ARTICLE IN PRESS
Biomaterials 24 (2003) 3655–3661
Biological reaction to alumina, zirconia, titanium and polyethylene
particles implanted onto murine calvaria
Hideki Warashina*, Shinji Sakano, Shinji Kitamura, Ken-Ichi Yamauchi, Jin Yamaguchi,
Naoki Ishiguro, Yukiharu Hasegawa
Department of Orthopaedic Surgery, School of Medicine, Nagoya University, 65 Tsuruma-cho, Showa-ku, Nagoya 4668550, Aichi, Japan
Received 21 February 2003
Abstract
Periprosthetic osteolysis is a serious problem that limits long-term survival of total hip arthroplasty. Ceramics have been
introduced as a joint surface material to reduce osteolysis due to wear particles. The aim of this study is to investigate the biological
reaction of ceramic particles on murine calvarial bone, in comparison with polyethylene and titanium particles. Sixty CL/BL6 mice
were divided into five groups according to the materials implanted onto the murine calvariae: control, Al2O3, ZrO2, high-density
polyethylene (HDP) and Ti6Al4V. One week after the implantation, each calvarial tissue was dissected and the release of
proinflammatory mediators (IL-1b; IL-6, TNF-a) and bone resorption were assessed. The particles of HDP and Ti6Al4V induced
three and two times larger osteolytic lesions than the control, respectively. The levels of IL-1b and IL-6 were significantly elevated in
the medium subcultured with the calvariae of HDP and Ti6Al4V groups. Any particle type did not increase the levels of TNF-a:
There were no significant differences observed in the levels of proinflammatory mediators or osteolytic area among Al2O3, ZrO2 and
control groups. The inflammatory response and bone resorption induced by ceramic particles were much smaller than those induced
by HDP and Ti6Al4V. These biological features suggest the biocompatibility of ceramics as a joint surface material for artificial
joints.
r 2003 Elsevier Science Ltd. All rights reserved.
Keywords: Ceramics; Particle; Cytokines; Osteolysis; Murine calvariae
1. Introduction
Aseptic failure of joint prostheses has emerged as a
serious orthopaedic problem affecting the long-term
success of total hip arthroplasty (THA) [1]. Failures of
THA due to osteolysis are described in several reports
[2–4]. Osteolysis is presumed to decrease the stability of
THA thorough the biological reaction to particulate
wear debris generated from prostheses [5,6]. In the
fibrous membrane surrounding aseptically loose implants, there appears a foreign-body reaction due to
implant-derived wear particles, such as polyethylene,
metal and polymethylmethacrylate [7–10]. The wear
particles associated with the macrophage response
correspond to periprosthetic osteolysis by inducing
proinflammatory mediators and activating mononuclear
precursor cells [11–14]. Studies on the macrophage
*Corresponding author. Tel.: +81-52-741-2111; fax: +81-52-7442260.
reaction to wear particles have indicated that the release
of cytokines, such as tumor necrosis factor (TNF),
interleukin-6 (IL-6), interleukin-1 alpha (IL-1a), interleukin-1 beta (IL-1b), and prostaglandin E2, is predominately correlated with osteolysis [12–16]. Merkel
et al. reported that polyethylene particles could not
induce osteolysis when they were implanted on murine
calvaria lacking TNF receptor but could when implanted on wild type [17]. Polyethylene particles also
affect proliferation and phenotype expression of osteoblast [18].
After the recognition of failures due to osteolysis
induced by polyethylene debris, ceramic on ceramic
THA has become a focus of attention in the field
of orthopaedic implants. Since Boutin introduced
alumina on alumina THA in 1972 [19], ceramic
THA has been clinically used worldwide, mainly
in Europe. Initial complications such as femoral
head fracture and breakage of the ceramic sockets
have been considerably reduced by improvement in
0142-9612/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0142-9612(03)00120-0
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design and the quality of ceramics. It was reported
that ceramic on ceramic bearings were durable in
terms of annual wear lower than 5 mm, resulting in
less osteolysis [20,21]. Huo et al. found no osteolysis
in ceramic on ceramic THA after a mean implantation time of 9 years [22]. Bizot et al. reported
97.4% survival rates of alumina on alumina THA after
9 years follow-up [23]. The long-term evaluation of
alumina on alumina THA also showed 69.3% excellent
and 19% good results [24]. However, a few reports have
demonstrated poor results of ceramic on ceramic THA
[25–27].
In laboratory experiments, a number of reports
have been published about osteolysis induced by
polyethylene and metal wear debris [8,9,11–13]. On
the other hand, information about the cellular response
to ceramic particles is still limited. Ceramic particles
demonstrated to induce less foreign body reaction
and apoptotic cell death in the periprosthetic tissues
retrieved from loosened THA [28,29]. Implantation
of discs and tubes of Al2O3, ZrO2 and TiO2 did not
have toxic, immune or carcinogenic effects in rabbit
muscle [30]. No ceramic-specific damage of the cells
was also observed in cultured macrophages and
fibroblasts [31,32]. Catelas et al. showed that release
of TNF-a was lower with alumina particles than
with polyethylene particles when applied into mouse
macrophage cells [33]. These observations indicate
biocompatibility of ceramic materials. In contrast,
periprosthetic osteolysis and fibrous tissue with concentrated ceramic particles have been observed around
failed alumina on alumina THA [26,27,34]. Nagase et al.
detected the biological reaction to alumina particles
using a chemiluminescence assay for reactive oxygen
species [35]. The release of bone resorbing mediators
(IL-6, TNF-a; and IL-1a) from macrophages by alumina
ceramic particles was also described [36]. These findings
indicate that osteolysis may occur due to biological
reaction by ceramic particles, implying the discrepancy
with the biocompatibility of ceramics. The biological
effects of ceramic particles seem still complicated.
Moreover, to our knowledge, there have been no
in vivo study that analyzed the skeletal tissue response
to ceramic particles.
To better understand the efficacy of ceramics as
a joint surface material, more information is necessary
about the biological reaction to ceramic particles. In
the current study, the biological responses to phagocytosable ceramic particles of Al2O3 and ZrO2 were
investigated in comparison with particles of HDP
and Ti6Al4V. The particles of Al2O3, ZrO2, HDP and
Ti6Al4V were implanted onto murine calvariae, and the
bone reaction was assessed histologically and biologically. Induction of proinflammatory mediators,
IL-1, IL-6 and TNF-a; by each particle type was
analyzed by enzyme-linked immunoassay.
2. Materials and methods
2.1. Particle preparation
Particles of Al2O3 (Kyocera, Kyoto, Japan), ZrO2
partially stabilized with yttrium (Kyocera, Kyoto,
Japan), and Ti6Al4V (Zimmer, Warsaw, IN, USA)
were used in the phagocytable range 2.170.4 mm for
Al2O3, 1.570.6 mm for ZrO2 and 1.171.3 mm for
Ti6Al4V. Medical grade high-density polyethylene
(HDP) particles were obtained from Sumitomo Fine
Chemical Co. (Tokyo, Japan). The mean size of the
HDP particles was 4.171.4 mm. These particles were
suspended in distilled water and filtered using a
microfiltration system (All Glass Filter system, Millipore, Ashby, MA, USA) to obtain particles less than
5 mm in diameter followed by freeze-drying. The
particles were gas-sterilized with ethylene oxide and
allowed to aerate for at least 24 h before use [33]. All
particles were suspended in sterile phosphate-buffered
saline (PBS) at a concentration of 1.0 109 particles/ml.
Scanning electron microscopy (S-800S, HITACHI,
Tokyo, Japan) was used to determine the size of the
particles. To exclude the effects of endotoxin, endotoxin
attached to the particles was assessed by Kinetic-QCL
(Biowhittaker, Walkersville, MD, USA) [37]. All of the
particles used in this study contained endotoxin levels
below those able to activate macrophages (o0.001 EU/
ml) [38].
2.2. Experimental protocol
A murine calvarial osteolysis model was used in this
study [39]. The institutional guidelines for the care and
use of laboratory animals at Nagoya University were
strictly followed. Sixty CL/BL6 male mice aged 12
weeks with a mean weight of 23.2 g (21.7–27.4 g) were
divided into five groups according to the implanted
materials: control, Al2O3, ZrO2, HDP and Ti6Al4V.
Each mouse was anesthetized with an intraperitoneal
injection of pentobarbital. Using sterile technique the
scalp was incised longitudinally to expose the external
cranial periosteum. The periosteum was removed until
coronal, sagittal and lamboid sutures of the calvaria
were visible. One hundred microliters of each particle
suspended solution was applied directly on the surface
of the calvaria. For the control group, PBS without
particles was used. The skin was then closed tightly with
skin clips and sealed with Dermabonds (ETHICON,
Somerville, NJ, USA) to prevent leakage of the
suspended solution. The animals were killed at 1 week
postoperatively by cervical dislocation. The calvariae
were removed by dissecting the bone free from the
underlying brain. Six murine calvariae of each group
were used for histological analysis and the others were
used for organ culture.
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H. Warashina et al. / Biomaterials 24 (2003) 3655–3661
2.3. Histological analysis
3. Results
The specimens were fixed in 10% phosphate-buffered
formalin, decalcified in 14% EDTA, dehydrated in
graded alcohols, and embedded in paraffin. Each
calvarial tissue specimen was sectioned with the
thickness of 4 mm on the sagittal plane. Three
sections approximately 2–3 mm lateral to the midsagittal
suture were stained with hematoxylin-eosin. Whole
view of each section was scanned and stored in a
computer (PCG-SR1/BP, SONY, Tokyo, Japan),
and image analysis was performed using NIH Image
1.62 to quantify osteolytic lesions and residual
bone. Percentage of osteolytic area (OL) was indicated by the ratio of inflammatory granulation tissue
in the calvaria, and percentage of bone area (BO) by the
ratio of osseous tissue that includes trabecular bone
region.
3.1. Histological analysis
2.4. Organ culture
The dissected tissue samples were weighed and
cultured in serumless medium (10 ml/g weight) (Dulbecco’s Modified Eagles Media, Life Technologies,
Gaithersburg, MD, USA) with 1% penicillin and
streptomycin for 72 h at 37 C with 5% CO2. Culture
medium was harvested at the end of the culture period
and stored at 80 C until the assay for IL-1b; IL-6 and
TNF-a:
2.5. ELISA for IL-1b, IL-6, TNF-a
The release of IL-1b; IL-6 and TNF-a from dissected
murine calvariae into the medium was measured with
the enzyme-linked immunoassay (ELISA) kit specific for
mice IL-1b; IL-6 and TNF-a (TFB, Tokyo, Japan). The
assays were performed according to the manufacturer’s
instructions. Photometric measurements were conducted
at 450 nm using a model MICRO PLATE READER
(MPR-A4i, Tokyo, Japan). The lower limit for detection
in each assay was 7 pg/ml for IL-1b and 3 pg/ml for IL-6
and TNF-a:
2.6. Statistical analysis
The statistical analysis was carried out using the
Stat View version 4.5 (Abacus Concepts, Berkeley,
CA, USA). Differences in mean values of variables
between groups were assessed by one-way analysis
of variance (ANOVA) and student’s two-sample test
(two-tailed) to allow comparisons. Prior to the analysis,
the percentage data were arcsin transformed to normalize the data. A value of po0:05 was considered
significant.
3657
In the sections from the control tissues, little
inflammatory reaction was observed, and trabecular
bone was well conserved (Fig. 1A). The tissues exposed
to HDP and Ti6Al4V showed a marked inflammatory
reaction with highly vascularized granulation containing
macrophages and multi-nucleated giant cells (Figs. 1B
and C). Marked osteolysis was observed adjacent to
these inflammatory reaction tissues. The inflammatory
reaction seemed to be more vigorous in HDP group
than in Ti6Al4V group. The osteolysis in these groups
reduced the bone volume of murine calvariae extensively. Particles of Al2O3 and ZrO2 induced a foreignbody response with inflammatory reaction; however,
these tissue reactions were less marked than those of
HDP or Ti6Al4V (Figs. 1D and E). The histological
findings did not differ between Al2O3 and ZrO2 groups.
Tissue reactions were quantitatively evaluated by OL
and BO (Fig. 2). The calvariae implanted with HDP
showed the greatest OL (52.176.9%) (Fig. 2A).
Particles of Ti6Al4V also induced large OL
(32.872.1%). In the control group, OL was
17.174.4%. The mice implanted with Al2O3 or ZrO2
showed a slightly larger OL than the control. In Al2O3
and ZrO2 groups, OL was 21.7712.4% and
21.679.8%, respectively. The OL by HDP particles
was three times and that of Ti6Al4V was one and a half
times larger than in the control group. Subsequently,
HDP group showed the smallest BO (40.074.2%) (Fig.
2B). In the control group, BO was 60.373.4%. The
mice implanted with Ti6Al4V had BO of 48.174.8%.
The Al2O3 and ZrO2 groups kept BO of 53.579.0% and
55.072.2%, respectively. There were no significant
differences between Al2O3, ZrO2 and the control group
in either OL or BO.
3.2. The proinflammatory mediators in organ culture
3.2.1. Interleukin-1b
Significantly elevated levels of IL-1b were identified
in the medium subcultured with the calvariae implanted
with HDP and Ti6Al4V (HDP: 183.57133.7 pg/ml,
Ti6Al4V: 155.2796.2 pg/ml), compared with that of
the control (10.473.6 pg/ml) (n ¼ 6; po0:01) (Fig. 3).
The particles of HDP induced the highest level of
IL-1b among all the materials. The mean value of IL-1b
in HDP group reached 18-fold that of the control
group. Although IL-1b was induced by Al2O3 and
ZrO2 particles (16.774.9 and 15.175.5 pg/ml, respectively), the levels were very low. The levels of IL-1b
in the medium of Al2O3 and ZrO2 groups were almost
the same as that of the control group. There was no
significant difference observed in the levels of
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Fig. 1. Histological appearance of murine calvarial tissues (stain: hematoxylin and eosin; magnification: 200). (A) The control section showed few
inflammatory and osteolytic changes. (B, C) The sections of HDP (B) and Ti6Al4V (C) groups showed a marked inflammatory reaction and large
osteolysis. (D, E) The sections of Al2O3 (D) and ZrO2 (E) groups showed a little inflammation with small osteolysis.
IL-1b between Al2O3 or ZrO2 group and the control
group.
3.2.2. Interleukin-6
High levels of IL-6 were detected in HDP
(27.679.7 ng/ml) and Ti6Al4V (22.177.8 ng/ml) groups
when compared with the control (8.670.5 ng/ml) in
organ cultures of murine calvariae (n ¼ 6; po0:01). The
calvariae implanted with Al2O3 and ZrO2 showed
slightly higher levels of IL-6 (Al2O3: 12.073.4 ng/ml,
ZrO2: 10.271.7 ng/ml) than the control group, although
this difference was not significant (Fig. 4).
3.2.3. TNF-a
HDP, Ti6Al4V, Al2O3, and ZrO2 particles induced
TNF-a to the level of 7.173.9, 5.872.1, 5.072.5, and
5.974.0 pg/ml, respectively. The level of TNF-a in the
control group was 4.470.9 pg/ml. In contrast to IL-1b
and IL-6, secretion of TNF-a was not marked in any
treated group. No statistically significant difference was
found among the groups.
4. Discussion
Wear debris produced on the weight-bearing surface
is one of the key factors affecting the longevity of
artificial joints. In the current study, particles of HDP
and Ti6Al4V induced large osteolytic lesions in murine
calvaria. Histological examination revealed an intense
inflammatory reaction to HDP and Ti6Al4V. These
results are compatible with the theory that the tissue
reaction to polyethylene particles is one of the major
causes of osteolysis around THA [8,9]. A marked
inflammatory reaction to Ti6Al4V was also reported
[9,39,40]. On the other hand, the Al2O3 and ZrO2
particles used in this study induced only small osteolytic
lesions associated with little inflammatory reaction.
Quantitative image analysis revealed that ceramic
particles are extremely less bone-resorptive. These
findings indicate that the biological reaction and bone
deterioration induced by ceramic particles are much less
extensive than those induced by HDP or Ti6Al4V.
Biological reactions through the phagocytosis of wear
debris by macrophages have been observed in the
periprosthetic tissues [8–10]. Macrophages are thought
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Fig. 4. The levels of IL-6 released from murine calvarial tissues with
each particle type in organ culture. Significantly elevated levels of IL-6
were detected in HDP and Ti6Al4V groups (*po0:05). Particles of
HDP stimulated the tissues to secrete the highest levels of IL-6
reaching three-fold of that of the control group. Although IL-6 was
induced by Al2O3 and ZrO2 particles, these values were not
significantly different from the control.
Fig. 2. Graphs showing OL induced by each particle type and
remaining BO. (A) Particles of HDP induced the largest OL. The mice
implanted with Al2O3 or ZrO2 showed a slightly larger OL than the
control. (B) BO of HDP group showed the smallest value. There was
no difference observed in BO among the groups of Al2O3, ZrO2 and
the control.
Fig. 3. The levels of IL-1b released from murine calvarial tissues with
each particle in organ culture. Significantly elevated levels of IL-1b
were identified in HDP and Ti6Al4V groups (*po0:05). Although IL1b was induced by Al2O3 and ZrO2 particles, these stimulations were
not significant compared with the control.
to release proinflammatory cytokines that activate
osteoclasts and induce osteoclast-like cell formation
[11–16,41]. Cytokines activating osteoclasts are present
in the pseudosynovial membrane and interfacial tissues
retrieved at revision surgery [41,42]. In this study, large
amounts of IL-1b and IL-6 were induced by HDP and
Ti6Al4V particles implanted onto murine calvariae. IL1b and IL-6 have been reported as cytokines crucial to
osteolysis and are released from particle-stimulated
macrophages and fibroblastic cells [12,13,41]. IL-1b
and IL-6 are regarded to regulate bone resorption
through the differentiation of osteoclasts from precursor
cells and/or the activation of existent osteoclasts [43,44].
These observations indicate that the osteolytic pathway
from polyethylene and Ti6Al4V particles to bone
resorption may be mediated by proinflammatory cytokines. TNF-a is an important cytokine that is also
involved in osteolysis through osteoclast activation and
differentiation [16,17]. However, the author could not
induce a significant increase in TNF-a by the implantation of any type of particle. TNF-a is reported to be an
early expressing molecule, named the first cytokine, that
is secreted in the early stage of the osteolysis process by
particle-phagocytosed macrophages. Thus, secretion of
TNF-a may have occurred in the early days after
implantation of the particles onto murine calvariae and
have already decreased on the seventh day postimplantation when the calvariae were collected.
In contrast to HDP and Ti6Al4V, particles of Al2O3
and ZrO2 did not induce IL-1b or IL-6 extensively when
implanted onto murine calvariae. These results were well
correlated with the histological findings that particles of
HDP and Ti6Al4V induced extensive osteolysis with an
intense inflammatory reaction, whereas ceramics produced only little osteolysis with less inflammation. Cell
toxicity and signal activation for cytokine production
induced by ceramic particles might be lower than those
induced by HDP and Ti6Al4V. Very few studies have
investigated the biological effects of ceramic debris. The
biological reaction of ceramics was reported to be weak
in experiments performed using subcutaneous, intraarticular and peritoneal administration [31]. Catelas et al.
demonstrated that ceramic (Al2O3 and ZrO2) and HDP
particles induce macrophage apoptotic cell death in vitro
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[45]. They also noted that Al2O3 and ZrO2 did not
release high levels of inflammatory mediators, while
HDP did in in vitro experiments [33]. In cultured
fibroblasts, ceramic powder showed no cytotoxic effect
[32]. These observations are in accordance with the
current results and suggest the biocompatibility of
ceramics as materials for orthopedic implants. In
addition, the in vivo wear rate of ceramic on ceramic
THA is described as being 4000 times less than that of
metal on polyethylene THA [46]. Taken together with
the biochemical reaction in the tissues and durability as
the weight-bearing surface, it can be said that ceramics is
a promising material for joint prostheses.
Although most studies performed on ceramic materials showed biological compatibility to the tissues, some
have also described the possibility of ceramics inducing
an inflammatory reaction. It was mentioned that
ceramic particles had inflammatory potential in a rat
air pouch model [47]. Clinical reports have shown
osteolysis around ceramic THA [26,27]. It was recently
reported that periprosthetic tissues around loose ceramic THA contain large amounts of ceramic particles
with inflammation, while those around stable THA
contain few ceramic particles with less inflammation
[28]. These observations suggest that the biological
reaction to the materials is not the only factor involved
in implant failures in THAs. Aspenberg et al. have
maintained that fluid pressure could be the main cause
of osteolysis [48]. Improvement of polyethylene by
cross-linking is lately expected to decrease osteolysis
by reducing polyethylene wear [49]. Thus, clinically
significant osteolysis is likely the result of multiple
factors. Further studies will be needed to elucidate the
cause of periprosthetic osteolysis in which biological,
mechanical as well as tribiological factors are implicated.
In this study, particles of Al2O3 and ZrO2 showed
very little biological reaction compared to HDP and
Ti6Al4V, when implanted onto murine calvariae.
Osteolytic lesions induced by Al2O3 and ZrO2 were
extremely small correlated with little production of IL1b and -6. Moreover, use of ceramics like Al2O3 and
ZrO2 which are resistant to wear may result in lower
particle load [21,22]. Thereby, these results support
ceramics as a desirable bearing surface material for
artificial joints.
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