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Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.intl.elsevierhealth.com/journals/dema

Osseointegration of zirconia dental implants in

animal investigations: A systematic review and
meta-analysis

Stefano Pieralli a,b,∗ , Ralf-Joachim Kohal a , Emilia Lopez Hernandez a ,

Sam Doerken c , Benedikt Christopher Spies a,b
a Medical Center — University of Freiburg, Center for Dental Medicine, Department of Prosthetic Dentistry, Faculty of
Medicine — University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
b Charité — Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), CC 3 Dental and Craniofacial Sciences,

Department of Prosthodontics, Geriatric Dentistry and Craniomandibular Disorders, Aßmannshauser Straße 4-6,
14197 Berlin, Germany
c Medical Center — University of Freiburg, Center for Medical Biometry and Medical Informatics, Institute for Medical

Biometry and Statistics, Faculty of Medicine — University of Freiburg, Hebelstr. 11, 79104 Freiburg, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Objective. To determine the osseointegration rate of zirconium dioxide (ZrO2 ) dental implants
Received 14 September 2017 in preclinical investigations.
Received in revised form Data. Data on the osseointegration rate was extracted considering the bone to implant con-
17 October 2017 tact (BIC), removal torque analysis (RTQ) and push-in tests. Meta analyses were conducted
Accepted 18 October 2017 using multilevel multivariable mixed-effects linear regression models. The Šidák method
Available online xxx was used in case of multiple testing.
Sources. An electronic screening of the literature (MEDLINE/Pubmed, Cochrane Library and
Keywords: Embase) and a supplementary manual search were performed. Animal investigations with
Ceramics a minimum sample size of 3 units evaluating implants made of zirconia (ZrO2 ) or its com-
Dental implants posites (ZrO2 > 50 vol.%) were included.
BIC Study selection. The search provided 4577 articles, and finally 54 investigations were included
RTQ and analyzed. Fifty-two studies included implants made from zirconia, 4 zirconia composite
Push-in implants and 37 titanium implants. In total, 3435 implants were installed in 954 animals.
Conclusions. No significant influence of the evaluated bulk materials on the outcomes of
interest could be detected. When comparing different animal models, significant differences
for the evaluated variables could be found. These results might be of interest for the design
of further animal investigations.
© 2017 The Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

∗
Corresponding author at: Charité — Universitätsmedizin Berlin, Department of Prosthodontics, Aßmannshauser Straße 4-6, 14197 Berlin,
Germany.
E-mail address: stefano.pieralli@charite.de (S. Pieralli).
https://doi.org/10.1016/j.dental.2017.10.008
0109-5641/© 2017 The Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
DENTAL-3042; No. of Pages 12
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Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Screening process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Eligibility criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00
2.5. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Screening process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.1. BIC (Fig. 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.2. RTQ (Fig. 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.3. Push-in (Fig. 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

additive sintering of a porous slurry or subtractive techniques

1. Introduction like acid etching and/or sand blasting. Additionally, when
dealing with injection molded implants, a micro-roughened
Ceramic dental implants have been commercially available surface can be produced without the need for cost inten-
since almost 40 years [1]. Initially made from mono- or poly- sive post-processing by texturing the inner surface of the
crystalline aluminum oxide (Al2 O3 ), this bulk material was mold. However, it still remains unknown, which represents
retired from the market for apparent mechanical weakness the most favorable surface modification technique by means
resulting in a poor clinical outcome [2]. Nowadays, ceramic of its osseointegration capacity. Several pre-clinical investiga-
dental implants are mainly produced from yttria-stabilized tions examined the influence of the bulk material (zirconia,
tetragonal zirconia polycrystal (Y-TZP), offering improved frac- composites) and surface modification on different aspects of
ture toughness and flexural strength [3]. Several clinical the osseointegration rate. The method mostly used to evalu-
investigations addressing the outcome of implants made from ate the implant-bone system bond was the histomorphometic
Y-TZP have been published in recent years. A recent sys- analysis of the bone in contact to the implant (BIC). Further
tematic review including human studies showed promising methods for the evaluation of the implant anchorage in bone
results in relation to survival rate and marginal bone loss (MBL) were the removal torque analysis (RTQ) that quantified the
after one year of function when supporting single crowns (SCs) torque (Ncm) needed to explant a fixture and the push-in test
and three-unit fixed dental prostheses (FDPs) [4]. Neverthe- that calculated the combination of the shear strength (bone
less, even for this indication, clinical long-term data are still in contact to the axial part of the fixture) and compressive
missing. In regard to preclinical investigations, biological [5–7] strength of the bone at the apex of the dental implant. In gen-
and physical [8,9] properties of ZrO2 implants were evaluated eral, preclinical investigations were designed with different
and lead to results comparable to the gold standard tita- animal models (e.g. monkeys, dogs, pigs, rats, rabbits, sheep)
nium implants. Contemporary animal-based research mainly leading to results that might not be comparable and, there-
addresses new composite materials such as the binary sys- fore, reliable for clinical implications on the performance in
tem alumina toughened zirconia (ATZ) or ternary systems humans. Therefore, since preclinical animal experiments rep-
containing ceria stabilized zirconia for its better resistance resent the final approval in order to design human studies,
to aging processes [10]. Moreover, new fabrication methods systematic reviews of animal investigations might provide
like ceramic injection molding (CIM), thought to be more eco- important knowledge on how to design these trials and on
nomic for mass-production than subtractive processing, are how one can interpret the gathered data.
currently evaluated. In regard to the osseointegration capa- The objective of the present systematic review was to
bility of such zirconia composite or injection molded ceramic evaluate the influence of multiple variables (follow-up time,
implants, several animal investigations were conducted over animal type, implant location, implant surface characteristics,
the last years. In regard to the mechanism of bone apposi- loading mode, and fabrication method) on the osseointe-
tion on zirconia-based material surfaces it is assumed that gration rate of zirconia dental implants in different animal
specific post-processing surface modifications can influence models. The null hypothesis supposed no distinction between
the osseointegration in terms of healing time and quality these variables in relation to BIC, RTQ and push-in test. Fur-
of the bond [11]. When producing zirconia dental implants, thermore, no influence of the animal species was assumed.
micro-roughening of the surface can be achieved by either

Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
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2. Materials and methods
2.1. Study design
This systematic review and meta-analysis followed the
PRISMA statement (preferred reporting items for systematic
reviews and meta-analyses) of 2009 [12] and adapted the
PICO question (patient, intervention, comparison, outcomes)
to these preclinical investigations:
• Patient: Animals
• Intervention: Implant placement
• Comparison: Titanium implants
• Outcomes: BIC, RTQ, push-in
2.2. Search strategy
An electronic search was conducted among three databases,
namely MEDLINE (PubMed), Cochrane Register and Embase.
The search strategy for each database was a specific combi-
nation of subject headings and text words. The screening was
performed until January 2016, and no further time-limitations
were applied. To complete the search, a manual screening
of the references of the included articles was conducted.
Finally, all the publications found were collected in a software
database (EndNote X6; Thomson Reuters).
2.3. Screening process
The searching term selected for MEDLINE/PubMed consisted
of medical subject headings (MeSH) and text words with no
further limitations:
(((((dental implants[MeSH Terms]) AND ceramics[MeSH
Terms]))OR ((dental implantation[MeSH Terms]) AND ceram-
ics[MeSHTerms]))) OR (((((zirc*) OR tzp*) OR atz*)) AND
((((implant)OR implants) OR implantation) OR implanted)).
Furthermore, the search idiom was adapted for each of the
different databases.
2.4. Eligibility criteria
The present systematic review was limited to studies that met
the following inclusion criteria:
• Language: English, German, Italian, Spanish
• Preclinical animal investigation
• Minimum sample size of 3 animals
• Number and location of the implants defined
• Implants made of ZrO2 or its composites (ZrO2 >50 vol.%)
• Mean BIC, mean RTQ or mean push-in test values reported
Other study designs (e.g. clinical investigations, in-vitro
studies, cell culture models, reviews), different bulk mate-
rials (e.g. PEEK, zirconium, Al2 O3 ) and investigations with
an unclear outcome were excluded. Outcomes of interest
were considered BIC [%], RTQ [Ncm] and push-in [N] tests
values. The overall number of animals and implants used
in the included investigations were reported as well as
the follow-up time (in weeks). Furthermore, multiple vari-
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
3
ables were considered like the type of animal (dogs, rabbits,
rats, monkeys, sheep, pigs, minipigs) and the location of
the implant (maxilla, mandible, femur, tibia, skull, pelvis,
cranium, humeri). Data regarding the implant bulk mate-
rial (TZP = tetragonal zirconia polycrystal; Zr-based composite;
Ti = titanium) and the loading mode were extracted. Additional
information about the surface topography was extracted.
Implants with a smooth surface (machined) and implants
with post-processed (additive or subtractive) surfaces were
considered separately. Modified surfaces included additive
procedures, like coating with different materials and subtrac-
tive methods like chemical modifications (e.g. acid etching),
laser induced superficial alteration or mechanical procedures
(e.g. sandblasting). Implants were also classified according
to their production in machined or molded. Furthermore,
the surface roughness values expressed in arithmetical mean
height of a line (Ra) or in its extension to a surface (Sa) were
reported. In order to permit accurate statistical analyses, the
standard deviation values of every outcome of interest were
reported if present. Two authors (S.P. and E.L.H.) independently
screened the data. After the first screening of the databases all
duplicates were eliminated and the remaining articles were
selected per title and abstract. Subsequently the full-texts of
the residual studies were analyzed. To score the inter-reviewer
agreement the Cohen’s kappa-test was used and any dis-
agreement was resolved by discussion with a third author
(R.J.K.). Finally, in case of incomplete or missing data, the corre-
sponding authors of the included investigations or the implant
manufacturers were contacted and asked for further informa-
tion.
2.5. Statistical analyses
Multiple observations were extracted from each of the
included studies. One observation consisted of the mean out-
come value (BIC, RTQ, push-in) of a specific cohort of implants
(e.g. titanium, additive post processing, no loading) extracted
from each of the included studies. Consequently, one obser-
vation can include in between 6 and 156 implants. To analyze
the effect of the specific variables on the outcome of interest
(e.g. BIC, RTQ or push-in) a multivariable mixed-effects linear
regression model was used for each outcome with a random
intercept to cluster observations by their respective studies.
Independent variables were follow-up time (weeks), material
(titanium, zirconia, composite), type of post processing modi-
fications (additive, subtractive, smooth) and loading (yes, no).
Because too many studies had no information on the surface
roughness and injection molding, the effect of these variables
had to be assessed separately. For this, the same model as
before was fitted with the addition of one variable for rough-
ness Ra, and its effect was extracted from this model. The
same method was used to assess Sa and injection molding
(machined, injection molded). Ra and Sa were divided into
three groups. The first group included values <1 ␮m, the sec-
ond group 1–2 ␮m and the third group >2 ␮m, representing the
roughness range of commercially available implant surfaces
[13].
To evaluate studies according to the precision of their
results, a weighting had to be used. However, since the stan-
dard errors of the effect sizes of the effect of interest were not
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present systematic review (Table 2). The results of the Cohen’s

Table 1 – Reasons for exclusion after the full-text
evaluation. kappa-test provided an interrater agreement of 95%.

Article Reason for exclusion

Steflik et al. (1997) No zirconia implants 3.2. Meta-analyses
Pinkert et al. (1987) No zirconia implants
Alzubaydi et al. (2009) No zirconia implants A total of 54 articles published between 1992 [14] and
Lee et al. (2004) No zirconia implants 2015 [15–24] were included and analyzed in the present
Kong et al. (2002) No zirconia implants meta-analysis (Table 2). Regarding the implant bulk mate-
Kettner et al. (1997) No zirconia implants
rial, zirconia implants were examined in most of the
Steflik et al. (1997) No zirconia implants
included investigations (n = 52), whereas zirconia compos-
Suzuki et al. (1990) No zirconia implants
Ferguson et al. (1999) No zirconia implants ite implants were evaluated only in 4 studies [15,17,20,24]
Steflik et al. (1993) No zirconia implants conducted in 2015 and 2016. Titanium implants were eval-
Koch et al. (2013) Only soft tissue parameters evaluated uated in 37 of the included studies and analyzed as
Tao et al. (1994) Article written in chinese control group. In total, the included articles evaluated
Yliheikkila et al. (1996) No BIC, RTQ, push-in measurements 3435 implants installed in 954 animals. Overall, 49 stud-
Steflik et al. (1989) No BIC, RTQ, push-in measurements
ies evaluated the BIC [6,7,14–21,23–61], 16 studies examined
Christel et al. (1989) No BIC, RTQ, push-in measurements
Li et al. (1997) No BIC, RTQ, push-in measurements
the RTQ [18,19,22,23,34,40,42,45,47,51–54,61–64] and 3 stud-
Benedittis et al. (1999) No BIC, RTQ, push-in measurements ies analyzed the push-in test [7,24,38]. In 15 investigations,
Depprich et al. (2008) No BIC, RTQ, push-in measurements more than one of these primary outcomes were evaluated
Zhu et al. (2010) No BIC, RTQ, push-in measurements [7,19,23,24,34,38,40,42,45,47,51–53,61]. From the included arti-
Aldini et al. (2002) No BIC, RTQ, push-in measurements cles, 307 observations were extracted (mean BIC/RTQ/push-in
Steflik et al. (1999) No BIC, RTQ, push-in measurements
values for the three included implant bulk materials after dif-
Piconi et al. (1998) No BIC, RTQ, push-in measurements
ferent observation periods). The mean observation period was
Fini et al. (2000) No BIC, RTQ, push-in measurements
Nishihara et al. (1994) No BIC, RTQ, push-in measurements 8.0 ± 9.6 weeks.
Li et al. (1994) No BIC, RTQ, push-in measurements
Lee et al. (2013) Unclear data
3.2.1. BIC (Fig. 2)
For the BIC analyses, a model with imputed weights was used
reported in many of the investigations, a different measure to include studies that did not report the standard devia-
had to be used to weight each study for the meta-analysis. tion values. The BIC varied between 0% after one week in
As most of the studies reported the standard deviation of the pig maxillae [59] and 89.09% after 90 weeks in rabbit femurs
outcome of interest, the reciprocal of the standard deviation of [52]. 879 animals and 2916 implants were considered for
the outcome was used to obtain a relative weighting for each the BIC calculations based on 249 observations. Overall, tita-
study. In cases where no standard deviation was reported, nium implants showed a BIC of 60.70 ± 4.76% (mean ± SE) after
missing values were imputed by taking the median standard the mean follow-up time. In comparison, zirconia implants
deviation of observations with the same number of up follow showed a reduced BIC of −3.47% and composite materi-
up weeks. als and increased BIC of +1.90%. However, both materials
In addition, pairwise comparisons between animal type, were not significantly different from titanium (p > 0.31). Sim-
implant location, implant bulk material and surface rough- ilarly, implant loading (+11.32% if loaded, p = 0.16), implant
ness (Ra, Sa) were done. Further models were stratified by processing (−5.52% if machined, p = 0.45), surface roughness
animal type. The Šidák correction was used to obtain adjusted (multiple pairwise comparisons of the categories Ra/Sa <1 ␮m,
p-values in case of multiple testing. Finally, calculations were 1–2 ␮m, and >2 ␮m; p > 0.16), animal type (multiple pairwise
done using STATA, version 14.2 (Stata Corp., College Station, comparisons; p > 0.75) and location of the installed implant
TX, USA). (multiple pairwise comparisons; p > 0.39) did not have a sig-
nificant effect on the BIC. Compared to additive changes in
the surface topography, a significantly reduced BIC of −9.07%
3. Results (p = 0.03) resulted from subtractive surface modifications and
of −13.15% (p = 0.02) in case of no surface modification (i.e.,
3.1. Screening process implants with a smooth surface).
When stratifying the dataset according to the animal
After the initial screening a total of 4577 articles were obtained. type, several significant distinctions were found. For example,
Thereafter 1284 duplicate articles were eliminated and fur- investigations in pigs showed a reduced BIC (−10.07%, p < 0.01)
ther 3213 studies were excluded by title and abstract. The of zirconia implants compared to titanium implants. Com-
full-texts of the remaining 80 articles were evaluated and lead pared to additive post processing modifications of the implant
to the exclusion of further 26 studies (Fig. 1). Most frequent surface, subtractive surface modifications were found to be
reasons for exclusion were the absence of BIC, RTQ, push-in controversial (pigs +21.90%, p < 0.01; rats −41.82%, p < 0.01; rab-
tests measurements and the use of implant materials not rel- bits −9.0%, p < 0.01). Furthermore, smooth surfaces showed
evant for the present systematic review. Moreover, the reasons reduced amounts of BIC when installed in rats (−24.14%,
for exclusion of all the non-selected articles were reported p < 0.01) or rabbits (−17.40%, p < 0.01). Finally, a positive influ-
in detail (Table 1). Finally, 54 full-texts were analyzed in the ence of loading was found in dogs investigations (+11.27%,

Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
 DENTAL-3042; No. of Pages 12
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review

Table 2 – Overview of the studies included in the statistical analyses.

Author (Ref.) Animals Implants F-Up [weeks] Bulk material Bulk proc. Surface proc.c Load. Outcome

n type na /nb loc. Y-TZP Comp. Tit. Mold. Mach. Add. Subtr. BIC RTQ P-I
√ √
Hayashi et al. [14] 26 d 156/52 f 4–96 x x NR NR NR NR x x x
√ √ √ √
Akagawa et al. [25] 4 d 12/12 md 12 x x x x NR /x x x
√ √ √
Hayashi et al. [26] 19 d 76/8 f 4–12 x x NR NR x x x x
√ √

ARTICLE IN PRESS
Chang et al. [27] 108 rb 108 t 2–24 x x NR NR x x x x x

d e n t a l m a t e r i a l s x x x ( 2 0 1 7 ) xxx–xxx
√ √ √ √
Akagawa et al. [28] 8 mo 28/28 md 52–104 x x x x x x x
√ √ √ √
Dubruille et al. [29] 9 d 24/12 md 44 x x x/NR x/NR x x x
√ √ √ √
Stanic et al. [30] 14 r 28/28 f 4–8 x x x /x NR x x x
√ √ √
Schreiner et al. [31] 12 m 24/4 f 12 x x NR NR x x x x
√ √
Scarano et al. [32] 5 rb 20/20 t 4 x x NR NR NR NR x x x
√ √ √ √
Aldini et al. [33] 20 r 40/40 f 4–8 x x x /x x x x x
√ √ √ √ √ √
Kohal et al. [6] 6 mo 24/24 m 56 x x x x x
√ √ √ √ √ √
Sennerby et al. [34] 12 rb 96/48 f/t 6 x x /x x x x
√ √ √ √ √
Hoffmann et al. [35] 4 rb 8/8 f 2–4 x x x x x x
√ √ √ √ √
Ferguson et al. [62] 15 s 108/108 p 2–8 x NR NR /x /x x x x
√ √ √ √
Depprich et al. [36] 12 m 48/48 t 1–12 x NR NR x x x x
√ √ √ √ √ √
Langhoff et al. [37] 15 s 110/110 p 2–8 x x /x /x x x x
√ √ √ √ √ √ √
Kohal et al. [5] 42 r 84/56 f 2–4 x x /x /x x x
√ √ √ √ √
Gahlert et al. [39] 15 p 30/30 m 4–12 x x x x x x
√ √ √ √ √ √
Rocchietta et al. [40] 18 rb 143/130 f 3 x x x x x
√ √ √ √ √
Lee et al. [41] 40 rb 80/80 f 3–6 x x x x x x
√ √ √ √ √
Gahlert et al. [63] 16 p 64/59 m 4–12 x x x x x x
√ √ √ √ √ √
Schliephake et al. [42] 12 m 72/36 md 4–13 x x x x x
√ √ √ √ √ √
Koch et al. [43] 6 d 48/36 md 16 x x /x /x x x x
√ √ √ √ √
Stadlinger et al. [44] 7 m 21/21 md 4 x x x x x x
√ √ √ √ √
Shin et al. [45] 5 rb 20/10 t 6 x x x x x x
√ √ √ √ √
Gahlert et al. [46] 18 m 36/34 m 4–12 x x x x x x
√ √ √ √ √
Bormann et al. [64] 17 m 136/102 m 4–12 x x x x x x
√ √ √ √ √ √
Hoffmann et al. [47] 48 rb 96/48 f 6–12 x x x /x x x

5
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Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review

– Table 2 (Continued)
Author (Ref.) Animals Implants F-Up [weeks] Bulk material Bulk proc. Surface proc.c Load. Outcome

n type na /nb loc. Y-TZP Comp. Tit. Mold. Mach. Add. Subtr. BIC RTQ P-I
√ √ √
Mai et al. [48] 6 r 6/6 c 4–8 x x NR NR x x x x
√ √ √ √ √
Moller et al. [49] 8 p 64/64 s 4–12 x x x x x x
√ √ √ √ √ √
Aboushelib et al. [50] 40 rb 60/60 f 4–6 x x /x /x x x x
√ √ √ √ √ √
Park et al. [51] 20 rb 80/60 t 4 x x x /x x x
√ √ √ √ √ √ √
Salem et al. [52] 30 rb 90/45 f 4–12 x x /x /x x x

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√ √ √ √ √ √
Chung et al. [53] 25 rb 100/16 t 4 x x x /x /x x x

d e n t a l m a t e r i a l s x x x ( 2 0 1 7 ) xxx–xxx
√ √ √ √ √ √ √
Kohal et al. [7] 56 r 112/56 f 2–4 x x /x /x x x
√ √ √ √ √ √
Delgado-Ruiz et al. [71] 6 d 51/48 md 12 x x x /x x x
√ √ √ √ √
Mueller et al. [55] 10 p 97/97 s 8–16 x x x x x x
√ √ √ √ √ √
Delgado-Ruiz et al. [54] 12 d 96/96 md 4–12 x x x x x
√ √ √ √
Hirota et al. [56] 6 rb 12/12 f/t 12 x x NR NR /x /x x x x
√ √ √ √ √
Calvo-Guirado et al. [58] 6 d 48/48 md 4–12 x x x x /x x x
√ √ √
Saulacic et al. [59] 12 m 72/72 m 1–8 x x NR NR x x x x
√ √ √ √
Gredes et al. [60] 16 p 64/64 md 12 x NR NR x x x x
√ √ √ √ √ √
Shon et al. [61] 25 rb 100/60 t 4 x x x /x /x x x
√ √ √ √ √ √
Thoma et al. [16] 6 d 48/47 md 24 x x x x x
√ √ √ √ √ √
Schierano et al. [17] 16 m 128/128 t 1–8 x x /x /x x x x
√ √ √ √ √
Montero et al. [18] 8 d 32/32 md 20 x x x /x x x x
√ √ √ √ √ √
Kim et al. [19] 16 rb 64/40 t 4 x x x /x x x
√ √ √ √ √
Igarashi et al. [20] 5 d 18/18 md 12 x x x x x x
√ √ √ √ √ √
Calvo-Guirado et al. [21] 20 rb 80/80 t 1–4 x x /x /x x x x
√ √ √ √ √ √
Calvo-Guirado et al. [21] 6 d 48/48 md 4–12 x x x x x
√ √ √ √ √
Oh et al. [22] 3 d 15/15 h 12 x x x /x x x x
√ √ √ √ √ √
Shon et al. [23] 28 rb 112/48 t 2–4 x x x /x /x x x
√ √ √ √ √ √
Chappuis et al. [15] 7 m 42/42 m 4–8 x x x x x
√ √ √ √ √ √ √
Kohal et al. [67] 28 r 56/28 f 2–4 x x /x /x x x
a
Total number of implants included in the investigation.
b
Total number of implants extracted for the review.
c
Some studies included multiple types of surface treatments; d = dog; rb = rabbit; r = rat; m = monkey; s = sheep; p = pig; m = maxilla; md = mandible; f = femur; t = tibia; s = skull; p = pelvis; c = cranium;
h = humeri; NR = not reported; loc.=location; F-Up = follow-up; Comp.=zirconia composite; Tit.=titanium; Mold.=molded; Mach.=machined; Add.=additive; Subtr.=subtractive; Load.=loading; P-
I = push-in test.
DENTAL-3042; No. of Pages 12
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Fig. 1 – Flowchart according to the PRISMA guidelines.

p < 0.02). Investigations on sheep were too sparse for individual rial. No investigation evaluating the RTQ was conducted with
analysis. rats.

3.2.2. RTQ (Fig. 3) 3.2.3. Push-in (Fig. 4)

Push-in tests were performed in a limited number of the
For the evaluation of the RTQ, included studies with imputed
included investigations (all the push-in tests were conducted
weights and implants made of zirconia or titanium were eval-
in rats’ femora). Furthermore, the insufficient amount of
uated. No data on composite materials was available. For the
standard deviation values reported in the included studies
statistical analyses, the same regression model as used for
did not allow for weighting calculations. 126 animals and
BIC analyses was applied. The results found in the included
252 implants were considered for the push-in test calcula-
literature ranged between 12 Ncm measured after six weeks
tions from 16 observations. Overall, titanium implants showed
in rabbit tibiae [34] and 240 Ncm measured after 96 weeks in
push-in values of 51.57 ± 9.11 N after the mean follow-up time.
loaded implants located in dog mandibles [54]. 302 animals
In comparison, zirconia (+2.53 N) and composite (−9.90 N)
and 1392 implants were considered for the RTQ calcula-
implants showed no significant difference (p > 0.15). Compa-
tions based on 101 observations. Overall, titanium implants
rable to the RTQ results mentioned above, smooth implant
showed a RTQ of 102.71 ± 15.98 Ncm after the mean follow-
surfaces revealed significantly reduced push-in outcomes
up time. No significant difference was found for zirconia
(−25.42 N, p < 0.01). The type of roughening (additive or sub-
implants (−7.31 Ncm, p = 0.44). In general, smooth implant sur-
tractive) did not affect the outcome (−7.53 N for subtractive
faces (−43.85 Ncm, p = 0.03) and implant loading (+40.78 Ncm,
procedures; p = 0.41). The remaining variables examined did
p < 0.01) significantly influenced the RTQ. A roughness of
not show a statistically significant influence or could not be
Ra >2 ␮m and Sa >2 ␮m resulted in a positive effect (com-
evaluated due to an insufficient amount of data.
pared to <1 ␮m and 1–2 ␮m, p < 0.03). Compared to machined
implants, molded implants revealed higher RTQ outcomes of
+41.24 Ncm. However, this difference did not reach statistical 4. Discussion
significance (p = 0.06).
Again, animal-specific analyses showed multiple sig- Systematic reviews and meta-analyses aim to gather and sum-
nificant differences. Investigations with dogs showed a marize the outcomes of multiple investigations and, therefore,
significantly reduced RTQ of −1.07 Ncm (p < 0.01) for zirco- to present a more comprehensive and conclusive outcome
nia implants compared to titanium implants and a positive as when compared to the readership analyzing the single
effect of smooth implant surfaces (+14.42 Ncm, p < 0.01) when included studies separately [65]. However, multiple types of
compared to coated ones. Contrarily, experiments in rabbits risk of bias, different study designs and non-standardized
showed a positive influence of additive surface modifications procedures of the included studies can cause difficulties in cre-
(+26.68 Ncm, p < 0.01), irrespective of the implant bulk mate- ating an overall dataset to be systemically analyzed resulting

Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
DENTAL-3042; No. of Pages 12
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Fig. 2 – Mean BIC [%] of implants installed in animals (a: overall, b: zirconia, c: zirconia composites, d: titanium) after
different healing periods [weeks]. The green spots represent single observations gathered from the included studies. Spot
size are relative to the weighting of the observations. Mean BIC increased by 0.469% per week of healing (For interpretation
of the references to color in this figure legend, the reader is referred to the web version of this article.).

in a sufficient level of evidence. Nowadays, systematic reviews
of pre-clinical animal investigations are, unfortunately, still
sparse. However, they might contribute to the quality improve-
ment of future animal based investigations and to the choice
of an appropriated animal model for specific experiments.
Systematic reviews might permit a conscious and evidence-
based transition between preclinical and clinical studies [66].
In the present work, a total of 54 full-texts were included,
and the follow ups ranged between one [36] and 143 [40] weeks
of observation after implant installation. Of the included
studies, 17 evaluated osseointegration in rabbits, 14 in pigs
(included mini pigs), 13 in dogs, six in rats and two each in
monkeys and sheep.
In the first instance, all animal species were pooled
together to assess the outcomes of interest (BIC, RTQ, push-
in). When analyzing this pooled data, a positive influence
of additive towards subtractive and machined implant sur-
faces was found for the BIC. In RTQ and push-in experiments,
machined surfaces showed significantly inferior outcomes
compared to both additive and subtractive surface texturing
procedures. Overall, no significant differences between zir-
conia, its composites and the “gold standard” titanium were
found. In conclusion, only an increased surface roughness and
implant loading were found to affect the variables of interest
when analyzing the gathered data irrespective of the animal
species.
Thereafter, all outcomes were assessed separately (i.e.,
animal specific). In contrast to the pooled dataset, a signifi-
cantly reduced BIC could be calculated for zirconia implants
installed in pigs and, likewise, a significant reduced RTQ was
found for zirconia implants installed in dogs when titanium
implants served as reference. Interestingly, the type of sur-
face post-processing method (additive or subtractive) resulted
in controversial results dependent on the selected animal
model. As an example, subtractive roughening procedures
resulted in significantly increased BIC values in pigs but in
significantly reduced values in rats and rabbits when addi-
tive procedures were used as reference. In contrast to the
general findings of a positive effect of increasing the surface
roughness, smooth implant surfaces showed superior RTQ
outcomes in experiments with dogs. These controversial find-
ings might be related to different surface treatments of the

Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
DENTAL-3042; No. of Pages 12
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Fig. 3 – Mean RTQ [Ncm] of implants installed in animals (a:
overall, b: zirconia, c: titanium) after different healing
periods [weeks]. The green spots represent single
observations gathered from the included studies. Spot size
are relative to the weighting of the observations. Mean RTQ
increased by 12.0 Ncm per week of healing (For
interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.).
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
9
Fig. 4 – Mean push-in values [N] of implants installed in
animals (not material specific) after different healing
periods [weeks]. The green spots represent single
observations gathered from the included studies. Spot size
are relative to the weighting of the observations. Mean
push-in increased by 3.14 N per week of healing (For
interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.).
modified implants but might also be accounted for by different
bone characteristics of the animals and locations. Moreover, it
is assumed that not only the animal model and/or bone loca-
tion but also the investigator itself and his specific setup might
significantly influence the results since both variables can be
considered confounded (e.g., Hayashi et al. were included with
multiple investigations using solely dog models and Hoffman
and collaborates were included with multiple investigations
using solely rabbit models). This clearly demonstrates the dif-
ficulty of directly comparing the results of single pre-clinical
animal studies and, therefore, advises the necessity of a con-
trol group and standardized methods when performing such
experiments. The obtained data seems to be solely compara-
ble within the results of the same work or with stringently
standardized and identical setups. However, such a level
of standardization is not available to date. The controversy
of some results when analyzing the dataset animal-specific
highlights the importance of human observational studies in
a second instance and shows that animal studies are liable
to give a first insight in the in-vivo performance of biomed-
ical devices but do not compensate for clinical trials before
bringing products and procedures to market maturity.
The difficulty in standardizing the setups and measure-
ments might be exemplified by the different methodologies
applied in the included studies in visualizing and measur-
ing the BIC. This value expresses the direct contact between
fixture and bone along the implant surface projected on an X-
ray in percent. Two-dimensional data of a specific section are
provided. However, the peri-implant area could offer infinite
microscopic fields available for BIC evaluation. Therefore, a
correct and unbiased pattern of histological pieces together
with the reference of their exact location at the implant
(e.g. neck, middle part, apex) is mandatory. In addition, stan-
DENTAL-3042; No. of Pages 12
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dardized techniques for image taking and processing are
recommended. In some investigations, the histomorphometic
analyses were performed in sites with different bone quality
(e.g. compact or spongy bone) as for example in the study of
Schreiner et al. [31] or at different levels of the implant body
[29]. In both cases, mean values were used for the statisti-
cal analyses of the present systematic review. In most of the
included investigations, the bone samples were cut along the
long axis of the fixture. However, in some cases they were pre-
pared transversally as in the investigation of Kohal et al. [24].
Therefore, limitations of this technique and significant differ-
ences among the used procedures have to be kept in mind.
Microcomputed tomography might be considered a valuable 3-
D alternative. However, a lower image quality and the potential
presence of artifacts have to be mentioned [67].
Since the presented overall data suggest no significant
difference in the osseointegration capacity of the included
bulk materials, future efforts might, among others, pre-
dominantly address economic aspects (production) and the
development of composite materials which are not prone to
hydrothermal aging (low temperature degradation) but are
able to transform from the tetragonal into the monoclinic
phase for enhancing transformation toughening. As an exam-
ple, injection-molding with a micro-roughened inner surface
of the mold might be capable in significantly reducing the
retail costs of ceramic dental implants compared to tool
wearing subtractive manufacturing with cost-intensive prost-
processing of the surface. Moreover, a recent project funded
by the European Community evaluated novel ceria-stabilized
zirconia-alumina-aluminate composite ceramics with dif-
ferent surface topographies [68,69]. This material showed
promising results in terms of cellular functions, bone affinity
and biofilm formation while retaining its features in terms of
mechanical properties [70]. Further research should evaluate
implants made from such composites or produced by more
economic techniques in randomized controlled equivalence
trials to verify their clinical reliability.
It is considered necessary by the authors of the present
work, to remark the importance of reporting standard devi-
ation values in the results in order to permit more accurate
statistical analyses. Unfortunately, the present screening
indicated several missing standard deviation values in the
included literature that had to be imputed as described in the
material and methods section above. This might be considered
a limitation of the present review.
A further limitation consists in the “heterogeneity” of the
variables considered. Different methods of surface characteri-
zations (e.g. laser, acid etching, and sand-blasting) or molding
techniques (e.g., powder injection molding or ceramic injec-
tion molding) were pooled in groups (e.g., “subtractive” or
“molded”). Apart from these necessary considerations, the
authors designed the review according to the available guide-
lines.
5. Conclusions
No significant differences in terms of osseointegration rate
between the included implant bulk materials could be found.
Contrarily, the animal species and surface modification
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
(i.e., increased surface roughness) seem to have significant
influence the osseointegration process. More efforts in the
standardization of animal investigation designs are needed.
Data on molded implants and new developed zirconia com-
posite materials is still scarce.
references
[1] Sandhaus S. Tecnica e strumentario dell’impianto C.B.S.
(Cristalline Bone Screw). Inf Odontostomatol 1968;4:19–24.
[2] Andreiotelli M, Wenz HJ, Kohal RJ. Are ceramic implants a
viable alternative to titanium implants? A systematic
literature review. Clin Oral Implants Res 2009;20(Suppl.
4):32–47.
[3] Piconi C, Maccauro G. Zirconia as a ceramic biomaterial.
Biomaterials 1999;20:1–25.
[4] Pieralli S, Kohal RJ, Jung RE, Vach K, Spies BC. Clinical
outcomes of zirconia dental implants. J Dent Res
2017;96:38–46.
[5] Kohal RJ, Baechle M, Han JS, Hueren D, Huebner U, Butz F.
In vitro reaction of human osteoblasts on
alumina-toughened zirconia. Clin Oral Implants Res
2009;20:1265–71.
[6] Kohal RJ, Weng D, Bächle M, Strub JR. Loaded custom-made
zirconia and titanium implants show similar
osseointegration: an animal experiment. J Periodontol
2004;75:1262–8.
[7] Kohal RJ, Bächle M, Att W, Chaar S, Altmann B, Renz A, et al.
Osteoblast and bone tissue response to surface modified
zirconia and titanium implant materials. Dent Mater
2013;29:763–76.
[8] Spies BC, Nold J, Vach K, Kohal RJ. Two-piece zirconia oral
implants withstand masticatory loads: an investigation in
the artificial mouth. J Mech Behav Biomed Mater
2016;53:1–10.
[9] Guazzato M, Albakry M, Ringer SP, Swain MV. Strength,
fracture toughness and microstructure of a selection of
all-ceramic materials. Part II. Zirconia-based dental
ceramics. Dent Mater 2004;20:449–56.
[10] Dehestani M, Adolfsson E. Phase stability and mechanical
properties of zirconia and zirconia composites. Int J Appl
Ceram Technol 2013;10:129–41.
[11] Manzano G, Herrero LR, Montero J. Comparison of clinical
performance of zirconia implants and titanium implants in
animal models: a systematic review. Int J Oral Maxillofac
Implants 2014;29:311–20.
[12] Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA
Group. Preferred reporting items for systematic reviews and
meta-analyses: the PRISMA statement. PLoS Med
2009;6(7):e1000097
https://doi.org/10.1371/journal.pmed.1000097.
[13] Sammons RL, Lumbikanonda N, Gross M, Cantzler P.
Comparison of osteoblast spreading on microstructured
dental implant surfaces and cell behaviour in an explant
model of osseointegration. A scanning electron microscopic
study. Clin Oral Implants Res 2005;16:657–66.
[14] Hayashi K, Matsuguchi N, Uenoyama K, Sugioka Y.
Re-evaluation of the biocompatibility of bioinert ceramics in
vivo. Biomaterials 1992;13:195–200.
[15] Chappuis V, Cavusoglu Y, Gruber R, Kuchler U, Buser D,
Bosshardt DD. Osseointegration of zirconia in the presence
of multinucleated giant cells. Clin Implant Dent Relat Res
2016;18:686–98.
[16] Thoma DS, Benic GI, Munoz F, Kohal R, Sanz Martin I,
Cantalapiedra AG, et al. Histological analysis of loaded
DENTAL-3042; No. of Pages 12
ARTICLE IN PRESS
d e n t a l m a t e r i a l s x x x ( 2 0 1 7 ) xxx–xxx
zirconia and titanium dental implants: an experimental
study in the dog mandible. J Clin Periodontol 2015;42:967–75.
[17] Schierano G, Mussano F, Faga MG, Menicucci G, Manzella C,
Sabione C, et al. An alumina toughened zirconia composite
for dental implant application: in vivo animal results.
Biomed Res Int 2015, http://dx.doi.org/10.1155/2015/157360
[ePub only].
[18] Montero J, Bravo M, Guadilla Y, Portillo M, Blanco L, Rojo R,
et al. Comparison of clinical and histologic outcomes of
zirconia versus titanium implants placed in fresh sockets: a
5-month study in beagles. Int J Oral Maxillofac Implants
2015, http://dx.doi.org/10.11607/jomi.3668 [Epub ahead of
print].
[19] Kim HK, Woo KM, Shon WJ, Ahn JS, Cha S, Park YS.
Comparison of peri-implant bone formation around
injection-molded and machined surface zirconia implants
in rabbit tibiae. Dent Mater J 2015;34:508–15.
[20] Igarashi K, Nakahara K, Haga-Tsujimura M, Kobayashi E,
Watanabe F. Hard and soft tissue responses to three
different implant materials in a dog model. Dent Mater J
2015;34:692–701.
[21] Calvo-Guirado JL, Aguilar-Salvatierra A, Delgado-Ruiz RA,
Negri B, Fernandez MP, Mate Sanchez de Val JE, et al.
Histological and histomorphometric evaluation of zirconia
dental implants modified by femtosecond laser versus
titanium implants: an experimental study in fox hound
dogs. Clin Implant Dent Relat Res 2015;17:525–32.
[22] Oh GJ, Ban JS, Lim HP, Yun KD, Lee KM, Vang MS, et al.
Analysis of removal torque of injection molded zirconia
implants; an experimental study on beagles. J Nanosci
Nanotechnol 2015;15:339–41.
[23] Shon WJ, Woo KM, Kim HK, Kwon HB, Shin SY, Park YS.
Time-dependent periimplant bone reaction of acidic
monomer-treated injection molded zirconia implants in
rabbit tibiae. Implant Dent 2015;24:287–93.
[24] Kohal RJ, Bachle M, Renz A, Butz F. Evaluation of alumina
toughened zirconia implants with a sintered, moderately
rough surface: an experiment in the rat. Dent Mater
2016;32:65–72.
[25] Akagawa Y, Ichikawa Y, Nikai H, Tsuru H. Interface histology
of unloaded and early loaded partially stabilized zirconia
endosseous implant in initial bone healing. J Prosthet Dent
1993;69:599–604.
[26] Hayashi K, Inadome T, Tsumura H, Mashima T, Sugioka Y.
Bone-implant interface mechanics of in vivo bio-inert
ceramics. Biomaterials 1993;14:1173–9.
[27] Chang YS, Oka M, Nakamura T, Gu HO. Bone remodeling
around implanted ceramics. J Biomed Mater Res
1996;30:117–24.
[28] Akagawa Y, Hosokawa R, Sato Y, Kamayama K. Comparison
between freestanding and tooth-connected partially
stabilized zirconia implants after two years’ function in
monkeys: a clinical and histologic study. J Prosthet Dent
1998;80:551–8.
[29] Dubruille JH, Viguier E, Le Naour G, Dubruille MT, Auriol M,
Le Charpentier Y. Evaluation of combinations of titanium,
zirconia, and alumina implants with 2 bone fillers in the
dog. Int J Oral Maxillofac Implants 1999;14:271–7.
[30] Stanic V, Aldini NN, Fini M, Giavaresi G, Giardino R,
Krajewski A, et al. Osteointegration of bioactive glass-coated
zirconia in healthy bone: an in vivo evaluation. Biomaterials
2002;23:3833–41.
[31] Schreiner U, Schroeder-Boersch H, Schwarz M, Scheller G.
Improvement of osseointegration of bio-inert ceramics by
modification of the surface — results of an animal
experiment. Biomed Tech (Berl) 2002;47:164–8.
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
11
[32] Scarano A, Di Carlo F, Quaranta M, Piattelli A. Bone response
to zirconia ceramic implants: an experimental study in
rabbits. J Oral Implantol 2003;29:8–12.
[33] Aldini NN, Fini M, Giavaresi G, Martini L, Dubini B, Ponzi
Bossi MG, et al. Osteointegration of bioactive glass-coated
and uncoated zirconia in osteopenic bone: an in vivo
experimental study. J Biomed Mater Res A 2004;68:264–72.
[34] Sennerby L, Dasmah A, Larsson B, Iverhed M. Bone tissue
responses to surface-modified zirconia implants: a
histomorphometric and removal torque study in the rabbit.
Clin Implant Dent Relat Res 2005;7(Suppl. 1):S13–20.
[35] Hoffmann O, Angelov N, Gallez F, Jung RE, Weber FE. The
zirconia implant-bone interface: a preliminary histologic
evaluation in rabbits. Int J Oral Maxillofac Implants
2008;23:691–5.
[36] Depprich R, Zipprich H, Ommerborn M, Naujoks C,
Wiesmann HP, Kiattavorncharoen S, et al. Osseointegration
of zirconia implants compared with titanium: an in vivo
study. Head Face Med 2008;4:30–7.
[37] Langhoff JD, Voelter K, Scharnweber D, Schnabelrauch M,
Schlottig F, Hefti T, et al. Comparison of chemically and
pharmaceutically modified titanium and zirconia implant
surfaces in dentistry: a study in sheep. Int J Oral Maxillofac
Surg 2008;37:1125–32.
[38] Kohal RJ, Wolkewitz M, Hinze M, Han JS, Bächle M, Butz F.
Biomechanical and histological behavior of zirconia
implants: an experiment in the rat. Clin Oral Implants Res
2009;20:333–9.
[39] Gahlert M, Rohling S, Wieland M, Sprecher CM, Kniha H,
Milz S. Osseointegration of zirconia and titanium dental
implants: a histological and histomorphometrical study in
the maxilla of pigs. Clin Oral Implants Res 2009;20:1247–53.
[40] Rocchietta I, Fontana F, Addis A, Schupbach P, Simion M.
Surface-modified zirconia implants: tissue response in
rabbits. Clin Oral Implants Res 2009;20:844–50.
[41] Lee J, Sieweke JH, Rodriguez NA, Schupbach P, Lindstrom H,
Susin C, et al. Evaluation of nano-technology-modified
zirconia oral implants: a study in rabbits. J Clin Periodontol
2009;36:610–7.
[42] Schliephake H, Hefti T, Schlottig F, Gedet P, Staedt H.
Mechanical anchorage and peri-implant bone formation of
surface-modified zirconia in minipigs. J Clin Periodontol
2010;37:818–28.
[43] Koch FP, Weng D, Kramer S, Biesterfeld S, Jahn-Eimermacher
A, Wagner W. Osseointegration of one-piece zirconia
implants compared with a titanium implant of identical
design: a histomorphometric study in the dog. Clin Oral
Implants Res 2010;21:350–6.
[44] Stadlinger B, Hennig M, Eckelt U, Kuhlisch E, Mai R.
Comparison of zirconia and titanium implants after a short
healing period. A pilot study in minipigs. Int J Oral
Maxillofac Surg 2010;39:585–92.
[45] Shin D, Blanchard SB, Ito M, Chu TM. Peripheral quantitative
computer tomographic, histomorphometric, and removal
torque analyses of two different non-coated implants in a
rabbit model. Clin Oral Implants Res 2011;22:242–50.
[46] Gahlert M, Roehling S, Sprecher CM, Kniha H, Milz S,
Bormann K. In vivo performance of zirconia and titanium
implants: a histomorphometric study in mini pig maxillae.
Clin Oral Implants Res 2012;23:281–6.
[47] Hoffmann O, Angelov N, Zafiropoulos GG, Andreana S.
Osseointegration of zirconia implants with different surface
characteristics: an evaluation in rabbits. Int J Oral Maxillofac
Implants 2012;27:352–8.
[48] Mai R, Kunert-Keil C, Grafe A, Gedrange T, Lauer G,
Dominiak M, et al. Histological behaviour of zirconia
implants: an experiment in rats. Ann Anat 2012;194:561–6.
DENTAL-3042; No. of Pages 12
ARTICLE IN PRESS
12 d e n t a l m a t e r i a l s x x x ( 2 0 1 7 ) xxx–xxx
[49] Moller B, Terheyden H, Acil Y, Purcz NM, Hertrampf K,
Tabakov A, et al. A comparison of biocompatibility and
osseointegration of ceramic and titanium implants: an
in vivo and in vitro study. Int J Oral Maxillofac Surg
2012;41:638–45.
[50] Aboushelib MN, Salem NA, Taleb AL, El Moniem NM.
Influence of surface nano-roughness on osseointegration of
zirconia implants in rabbit femur heads using selective
infiltration etching technique. J Oral Implantol
2013;39:583–90.
[51] Park YS, Chung SH, Shon WJ. Peri-implant bone formation
and surface characteristics of rough surface zirconia
implants manufactured by powder injection molding
technique in rabbit tibiae. Clin Oral Implants Res
2013;24:586–91.
[52] Salem NA, Abo Taleb AL, Aboushelib MN. Biomechanical
and histomorphometric evaluation of osseointegration of
fusion-sputtered zirconia implants. J Prosthodont
2013;22:261–7.
[53] Chung SH, Kim HK, Shon WJ, Park YS. Peri-implant bone
formations around (Ti,Zr)O(2)-coated zirconia implants with
different surface roughness. J Clin Periodontol
2013;40:404–11.
[54] Delgado-Ruiz RA, Calvo-Guirado JL, Abboud M,
Ramirez-Fernandez MP, Mate-Sanchez de Val JE, Negri B,
et al. Histologic and histomorphometric behavior of
microgrooved zirconia dental implants with immediate
loading. Clin Implant Dent Relat Res 2014;16:856–72.
[55] Mueller CK, Solcher P, Peisker A, Mtsariashvilli M, Schlegel
KA, Hildebrand G, et al. Analysis of the influence of the
macro- and microstructure of dental zirconium implants on
osseointegration: a minipig study. Oral Surg Oral Med Oral
Pathol Oral Radiol 2013;116:e1–8.
[56] Hirota M, Hayakawa T, Ohkubo C, Sato M, Hara H, Toyama T,
et al. Bone responses to zirconia implants with a thin
carbonate-containing hydroxyapatite coating using a
molecular precursor method. J Biomed Mater Res B Appl
Biomater 2014;102:1277–88.
[57] Calvo-Guirado JL, Aguilar Salvatierra A, Gargallo-Albiol J,
Delgado-Ruiz RA, Mate Sanchez JE, Satorres-Nieto M.
Zirconia with laser-modified microgrooved surface vs.
titanium implants covered with melatonin stimulates bone
formation. Experimental study in tibia rabbits. Clin Oral
Implants Res 2015;26:1421–9.
[58] Calvo-Guirado JL, Aguilar-Salvatierra A, Gomez-Moreno G,
Guardia J, Delgado-Ruiz RA, Mate-Sanchez de Val JE.
Histological, radiological and histomorphometric evaluation
of immediate vs. non-immediate loading of a zirconia
implant with surface treatment in a dog model. Clin Oral
Implants Res 2014;25:826–30.
[59] Saulacic N, Erdosi R, Bosshardt DD, Gruber R, Buser D. Acid
and alkaline etching of sandblasted zirconia implants: a
histomorphometric study in miniature pigs. Clin Implant
Dent Relat Res 2014;16:313–22.
[60] Gredes T, Kubasiewicz-Ross P, Gedrange T, Dominiak M,
Kunert-Keil C. Comparison of surface modified zirconia
implants with commercially available zirconium and
titanium implants: a histological study in pigs. Implant Dent
2014;23:502–7.
Please cite this article in press as: Pieralli S, et al. Osseointegration of zirconia dental implants in animal investigations: A systematic review
and meta-analysis. Dent Mater (2017), https://doi.org/10.1016/j.dental.2017.10.008
[61] Shon WJ, Chung SH, Kim HK, Han GJ, Cho BH, Park YS.
Peri-implant bone formation of non-thermal atmospheric
pressure plasma-treated zirconia implants with different
surface roughness in rabbit tibiae. Clin Oral Implants Res
2014;25:573–9.
[62] Ferguson SJ, Langhoff JD, Voelter K, von Rechenberg B,
Scharnweber D, Bierbaum S, et al. Biomechanical
comparison of different surface modifications for dental
implants. Int J Oral Maxillofac Implants 2008;23:1037–46.
[63] Gahlert M, Rohling S, Wieland M, Eichhorn S, Kuchenhoff H,
Kniha H. A comparison study of the osseointegration of
zirconia and titanium dental implants: a biomechanical
evaluation in the maxilla of pigs. Clin Implant Dent Relat
Res 2010;12:297–305.
[64] Bormann KH, Gellrich NC, Kniha H, Dard M, Wieland M,
Gahlert M. Biomechanical evaluation of a microstructured
zirconia implant by a removal torque comparison with a
standard Ti-SLA implant. Clin Oral Implants Res
2012;23:1210–6.
[65] Stevens KR. Systematic reviews: the heart of evidence-based
practice. AACN Clin Issues 2001;12:529–38.
[66] de Vries RB, Wever KE, Avey MT, Stephens ML, Sena ES,
Leenaars M. The usefulness of systematic reviews of animal
experiments for the design of preclinical and clinical
studies. ILAR J 2014;55:427–37.
[67] Kohal RJ, Schwindling FS, Bächle M, Spies BC. Peri-implant
bone response to retrieved human zirconia oral implants
after a 4-year loading period: a histologic and
histomorphometric evaluation of 22 cases. J Biomed Mater
Res B Appl Biomater 2016;104:1622–31.
[68] Altmann B, Karygianni L, Al-Ahmad A, Butz F, Bächle M,
Adolfsson E, Fürderer T, Courtois N, Palmero P, Follo M,
Chevalier J, Steinberg T, Kohal RJ. Implant materials:
assessment of novel long-lasting ceria-stabilized
zirconia-based ceramics with different surface topographies
as implant materials. Adv. Funct. Mater 2017;27,
http://dx.doi.org/10.1002/adfm.201770238 [ePub ahead of
print].
[69] Palmero P, Fornabaio M, Montanaro L, Reveron H, Esnouf C,
Chevalier J. Towards long lasting zirconia-based composites
for dental implants. Part I: innovative synthesis,
microstructural characterization and in vitro stability.
Biomaterials 2015;50:38–46.
[70] Reveron H, Fornabaio M, Palmero P, Furderer T, Adolfsson E,
Lughi V, et al. Towards long lasting zirconia-based
composites for dental implants: transformation induced
plasticity and its consequence on ceramic reliability. Acta
Biomater 2017;48:423–32.
[71] Delgado-Ruiz RA, et al. Implant stability and marginal bone
level of microgrooved zirconia dental implants: a 3-month
experimental study on dogs. Vojnosanit Pregl
2014;71(5):451–61.