactions
and initiation of bone formation while biodegradation rate should be math to cell
proliferation, choosing pore site must be done with care in these applications because
it has a direct effect on decreasing mechanical strength. In the drug delivery issue,
porous has to have enough space to achieve highest load capacity of the drug.
The Role of HA in preventive and curative dentistry is also studied well, due to the
high similarity of HA to teeth HA is known as a promising agent for remineralizing
early lesion and cure dentin hypersensitivity. It is used highly as an additive to
mouthwashes and toothpaste and promising data have been reported.
In this chapter, we reviewed HA nanoparticles, and summarize HA advantages and
disadvantages for each application, several investigations and innovative methods are
required to achieve the HA nanoparticles that would be utilizable in clinical treatment.
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Hydroxyapatite for Biomedicine

and Drug Delivery

Behrad Ghiasi, Yahya Sefidbakht and Maryam Rezaei

Hydroxyapatite (HA) is a member of the calcium phosphates family (Table 1) and

B. Ghiasi · Y. Sefidbakht (B)

© Springer Nature Switzerland AG 2019 85

Table 1 Characteristics of CaP family

2 Different Synthesis Methods

Variety of methods are published to synthesise HA or extract it from natural resources

Fig. 2 Co-precipitation process, and schematic setup

Fig. 3 The typical procedures of HA synthesis

Fig. 4 HA advantages and disadvantages and biomedical applications

Furthermore, investigators suggest that HA or HA Derivatives can be considered

Likely, more bone defects are consequences of Accident, osteoporosis, neoplasms,

However, the insufficient mechanical strength of pure HA restricts its application

Fig. 5 Schematic of HA application in bone regeneration

ment of nutrient diffusion and vascularization can be obtained by interconnected

osteogenic potential of NCDs-HA by a zebrafish jaw bone regeneration model and

Table 2 Antibacterial loaded HA, drug and purpose

is a wide range of microorganisms in oral microflora, about 400 different species,

The remineralizing of enamel depends on physiochemical mechanism since there

Among several components of calcium-based bioceramics, hydroxyapatite (HA) is

Fig. 6 Three generations of nanoparticles engineered for biomedical applications

Table 3 Different types of HA used for drug delivery

Fig. 10 Schematic diagram of the porous HA scaffold containing Dex-loaded PLGA

Cellulose/HA-nanocomposites have good cytocompatibility and relatively high

by HANP may favour the incorporation of VCR (vincristine) high concentration

Nanohydroxyapatite is one of the well-studied members of CaP ceramics due to

To fabricate a desirable HA particle, many investigators suggest a combination of

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