ARTICLE IN PRESS

Biomaterials 24 (2003) 4565–4571

Mechanically stable implants of synthetic bone mineral by

cold isostatic pressing
D. Tadic, M. Epple*
Solid State Chemistry, Faculty of Chemistry, University of Bochum, D-44780 Bochum, Germany
Received 6 December 2002; accepted 8 April 2003

Abstract

A calcium phosphate phase that is equivalent in composition (carbonate content) and crystallinity (nanocrystals) to the mineral
phase of bone was prepared by a continuous precipitation method. The powder was compacted by cold isostatic pressing into
desired shapes with high compressive strength (range of 20–50 MPa, depending on the geometry). It is concluded that such implant
materials can be prepared with a fine-tuned biodegradability in combination with a high mechanical strength. The high mechanical
strength of the objects also permits further mechanical shaping procedures like drilling or cutting.
r 2003 Elsevier Ltd. All rights reserved.

Keywords: Calcium phosphates; Cold isostatic pressing; Bone substitution materials; Mechanical stability; Porosity

1. Introduction Currently, the most prominent synthetic calcium

There is a wide range of applications where calcium
phosphates are used as biomaterials [1–5], e.g. as
synthetic bone graft [3,6–10], drug carrier [11,12] or
coating on metal prostheses (like hip endoprostheses or
dental implants [13–16]). Especially in the field of bone
substitution materials, synthetic calcium phosphates
have some advantages over other materials. Autograft
sources (transplanted bone, e.g. from the iliac crest)
show an excellent osteoinductivity, but they are not
available in unlimited amounts and also require a
secondary operation [17]. In the case of allografts or
xenografts, there are concerns about a possible con-
tamination with infectious material (e.g. HIV, hepatitis
or BSE). Due to these reasons, there is an ongoing
interest in synthetic calcium phosphates as bone grafts
because they are highly biocompatible, nontoxic,
biodegrabable, cause no immunological or irritating
response, have excellent osteoconductive ability and can
be optimised for many specific applications [1,5]. Such
materials can be prepared in virtually unlimited amount
as no biological source is needed.
*Corresponding author. Tel.: +49-234-3224-151; fax: +49-234-
3214-558.
E-mail address: matthias.epple@ruhr-uni-bochum.de (M. Epple).
phosphate bone graft materials are sintered hydroxya-
patite of high crystallinity [HAP; Ca10(PO4)6(OH)2;
synthetic or bovine origin], b-tricalcium phosphate [b-
TCP; Ca3(PO4)2; synthetic origin] and mixtures of both
(the so-called biphasic calcium phosphates; BCP).
Although they all show a good biocompatibility, it
must be noted that, strictly speaking, none of these
materials occurs in living systems. The mineral compo-
nent of bone is a so-called ‘‘biological apatite’’ in which
carbonate (about 3–5 wt%) substitutes phosphate ions
(it also contains small amounts of other ions). In
addition, all biologically formed apatites in bone, dentin
and mineralised tendons are nanocrystalline (with
enamel being the only exception) [1,5,18]. In terms of
composition, bone mineral is only roughly comparable
to sintered hydroxyapatite, due to the differences in
carbonate content and particle size [19] that influence
the solubility. This causes a very slow degradation of
sintered hydroxyapatite ceramics in vitro [20,21] and
in vivo [22], and there are also reports about a limited
in vivo degradation of b-TCP ceramics [23], although in
general both are considered to be highly biocompatible
materials [3,5,24].
From the clinical point of view, the goal is a full
integration of a bone graft into the dynamic human
organism where bone is continuously dissolved and

0142-9612/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0142-9612(03)00281-3
 ARTICLE IN PRESS
4566 D. Tadic, M. Epple / Biomaterials 24 (2003) 4565–4571
produced by remodelling. Necessary conditions are a
sufficient mechanical integrity, a controlled degradation
rate, and a bioactivity that stimulates a simultaneous
replacement by newly formed bone tissue. Implant
degradation and new bone formation must be balanced
in such a way that a mechanically weakened stage
during the healing process is avoided. It was the aim of
our research to prepare a synthetic carbonated hydro-
xyapatite with the chemical composition and crystal-
linity of bone mineral, taking into account recent work
on carbonated apatite by other groups [21,25–29].
Earlier [30] we have shown how to prepare bone-like
carbonated apatites by an easy continuous process in
unlimited amounts with constant quality. Here we show
for the first time that such material from precipitation
can be shaped into macroscopic objects of different size
and shape by cold isostatic pressing (CIP). These objects
have a high mechanical stability while their chemical
and crystallographic properties remain unchanged.
Further mechanical shaping (like drilling or cutting) is
possible, making available porous objects that are
suitable for bone tissue ingrowth.
2. Materials and methods
Biomimetic carbonated apatite comparable in chemi-
cal composition and crystallinity to bone mineral was
obtained by continuous fast precipitation in a special
crystallisation device [30]. Briefly, aqueous solutions of
(NH4)2HPO4 and (NH4)2CO3 with a molar ratio of
CO23 to PO34 of 0.5:1 were continuously mixed under
nitrogen atmosphere at 37 C with an aqueous solution
of Ca(NO3)2 to result in a Ca2+ to PO34 molar ratio of
1.67:1 after mixing. Both solutions were adjusted
previously to pH 10 with ammonia solution beforehand.
The obtained powder was immediately filtered to avoid
crystal growth and dried at 70 C. Further details on the
experimental set-up can be found in Ref. [30]. All
solutions were prepared with compounds of p.a. quality
from Merck (Darmstadt, Germany).
The precipitated and dried calcium phosphate powder
was analysed by X-ray diffraction (XRD; Bruker AXS
D8 Advance; CuKa), infrared spectroscopy (IR; KBr;
Perkin-Elmer 1720X), thermogravimetric analysis
(TGA; TG/DTA-S II, Seiko Instruments Exstar 6000,
25–1000 C; 10 K min 1) and scanning electron micro-
scopy (SEM; LEO 1530; gold-sputtered samples).
Elemental analysis of the samples gave a calcium
content of 34.7 wt% (by atomic absorption spectro-
scopy), a phosphate content of 51.6 wt% (by photo-
metry), a carbonate content of 4–5 wt% (by TGA;
400–1000 C) and a water content of 7–8 wt% (by TGA;
100–400 C). This corresponds to a molar Ca/P ratio of
1.59:1.
The dried carbonate apatite powders were ball-milled
and sieved to 250–400 mm particle size before processing.
Compact ceramic bodies of variable shape were
prepared by CIP (4000 bar) in a Dieffenbacher Isostat
press at room temperature (ca. 25 C). Mechanical
parameters were determined on an electromechanical
testing machine by Schenck Trebel RM 100 (100 kN)
with 0.5 mm min 1 on cylinders of different size accord-
ing to DIN EN 658-2. For each geometry, three objects
were investigated and the results were averaged.
3. Results and discussion
Fig. 1 shows X-ray diffraction patterns of carbonated
apatite (4–5 wt% carbonate content) before and after
CIP in comparison with natural human bone [19]. The
diffractogram shows two very broad peaks at 26 2Y
and 31–34 2Y that are typical for a poorly crystalline
(nanocrystalline) apatite. Note that CIP does not
influence the crystal structure of the obtained carbo-
nated apatite. This is supported by IR and TGA
experiments before and after pressing that showed no
change in the composition. In particular, the presence of
carbonate is still evident from the IR absorption bands
at 870, 1420, 1480 and 1540 cm 1 (Fig. 2). Typical
objects of different size and shape prepared by CIP are
shown in Fig. 3.
After precipitation from solution, the material con-
sists of almost uniform spheres with a diameter of about
20–40 nm (Fig. 4a). These are agglomerated to larger
particles of irregular shape in the micrometre-size range
(Fig. 4b). After CIP, macroscopic objects are obtained
that consist of the ‘‘fused’’ primary particles in un-
changed geometry (Figs. 4c and d). Again, we conclude
that the nanocrystalline structure is not changed by the
shaping process, i.e. that bone mineral-like material is
still present.
intensity / a.u.
natural bone
after CIP
before CIP
20 25 30 35 40
diffraction angle / °2θ
Fig. 1. X-ray powder diffractograms of synthetic carbonated apatite
before and after CIP. The structure does not change due to processing
and the similarity to bone mineral (broad diffraction peaks indicating a
small particle size) is evident.
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D. Tadic, M. Epple / Biomaterials 24 (2003) 4565–4571 4567

Preliminary attempts to prepare macroscopic objects strengths of 21.8–47.6 MPa (Table 1). Although the
by uniaxial hot pressing (4 kbar, 240 C) [30] showed geometry is not fully comparable with the earlier results,
that the mechanical stability of such objects was limited it is evident that the mechanical strength has improved
due to insufficient compaction (Table 1). In addition, by a factor of about 5–10. Apart from these numbers,
the objects were rather brittle, particularly at the edges. this is also demonstrated by an overall improved
This was decisively improved by the CIP technique. For mechanical stability towards manual scratching, torsion
cylinders of different diameters and heights, we obtained and bending, including the edges. Although compressive
Young’s moduli from 0.8 to 2.2 GPa and compression strength and Young’s modulus of the natural biomate-
rials bone and teeth are not achieved, the values are
within the range of other porous or compact calcium
P-O P-O phosphate-based biomaterials (Table 1). Isostatic press-
natural bone
C-O
ing of hydroxyapatite and sintered carbonated apatite at
OH 600 MPa (6 kbar) was also reported by Doi et al. [31],
H2O
after CIP P-O P-O but no mechanical properties were given.
C-O
H2O Even after CIP, the material retains some porosity. A
transmittance

C-O
density of 1.9 g cm 3 was determined. This is about 60%
before CIP
of the theoretical density of pure hydroxyapatite
H2O C-O
C-O (3.16 g cm 3), therefore we can conclude that the
P-O
porosity is about 40 vol%. Fig. 4c shows that these
P-O pores are in the nanometre range. An immersion of cold-
4000 3000 2000 1000 isostatically pressed cylinders in water for 24 h resulted
wave number / cm
-1
in an uptake of 0.15 ml water per gram of ceramic. The
objects are perfectly stable upon immersion in water, i.e.
Fig. 2. Infrared spectra of natural bone, and synthetic bone mineral
(carbonated apatite) before and after CIP. Clearly, there is no change
there is no disintegration.
induced by the CIP within the material. Note the similarity to bone, Mechanical shaping of these objects can be performed
especially the content of carbonate. by cutting and drilling. For example, we have prepared

Fig. 3. Different objects of bone mineral-like calcium phosphate, prepared by CIP.

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4568 D. Tadic, M. Epple / Biomaterials 24 (2003) 4565–4571

before CIP before CIP

(a) (b)

after CIP after CIP

(c) (d)
Fig. 4. Scanning electron micrographs of synthetic bone mineral. (a) Spherical nanoparticles as obtained after precipitation; (b) Agglomerates of the
precipitated nanoparticles; (c) Surface of a cold-isostatically pressed material. The nanoparticles are preserved. (d) Fracture surface of a cold-
isostatically pressed material.

Table 1
Mechanical parameters of cold-isostatically pressed samples in comparison with other biominerals (bone and teeth) and biomaterials (selection from
the literature)

Cold-isostatically pressed carbonated apatites Method of preparation Compressive Young’s modulus/

(this work; cylinders; height/diameter in mm) strength/MPa GPa

13/20 Uniaxial hot pressing (4 kbar, 240 C) 5–6 1.2–2.6

32/16 Cold isostatic pressing (4 kbar, 25 C) 21.8 1.6
16/16 Cold isostatic pressing (4 kbar, 25 C) 26.1 1.3
8/8 Cold isostatic pressing (4 kbar, 25 C) 47.6 2.2
8/4 Cold isostatic pressing (4 kbar, 25 C) 25.6 1.1
4/4 Cold isostatic pressing (4 kbar, 25 C) 27.5 0.8
Selected biominerals
Particles of bone [9] Morsellized to 2.171.3 mm diameter — 0.085–0.135
Trabecular bone [34] (Measured by nanoindentation) — 11.475.6
Compact human bone [3] — 133–193 11.5–27
Diaphyseal cortical bone [34] (Measured by nanoindentation) — 20.175.4
Dentine [3] — 250–350 11–17
Enamel [3] — 95–370 9–84
Selected biomaterials
Macroporous HAP with 40% porosity [35] Sintered at 1350 C 3078 1.470.4
Microporous HAP with 22% porosity [36] Pressing, followed by sintering above1000 C 348 —
TCP-HA composites without porosity [9] 3–5 mm diameter 0.442–0.525 0.442–0.525
Monoliths of calcium-deficient Pressed at 38 C and 0.8 kbar after mixing 84–172 5.97–7.31
hydroxyapatite (CDHA) [37] with 11–20 wt% water
Monoliths of carbonated apatite [37] Pressed at 38 C and 0.8 kbar after mixing 53–80 4.58–5.59
with 11–20 wt% water
HAP with 0.06% porosity [38] Uniaxial pressing, slip casting and starch — 84
consolidation
Dense HAP ceramics [3] — 120–900 35–120
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D. Tadic, M. Epple / Biomaterials 24 (2003) 4565–4571
18 mm
Fig. 5. Preparation of mechanically shaped objects as macroporous bone substitution materials.
objects with macropores of 500, 1000, and 1500 mm
diameter, depending on the drill size used (Fig. 5). Such
objects should be suitable as bone implants as osteo-
blasts are able to enter pores of this size. In vivo
experiments of HAP implanted in rabbits showed a
maximum in osteoconductivity at pore diameters of
about 130–260 mm [32] and 300 mm [33]. Of course, the
mechanical strength of porous implants will be smaller
than that of compact implants. Like all ceramics, these
synthetic bone materials are brittle and have a limited
elasticity (much smaller than that of natural bone).
It must be noted that it is not clear at the moment why
such mechanically strong objects are obtained by CIP.
Definitely, the temperature is too low for any true
sintering to occur. Currently, we assume that the high
specific surface area of the nanoparticles and the
residual water content lead to some ‘‘chemical sinter-
ing/surface melting/recrystallisation’’ under this high
pressure. CIP experiments with completely dry powders
did not give mechanically stable objects (i.e. they could
be crushed between the fingers), supporting this
assumption.
If the biological performance of different bioceramics
is compared, it must be noted that the biological
incorporation of a bone graft is a physiological process
controlled by the cells (mainly osteoblasts and osteo-
clasts) of the surrounding host bone. This biochemical
response is influenced by the geometry, the chemical
composition and the morphological and mechanical
properties of a given biomaterial. While a compact
synthetic bioceramic shows good mechanical properties
(Table 1), only the surface of ceramic will only be in
contact with tissue and there will usually be no ingrowth
of bone but only a degradation starting from the
surface. Consequently, compact materials achieve only
a geometrical fixation while porous materials provide a
mechanical interlock caused by ingrowth of bone tissue
into the pores. Due to this reason, porous bioceramics
are preferred in clinical practice. Clinical practice also
demands that a bone graft material is resorbed or
4569
13 mm
7 mm
16 mm
500-1500 µm
dissolved within a reasonable time, i.e. the implant is
finally replaced by new bone tissue. This is not the case
for sintered hydroxyapatite ceramics as they have a
much lower solubility than the nanocrystalline carbo-
nated bone mineral that is dissolved by osteoclasts.
We have shown previously that under acidic condi-
tions (pH 4.4, pure water), our synthesised carbonated
apatites showed a much higher solubility than sintered
calcium phosphate ceramics, like b-tricalcium phosphate
(b-TCP) or highly crystalline sintered hydroxyapatite
[30]. The surface of cold-isostatically pressed objects of
bone mineral-like apatite was investigated after the
simulated osteoclastic resorption (after 72 h at pH 4.4)
[30]. It shows ‘‘resorption pits’’ of about 2 mm diameter
that incorporate sub-micrometre-sized needles (Fig. 6).
These probably result from a recrystallisation in
solution at that pH where dicalcium phosphate dihy-
drate (DCPD) has precipitated. However, the amount of
foreign material is too small to be detected by X-ray
diffraction.
We therefore assume that macroscopic implants of
this synthetic bone mineral would participate in the
general remodelling process of the body and thus be
resorbed within a reasonable time. A macroporous
implant should also be degraded from within when bone
cells have grown into the macroporous material (500–
1500 mm).
4. Conclusions
By a continuous crystallisation method, it is possible
to prepare bone mineral-like calcium phosphates with
nanocrystallinity and a carbonate content as in bone
mineral in unlimited amounts with reproducible proper-
ties. By CIP, the precipitated powders can be processed
into objects of a desired shape with considerable
mechanical strength. Crystallinity and composition of
the material are not affected by this processing step.
This offers the possibility to prepare biomimetic
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4570 D. Tadic, M. Epple / Biomaterials 24 (2003) 4565–4571
after resorption
(a)
Fig. 6. Surface of cold-isostatically pressed material after 72 h at pH 4.4 resembling osteoclastic resorption). In low magnification (a), resorption pits
are seen. In higher magnification (b), the surface is covered by small needles, probably of DCPD that was reprecipitated under these conditions.
materials for optimal bone substitution. Further shaping
can be done by cutting and drilling, thereby creating
macroporous implants or geometrically designed im-
plants to meet individual implantation sites. Based on
earlier in vitro resorption experiments at pH 4.4 (see
above), we propose such materials as biomimetic bone
substitution materials that can be more easily resorbed
during bone formation in the defect than sintered
hydroxyapatite ceramics. As chemical composition,
crystallinity, geometry, and macroporosity can be
adjusted by the preparation process, we believe that
the biological requirements for different applications
(orthopaedic surgery, maxillofacial surgery) can be met
by choice of the appropriate material.
Acknowledgements
This project was supported by the Deutsche For-
schungsgemeinschaft (Bonn) and the Fonds der Che-
mischen Industrie (Frankfurt). We are grateful to Prof.
.
D. Stover, .
Dr. H.P. Buchkremer, Dr. E. Schuller and
Dr. M. Bram (Research Center Julich, . Institute for
Materials and Processes in Energy Systems) and to
Matthias Matthes for help with the cold isostatic
pressing, and to Prof. G. Eggeler and Dr. B. Skrotzki
(Materials Science, University of Bochum) for help with
mechanical testing.
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