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Biomaterials 25 (2004) 987994

A thorough physicochemical characterisation of 14 calcium

phosphate-based bone substitution materials in comparison to

natural bone

D. Tadic, M. Epple*

Solid State Chemistry, Faculty of Chemistry, University of Bochum, Universitatsstr. 150, D-44780 Bochum, Germany

Received 10 March 2003; accepted 22 July 2003

Abstract

Fourteen different synthetic or biological bone substitution materials were characterised by high-resolution X-ray diffractometry,

infrared spectroscopy, thermogravimetry, and scanning electron microscopy. Thus, the main parameters chemical composition,

crystallinity, and morphology were determined. The results are compared with natural bone samples. The materials fall into

different classes: Chemically treated bone, calcined bovine bone, algae-derived hydroxyapatite, synthetic hydroxyapatite, peptide-

loaded hydroxyapatite, and synthetic b-TCP ceramics.

r 2003 Elsevier Ltd. All rights reserved.

Keywords: Bone graft materials; Chemical analysis; Calcium phosphates

1. Introduction

Filling of bone defects is a significant question in

every day clinical work. Autogeneous bone is still the

most effective bone graft substitution material (gold

standard), fulfilling all essential physicochemical and

biological properties, despite its inherent limitations

(availability, post-operative pain) [15]. The most

common alternative to the autograft material are

(human) allografts or (animal, e.g. bovine) xenografts.

Allografts have the disadvantages of limited supply and

potential infectivity (e.g. HIV, Hepatitis). With xeno-

grafts there are the questions of unfavourable immune

response and also of infectivity.

Autogenous bone is osteogenic (the cells within a

donor graft synthesise new bone at the implantation

site), osteoinductive (new bone is formed by the active

recruitment of host mesenchymal stem cells from the

surrounding tissue, which differentiate into bone-form-

ing osteoblasts), osteoconductive (vascularisation and

new bone formation into the transplant) and highly

biocompatible [6]. This process is facilitated by the

presence of growth factors within the autogenous bone

material (mainly bone morphogenetic proteins [7]).These characteristics should be present in an ideal

substitute and all bone graft substitution materials can

be described by these characteristics [8].

Synthetic calcium phosphate ceramics [9] with their

excellent biocompatibility are common alternatives to

autogeneous bone, xenograft or allograft materials.

They have gained acceptance for various dental or

medical applications which include, e.g., fillers for

periodontal defects, alveolar ridge augmentation, max-

illofacial reconstruction, ear implants, spine fusion,

and coatings for metallic implants [1015]. Bone grafts

and synthetic calcium phosphates (such as b-tricalcium

phosphate; b-TCP, and hydroxyapatite; HAP) are

commonly used as blocks, cements, pastes, powders

or granules. The aim of this article is to describe

the chemical and physical properties of these bone

graft materials and to compare them to natural bone.

As model for autologous spongiosa, natural bone

samples were analysed. The biological performance

of a synthetic material depends on fundamental

parameters: chemical composition, morphology,

and biodegradability. A wide range of analytical

methods (IR, XRD, TG, REM) was used to investigate

these properties. As each of these methods has its

ARTICLE IN PRESS

*Corresponding author. Tel.: +49-234-3224-151; fax: +49-234-

3214-558.

E-mail address: [email protected] (M. Epple).

0142-9612/$- see front matterr 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/S0142-9612(03)00621-5

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bone by either thermal or chemical treatment. In

contrast, blocks of Cerasorbs are prepared by cold-

isostatic pressing, followed by mechanical drilling of

millimeter-sized holes.

The results of the X-ray diffraction experiments that

are indicative for the chemical composition (presence of

crystalline phases) are shown in Fig. 2.

Four of the five b-TCP ceramics show small amounts

of impurities besides the major phase (peaks marked

with asterisks in Fig. 2a). They all exhibit a high

crystallinity as indicated by the narrow diffraction

peaks. Bioresorbs contains some b-Ca2P2O7 (calcium

pyrophosphate; peak at 30.82Y) and a-TCP (peak at

22.92Y). Chronoss and Ceross contain some a-TCP

and some hydroxyapatite (peak at 31.62Y). Vitosss

contains some b-Ca2P2O7 (peaks at 29.0 and 30.22Y).

In all cases, the amount of foreign phases is very small.

Cerabones and Endobons are prepared by high-

temperature calcination from bovine bone, and conse-

quently the hydroxyapatite is highly crystalline (very

narrow diffraction peaks). Endobons also contains

small amounts of calcium oxide (CaO) that results from

decomposition of the carbonate content of the original

bone mineral (carbonated apatite; CaCO3-CaO+

CO2m; peak at 37.32Y) [17]. Traces of CaO are also

seen in Cerabones at the same position in 2Y: Theinorganic phase of PepGens is also a highly crystalline

hydroxyapatite (with no traces of CaO). Algipores is a

moderately crystalline hydroxyapatite phase with no

detectable foreign phases.

Ostims

is prepared by rapid precipitation, keepingthe crystals within the nanometer range. This is

indicated by the broad diffraction peaks in Fig. 2c that

correspond to synthetic hydroxyapatite. No foreign

phases are visible. Interestingly, the crystallinity is close

to that of BioOsss that is prepared from bovine bone.

Even smaller crystals lead to even broader diffraction

peaks. All bone-like samples fall into this category (Fig.

2d). They all contain hydroxyapatite-like mineral and

there are no distinct differences. The only exception

is a content of octacalcium phosphate (OCP;

Ca8H2(PO4) 5H2O) in Tutoplasts (bovine) as indicated

by asterisks in Fig. 2d (peaks between 21 and 242Y).

The diffraction peak broadening by small crystallites

can be semi-quantitatively estimated by the Scherrer

equation [18] (Table 1):

b1=2 Kl57:3=D cos Y: 1

Here, b1=2 is the peak width (as full-width at half

maximum) in 2Y; K is a constant that we set to 1 (asoften done), l is the X-ray wavelength in (A, D is the

average domain size (roughly the crystallite size) and Y

is the diffraction angle of the corresponding reflex. This

equation gives an estimate of the crystallite size. It

should be noted, however, that structural disorder and

strain phenomena, e.g. caused by carbonate substitu-tion, can also lead to a peak broadening effect [18].

Therefore, the given values should be mainly used for

comparison among the samples.

All bone samples have essentially the same aniso-

tropic crystal size, i.e. about 25 nm in c-direction [(0 0 2)

and (0 0 4)] and about 9 nm in a-direction [(2 1 0)/(1 2 0)

and (1 3 0)/(31 0)]. The Tutoplasts process does not

change the mineral particle size. BioOsss and Ostims

have slightly larger particles (about double as much in

each direction). In the case of BioOsss, this may be due

to the heating during the preparation as Rogers et al.

reported first structural changes in the mineral phase

between 200C and 400C [17]. Synthetic hydroxyapa-

tite and Algipores show almost isotropic particles

about three times larger than bone mineral particles in

each direction. For the highly crystalline samples

Cerabones, Endobons and PepGens, the diffraction

peak width is at the minimum given by the experimental

setup, therefore only a lower limit for the crystallite size

can be given (but see below for SEM pictures).

The infrared spectra are shown in Fig. 3. All b-TCP

ceramics are identical and show only the expected

calcium phosphate bands (Fig. 3a). The hydroxyapatite-

based ceramics in Fig. 3b show only calcium phosphate

ARTICLE IN PRESS

Chronos

Ceros

Bioresorb

Vitoss

-TCPceramics

Cerasorb

Hydroxyapatite-based materials

Ostim

BioOss Tutoplast

CerabonePepGen P-15

Fig. 1. Macromorphology of the different bone graft materials.

D. Tadic, M. Epple / Biomaterials 25 (2004) 987994 989

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bands in a sharp and split way, as indicative for the high

crystallinity. Algipores shows some carbonate bands

(approx. 1400 cm1) that are probably due to remnants

of the production process (from calcium carbonate

algae). Although PepGens contains a bioactive peptide,

there are no bands of organic material (as seen below).

This is due to the small amount present. In Fig. 3c,

nanocrystalline hydroxyapatite ceramics are shown. The

phosphate bands are generally broader because of the

small crystallite size. In addition, there are bands of

water, and, except for Ostims, of carbonate. This shows

that synthetic hydroxyapatite as well as BioOsss

contain small amounts of incorporated carbonate. The

bone samples that are shown in Fig. 3d all contain

ARTICLE IN PRESS

Table 1Estimation of the domain size from diffraction peak broadening of all investigated materials in nanometers

Diffraction line index (2 1 0) (1 3 0) (2 1 3)

(1 1 1) (0 0 2) (1 2 0) (3 1 0) (1 1 3) (2 2 2) (1 2 3) (0 0 4)

2y [] at Cu Ka (l 1:54 (A) 22.9 25.9 29.0 39.8 43.8 46.7 49.5 53.1PepGens >64 >54 >54 >56 >42 >57 >43 >44

Endobons >71 >64 >67 >63 >64 >62 >64 >64

Cerabones >64 >80 >65 >84 >56 >57 >58 >88

Algipores 59 65 45 40 29 44 38 36

Synthetic hydroxyapatite 30 38 25 29 40 26 33 42

Ostims 21 36 22 21 24 19 25 35

BioOsss 29 36 23 17 21 21 25 29

Kiel bone 19 24 10 8 23 19 15 25

Tumor bone 24 22 12 9 20 18 14 22

Callus bone 20 21 10 9 24 18 14 22Tutoplast (bovine)s 21 27 17 8 21 12 17 20

Tutoplast (human)s 14 27 18 9 13 16 19 22

20 25 30 35 40

**

*

*

*

**

*

Ceros

(R)

Cerasorb(R)

Chronos(R)

Bioresorb(R)

Vitoss(R)

inte

nsity

diffraction angle / 2

20 25 30 35 40

hydroxyapatite

(synthetic)

Ostim(R)

BioOss(R)

intensity


20 25 30 35 40

** ** *

Tutoplast(R)

(human)

Tumor

Bone

Tutoplast(R)

(bovine)

Callus

Bone

Kiel

Bone

intensity


(a) (b)

(c)

20 25 30 35 40

*

*

Endobon(R)

Cerabone(R)

PepGen

P15(R)

Algipore(R)

intensity


(d)

Fig. 2. X-ray diffraction data for all investigated samples. All data were either measured at or converted to the Cu Ka wavelength (1.54 (A). The

displayed range in 2y was chosen to optimally represent the relevant features.

D. Tadic, M. Epple / Biomaterials 25 (2004) 987994990

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collagen and organic tissue in variable amounts. In

addition to the bands of calcium phosphate, we can see a

multitude of bands that are related to the organic

material and incorporated water.

All samples were subjected to thermogravimetric

analysis [19] to determine the content of water, organic

material (like collagen), and mineral (calcium phos-

phate). A typical curve is shown in Fig. 4 (Tutoplasts

human). As derived from earlier experiments with massspectrometric analysis of the released gases, three ranges

of mass loss can be assigned to specific processes [16].

From room temperature to about 200C, incorporated

water is lost. Above about 300C, organic material like

collagen, fat tissue, proteins start to burn. At about

400C, only the mineral phase (calcium phosphate) is

left. If the mineral contains some carbonate in the form

of carbonated apatite, there is a mass loss between about

400C and 900C [16,20]. Therefore, it is possible to

determine the mineral content and its carbonate content

from such TG experiments. Note that all biological

apatites are carbonated apatites [15].

Table 2 shows all compositional data as determined

from TG experiments (average of two experiments). All

b-TCP phases, except for Vitosss, show no mass loss,

indicating the absence of any volatile or combustible

material. In the case of Vitosss, a small mass loss was

registered between 200C and 400C. This may be due

to an organic binder used for granulation. All calcined

hydroxyapatite samples (PepGens, Cerabones, and

Endobons) show no mass loss, as expected due to the

preparation of these materials by high-temperature

calcination. The amount of peptide in PepGens is too

small to result in a detectable mass loss.

ARTICLE IN PRESS

4000 3500 3000 2500 2000 1500 1000 500

P-OP-O

Ceros(R)

Cerasorb

(R)

Chronos(R)

Bioresorb(R)

Vitoss(R)

abs

orbance/a.u.

wave number / cm-1

4000 3500 3000 2500 2000 1500 1000 500

PepGen(R)

P-OP-O

C-OO-H Algipore

(R)

Endobon(R)

Cerabone(R)

absorbance/a.u.

wave number / cm-1

4000 3500 3000 2500 2000 1500 1000 500

P-O

P-OC-O

O-H

H-P-O

O-H

Hydroxyapatite

synthetic

BioOss(R)

Ostim(R)

absorb

ance/a.u.

wave number / cm-1

4000 3500 3000 2500 2000 1500 1000 500

N-HC-O

C-H

H-P-OP-O

P-O

O-HO-H

Bone

(Kiel)

Bone

(callus)

Bone

(tumor)

Tutoplast(R)

(bovine)

Tutoplast(R)

(human)

absorba

nce/a.u.

wave number / cm-1

(a)

(c) (d)

(b)

Fig. 3. Infrared spectroscopy on the bone graft materials with the bands assigned to structural features.

100 200 300 400 500 600 700 800 900

60

65

70

75

80

85

90

95

100

~ 3,6 %CO2

~9 %water

~ 26 %organic material

samplemass/%

temperature / C

Fig. 4. Typical thermogravimetric curve of Tutoplasts (bovine),

showing the three regions of mass loss that can be used to derive the

chemical composition.


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Algipores contains small amounts of water, probably

a small amount of organic material and some carbonate,

as indicated by the weight loss at high temperature

(decomposition of carbonated hydroxyapatite to hydro-

xyapatite and calcium oxide). Ostims contains about

40 wt% of water; the remainder is a carbonate-free

hydroxyapatite. BioOsss contains a small amount of

water but no detectable combustible material. The

inorganic phase is a carbonated hydroxyapatite. The

materials that still contain all or most of the organic

bone matrix (Kiel bone, natural bone, Tutoplasts

) havea similar composition with some water content (6

10wt%), some organic material (2050wt%) and

carbonated hydroxyapatite as mineral phase.

It is interesting to see that the carbonate content in the

bone-like materials (BioOsss, Kiel bone, Tutoplasts) is

highly variable. If we formally compute a weight ratio of

Ca5(PO4)3OH to CaCO3 in these samples, we obtain

values between 6 and 30. As the range in natural bone

samples is also highly variable (we found ratios from 13

to 37 in four bone samples [16]), we can conclude that

the identity with bone mineral is still present, even after

extensive chemical and moderate thermal treatment.

Fig. 5 shows representative SEM pictures that

illustrate the typical morphology of these classes of

materials. In Fig. 5a, Cerasorbs shows the granular

appearance of a sintered material with visible micro-

pores at high magnification. In Fig. 5b, the calcined

bovine bone (Cerabones) has the interconnecting

porous structure of the original bone. In higher

magnification, primary crystallites of sintered hydro-

xyapatite are visible with particle sizes of a few

micrometers. In Fig. 5c, the chemically converted algae

structure of Algipores can be seen. The graded porosity

(resembling cortical and cancellous bone, but on a much

ARTICLE IN PRESS

Table 2

Chemical composition, as derived from thermogravimetric experiments. The nature of the mineral phase was derived from previous diffraction

experiments

H2O

(wt%)

Soft tissue+organic

bone matrix (wt%)

Mineral

phase (wt%)

Formal content

of CaCO3 (wt%)

Content

of TCP

Formal content

of HAP (wt%)

Formal ratio

apatite: CaCO3 (w:w)

Bioresorbs 0 0 100 0 100

Chronoss

0 0 100 0 100

Ceross 0 0 100 0 100

Cerasorbs 0 0 100 0 100

Vitosss 0 1.2 98.8 0 98.8

PepGens 0 0 100 0 100

Endobons 0 0 100 0 100

Cerabones 0 0 100 0 100

Algipores 0.3 2.4 97.3 2.3 95 41

Ostims 40.4 0 \quad 59.6 0 59.6

BioOsss 3 0 97 3.4 93.6 28

Kiel bone 7.8 28.7 63.5 3.7 59.8 16

Tumor bone 5.7 21.2 73.1 5.2 67.9 13

Callus bone 6.9 47.7 45.4 1.4 44 31

Tutoplasts (bovine) 9 26 65 8 57 7

Tutoplasts (human) 9.5 34 56.5 7.5 49 6.5

Note the traces of impurities in some cases (Fig. 2).

(a) (b)

(c) (d)

Fig. 5. SEM pictures of four representative bone graft materials. (a)

Cerasorbs, (b) Cerabones, (c) Algipores and (d) Tutoplasts

(bovine).


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smaller dimension) is due to the biological requirements

of the algae. At high magnification, we can see theprimary particles of a micrometer or less. In Fig. 5d, the

chemically treated bovine bone material Tutoplasts is

shown. As in Fig. 5b, we can see the interconnecting

macroporosity of bone; however, as this material was

not sintered, it still contains the collagen matrix. At high

magnification, we do not see sintered hydroxyapatite

but the fibrous structure of the original bone.

Table 3 summarises all structural and morphological

information in a concise way. It can be seen that these

materials strongly differ in their composition. It is also

clear the mere denomination calcium phosphate

ceramics is by no means sufficient to fully characterise

a material. With respect to biodegradability, it is

possible to make some reasonable predictions, based

on literature data. b-TCP ceramics are faster degradable

than HAP ceramics [2123]. In addition, there is a

difference between sintered HAP ceramics and precipi-

tated HAP ceramics, the former showing a very slow (if

any) biodegradation. If the crystallite size of the HAP

ceramics is very small (like in bone) and/or if there is

carbonate incorporated, the biodegradation is strongly

enhanced due to a higher solubility [2226]. Even more

strongly, this applies to bone grafts that still contain the

collagen matrix. In these cases, usually a fast biode-

gradation is observed and a biological potency of the

incorporated bone matrix is postulated [7,27].

5. Conclusions

14 different bone graft materials were investigated,

and the results were compared to synthetic hydroxy-

apatite and natural bone samples (as reference for

autologous bone). Their composition and morphology is

strongly different, therefore the materials cover a wide

range of applications, ranging from permanent implants

to rapidly degradable implants with osteogenic potency.

Acknowledgements

This project was supported by the Fonds der

Chemischen Industrie (Frankfurt am Main, Germany).

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ARTICLE IN PRESS

Table 3

Summary of all data obtained for the different materials. The mechanical stability of granulates refers to their ability to retain a cm-sized three-

dimensional shape

Sample Chemical composition Crystallinity Morphology Expected

biodegradability

Mechanical stability

BioResorbs b-TCP, traces of calcium

pyrophosphate and a-TCP

High Porous granulate Moderate Low

ChronOSs b-TCP, traces of a-TCP and

HAP


Ceross b-TCP, traces of a-TCP and

HAP


Cerasorbs b-TCP High Porous granulate; drilled

porous blocks

Moderate Low (granulate) to high

(blocks)

Vitosss b-TCP, traces of calcium

pyrophosphate and possibly

organic binder


PepGens HAP High Porous granulate Slow Low

Endobons HAP, traces of calcium oxide High Porous block (bone-like) Slow High

Cerabones HAP, traces of calcium oxide High Porous block (bone-like) Slow High

Algipores Carbonated HAP, traces of

organic binder (?)

Moderate Porous granulate Moderate Low

Ostims

HAP dispersed in water Nano Paste Fast NoneBioOsss Carbonated HAP, water Nano Porous granulate Fast Low

Kiel bone Carbonated HAP, water,

organic bone matrix

Nano Porous block (bone-like) Fast High

Callus bone Carbonated HAP, water,

organic bone matrix


Tumor bone Carbonated HAP, water,

organic bone matrix


Tutoplasts (bovine) Carbonated HAP, traces of

OCP, water, organic bone matrix


Tutoplasts (human) Carbonated HAP, water,

organic bone matrix



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