872594

review-article2019
JBF0010.1177/2280800019872594Journal of Applied Biomaterials & Functional MaterialsYousefi

JABFM Journal of Applied

Biomaterials &
Functional
Review Materials

Journal of Applied Biomaterials &

A review of calcium phosphate cements

Functional Materials
October-December: 1­–21
© The Author(s) 2019
and acrylic bone cements as injectable Article reuse guidelines:
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materials for bone repair and implant https://doi.org/10.1177/2280800019872594

DOI: 10.1177/2280800019872594
journals.sagepub.com/home/jbf

fixation

Azizeh-Mitra Yousefi

Abstract
Treatment of bone defects caused by trauma or disease is a major burden on human healthcare systems. Although
autologous bone grafts are considered as the gold standard, they are limited in availability and are associated with post-
operative complications. Minimally invasive alternatives using injectable bone cements are currently used in certain
clinical procedures, such as vertebroplasty and balloon kyphoplasty. Nevertheless, given the high incidence of fractures
and pathologies that result in bone voids, there is an unmet need for injectable materials with desired properties for
minimally invasive procedures. This paper provides an overview of the most common injectable bone cement materials
for clinical use. The emphasis has been placed on calcium phosphate cements and acrylic bone cements, while enabling
the readers to compare the opportunities and challenges for these two classes of bone cements. This paper also briefly
reviews antibiotic-loaded bone cements used in bone repair and implant fixation, including their efficacy and cost for
healthcare systems. A summary of the current challenges and recommendations for future directions has been brought
in the concluding section of this paper.

Keywords
Calcium phosphate cement, acrylic bone cement, fracture repair, bone void filler, implant fixation

Date received: 9 April 2019; revised: 30 June 2019; accepted: 30 July 2019

Introduction morbidity and limited availability,7 and may be associated

Osteoporosis is a condition characterized by low bone
mass and can lead to increased susceptibility to fractures in
the elderly.1 Worldwide, fractures resulting from osteopo-
rosis affect approximately one woman in three and one
man in five over the age of 50 years.2 In addition, approxi-
mately 2 million cases of trauma or disease-related bone
fractures occur every year in the United States alone, with
an estimated annual direct cost of $10 billion.3 The repair
rate of a bone defect is dependent on the wound size. When
the defect size is greater than the healing capacity of bone,
the fibrous connective tissue becomes dominant in the
bone defect.4,5 Bone grafting is considered to be the gold
standard for the treatment of traumatic bone defects.6
However, bone grafting has the drawback of donor site
with post-operative complications.8,9
As an alternative to autologous bone grafts, a wide vari-
ety of synthetic inorganic/organic or biological materials
have been explored as bone graft substitutes for the treat-
ment of bone defects.10 For thousands of years, humans
have made use of seashells, nuts, and so forth as potential
bone substitute materials.11 With the introduction of
Department of Chemical, Paper and Biomedical Engineering, Miami
University, Oxford, OH, USA
Corresponding author:
Azizeh-Mitra Yousefi, Department of Chemical, Paper and Biomedical
Engineering, Miami University, 650 E High Street, Oxford, OH 45056,
USA.
Email: yousefiam@MiamiOH.edu

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2 Journal of Applied Biomaterials & Functional Materials
tissue-engineering approach and its successful application
in clinical trials,12,13 the concept of bone graft substitutes
has evolved significantly. The scaffold-based tissue engi-
neering aims to restore and maintain normal function in
injured and diseased bone.14–16 A fundamental requirement
for tissue-engineered bone grafts is the ability to integrate
with the host bone, while providing the capacity for load-
bearing and remodeling.17
Under certain circumstances, such as age-related bone
disintegration and osteoporosis, bone reconstruction
involving solid scaffolds may not be a feasible approach.18–20
Therefore, minimally invasive alternatives are sought in
certain orthopedic and maxillofacial procedures.18,21,22
Osteoporotic fracture of vertebral bodies is another exam-
ple where minimally invasive procedures are sought.
Vertebral fractures deform spine and cause chronic pain
while limiting patients’ freedom of movement.23,24
Vertebroplasty (VP) makes use of an injectable bone
cement (IBC) to restore the mechanical strength and stiff-
ness of the vertebral body,23 although its effectiveness as a
treatment modality for vertebral compression fractures is
yet to be established.25
Injectable biomaterials with appropriate functional
properties and self-setting characteristics at physiological
temperatures are essential for the success of these inter-
ventions. IBCs have been used for bone reconstruction and
in a wide range of bone augmentation procedures, such as
orthopedic and maxillofacial surgeries.26–28 Bone cements
are obtained by mixing a biomaterial in powder form with
a liquid, which can set once implanted as a paste within the
body.29 In terms of their chemical composition, IBCs may
be regrouped as calcium phosphate cements (CPCs), cal-
cium sulfate cements (CSCs), acrylic bone cements
(ABCs), and filamentary composite materials.26 As an
alternative, these IBCs can be classified on the basis of
their orthopedic applications. While ABCs are used for
high and medium load-bearing applications, CPCs and
CSCs are generally used for medium and low load-bearing
applications.26
Unlike the first-generation biomaterials that were
mostly inert, the second-generation bone substitute materi-
als intended for orthopedic applications are expected to
elicit a response from the body to favor osseointegra-
tion.30,31 This is true whether the biomaterial is designed
for mechanical fixation (e.g., metallic screws) or for the
repair or replacement of diseased or injured bone (e.g.,
bone graft extenders and substitutes).32 Calcium phos-
phates have been substantially used in the past few dec-
ades as second-generation biomaterials.31,33,34 The
chemical composition of CPCs is similar to the natural
bone, which means that the release of Ca 2+ and PO43−
ions may promote osteoconduction and osteogenesis.35,36
In addition, calcium phosphates offer fast or slow degrada-
tion rates depending on their Ca/P ratio31 and the type of
filler used.37–39 Scaffolds made of calcium phosphates
have been used in dentistry since the early 1970s and in
orthopedics since the 1980s.40 Hence, calcium phosphates
are gaining a special interest as bone graft substitutes in
periodontal and osteochondral regeneration and as poten-
tial carriers in controlled release systems.41–43
As for ABCs, poly(methyl methacrylate) (PMMA) has
evolved from ophthalmological and dental applications44,45
to orthopedics,46,47 for the fixation of prosthetic implants
as well as for remodeling osteoporotic and vertebral frac-
ture repair.48,49 In addition, PMMA has been used for total
joint replacement procedures, including hip, knee, ankle,
elbow, and shoulder.26,50–53 It has been shown that the
injection of PMMA can enhance the stability of hip frac-
ture fixation.54 Also, it has been shown that an osteoporotic
proximal femur can be mechanically stabilized through the
injection of PMMA into it.55 In general, PMMA bone
cement has a relatively high mechanical strength and
offers a suitable curing time and ease of application.56 The
ISO standard 5833 for bone cements requires a compres-
sive strength of ⩾ 70 MPa.57
There is a growing body of literature on the develop-
ment of new bone graft substitutes, making use of syn-
thetic inorganic/organic compounds as well as composites
of demineralized bone with various self-setting pastes.
Several review papers have provided overviews of the cur-
rent state-of-the-art in bone cement development and their
clinical applications.48,58–66 This paper briefly covers the
main classification of bone graft substitutes for bone
reconstruction. The main body of the paper describes the
most common injectable bone substitute materials for
orthopedic use, placing the emphasis on CPCs and ABCs.
Some alternative formulations for these cements have
been listed at the end of each section, while discussing the
prospect of the new formulations and future directions in
the field, including the advantages and drawbacks of anti-
biotic-loaded bone cements (ALBCs).28,67–69
Bone graft substitutes
Bone is an organic–inorganic tissue with a hierarchical
architecture that makes it a micro-/nano-composite.11,70 The
mineralized bone matrix consists of an organic phase
mainly composed of collagen (~35% dry weight), a mineral
phase of carbonated apatite (~65% dry weight), as well as
other non-collagenous proteins that form a stimulating
microenvironment for cellular functions.11 Collagen, a tri-
ple helix with a diameter of ~1.5 nm,71 has a Young’s mod-
ulus of 1–2 GPa and an ultimate tensile strength of 50–1000
MPa, whereas the mineral hydroxyapatite (HA) possesses a
Young’s modulus of ~130 GPa and an ultimate tensile
strength of ~100 MPa.11 The collagen phase is responsible
for the rigidity, viscoelasticity, and toughness of bone,
while the mineral phase provides structural reinforcement
and stiffness.11 The mechanical properties of bone depend
on its composition and structural organization, such as
Yousefi 3

Figure 1.  The four main types of bone graft substitutes: (a) granule; (b) block or pre-form; (c) hydraulic cement; and (d) putty. The
presence of pores in the size range of 0.1–1.0 mm (as seen in (a) and (b)) is essential for a rapid bone ingrowth. Reproduced with
permission from Bohner.76 Copyright © 2010 Elsevier Inc.

mineralization, collagen fiber orientation, porosity, as well
as on trabecular vs. cortical bone architecture.11,72
Autologous bone grafts are considered as the gold
standard in orthopedic surgery, but they are limited in
availability and associated with post-operative compli-
cations.73–75 A more future-oriented alternative to bone
grafting is to make use of synthetic bone graft substi-
tutes.76 Despite decades of research attempts to design
bio-inspired materials, mimicking the properties of natu-
ral bone tissue is not a trivial undertaking.42,72,77
Nevertheless, according to animal model studies, it has
been reported that materials with compressive properties
on the low end of human cancellous bone can encourage
new tissue growth.78–80
Synthetic bone graft substitutes are often in the form of
granules, typically with diameters ranging between 0.1
and 5 mm, or porous blocks (or sponges) (Figure 1(a) and
1(b)).76 Hydraulic cements represent a class of bone graft
substitutes that harden after in situ implantation or injec-
tion (Figure 1(c)).76 This includes cements such as calcium
sulfate hemihydrate (plaster of Paris) and CPC,76 as well as
magnesium phosphate cement.81,82 Besides granules,
porous blocks, and hardening pastes, non-hardening pastes
(putty) have also been proposed as bone graft substitutes.
These pastes typically consist of a mixture of granules and
a highly viscous hydrogel (Figure 1(d)).76
Table 1(a) provides a summary of some commercially
available bone graft substitutes and their mechanisms of
action.83 Commercial bone graft substitutes can be classi-
fied as (i) allograft based, (ii) ceramic based, (iii) factor
based, and (iv) polymer based. Allografts such as deminer-
alized bone matrix (DBM) are osteoinductive84 and pro-
vide a biological stimulus (proteins and growth factors),41
but may pose the risk of disease transmission and immuno-
genicity.85,86 Ceramics such as calcium phosphates, cal-
cium sulfates, and bioactive glasses have been extensively
used as bone graft substitutes.16,40 Growth factors such as
bone morphogenetic proteins (BMPs) have the ability to
recruit and signal to mesenchymal progenitor cells to dif-
ferentiate toward a bone-forming lineage.40,83 Finally, non-
degradable/degradable polymers as well as a variety of
their organic/inorganic composite systems make up the
market for some commercially available strips and inject-
able pastes (Table 1(a)). Compositions of some commer-
cially available IBCs are summarized in Table 1(b). This
review paper focuses on the two main classes of injectable
bone graft substitutes: (i) ceramic based (CPCs) and (ii)
polymer based (ABCs).
4 Journal of Applied Biomaterials & Functional Materials

Table 1.  (a) Summary of selected commercially available bone graft substitutes. Reproduced with permission from Ricciardi
and Bostrom.83 Copyright © 2013 Elsevier Inc. (b) Compositions of some commonly used commercially available injectable bone
cements. Modified from Lewis.26 Copyright © 2011 Wiley Periodicals, Inc.
(a) Selected commercially available bone graft substitutes.

Class Commercial Product Composition Claimed Mechanism of Action Formulations

Allograft DBX®(Synthes) DBM with sodium Osteoinduction, Putty, paste, mix,
based hyaluronate carrier osteoconduction injectable, strips
Grafton®(Medtronic) DBM fibers w/ w/o Osteoinduction, Putty, strips, crunch,
cancellous chips osteoconduction, osteogenesis gel, paste
Orthoblast®(Citagenix) DBM and cancellous chips Osteinduction, Putty, paste
in reverse phase medium osteoconduction
Ceramic Norian SRS®(Synthes) Calcium phosphate Osteoconduction, Injectable paste
based bioresorbable
Vitoss®(Stryker) Beta-tricalcium phosphate Osteoconduction, Putty, strips, injectable,
and bioactive glass osteoinductive w bone marrow morsels, shapes
aspirate, bioresorbable
ProOsteon®(Biomet) Corraline hydroxyapatite Osteconduction, bioresorbable Injectable granules or
and calcium carbonate block
BonePlast®(Biomet) Calcium sulfate Osteoconductive, Paste
bioresorbable
Osteoset®(Wright) Calcium sulfate Osteoconductive bioresorbable Pellets
Factor Infuse®(Medtronic) rhBMP-2 on bovine Osteoinductive Bovine collagen carrier
based collagen carrier
OP-1®(Stryker) rhBMP-7 with type I Osteoinductive Putty (with
collagen carrier carboxymethyl-cellulose
addition), paste
Polymer Healos®(DePuy) Crosslinked collagen and Osteoconductive, osteogenic Strips
based HA with bone marrow
Cortoss®(Stryker) Non-resorbable polymer Osteoconductive Injectable paste
resin with ceramic particles

(b) Selected commercially available injectable bone cements.

Cement Type / Brand Name Composition / Constituentsa,b Manufacturer / Supplier

Acrylic bone cements
CMW™1 Powder (40.00 g): 35.54 g PMMA, 3.64 g BaSO4, 0.82 g BPO DePuy CMW Blackpool,
Liquid (18.37 g): 18.22 g MMA, 0.15 g DMPT, 25 ppm HQ UK
Palacos® R Powder (40.00 g): 33.55 g poly(methyl acrylate, MMA), 6.13 g ZrO2, Heraeus Kulzer GmbH,
0.32 g BPO, 1.00 mg chlorophyll Hanau, Germany
Liquid (18.78 g): 18.40 g MMA, 0.38 g DMPT, 0.40 mg chlorophyll
Surgical Simplex® P Powder (40.00 g): 29.40 g poly(MMA, styrene), 6.00 g MMA, 4.00 g Stryker, Michigan, USA
BaSO4, 0.60 g BPO
Liquid (18.79 g): 18.31 g MMA, 0.48 g DMPT, 80 ppm HQ
Calcium phosphate cements
Biopex® α-TCP, TTCP, DCPD Mitsubishi Materials
Corp., Tokyo, Japan
Cerament® Powder: 40% hydroxyapatite (HA), 60% calcium sulfate (CaS) BoneSupport, Sweden
Liquid: iohexol and saline
chronOS Inject® Powder: 42 wt.% β-TCP, 21 wt.% MCPM, 31 wt.% β-TCP granules, 5 Oberdorf, Switzerland
wt.% Mg hydrogen phosphate trihydrate, < 1 wt.% sodium hydrogen
pyrophosphate Mg(SO4)2
Liquid: 0.5% solution of sodium hyalurone
Graftys® QuickSet Graftys® Powder: calcium phosphate salts and HydroxyPropylMethylCellulose Graftys, France
HBS (HMPC)
Liquid: phosphate-based (Na2HPO4) aqueous solution
Norian® Skeletal Repair α-TCP, CaCO3, MCPM Synthes, Inc.,West
System Chester, PA, USA
aMMA: methylmethacrylate; BPO: benzoyl peroxide; DMPT: N, N-dimethyl-p-toluidie; HQ: hydroquinone; TCP: tricalcium phosphate; TTCP: tetra-

calcium phosphate; DCPD: dicalcium phosphate dihydrate; MCPM: monocalcium phosphate monohydrate.
bCompositional details for the acrylic bone cements and chronOs Inject® cement were taken from products’ brochures.
Yousefi 5

Table 2.  Existing calcium phosphates and their major properties. Reproduced with permission from Dorozhkin.87 Copyright ©
2012 Elsevier Inc.

Molar ratio Compound Formula Solubility at 25°C pH stability

(Ca/P) (range)
−logKs g l−1
0.5 Monocalcium phosphate Ca(H2PO4)2·H2O 1.14 ∼18 0.0–2.0
monohydrate (MCPM)
0.5 Monocalcium phosphate anhydrous Ca(H2PO4)2 1.14 ∼17 a

(MCPA or MCP)
1 Dicalcium phosphate dihydrate CaHPO4·2H2O 6.59 ∼0.088 2.0–6.0
(DCPD), mineral brushite
1 Dicalcium phosphate anhydrous CaHPO4 6.9 ∼0.048 a

(DCPA or DCP), mineral monetite

1.33 Octacalcium phosphate (OCP) Ca8(HPO4)2(PO4)4·5H2O 96.6 ∼0.0081 5.5–7.0
1.5 α-Tricalcium phosphate (α-TCP) α-Ca3(PO4)2 25.5 ∼0.0025 b

1.5 β-Tricalcium phosphate (β-TCP) β-Ca3(PO4)2 28.9 ∼0.0005 b

1.2–2.2 Amorphous calcium phosphates CaxHy(PO4)z·nH2O, n = 3–4.5, c c ∼5–12d

(ACP) 15–20% H2O
1.5–1.67 Calcium-deficient hydroxyapatite Ca10−x(HPO4) ∼85 ∼0.0094 6.5–9.5
(CDHA or Ca-def HA)e x(PO4)6−x(OH)2−x (0 < x < 1)
1.67 Hydroxyapatite (HA, HAp or OHAp) Ca10(PO4)6(OH)2 116.8 ∼0.0003 9.5–12
1.67 Fluorapatite (FA or FAp) Ca10(PO4)6F2 120 ∼0.0002 7–12
1.67 Oxyapatite (OA, OAp or OXA)f Ca10(PO4)6O ∼69 ∼0.087 b

2 Tetracalcium phosphate (TTCP or Ca4(PO4)2O 38–44 ∼0.0007 b

TetCP), mineral hilgenstockite

aStableat temperatures above 100°C.
bThese compounds cannot be precipitated from aqueous solutions.
cCannot be measured precisely. However, the following values were found: 25.7 ± 0.1 (pH 7.40), 29.9 ± 0.1 (pH 6.00), 32.7 ± 0.1 (pH 5.28). The

comparative extent of dissolution in acidic buffer is: ACP >> α-TCP >> β-TCP > CDHA >> HA > FA.
dAlways metastable.
eOccasionally referred to as “precipitated HA” (PHA).
fThe existence of OA remains questionable.

Calcium phosphate cements
Composition and cement formation
Some available calcium phosphates, with their composi-
tion, standard abbreviations and solubility data are listed in
Table 2.87 The clinical potential of calcium phosphate
materials further increased when a self-setting CPC was
developed in the early 1980s.88,89 CPCs are generally
formed by combining one or more calcium phosphate
powders with a liquid phase, which is usually water or an
aqueous solution,90–92 although water-immiscible liquids
have also been used to improve handling and cement prop-
erties.93 Upon mixing, the produced paste is able to set and
harden within the body. Unlike ABCs, which undergo
polymerization during hardening, CPCs set as a result of
dissolution and precipitation, while the entanglement of
the precipitated crystals is responsible for hardening.90 A
recent study by Mellier et al.94 made use of ovine whole
blood as a liquid phase for CPCs. The formation of a 3D
clot-like network and its interaction with the precipitated
apatite crystals resulted in a microstructure that was more
sensitive to biological degradation and promoted new
bone formation.94
As Figure 2 shows, CPCs can be classified by the num-
ber of components in the solid phase (single or multiple),
type of setting reaction (hydrolysis or acid–base reaction),
setting mechanism and microstructure evolution during
setting, and the type of end product.90 Although a large
number of formulations has been used to produce
CPCs,87,95–100 the CPCs developed to date have only two
different end products: precipitated HA or brushite (dical-
cium phosphate dihydrate, DCPD).90 This is anticipated,
since HA is the most stable calcium phosphate at pH >
4.2, whereas brushite is the most stable one at pH < 4.2.90
Changing the powder-to-liquid ratios can lead to
CPCs with a variety of self-setting times.101,102 According
to ISO/DIS 18531 for CPCs, the setting time is the “time
required from the start of powdered agent and liquid
agent blending until hardening of the cement.”103
Reducing the powder-to-liquid ratio of CPCs increases
the injectability104 while increasing the setting time and
affecting the mechanical properties of CPCs after set-
ting.105 Although CPCs have demonstrated self-setting
both in simulated body fluid (SBF) and in vivo in rats,
the properties of CPCs set in SBF are expected to differ
from those of CPCs set in vivo.102
6 Journal of Applied Biomaterials & Functional Materials

Figure 2.  Classification of calcium phosphate cements, with examples of the most common formulations. From top to bottom
the cements are classified by the type of end product (apatite or brushite), number of components in the solid phase (single or
multiple), type of setting reaction (hydrolysis or acid–base reaction), setting mechanism and microstructure evolution during setting.
Scanning electron micrographs of set apatite and brushite cements obtained by the hydrolysis of α tricalcium phosphate (α-TCP)
and by reaction of β-TCP with MCPM (monocalcium phosphate monohydrate) respectively, are also shown. Reproduced with
permission from Ginebra et al.90 Copyright © 2012 Elsevier Inc.

From a biological perspective, CPCs are attractive
because they have proven to be biocompatible, osteocon-
ductive, and bioresorbable,106–110 while they offer an intrin-
sic microporous structure100 for the transport of nutrients
and metabolic waste products.111 Given the excellent bio-
compatibility and osteoconductivity of CPCs, these
cements are great candidates for various clinical applica-
tions. For example, CPCs are considered as the most suit-
able injectable biomaterials to accommodate narrow and
irregular bone defects.18 In addition, CPCs can be injected
to form a bioactive scaffold in situ under physiological
conditions.101 The lack of macropores is considered a
major limitation for the widespread use of CPCs.112
Introducing macropores in CPCs has shown to be benefi-
cial, as macroporous structures can facilitate bone ingrowth
and aid in fast resorption of CPCs.111 For example, the
porosity of CPCs can be enhanced via the use of calcium
carbonate,100,113 polymers,114,115 and foaming agents.116,117
In addition, the porosity and microstructure of CPCs can
be altered by adjusting the process parameters, such as the
liquid-to-powder ratio and the particle size of the powder
phase.90 Ease of handling is also of paramount importance
for the commercial success of injectable bone graft substi-
tute materials.76 Some examples of poor handling include
the use of non-reproducible or complicated mixing proce-
dures,76 poor injectability of a cement paste,38,91 or the
Yousefi 7
Figure 3.  Phase separation mechanisms observed during extrusion of pastes and their location in the extruder. Schematic diagram
is not to scale. Reproduced with permission from O’Neill et al.89 Copyright © 2017 Elsevier Inc.
release and migration of fine particles caused by the lack
of paste cohesion.91,118
Cement injectability
Separation of the solid and liquid phases during cement
delivery is the primary cause of poor injectability of CPCs.89
Some studies have developed theoretical models to gain an
in-depth understanding of the solid–liquid phase separa-
tion.119–121 Figure 3 depicts the schematics of the phase sep-
aration during paste extrusion and their location in the
extruder.89 Phase separation mechanisms identified in dif-
ferent studies include: (i) filtration in the barrel, where the
drainage of the liquid phase caused by the exerted pressure
leads to consolidation of the solid phase;122 (ii) suction,
caused by dilation of the powder network while flowing into
the die;119 and (iii) filtration in the needle (or die land), exac-
erbated with the formation of solid mats.89,123 (Figure 3).
Two key aspects should be considered when testing the
injectability of CPCs:38 (1) defining a suitable experimen-
tal setup for injectability measurements, and (2) investigat-
ing adequate compositions and parameters that could
affect injectability. The injectability of CPCs is commonly
assessed using the syringe ejection method.124–127 For
example, Wang et al.127 used a needle with an inner diam-
eter of 1.6 mm for injectability measurements. The as-pre-
pared paste was poured into the syringe 2 min after mixing
the cement powder and liquid. Then, 1 kg vertical
compressive load was applied on top of the plunger and
the expelled paste was collected for 2 min. The following
equation was used to calculate the injectability:
Pastevolumeexpelled
from the syringe
Injectability % = (1)
Total paste volumebefore
injecting
Nevertheless, this method should be used with caution and
may lead to inconsistent results, particularly when certain
additives are present in the formulation. For example, add-
ing polyvinyl alcohol (PVA) into a cement paste has been
shown to highly enhance the injectability of CPCs.128
However, this increase of cement injectability in the pres-
ence of PVA has been attributed to the increase of setting
time only.38 Hence, both the injectability and setting time
should be reported, while making sure that the injectability
of a cement is measured after a specific time interval (e.g.,
50% of the setting time).
In a review paper, Habraken et al.91 highlighted major
research achievements related to calcium phosphate mate-
rials in the past 15 years: as biologically active agents, car-
riers for gene or ion delivery, and bone graft substitutes. In
another review paper, Zhang et al.129 discussed the role of
key processing parameters (e.g., particle size, cement
composition, and additives) on the setting properties of
CPCs and their handling and mechanical performance.
8 Journal of Applied Biomaterials & Functional Materials
Some alternative formulations
O’Neill et al.89 elaborated on the properties of CPCs that
are essential for their clinical success. The paper discusses
how the presence of powder or liquid additives can have a
positive or detrimental effect on the delivery process of
CPCs. For example, the size and proportion of solid addi-
tives relative to the bulk calcium phosphate powder can
affect its packing ability.89 It has been shown that the addi-
tion of fine fillers (~1 µm in diameter) alters the packing
ability, reduces the water demand, and increases injectabil-
ity.89,97 The addition of large glass beads or microspheres
of poly(lactic-co-glycolic) acid (PLGA) either decreases
or increases injectability depending on the size and wt% of
the beads.95,96 Other additives, such as gelatinized starch,
can increase the compressive strength, compressive modu-
lus, and strain energy density of CPCs.130
Some studies have aimed at improving the cohesion of
CPCs, arguing that these cements can get disintegrated in
the presence of water and blood.18,131 For example, the set-
ting properties of a cement are affected when blood or bio-
logical fluids are present at the injection site.131 Gelling
agents have been used in some studies to improve the han-
dling properties and cohesion of CPCs,131,132 including
glycerin, gelatin, cellulose derivatives, alginic acid salts,
and chitosan.131,133 Alternatively, water-immiscible carrier
liquids have been proposed to improve the cohesion of
injectable CPCs.93 Table 3 shows a selection of studies
investigating a few alternative CPC formulations and sum-
marizes the key findings of these studies.
The resorbability of calcium phosphates can be con-
trolled through the regulation of Ca/P ratio (see Table 2).
Compounds with Ca/P ratio of less than 1 are not suitable
for biological implantation because of the higher speed of
hydrolysis with decreasing Ca/P ratio.31 While β-tricalcium
phosphate (β-TCP) with Ca/P ratio of 1.5 has been classi-
fied as a resorbable calcium phosphate material, the
resorbability of HA depends on several factors. For exam-
ple, sintered HA with a stoichiometric Ca/P molar ratio of
1.67 may not show resorbability. Nevertheless, HA
becomes resorbable in the presence of certain impurities
and structural defects, or when its grain size is reduced to
nano-scale.134 To enhance resorbability of CPCs, pore-
forming additives, such as water-soluble polymers, glu-
cose,135 biodegradable polymers (e.g., PLGA136,137),
collagen,138 and biphasic calcium phosphate (BCP) gran-
ules,139 have been proposed. However, these additives may
alter the physiochemical characteristics of CPCs, includ-
ing the setting time, viscosity, dispersibility, and compres-
sive strength.139,140
Self-setting gelatin-based HA foams have been pro-
posed for the treatment of bone defects.112 The team
reported a suitable injectability and cohesion for the formu-
lation, an interconnected porous structure, and good in vivo
biocompatibility in rabbits. Additional functionalization
with soybean extract slightly reduced the degradation rate
and positively influenced bone formation in a critical-size
bone defect in rabbits.112 Similarly, an injectable cement
made of calcium-deficient HA and foamed gelatin has been
shown to promote bone ingrowth.141 The bubble volume
caused by foaming appeared to increase the ductility of the
cement. Hence, the brittle characteristic of the ceramic was
reduced in the presence of the organic phase.141
Incorporation of polylactic acid (PLA) and phosphate glass
fibers into CPCs has also been proposed to achieve a less
brittle CPC matrix.142
A combination of nano-hydroxyapatite (nHA) as the
solid phase and a modified sodium phosphate solution as a
mixing liquid has been proposed to improve the cohesion
of CPCs in aqueous media as well as in human blood.18
HA has a broad range of clinical applications, has been
used in bone cements for the repair of craniofacial and
dental defects,106,143 and has proven to be osteoconductive
as a 3D scaffold and bone graft substitute material.144–151 In
particular, nHA has a higher surface area and a higher reac-
tivity152 favoring cell adhesion and proliferation of mesen-
chymal stems cells (MSCs), alkaline phosphatase activity,
calcium deposition, and osteogenic gene expression.153–155
Hence, nHA has a greater potential for stimulating new
bone growth compared with conventional HA, making it
superior for bone reconstruction.43,150,156
Stimulation of bone formation at the defect site in
osteoporotic patients has motivated the development of
some new cement formulations. In particular, ionic addi-
tives are often considered as viable alternatives to growth
factors, not only because they are considerably less expen-
sive, but also there is a lower risk that their delivery would
result in adverse effects.159 For example, strontium (II)
( Sr 2+ ) can promote bone formation and inhibit bone
resorption, and is frequently used in the treatment of osteo-
porosis.98,160 A local release of strontium ions into the bone
defect site has proven to be a more effective approach than
orally administered strontium.98,161 In vitro trials of stron-
tium-modified cements (SrCPC) have revealed an
enhanced cell proliferation and osteogenic differentiation
of human bone-marrow-derived MSCs (hMSCs).157 In a
study by Thormann et al.,161 SrCPC-treated rats showed a
statistically higher bone volume fraction (BV/TV) com-
pared with the defect areas filled with CPC. Also, there
was more bone formation at the bone–cement interface for
the SrCPC compared with CPC.
The efficacy of the local bisphosphonate (BP) delivery
via calcium-deficient apatite (CDA) granules and CPCs
has also been investigated.110,162 Systemic administration
of BPs is the main pharmaceutical treatment option for
osteoporosis, as BPs effectively increase bone density and
prevent bone loss, and thereby reduce the risk of vertebral
and non-vertebral fractures.110,163 The efficacy of a CPC
loaded with BP was evaluated by Verron et al.110 for the
local BP delivery in a preclinical large animal model
Yousefi 9

Table 3.  Selection of studies investigating alternative CPC formulations.

Authors Primary Additive(s) Additive Findings

Powder Amount (wt%)
Heinemann α-TCP Castor oil 14.7 and 4.9 The oil-based liquid generated a water-immiscible cement that was
et al.93 ethoxylate 35 injectable and showed improved cohesion, a higher compressive
and hexadecyl- strength, and prolonged shelf life compared with the conventional
phosphate cement. The product of the setting reaction was identified to be
nanocrystalline HA. A resorbability similar to the conventional
cement was anticipated because of the identical mineral structure of
the set products.
van Houdt α-TCP PLGA 30 and 50 PLGA microspheres or milled PLGA particles led to similar CPC
et al.136 porosity and degradation. Increasing the amount of PLGA porogen
accelerated the in vitro degradation of CPC/PLGA. Using a distal
femoral condyle in vivo model in rats, the CPC/PLGA formulations
prepared with milled PLGA showed favorable bone responses,
particularly at 50 wt% PLGA.
Smith α-TCP Glucose 10, 20, 30, 40 Glucose microparticles (GMPs) with two sizes ranges (100–150
et al.135 microparticles µm and 150–300 µm) were used as porogens to introduce
(GMPs) macroporosity within CPCs. Setting times increased for GMP/
CPC formulations compared with control CPC. The local pH was
maintained at a neutral pH range over 8-week of in vitro degradation
study, but the inclusion of GMPs had a detrimental effect on the
compressive strength.
Tödtmann α-TCP Mineralized 2.5 Cement formulations with mineralized collagen type I, either in
et al.138 collagen type I combination with osteocalcin or phosphoserine, resulted in an
increase of new bone formation in cyst-like jaw defects of minipigs.
An increase in the resorption rate was reported for the cement
formulations containing osteocalcin and phosphoserine.
Schumacher α-TCP Strontium 0.72–2.21 Strontium (II) (Sr 2+ ) was introduced into the cement either by
et al.98,157 (Sr) adding SrCO3 to an α-TCP-based cement precursor mixture
(A-type) or by substitution of CaCO3 by SrCO3 during precursor
composition (S-type).The S-type cement (SrCPC) prolonged the
setting time and increased the compressive strength by up to 90%,
while enabling the release of Sr 2+ .98 SrCPCs appeared to significantly
enhance cell proliferation and osteogenic differentiation of hMSCs.157
Zhu et al.158 β-TCP/ Strontium 3–12 The presence of strontium and its concentration played a significant
HA (Sr) (molar ratio) role in the phase compositions, setting time, compressive strength,
in vitro degradation rate and cytotoxicity of the biphasic cement.
Pure biphasic cements exhibited a higher stiffness compared with
Sr-modified cements. Also, a higher amount of Sr-β-TCP in biphasic
cement was associated with a higher degradation rate.
Zheng Calcium Carbon 2 Carbon fiber-reinforced CCPSC was reported to possess moderate
et al.35 phosphate fiber (1 µm biodegradability and favorable osteoconductivity. Carbon fibers
silicate diameter) significantly improved the mechanical properties of the CCPSC
(CCPSC) cement. A small amount of osteoid found at the heterotopic site
1 month after implantation was attributed to potential short-term
osteoinductivity of the cement formulation.

(ewes). To quantify bone formation, the team used three
regions of interest (ROI) in microcomputed tomography
(µCT). Implantation of CPC ± BP significantly improved
bone volume fraction (BV/TV) in each ROI of implanted
vertebral bodies compared with non-implanted ones. The
BV/TV appeared twice as large on the largest ROI (1.2
mm) in the presence of CPC-BP compared with non-
implanted vertebrae. These effects on BV/TV were slightly
superior with CPC-BP (e.g. 85% at 1.2 mm) compared
with CPC alone (79.5% at 1.2 mm).
Acrylic bone cements
Composition and cement formation
For several decades, ABCs have played an important role
in orthopedic surgery.48 The commercial ABCs are mar-
keted as a two-component system (see Table 1(b)).26 The
powder phase primarily consists of PMMA (82–89 wt%),
an inorganic radiopacifying agent such as barium sulfate
or zirconium dioxide (10–15 wt%), as well as benzoyl
peroxide (BPO; 0.5–2.6 wt%) that acts as a catalyst for
10 Journal of Applied Biomaterials & Functional Materials

Figure 4.  Schematic diagram showing (a) the decomposition of BPO leaving a benzoyl radical and a benzoyl anion; (b) how these
benzoyl radicals initiate polymerization of MMA; and (c) formation of a polymer chain. Reproduced with permission from Dunne
and Ormsby.164 Copyright © 2011 Dunne and Ormsby. (d) A typical curing curve for PMMA bone cement where Tmax is the
maximum temperature reached, Tset is the setting temperature and Tamb is the ambient temperature. Reproduced with permission
from Dunne and Ormsby.164 Copyright © 2011 Dunne and Ormsby. (e) Viscosity during setting of three commercial PMMA
cements at 37°C. Reproduced with permission from Nicholas et al.172 Copyright © 2007 Springer.

the polymerization reaction. The liquid phase is largely
methyl methacrylate (MMA) monomer (98 wt%), with 2
wt% N, N-Dimethyl-p-toluidine (DmpT) to accelerate
polymerization.164
The polymerization reaction of an ABC is schemati-
cally shown in Figure 4(a–c).164 During this reaction, the
DmpT causes BPO to decompose and produce a benzoyl
radical and a benzoyl anion (Figure 4(a)). Then, the ben-
zoyl radicals initiate the polymerization of MMA (Figure
4(b)). The active centers formed at this step combine with
additional molecules to form a polymer chain (Figure
4(c)).164 The paste formed during the reaction is a viscous
fluid, which allows the polymerizing cement to be injected
by the surgeon into the site of interest (for example, in VP
and balloon kyphoplasty (BKP), into a fractured vertebral
body),48,165 or into the prepared bone canal prior to implant-
ing an implant (hip replacement).164
A typical temperature-versus-mixing time curve during
the curing of a PMMA bone cement is shown in Figure
4(d),164 revealing a highly exothermic polymerization reac-
tion. The peak temperature (Tmax) is the maximum tempera-
ture attained during polymerization (curing) process.166
This is considered a drawback, as the high temperature dur-
ing curing may reach up to 110°C.56,164 High temperatures
can lead to thermal necrosis of the bone cells and extensive
bone damage,164,167 since collagen denatures with pro-
longed exposure to temperatures in excess of 56°C.168,169 In
addition, PMMA bone cement is not absorbable, with no
functions of bone conduction or induction.170
The dough time shown in Figure 4(d) represents the
time elapsed between the initial mixing and the time the
paste reaches a homogeneous dough-like state. As speci-
fied in the British Standard BS 7253 (ISO 5833),57 at this
point, the cement dough no longer sticks to powderless
surgical gloves (typically 2–3 min after initial mixing).164
The working time is the period between the end of the
dough time until the cement can no longer be manipu-
lated.164 Finally, the setting time of the cement is usually
defined as the time when the temperature rise is halfway
between the maximum temperature (Tmax) and the ambient
temperature (Tamb), as described in ISO 5833.57
Cement characteristics
Commercially available brands of ABC have similarities
and differences on the basis of their chemical composition,
bead size of the prepolymerized PMMA in the powder,
powder particle size distribution, molecular weight of the
Yousefi 11
powder, and molecular weight of the cured cement (see
Table 1(b)).26 The viscosity rise as a function of mixing
time differs among the various brands.26,171–173 Figure 4(e)
shows how the viscosities of three commercial PMMA
bone cements at 37°C increase with time and reach a maxi-
mum of ~75 kPa.s in all three cases, at which the cements
turn into an elastic solid.172 The viscosity can influence the
injectability of the cement, as well as its leakage, extent of
retention within the vertebral body, and final mechanical
properties.174–176 Several research and review papers have
reported on the kinetics of cure reactions for thermosetting
resins.177–181 Studying the effect of experimental factors on
the reaction kinetics may guide the development of ABCs,
and therefore, the design of experiments can be an effective
approach to bone cement design, by enabling the identifica-
tion of the dominant factors that influence its properties.182
There is a limited number of literature reviews on vis-
coelastic properties of IBCs.26,183–185 The rheological prop-
erties of a cement may play a significant role in the
formation of pores during cement mixing and delivery.
Such pores could contribute to crack formation and implant
loosening over time.164 In addition, properties such as
creep, stress relaxation, and damping can influence the
long-term performance of a cemented implant. A recent
review paper by Lewis26 has identified the key properties
of ABCs for six commercial formulations in orthopedic
use. The paper investigated how the viscoelastic properties
of the cements were influenced by several relevant param-
eters, such the monomer-to-polymer ratio, polymerization
pressure, cement mixing method, duration of cement mix-
ing, length of aging time, test medium composition, test
frequency, and temperature.26 It was reported that the par-
ticle size distribution of the powder, as well as the tem-
perature and frequency of the tests, was among the most
influential variables affecting the damping behavior of the
ABCs.26
Some alternative formulations
Despite the widespread use of commercially available
plain PMMA bone cement, mainly due to its outstanding
compressive strength and functional performance, it has
several major drawbacks. PMMA is not remodeled in the
body,1,6 and the exothermic reaction of PMMA cement
fixation can impair fracture healing. Moreover, its high
elastic modulus can result in stress shielding and implant
loosening.186 Hence, the use of PMMA cement to stabi-
lize and/or reinforce fractured vertebral body (for exam-
ple, in VP and BKP) can lead to extensive bone stiffening
and potential fractures at the adjacent vertebral bod-
ies.187 In addition, the mechanical failure of the cement
can lead to premature failure of an implant.188 In a recent
review of the literature, Lewis189 has summarized the
properties of some nanofiller-loaded PMMA bone
cement composites.
Many studies have aimed at developing alternative for-
mulations that could eliminate these drawbacks. On the
basis of the shortcomings addressed in these studies, the
new formulations can be grouped into 16 categories as
described by Lewis.190 This review paper focuses on the
formulations that aim to reduce the peak temperature,
improve the mechanical properties, and impart bioactivity
to PMMA cements. For example, adding chitosan or
starch-stabilized polyethylene glycol to PMMA bone
cement has been shown to reduce the maximum curing
temperature of the cement.56,166 Although chitosan did not
appear to affect the tensile properties, it increased the com-
pressive strength of the chitosan/PMMA cement.166
Chitosan is expected to degrade over time in vivo as the
new bone tissue forms, which could enable the generation
of a porous network over time for bone ingrowth.
Some studies have investigated the copolymerization of
MMA with other materials, such as the hydrophilic acrylic
acid (AA)191 as well as 2-hydroxyethyl methacrylate
(HEMA) and diethyl 2-(methacryloyloxy)ethyl phosphate
(DMP).192 Copolymers of MMA and AA, modified using
4-iodo phenyl isocyanate and 3,4,5-triiodo phenyl isocy-
anate as the radiopacifying agents, generated radiopaque
composites as bone cement materials.191 Silk sericin has
also shown to enhance hydrophilicity of MMA-based
copolymers while imparting antibacterial ability.193 In
another study, the presence of DMP/PHEMA segments
improved the thermal behavior of the MMA-based copoly-
mer via reducing the glass transition temperature.192
Moreover, the incorporation of a commercial block copol-
ymer, Nanostrength® (NS), into the liquid phase of the
PMMA bone cement has been shown to improve the frac-
ture toughness of the cement.194 Table 4 lists some other
alternative PMMA cement formulations and briefly sum-
marizes key findings of the cited studies.
Various magnetic materials, such as magnetite (Fe3O4),
have been shown to generate heat in an alternating mag-
netic field.125,195 Hence, these materials have been widely
studied for the minimally invasive treatment of cancer
through hyperthermia of metastatic bone tumors.202,203
Adding magnetite has shown to increase the setting time of
PMMA cement and decrease the maximum temperature
during setting.195 The addition of 30–50 wt% Fe3O4 did not
seem to significantly impact the compressive strength of
PMMA-based bone cements.195,196
Reduction of bacterial adhesion on the cement surface
can be achieved by favoring the direct bonding of the
cement to the bone.197 One strategy for improving the
bone-bonding ability is through the addition of bioactive
fillers such as bioactive glasses and glass–ceram-
ics62,197,198,204,205 as well as HA.199,200,204,206 Bioactive glass
acts as a nucleating agent for the precipitation of HA on the
surface of PMMA cement.62,197 It has been well established
that HA is an osteoconductive material,31,147 and thereby
can improve the in vivo biocompatibility of PMMA bone
12 Journal of Applied Biomaterials & Functional Materials

Table 4.  Selection of studies investigating alternative PMMA bone cement formulations to improve the mechanical properties or
to impart magnetic or bioactive characteristics.

Author Additive Quantity of the Findings

additive (wt%)
Kawashita Magnetite 40, 50, 60 Increasing the Fe3O4 content increased the setting time of the cement
et al.195 nanoparticles and decreased the peak temperature during setting. The cements had a
(Fe3O4) compressive strength of ~90 MPa, adequate for clinical applications. Unlike
the standard PMMA cement, the surface temperature of the samples
containing 40% and 50% Fe3O4 increased rapidly in a magnetic field of 300
Oe (over 70°C within tens of seconds).
Li et al.196 Magnetite 30 and 50 The addition of 30% Fe3O4 did not significantly alter the compressive
nanoparticles strength of the cement or the proliferation of rat fibroblast cells on the
(Fe3O4) cement. The mean diameter of Fe3O4 (11–35 nm) appeared to affect the
heating capability in AC magnetic fields, depending on the magnetic field
(40–300 Oe) and frequency (100 kHz and 600 kHz).
Miola Silver-containing 30 The silver release was greater on the first week, when the rate of infection
et al.197 bioactive glass development was higher, and enabled significant antibacterial effect toward
S. aureus strain. The glass acted as a nucleating agent for the precipitation of
hydroxyapatite on the surface of the cement by a biomimetic mechanism.
Mouse fibroblast L-929 cell line was used to verify the non-cytotoxic effect
of the composites.
Mousa Apatite- 50 and 70 Adding 70 wt% dry-silanated AW-GC to PMMA cement maintained or
et al.198 wollastonite glass increased the bending strength, fracture toughness, and osteoconductivity,
ceramic (AW- but reduced the elastic strain. Small-diameter PMMA beads improved the
GC) handling properties, the mechanical properties and the bioactivity of the
PMMA-based cement.
Verné Ferrimagnetic 10–20 The composites supported the growth of hydroxyapatite on their surface
et al.62 bioactive glass after 28 days of immersion in a simulated body fluid (SBF). Iron leaching test
ceramic (SC-45) revealed a negligible release of iron, while cytotoxicity assays with human
osteoblasts indicated good cell viability and biocompatibility.
Serbetci Hydroxyapatite 7.7 and 14.3 Very few foreign body giant cells were reported for HA-containing cement,
et al.199 (HA) which was attributed to the improved in vivo biocompatibility (in rabbits) in
the presence of HA. Addition of HA into the PMMA cement also increased
the viscosity, improved the workability, decreased the polymerization
temperature, and increased the modulus. The changes in the compressive
strength depended on the PMMA brand.
Li et al.186 Nano-HA coated 15 The new formulation reduced the elastic modulus from 1.91±0.08 GPa to
recombinant 1.21±0.12 GPa. The in vivo results in rabbits suggested a significantly higher
human collagen bone growth for the modified PMMA group when compared with their
standard PMMA counterparts.
Arens Bone marrow 15 (HA) The maximum temperature during curing decreased from ~61°C to 38°C
et al.187 from sheep and and the Young’s modulus decreased from 1830 to 740 MPa by adding 7.5 ml
hydroxyapatite bone marrow to 23 ml cement. The samples had a porosity of up to 51%,
(HA) with pores ranging between 30 and 250 μm.
Hernández Strontium 10 and 20 Incorporation of SrHA negatively influenced the handling and mixing
et al.200 hydroxyapatite properties, emphasizing the need for surface treatment of SrHA particles.
(SrHA) The surface-treated particles improved the compressive strength of the
cements, although this effect was significant for 20 wt% SrHA only.
Slane Silver 0.25–1.0 The cement formulations modified with AgNPs significantly reduced biofilm
et al.201 nanoparticles formation on the surface of the cement, demonstrating a potential for
(AgNPs) preventing bacterial adhesion, but showed no antimicrobial activity against
planktonic bacteria. Mechanical properties were not substantially changed
when compared with the standard cement.

cement.49,199 Biological materials, such as collagen186 and
bone marrow,187 have also been investigated in combina-
tion with bioactive fillers.
Arens et al.187 studied the effect of adding freshly har-
vested bone marrow from sheep to a PMMA cement
formulation containing 15 wt% HA. Besides a reduction in
modulus in the presence of bone marrow, a higher initial
cement viscosity immediately after mixing with bone mar-
row was deemed beneficial, as a result of a reduced risk of
leakage upon injection.23,187,207,208 In vertebral body
Yousefi 13
augmentation procedures, such as VP and BKP, cement
leakage can result in life-threatening cardiac injury209 as
well as pulmonary and cerebral embolism.210–212
Li et al.186 added 15 wt% recombinant human collagen,
coated with HA nanoparticles, to a commercial PMMA
cement (C-PMMA) during the early dough stage. Both
C-PMMA and the modified cement (MC-PMMA) were
implanted in rabbits to examine bone ingrowth and bone
affinity index after 4, 12, and 24 weeks. The team reported
a significantly higher bone growth for the MC-PMMA
group, when compared with their C-PMMA counterparts
(p<0.05).186 Load transfer at the cement–bone interface is
mainly influenced by direct contact at this zone. Improving
the cement–bone bonding can increase the cement–bone
contact area and, hence, lead to a more uniform load trans-
fer in VP and BKP.186
Drug-loaded bone cements
Silver-containing bioactive agents have been shown to
reduce the risk of infection197,201 while enhancing the bone-
bonding ability of the cement.197 Some new generations of
bone cements offer antibiotic-loaded PMMA and CPC for-
mulations.26,67,213–217 PMMA bone cement is a good carrier
for sustained release of antibiotics in the site of infection.214
This is particularly important since chronic infection of joint
prostheses requires surgical removal of the implant so as to
eradicate the infection.48 Several recent papers have
reviewed the efficacy and safety of ALBC and highlighted
the current state-of-the art in drug-eluting ceme
nts.28,59–61,218,219 Nevertheless, a recent systematic review
comparing deep prosthetic joint infections between total
knee arthroplasty patients, treated with either ALBC or
plain bone cement, has argued that ALBC would not sub-
stantially reduce prosthetic joint infections, and thereby
could be considered as an unnecessary cost to the healthcare
system.68 The cost efficiency profile of ALBC in routine pri-
mary hip and knee arthroplasty seems to be different in the
United States compared with Europe.220 A significant hospi-
tal overhead cost has been reported in the United States with
the use of ALBC, compared with plain bone cement, as
ALBC could cost as high as $350–$400 per batch compared
with $60–70 per batch of plain bone cement.69
It should be noted that CPCs have also been used with
other biologically active products (e.g., analgesics and con-
trast agents). For example, Dupleichs et al.221 have investi-
gated the efficacy of analgesic CPCs loaded with either
bupivacaine or ropivacaine. The bupivacaine-loaded cement
demonstrated an earlier return to full functional recovery
than the ropivacaine-loaded cement, while CPCs retained
their mechanical and biological properties. In another study,
Le Ferrec et al.222 loaded CPCs with Xenetix® radiopaque
agent and reported that incorporating up to 70 mg/mL of
Xenetix® into CPCs did not affect the injectability, setting
time, and cohesion of the composite. Upon injection in a
bone defect in rats, the Xenetix®-loaded CPC appeared to
be biocompatible.222 A recent review paper by Parent et al.223
has elaborated on the design of CPCs for drug delivery
applications, with an emphasis on the parameters affecting
the loading and release of therapeutic substances. In addi-
tion, a paper by Ginebra et al.90 provides an overview of
drug release from CPCs for low molecular weight drugs
(e.g., antibiotics, non-steroidal anti-inflammatories, anti-
cancer drugs, and anti-osteoporotics) and for high molecular
weight molecules (e.g., growth factors and other proteins).
The paper also provides a summary of some CPC formula-
tions intended for ion release (e.g., calcium, phosphate,
strontium, silicate, zinc, and magnesium).
Conclusions
An aging population and sports-related injuries have led to
a dramatic increase in bone-related diseases and bone frac-
tures.76 When biomaterials and medical devices are
designed to replace a degenerated or diseased joints, these
materials may highly benefit from multi-functional char-
acteristics that can meet the biomechanical and biological
requirements of the bone.164 ABCs composed of PMMA
have adequate compressive strength, but suffer from high
elastic moduli,186 high polymerization temperatures,56,164
and lack of remodeling in the body.1,6 In addition, cardiac
complications and embolism caused by PMMA cement
injection and subsequent cement leakage have been
reported in several studies.209–212 Hence, alteration in
cement formulation is a rapidly evolving field.209 Bone
cement formulations combining PMMA with bone mar-
row187 or nano-HA coated human collagen186 have been
proposed to reduce the modulus of PMMA cement while
improving its biocompatibility. In addition, porous PMMA
cements loaded with bioactive glass have been used to
improve osseointegration and provide a better mechanical
stability and biological integration.48
CPCs are osteoconductive,106–110 release no heat,170 and
can be shaped arbitrarily because of their self-setting char-
acteristic. However, they are associated with the problems
of low strength, high brittleness, and low cohesion in aque-
ous environment.130 These shortcomings hinder their
applications as loading-bearing bone substitutes in clinical
settings and minimally invasive orthopedic surgeries.
Hence, there is an unmet need for tougher and biologically
active bone cement materials. Reinforcement of injectable
CPCs using different materials such as gelatinized
starches,130 mixtures of CPCs/PMMA cement,99 and com-
posites of nano-HA/PMMA cement49 have been consid-
ered. The addition of carbon nanotubes has been shown to
improve the mechanical properties of CPCs, particularly
their fracture strength and toughness.39,164 In another study,
an injectable bone substitute material made of calcium-
deficient HA and foamed gelatin has been proposed to pro-
mote bone ingrowth.141 Recently, a copper-doped CPC
14 Journal of Applied Biomaterials & Functional Materials
formulation has demonstrated that copper could be a
dually effective ion: toxic for bacteria while being benefi-
cial for the healthy cells. This is based on the increased
viability of human glial E297 cells, murine osteoblastic
K7M2 cells, and human primary lung fibroblasts in the
presence of the cement.159
Both ABC and CPC classes are relatively inadequate in
terms of key biological requirements and functional
mechanical properties. Taking advantage of the benefits
offered by the other class and making use of nanostructured
materials can potentially lead to superior bone cement for-
mulations for orthopedics applications. Manufacturing,
safety, and regulatory issues should be kept in mind when it
comes to nanomaterials.164 Making use of osteoinductive
materials, such as DBM, has also proven to offer a biologi-
cal stimulus to promote osteogenic differentiation of MSCs
and other osteoprogenitor cells.41,84
Most CPCs have apatite precipitation, which reduces
the resorbability under physiological conditions because
of the low degradability of HA. Enhancing the bioresorb-
ability of bone cements can pave the way to the develop-
ment of new bone substitute materials and drug delivery
systems.39 The current market for resorbable bone graft
substitutes is small compared with the medical device mar-
ket or the drug market. However, it is a fast-growing field,
with materials ranging from metallic alloys to polymers
and from injectable cements to complex porous struc-
tures.76 Rigorous preclinical and clinical trials are neces-
sary to confirm the cost-effectiveness of new injectable
bone graft substitutes and assert their benefit-to-risk
ratios.83 As for ALBCs, the use of ALBC in routine pri-
mary hip and knee arthroplasty appears to remain contro-
versial because of the high cost and limited efficacy
reported in some recent studies.68,220
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Azizeh-Mitra Yousefi https://orcid.org/0000-0002-9096-3147
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