ARTICLE IN PRESS

Biomaterials 27 (2006) 21712177

www.elsevier.com/locate/biomaterials

Leading Opinion

Calcium phosphate cements: Competitive drug carriers for the

musculoskeletal system?$
Maria-Pau Ginebra, Tania Traykova, Josep A. Planell
Center of Reference for Bioengineering of Catalonia (CREBEC), Division of Biomaterials, Biomechanics and Tissue Engineering, Department of Materials
Science and Metallurgical Engineering, Technical University of Catalonia (UPC), Av. Diagonal 647, 08028 Barcelona, Spain
Received 23 June 2005; accepted 14 November 2005
Available online 2 December 2005

Abstract
This paper attempts to provide an insight in the application of calcium phosphate cements (CPC) in the eld of drug delivery devices
for the musculoskeletal system. Their ability to set once implanted within the body, giving a highly microporous material, allows
incorporation of many types of drugs and biologically active molecules, without losing activity and denaturalization. Additionally, by
being injectable these materials can be used in the growing market for new technologies of minimally invasive surgery, and in the
treatment of difcult accessible sites. All these characteristics, together with the excellent biological behaviour of CPC, make them good
candidates for drug delivery devices to be used in the pharmacological treatment of a great number of diseases of the bone tissue.
r 2005 Elsevier Ltd. All rights reserved.
Keywords: Drug delivery; Calcium phosphate cements; Bone regeneration; Bone healing; Bone cements

1. Introduction
The incidence of musculoskeletal disorders, such as
osteoporosis and osteoarthritis has increased strongly in
the last decades, due to the increasing life expectancy. In
parallel, also the number of medications to treat and even
prevent these diseases has expanded dramatically in recent
years [1]. When once only surgical options were available
to treat some diseases at their end-stage, there are now
treatments based on new drugs and active substances,
targeted at the early steps of these musculoskeletal diseases.
A key issue in these treatments is to maximize the drug
access to specic bone sites, and to be able to control the
release of drugs, in order to maintain a desired drug
$
Editors Note: Leading Opinions: This paper is one of a newly
instituted series of scientic articles that provide evidence-based scientic
opinions on topical and important issues in biomaterials science. They
have some features of an invited editorial but are based on scientic facts,
and some features of a review paper, without attempting to be
comprehensive. These papers have been commissioned by the Editor-inChief and reviewed for factual, scientic content by referees.
Corresponding author.
E-mail address: maria.pau.ginebra@upc.edu (M.-P. Ginebra).

0142-9612/$ - see front matter r 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2005.11.023

concentration level for long periods of time without

reaching a toxic level or dropping below the minimum
effective level [2]. For this reason, a major effort has been
done focused on the development of materials that are
capable of releasing drugs by a reproducible and predictable kinetics. A potential substrate to be used as drug
carrier must have the ability to incorporate a drug, to
retain it in a specic target site, and to deliver it
progressively with time in the surrounding tissues.
A range of materials has been employed as drug carriers,
most of them being stable or biodegradable polymers.
However, in the eld of the pharmacological treatment of
skeletal disorders, the specic characteristics of bone tissue
should be considered. Thus, an ideal drug carrier for bone
should be bioactive, which would ensure the ability of the
materials to bond to bone tissue, and resorbable to allow
its progressive substitution by newly formed bone. Additional advantages are provided if the material is injectable,
since it would improve ease of administration, by allowing
minimally invasive surgical techniques. All these properties
are very well tted by calcium phosphate cements (CPC),
and therefore they should be competitive candidates to be
used for this application.

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2. CPC as drug-carrier materials

The development of CPC was an important breakthrough in the eld of bioceramics for bone regeneration,
since it supplied a material which was mouldable and
which had the capacity of self-setting in vivo, within the
bone cavity [3,4]. In addition, the development of injectable
calcium phosphate cement formulations established good
prospects for minimally invasive surgical techniques developed in recent years, less aggressive than the classical
surgical methods. Their ability to set once implanted within
the body, giving a highly microporous material, allows
incorporation of many types of drugs and biologically
active molecules, without losing activity and denaturalization. Therefore, the possibility to use CPCs not only as
bone substitutes, but as carriers for local and controlled

supply of drugs is very attractive and can be useful in

treatments of different skeletal diseases, which normally
require long and painful therapies, as well as for accelerating the rate of bone fracture healing.
Unlike calcium phosphate ceramics employed as drugdelivery systems, where the drugs are usually absorbed on
the surface, in CPCs the drugs can be incorporated
throughout the whole material volume, by adding
them into one of the two cement phases. This fact can
facilitate the release of drugs for more prolonged
times. Several studies related to the application of both
commercial and experimental CPCs as drug carriers have
been published. Some of the most relevant are summarized
in Table 1, which cover different carrier/drug combinations, in terms of both CPC formulations, and drug
systems.

Table 1
Some representative studies on CPC as drug carriers, for different drugs and CPC formulations
Cement formulation

Drug

Group

Type of study

References

b-TCP, MCPM (brushite cement)

TTCP, DCP
TTCP, DCP

Antibiotic
Antibiotic
Antibiotic

In vitro
In vitro
In vitro

[5,6]
[7]
[8]

TTCP, DCP
TTCP, DCP, chitosan
TTCP, a-TCP
ACP, DCPD
TTCP, DCPD

Gentamicin
Flomoxef sodium
Gentamicin, Amikacin and
Ceftiofur
Gentamicin
Flomoxef sodium
Tetraciclin
Gentamicin
Vancomicin

Antibiotic
Antibiotic
Antibiotic
Antibiotic
Antibiotic

[9]
[10]
[11]
[12]

Non specied
a-TCP, TTCP, DCPD
TTCP, DCPD
TTCP, DCPD

Tobramicin
Albecacin sulphate
Mercatopurine
Estradiol

Antibiotic
Antibiotic
Anticancer drug
Hormone

TTCP, DCPD

Estradiol

Hormone

TTCP, DCPD, HA

Salicylic acid

TTCP, DCPD, HA

Indomethacine

a-TCP

Metacrilamide derived from

salicylic acid
Nifedipine
rhTGF-b1
rhTGF-b1
rhTGF-b1
rhTGF-b1
rhBMP-2

Analgesic,
antiinammatory
Antiinammatory,
non- steroid
Analgesic,
antiinammatory
Calcium antagonist
Growth factor
Growth factor
Growth factor
Growth factor
Growth factor

In
In
In
In
In
In
In
In
In
In
In
In
In
In

rhBMP-2
rhBMP-2
Osteocalcin and collagen
Insulin and albumin

Non specied
a-TCP, TTCP, DCPD
a-TCP, TTCP, DCPD
a-TCP, DCP, CaCO3, HA
a-TCP, TTCP, DCPD
b-TCP, MCPM, calcium sulphate (brushite
cement)
a-TCP, DCP, CaCO3, HA, PLGA
microparticles
ACP, DCPD
a-TCP, DCP, CaCO3, HA
TTCP, DCP

vivo
vitro
vitro
vitro
vitro
vivo
vitro
vivo
vitro
vitro
vivo
vitro
vivo
vitro

[13]
[14]
[15]
[16,17]
[18]
[19]
[20]

In vitro
In vivo
In vitro

[2124]
[25]

In
In
In
In
In
In

vitro
vitro
vitro
vitro
vivo
vivo

[26]
[27]
[28]
[29]
[30]
[31]

Growth factor

In vivo

[32]

Growth factor
Proteins
Proteins

In vivo
In vitro
In vitro

[3335]
[36]
[37]

CPCs are apatitic cements, unless otherwise stated.

Abbreviations: DCP, dicalcium phosphate, CaHPO4; DCPD, brushite, dicalcium phosphate dihydrate CaHPO4
2H2O; HA, hydroxyapatite,
Ca10(PO4)6(OH)2; MCPM, monocalcium phosphate monohydrate Ca(H2PO4)2
H2O; a-TCP, alpha-tricalcium phosphate, a-Ca3(PO4)2; b-TCP betatricaclium phosphate, b-Ca3(PO4)2;TTCP, tetracalcium phosphate, Ca4(PO4)2O; ACP, amorphous calcium phosphate; PLGA, poly (lactic-co-glycolic
acid); rhTGF-b1, human recombinant-transforming growth factor-b1; rhBMP-2, human recombinant-bone morphogenetic protein-2.

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2.1. Antibiotics
Major attention has been paid to antibiotics, due to their
wide areas of application: either as prophylactics to prevent
infections produced during surgical interventions, or in
general in the treatment of bone infections. In fact, one of
the key factors for the success of surgical interventions
aimed at the implantation of a prosthesis or of an
osteoconductive material is the prevention from bacterial
infections. Wound contamination, or postoperative infections following fracture repair, implantation of joint
prosthesis or spine surgery, can cause serious problems.
For this reason antibiotics are often provided as prophylactics, either orally or intravenously. However, the little
accessibility of the site of infection to antibiotics delivered
systemically lengthens often the treatment of bone infections over 1 year.
Traditionally, a method applied to control locally the
bone tissue infections has been the implantation of
polymethylmethacrylate spheres (PMMA) loaded with
gentamicin sulphate in the infection site. However, PMMA
spheres are nonresorbable and must be removed after some
months and replaced with other materials able to facilitate
bone regeneration. Antibiotics can be likewise incorporated in hydroxyapatite or b-tricalcium phosphate ceramic
blocks, although their resorption rates are slow, and it is
difcult to shape ceramics with complex form in order to
be tted into any type and size of bone defect. An
alternative material proposed some decades ago was
calcium sulphate hemihydrate, which can be used in the
form of cement [38]. The main disadvantage of this
material comes from its low mechanical strength and very
high resorption rate. In this context, the use of CPCs,
combined with different antibiotics can be very helpful in
order to overcome the different drawbacks mentioned
above.
2.2. Antiinflammatory, anticancer and other drugs
CPC have been considered as appropriate matrixes for
the incorporation of other drugs with potential application
in the musculoskeletal system, such indomethacine, an
anti-inammatory, nonsteroidal drug with wide application in different pathologies, such as chronical joint
rheumatism [2124], or some anticancer drugs such as
mercatopurine [16,17]. Other studies have investigated the
incorporation of some hormones, such as estradiol, a
feminine sexual hormone with estrogenic activity, which
can be used in the treatment of symptoms caused by the
decit of estrogens during menopause, such as mineral
resorption and bone loss [19].
2.3. Growth factors
A large number of osteogenic factors, peptides and small
molecules have been associated with accelerated bone
healing in animal models and human clinical trials. Growth

2173

factors are a large group of polypeptides, able to transmit

signals which affect cellular activity [39]. Among them, the
superfamily of b-trasforming growth factors (TGFb-SF) is
especially relevant for bone regeneration. It includes the
transforming growth factors b1, b2, b3, and the bone
morphogenetic proteins (BMP). In the last years the
recombination techniques have made possible the industrial production of human growth factors in big quantities
and high purity. However, injection of this type of
substances alone cannot induce tissue formation and
regeneration, since protein diffuses very fast from the
implantation site. Therefore, it is necessary to have
available carriers which allow for the controlled administration of these factors at adequate therapeutic levels, and
their vectoring towards local tissue targets and cells. This is
necessary to allow large quantities of bone-forming
precursor cells to migrate proliferate and differentiate into
osteogenic cells that induce healing at the fracture site.
Some studies in vitro demonstrated that combinatory use
of these factors with calcium phosphate ceramics resulted
in improved bone growth due to adsorption of big doses of
the osteogenic factors on the ceramic surface, which were
subsequently released [40,41]. The self-setting ability and
osteoconductivity of CPCs are very relevant for this
application. Additionally, if an appropriate resorption rate
is assured, the incorporation of growth factors into CPCs
can supply a material with a great regenerative potential,
applicable in several bone diseases such as osteoporosis, or
to enhance bone healing in fractures.
In general, the studies on CPC as drug delivery systems
tackle very different aspects, all of them relevant for this
issue. In the rst place, it is necessary to verify to which
extent the addition of the drug (either to the liquid or the
solid phases of the cement), interferes with the setting
reaction, modifying either the rheological behaviour or the
physico-chemical properties of the cement. Secondly, it is
necessary to characterize the kinetics of drug release in
vitro. Subsequently, the effectiveness of the cement to act
as carrier for drug delivery in vivo must be assessed and
carefully characterized. And as the nal step, still to arrive,
the clinical performance of the drug delivery system must
be evaluated.
3. Effect of drug incorporation on the physico-chemical
properties of CPCs
The setting reaction of CPCs can be affected or modied
by introducing a drug either to the powder phase or to the
liquid phase, and as a consequence the physico-chemical
and mechanical properties can change [57,11,14]. In
general, in apatitic cements antibiotics tend to increase
their setting times and reduce the mechanical strength
[7,11,14]. This decrease of mechanical strength can be
attributed to different factors, such as increased porosity or
to some inhibition of the setting reaction, as suggested by
the presence of certain amount of reactants in the set
cements when the antibiotic quantity increases.

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In other cases the change in the setting properties are

caused by some chemical interaction with the dug, which can
modify the kinetics of the dissolution-precipitation reaction
and the morphology of the precipitated crystals. Thus, Ratier
et al. [11] attributed the reduction of mechanical properties in
an apatitic cement caused by the addition of tetracycline, to
the ability this antibiotic to chelate Ca-atoms. The hypothesis
was supported by the fact that when the antibiotic was
introduced already complexed with calcium, the interactions
antibiotic-cement could be limited, and bigger amounts could
be added without inuencing the setting and mechanical
properties of the CPC. In the same direction, a strong effect
was observed in the rheological and mechanical properties of
an a-TCP-based cement when an amino salicylic acid derived
methacrylamide with calcium complexation ability was added
[25]. In another CPC, in this case a brushite one, the increase
of setting time and mechanical strength was attributed to the
presence of sulphate ions in the antibiotic, which modied the
morphology of the precipitated crystals [5].

4. Drug release kinetics from CPCs

It is well known that the release of drugs from any drug
delivery device depends on different factors such as the
microstructure, the type of bond between the drug and the
matrix which holds it, and the mechanism of degradation
(if any) of the matrix. The drug delivery devices are usually
classied in three types depending on the mechanism which
controls drug liberation [42,43]: (a) Devices controlled by
diffusion. The drug is incorporated into a nonbiodegradable matrix, or is surrounded by a stable membrane
through which it should diffuse. In this case, the release
kinetics is dependent only on the physical diffusion process
through the matrix or through the membrane outwards.
(b) Devices controlled by chemical processes. The drug is
introduced in a biodegradable matrix. The liberation
kinetics is linked to the kinetics of matrix degradation.
(c) Devices controlled externally and/or electronically.
Generally speaking, CPC could be ascribed to the rst
type of devices, where drug release is diffusion-controlled.
Although some CPC are resorbable, in most of the CPC
studied as drug-carriers the rate of matrix degradation (e.g.
the cement itself) is much lower than the rate of drug
liberation. For that reason it is possible to assume that the
drug release is mainly controlled by the process of diffusion
though the cement matrix and not by the degradation of
the same.
During cement setting, dissolution of calcium phosphates from the powder phase takes place, which is
followed by precipitation of the new phase, which is in
most cases precipitated hydroxyapatite. Despite the fact
that the drug can be partly dissolved in this precipitated
phase, as a rule it can be considered that the concentration
of the drug is higher than its solubility in the matrix, and
therefore the most part of the drug will be dispersed in the
matrix. In this particular case, the drug-release kinetics

follows Higuchis law [44], at least at the initial stages (until

around 60% drug is released).
In addition, we have to consider that the matrix
containing the dispersed drug, i.e. the CPC, is very porous.
Indeed, it is formed by a mesh of interlocking of crystals
which creates an open microporosity. This porous structure
can vary depending on the starting materials and conditions, but normally it is higher than 30%. Pore sizes can
differ as well, but generally they are in the nano-micro
range, usually lower than 10 mms. In this case, it can be
assumed that the effective diffusion coefcient of the
matrix will be proportional to CPC porosity and inversely
proportional to its tortuosity. Therefore, the drug liberation kinetics will be controlled by the following expression,
as it has been shown by a series of works from Otsuka et al.
[16,17,20,21,23] with different cements and drugs, and
conrmed by other authors [5,6]:
 0
1=2
De
M t AM 0
C S 2C 0  eC S t
,
(1)
t
where Mt is the amount of drug released for time t, A is the
surface area of the device, M0 is the total amount of drug,
D0 is the diffusion coefcient of the cement structure, e is
the cement porosity and t is the tortuosity of the cement,
Cs is the solubility of the drug in the matrix, and C0 is the
initial concentration of the drug in the matrix.
4.1. Effect of porosity
According to Eq. (1), the rate of drug liberation is
controlled by drug diffusion through pores, and will
depend on the microstructural features of CPC. Indeed, it
has been shown for different drugs that it increases with
higher porosity of the CPC [16,17,20], which can be easily
controlled by liquid-to-powder ratio.
In this sense it must be pointed out that any modication
of the geometric pore structure of the cement matrix during
the drug release period will affect the delivery pattern. This
change in pore structure can be produced either by a
resorption of the CPC, or by the formation of an apatitic
layer on the cement surface or even within the pores, due to
its bioactive character, as reported in several studies by
Otsuka et al. [16,21,24].
Any resorption of the CPC will modify the pore
structure and affect the drug release pattern. Indeed, up
to now it has been considered that CPC do not degrade
while drug is released, or, in other words, that the porosity
of the matrix is maintained constant during drug delivery.
However, some authors have shown certain degree of
degradation of CPC during drug liberation. For example,
Otsuka [22] showed an increase of porosity in a carbonated
hydroxyapatite cement during the release of indomethacine, which was ascribed to the cement degradation. In this
case, the higher resorption rate of the cement was explained
by the fact that the addition of different amounts of
NaHCO3 to a TTCP/DCPD cement resulted in a

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carbonated apatite more soluble than the stoichiometric

HA used in previous studies. Resorption of carbonated HA
with time produced an increase of porosity, which
increased the drug release rate. If porosity does not remain
constant, drug release kinetics does not follow Higuchis
law, and the drug diffusion through the CPC matrix is not
any longer the only mechanism which controls drug
liberation. In the case of brushite cements, the degradation
rate is much higher than that of apatite cements, and
therefore is more important to consider these phenomena.
4.2. Effect of the drug nature
Another factor that affects the release kinetics is the drug
that is incorporated in the CPC. It is difcult to compare
the drug release kinetics reported by different studies, due
to the great differences in the experimental conditions. In
most cases not only the drugs and the concentrations
studied are different, but also the CPCs used as carriers, the
geometry, the conditions of measurement of drug release,
etc. However, it seems clear that the release kinetics
depends strongly on the type of drug incorporated in the
cement, as it conditions the interaction drug/matrix. In
general, the release of antibiotics from the cements appears
to be fast. Thus, Takechi reported a total amount of
liberated antibiotic (omoxef sodium) in a TTCP/DCP
cement between 55% and 60% after 72 h [7]. Bohner et al.
reported a total amount of antibiotic released within 7
days, in the case of gentamicin incorporated in a brushite
cement [5].
Moreover, this can vary also depending on the type of
antibiotic. In a comparative study the release kinetics of
three antibiotics, i.e. gentamicin, amikacin and ceftiofur
incorporated either in a commercial CPC or in PMMA
spheres was analysed [8]. The results after 30 days showed
faster antibiotic liberation from CPC than from the
polymer. In both carriers the concentrations of liberated
gentamicin and amikacin were higher than the critical
doses for preventing bacterial effects. However, the
liberation of ceftiofur from both materials remained within
the right levels only during 7 days, being therefore
inadequate when the bactericide effect has to be prolonged
in time.
In the cases where antibiotic release is considered to be
excessively fast, a possible strategy is to incorporate some
polymers in the CPC, in order to retard drug liberation. In
this sense some studies have been carried out aiming at
the formation of a gel into the cement pores which served
as matrix for the antibiotic, by the addition of some gelforming substance such as sodium alginate or chitosan
[7,10]. Another strategy consists in the formation of a
complex with the antibiotic, for instance by the addition of
polyacrylic acid (PAA) to the CPC [6].
The situation is very different in the case of growth
factors, where the release kinetics seems to be very slow.
This can be related to the high binding afnity of the
protein for calcium phosphate ceramics. Recently, Blom et

2175

al. analysed the release kinetics of human recombinant

TGF-b1 (rhTGF-b1) in two CPCs [28,29]. Initially there
was a fast elution of rh TGF-b1 during the rst day,
followed by a very slow release during the following weeks.
Interestingly, the results suggested that the growth factor
was released only from the supercial layer in contact with
the surrounding medium, and not from the whole volume
of the CPC. Similar trends are observed in the drug release
behaviour of rh-BMP-2 loaded in a poly(DL-lactic-coglycolic acid, PLGA)/CPC composite [32], where the nanoporosity of the CPC not only did not facilitate the release
of the protein, but further limited it because of the high
binding afnity of the protein for CPC.
4.3. Autoregulation
One of the most exciting challenges in controlled drug
delivery lies in the eld of responsive delivery systems, with
which it will be possible for instance to deliver drugs
through implantable devices in response to a measured
blood level. This is the approach adopted by Otsuka et al.
who studied the rate of release of estradiol incorporated in
a CPC, both in vitro and in vivo, by subcutaneous
implantation in rats [18,19]. The rate of estradiol liberation
in vitro was inversely proportional to calcium concentration in solution. Consistently, in vivo release of estradiol
was faster in rats which had lower concentrations of
vitamin D and Ca, compared to healthy rats, suggesting the
autoregulatory mechanism of estradiol liberation. The
bone mass of the recovery model rats was greater after
the experiment than before, suggesting that the severity of
osteoporosis in these animals could be reduced by the
implantation of this estradiol-loaded apatite cement.
5. In vivo assessment
The number of in vivo studies is still low, and most of
them have been performed in small animals, with the
intrinsic limitations for results extrapolation to humans.
The efcacy of several CPCs as carriers for antibiotics has
been assessed in different animal models. Himanashi et al.
[13] showed that the therapeutic level of vancomicin loaded
in a CPC in different concentrations, and implanted in
tibial condyles of rabbits, was maintained after several
weeks. Stallmann et al. [9] veried the efcacy of a
gentamicin-loaded commercial CPC to reduce the development of osteomyelitis in Stafilococus aureus-vaccinated
rabbits, when it was implanted in the femoral channel.
A relevant question is whether it is reliable to extrapolate
the in vitro drug delivery kinetics results to the in vivo
behaviour of the drug carrier, even more in a material, such
as CPC, which is far from inert when implanted. Indeed,
surface changes in the cement such as the formation of an
apatitic layer on the surface of the material caused by its
bioactive character, or either by protein adsorption must
be expected, that can modify the drug release kinetics. In
this sense, different liberation rates were observed in an

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indomethacine-loaded CPC when the concentrations of

released drug in vitro and in vivo, in a rat model, were
compared. A linear relation at the initial stage was
observed in both cases, but liberation in vivo was much
slower than liberation in vitro during the last stage of the
study [23]. Moreover, the half-life of indomethacine in
plasma was much higher when drug was introduced via
cement implantation, rather than when it was injected
subcutaneously.
The in vivo results obtained by osteogenic factor-loaded
CPC are very encouraging. A complete series of in vivo
studies has been published by Seeherman et al., where
different injectable osteogenic factor/carrier combinations
have been reviewed in different large-animal models
[3335]. Among all the carriers studied, a commercial
resorbable CPC is considered to be the best one as carrier
of recombinant human BMP-2 in terms of bone healing
after 10 weeks, in a bular osteotomy, in a nonhuman
primate model. One of the main advantages of this carrier
is that it can be implanted by a single percutaneous
injection. Bone healing was accelerated by approximately
40%, as compared to untreated osteotomy sites. Similar
results were found by Ohura et al. who incorporated
different amounts of rhBMP-2 to a resorbable cement and
implanted them in critical fractures created in the femurs of
rats, observing an accelerated fracture consolidation [31].

6. Conclusions
CPC have specic properties which make them competitive drug carriers for the musculoskeletal system. Together with their injectability and low-temperature selfsetting ability, their bioactivity ensures an optimum
interaction with the bone tissue. The drug release kinetics
is affected by the variable resorption rate of CPCs, and by
the morphological changes caused by its bioactive character. There is still a lot to be done in terms of adjusting it
to different therapeutical needs and obtaining predictable
drug delivery systems. The incorporation of osteogenic
factors increases their potential as bone regeneration
materials, provided an appropriate resorption rate of the
CPCs is ensured.

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