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Received: 5 March 2019    Revised: 20 May 2019    Accepted: 20 May 2019

DOI: 10.1111/clr.13487

ORIGINAL RESEARCH

Soft tissue response to dental implant closure caps made of


either polyetheretherketone (PEEK) or titanium

Jordi Caballé‐Serrano1,2,3  | Vivianne Chappuis1  | Alberto Monje1  |


1 1,2
Daniel Buser  | Dieter D. Bosshardt

1
Department of Oral Surgery and
Stomatology, School of Dental Abstract
Medicine, University of Bern, Bern, Objective: Polyetheretherketone (PEEK) is a popular synthetic thermoplastic pol‐
Switzerland
2 ymer for medical applications, but its clinical use suffers from several limitations.
Robert K. Schenk Laboratory of
Oral Histology, School of Dental Therefore, the aim was to compare the soft tissue response to dental implant closure
Medicine, University of Bern, Bern,
caps made of PEEK or titanium as evaluated by the occurrence of multinucleated
Switzerland
3
Department of Oral and Maxillofacial
giant cells (MNGCs).
Surgery, School of Dental Material and methods: Forty‐two implants were placed in the maxilla of seven minia‐
Medicine, Universitat Internacional de
Catalunya, Barcelona, Spain
ture pigs. While commercially pure titanium (Ti) implants had a Ti closure cap, ceramic
implants made of either zirconia (Zr) or alumina‐toughened zirconia (Zr + Al) received
Correspondence
Dieter D. Bosshardt, Department of
a PEEK closure cap. Histomorphometry was performed to evaluate the number of
Oral Surgery and Stomatology, School small and large MNGCs being in contact with the PEEK or the Ti in different compart‐
of Dental Medicine, University of Bern,
Freiburgstrasse 7, 3010 Bern, Switzerland.
ments of the implant systems.
Email: dieter.bosshardt@zmk.unibe.ch Results: No histological signs of inflammation were noticed, and MNGCs were ob‐

Funding information
served on both PEEK and Ti closure caps and on all three implant types. Significantly
Dentalpoint AG in Switzerland, Grant/Award higher numbers of MNGCs were found on closure caps made of PEEK than on closure
Number: DP 2013-002
caps made of Ti on the external closure cap surface facing both soft (p = 0.0008 for
PEEK on Zr and p = 0.0016 for PEEK on Zr + Al) and hard tissues (p = 0.016 for PEEK
on Zr and p = 0.003 for PEEK on Zr + Al) as well as in the internal closure cap surface
(p = 0.014 for PEEK on Zr and p = 0.0088 for PEEK on Zr + Al). No statistically signifi‐
cant differences in the number of MNGCs were observed on the three implant types.
Conclusions: Significantly more MNGCs were in contact with PEEK than with Ti clo‐
sure caps.

KEYWORDS
abutment, dental implant, macrophage, multinucleated cell, PEEK, polyetheretherketone

1 |  I NTRO D U C TI O N Rust‐Dawicki, 1995; Kurtz & Devine, 2007). PEEK can be used to
fabricate medical implants with good chemical and physical prop‐
Polyetheretherketone (PEEK) is a semi‐crystalline colourless or‐ erties such as stability at high temperatures, resistance to corrosion
ganic thermoplastic polymer developed in 1978 (Eschbach, 2000) and stability to sterilization processes (Ma & Tang, 2014). Besides
with mechanical properties similar to human cortical bone (Wang the aforementioned favourable physical and chemical properties,
et al., 2010). PEEK was first applied in the 1980s for industrial pur‐ PEEK is biocompatible as shown in vitro (Wenz, Merritt, Brown,
poses (Feldman, 1986) and later used in the medical field (Cook & Moet, & Steffee, 1990) and in vivo in the orthopaedic arena (Rivard,

Clin Oral Impl Res. 2019;00:1–9. wileyonlinelibrary.com/journal/clr   © 2019 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
|
2       CABALLÉ‐SERRANO et al.

Rhalmi, & Coillard, 2002), not being mutagenic (Katzer, Marquardt, therefore PEEK closure caps were introduced. Nonetheless, there
Westendorf, Wening, & von Foerster, 2002), which makes PEEK a are almost no data regarding the tissue response to PEEK dental
biocompatible implant material for bone prostheses with demand‐ hardware. Therefore, the aim of the present study was to compare
ing mechanical and biological properties. However, PEEK may also the soft tissue response to dental implant closure caps made of ei‐
have some disadvantages in relation to mechanical strength, the ab‐ ther PEEK or Ti as evaluated by the presence of MNGCs.
sorption of liquids, leakage of undesirable by‐products and problems
during sterilization.
2 | M ATE R I A L A N D M E TH O DS
 PEEK is also used to produce dental materials (Cook & Rust‐
Dawicki, 1995; Kurtz & Devine, 2007) such as bone substitutes
2.1 | Animals and implants
(Wu et al., 2012). Since the 1990s (Cook & Rust‐Dawicki, 1995), a
series of studies investigating PEEK for producing dental implants Seven mature Goettinger miniature pigs with an average age of
have been published (Schwitalla & Muller, 2013). However, these 25 months (range: 22–33 months) and an average weight of 50 kg
reports focused on the osseointegration process (Poulsson et al., (range 45–60 kg) were used. Forty‐two implants were placed in
2014) and not on the integration of PEEK with the soft tissues at total, having even numbers in each group (i.e., N = 6 per group).
the histological level. In implant dentistry, PEEK is also used to The protocol was approved by the Committee for Animal Research,
fabricate soft‐tissue‐level prosthetic hardware such as implant State of Bern, Switzerland, according to the ARRIVE guidelines
prosthetic screws (Neumann, Villar, & Franca, 2014), transitional (Approval no. 53/12), using a study design that has been success‐
abutments for immediate aesthetics (Tetelman & Babbush, 2008) fully utilized in previous studies (Buser et al., 2004; Chappuis et
and healing abutments (Koutouzis, Richardson, & Lundgren, 2011). al., 2018; Saulacic, Bosshardt, Bornstein, Berner, & Buser, 2012;
A recent study analysing soft and hard tissue reactions to healing Saulacic, Erdosi, Bosshardt, Gruber, & Buser, 2014). A detailed
abutments showed no differences between Ti and PEEK (Rea et protocol of the study design, surgical procedure and animal eu‐
al., 2017). However, only histomorphometric data were reported, thanasia is described in a previous publication that used the same
not focusing on the PEEK–soft tissue interface. PEEK has also samples for the evaluation of osseointegration of dental implants
been used to fabricate frameworks or abutments of fixed dental (Chappuis et al., 2016). Animals were premedicated using keta‐
prosthesis with good chemical adhesion properties (Caglar, Ates, & mine (intramuscular [i.m.] 20 mg/kg), xylazine (i.m. 2 mg/kg), at‐
Yesil Duymus, 2018; Stawarczyk et al., 2013, 2014). Some proper‐ ropine (intravenous [i.v.] 0.05 mg/kg) and midazolam (i.v. 0.5 mg/
ties using PEEK prosthetic abutments include high rigidity and low kg) to allow intubation. Inhalation anaesthesia was performed
plaque affinity due to a high polishing capability and low porosity. with isoflurane (1.0%–1.5%). Fentanyl patches (5–10 mg/kg) and
These properties also made PEEK a suitable material for fabricating additional local anaesthesia were applied (Ultracaine, Articaine
partial removable denture frameworks (Zoidis, Papathanasiou, & 4% with epinephrine 1:200000, Sanofi‐Aventis AG) to ensure
Polyzois, 2015). intra‐ and postoperative analgesia. The animals received antibi‐
Despite favourable biomechanical properties, PEEK is biologi‐ otic prophylaxis for 3  days (Duplocillin LA, 12000 U.I./kg; MSD
cally inert (Briem et al., 2005; Wang et al., 2010), causing, for ex‐ Animal Health GmbH, Luzern, Switzerland). The present study was
ample, a low bone‐to‐implant contact (Koch et al., 2010; Kurtz & performed in three surgical phases. First, extracting the six maxil‐
Devine, 2007). Adverse tissue reactions to PEEK have also been lary incisors and allowing the sites to heal for 3 months; second,
described (Maldonado‐Naranjo, Healy, & Kalfas, 2015). In some implants were placed on one side of the maxilla, and third, after
cases, occasional and slight infiltration of inflammatory cells not 4 weeks of healing the remaining implants were placed in the con‐
characterized as a foreign body reaction were found throughout tralateral side of the maxilla following a split‐mouth design. One
a period of 3 years, when PEEK was implanted subcutaneously in implant of each type (three different types of implants) was placed
sheep (Nieminen et al., 2008). Other studies using lumbar bone spi‐ on one side of the anterior maxilla at the third surgical phase using
nal fusion devices found macrophages with occasional foreign body a systematic random protocol (Buser et al., 2004).
giant cells showing a mild chronic inflammatory response 6 months Three different dental implants were used: Ti implants made
after implantation (Toth et al., 2006). Development of multinucle‐ of commercially pure Ti (cpTi grade 4, TST, Thommen Medical
ated giant cells (MNGCs) is influenced by the surface chemistry AG—group Ti), Yttria‐stabilized zirconia with 5% yttria (Zerafil‐TZP,
and topography (Boehler, Graham, & Shea, 2011). Macrophages Dentalpoint AG—group Zr) and Alumina‐toughened zirconia with
and related cells can develop in bone and soft tissue compartments 4% yttria and 20% alumina (Zerafil‐ATZ, Dentalpoint AG—group
(Chazaud, 2014; Ginhoux & Jung, 2014; Miron & Bosshardt, 2016) Zr  +  Al). Implant sites were prepared according to the recommen‐
being a possible indicator of an inflammatory response or a foreign dations of the manufacturers. Ti implants had a Ti closure cap and
body reaction to the implanted biomaterial (Butterfield, Best, & both types of zirconia implants had a polyetheretherketone (PEEK;
Merrick, 2006; Fujiwara & Kobayashi, 2005). PEEK‐classix™ white, Invibio Ltd) closure cap. Ti closure caps were
Closure caps on Ti dental implants are made of Ti with no obvi‐ screwed, while ceramic implants were provided with press‐fit PEEK
ous complications reported in the literature. With the introduction closure caps. PEEK was pure without surface treatment. Ti and PEEK
of ceramic implants, it was not possible to use Ti closure caps and closure caps were inserted after implant placement.  Primary wound
CABALLÉ‐SERRANO et al. |
      3

closure was achieved to allow submerged healing. The animals were the internal compartment, two subregions were analysed, one being
euthanized yielding healing periods of 4 and 8 weeks. confined to the implant surface (either ceramic or Ti) and the other
one belonging to the surface of the PEEK or Ti closure caps. The dif‐
ferent regions of interest are presented in Figure 1.
2.2 | Histologic processing and analysis
The specimens were rinsed in water, dehydrated in ascending eth‐
2.4 | Statistical analysis
anol fractions, infiltrated and embedded in methylmethacrylate.
The embedded blocks were serially cut into 500‐μm‐thick ground A sample size calculation using the data from a preliminary observa‐
sections using a slow‐speed diamond saw with a coolant (Varicut® tion was performed. The pilot study revealed that there were up to
VC‐50; Leco). After mounting onto acrylic glass slides, the sections 10 times more multinucleated cells on PEEK closure caps than on
were ground to a final thickness of 80 μm (Knuth‐Rotor‐3; Struers) titanium closure caps. Using these values and establishing alpha risk
and superficially stained with toluidine blue/McNeal combined with at 0.05 and a target power of 0.8, a sample size of 6 was obtained.
basic fuchsin (Schenk, Olah, & Hermann, 1984). While checking for The arcsin approximation was used due to the presence of differ‐
the MNGCs on the biomaterial surfaces, we noticed that there were ent proportions of multinucleated cells on PEEK and on titanium.
large and much smaller MNGCs present on the different biomateri‐ Density of small cells and large cells was assumed to depend on sev‐
als. Therefore, we decided to categorize them into small (2–5 nuclei) eral categorical factors: “closure cap type” (Ti vs. PEEK on Zr implant
and large (>5 nuclei) multinucleated cells. Number of cells was nor‐ vs. PEEK on Zr + Al implant), “cell size” (small vs. large) and “healing
malized to the length of the surfaces analysed. period” (4 weeks vs. 8 weeks). Due to the number of missing values,
the full model could only be considered for the analysis of the exter‐
nal part of the cap. For the internal part of the cap, a reduced model
2.3 | Regions of interest
was used instead. In this reduced model, the factor healing period
Two major regions were delineated: (a) an external compartment was not considered. To quantify the effects of these factors on the
displaying the outer closure cap surface exposed to the surround‐ outcome, repeated‐measures ANOVA was performed according to
ing soft and hard tissues. As the external compartment was partially Brunner and Langer (Brunner & Puri, 2001). Thus, nonparametric
covered by bone after the process of osseointegration, two main methods were chosen due to the small sample size. The applications
subregions were analysed, namely bone and soft tissue regions, and used for the statistical analysis were nparLD (Noguchi, Gel, Brunner,
(b) an internal compartment represented by the area within the void & Konietschke, 2012) and exactRankTests (CRAN R‐project).
between the PEEK or Ti closure cap and the opposing dental implant For each model, a post hoc analysis was performed using Wilcoxon
surface, which was formed as a consequence of misfit. Regarding signed‐rank tests for the paired case and Mann–Whitney–Wilcoxon

(a)

F I G U R E 1   Schematic drawing of Ti
and Zr implants illustrating the different
compartments for the analysis of closure
(b)
caps made of (a) polyetheretherketone
and (b) Ti. The internal part represents
the gap between the implant connection
and the closure cap. In this gap, there
are two different surfaces, one belongs
to the implant fixture and the other to
the implant cover screw. The soft tissue
compartment represents the part of
the closure cap that is in direct contact
with the soft tissue, whereas the bone
compartment represents the part of the
closure cap, which is in direct contact with
bone
|
4       CABALLÉ‐SERRANO et al.

F I G U R E 2   Histological details of the different regions analysed on the polyetheretherketone (PEEK) closure caps. (a) Internal part of
the PEEK closure cap. (b) External compartment with bone facing the PEEK surface. (c) External compartment with tissue facing the PEEK
surface. Asterisks mark multinucleated giant cells

tests for the non‐paired case. Corrections for multiple testing were
3.1.2 | Soft tissue region
only applied in the case of significant effects. If there were no sig‐
nificant effects, the post hoc tests are of an explorative nature, and The factors “closure cap type” (p = 0.0048) and “cell size” (p = 0.0001)
thus, no corrections were performed. p‐Values < 0.05 were consid‐ reached statistical significance. Since neither the factor “healing pe‐
ered as statistically significant. riod” nor its interactions were significant, the factor “healing period”
could be pooled for the post hoc tests. Moreover, since the inter‐
action “closure cap type: cell size” was not statistically significant,
3 |   R E S U LT S the mean values of small and large cells were considered in order
to do group comparisons. Because the samples were not paired,
Healing was uneventful and without complications in all animals. Mann–Whitney–Wilcoxon tests were performed. The post hoc tests
Histologically, no signs of inflammation were noticed (Figure 2). showed a significantly lower number of MNGCs on Ti caps than on
Multinucleated giant cells were observed on all implant types and PEEK caps placed on Zr implants (p = 0.0008) and on PEEK caps
on both PEEK and Ti closure caps (Figure 2). Their number varied placed on Zr + Al implants, respectively (p = 0.0016; Figure 4).
depending on location and biomaterial.

3.2 | Internal compartment
3.1 | External compartment
3.2.1 | Closure cap surface
3.1.1 | Bone region
The factor “closure cap type” exhibited a high statistical signifi‐
In this region of interest, the factors “closure cap type” (p = 0.007), cance (p  <  0.0001). As neither “cell size” nor its interaction with
“cell size” (p = 0.0001) and the interaction amongst them (p = 0.0174) the “implant type” was significant, the mean (large and small cells)
showed statistical significances. Ti closure caps presented on aver‐ values were again considered for the group comparisons. Because
age up to 1 MNGC per surface unit, while Zr or Zr + Al closure caps the samples were not paired, Mann–Whitney–Wilcoxon tests were
contained up to 6 MNGCs per surface unit. As neither the factor performed to analyse the data. These tests showed a significantly
“healing period” nor its interactions reached statistical significance, lower number of MNGCs on Ti caps (on average up to two MNGCs
the data were pooled for the post hoc tests. For the comparison be‐ per surface unit) than on PEEK caps placed on Zr implants (on aver‐
tween “closure cap type” with “cell size,” Mann–Whitney–Wilcoxon age 9–12 MNGCs per surface unit) (p = 0.014) and on PEEK caps
tests were performed and for the comparison between “cell size” for placed on Zr  +  Al implants (on average 9–12 MNGCs per surface
the same “closure cap type” Wilcoxon signed‐rank tests were per‐ unit; p = 0.0088), respectively (Figure 5).
formed due to dependence. These tests showed a significantly lower
number of small MNGCs on Ti caps than on PEEK caps placed on Zr
3.2.2 | Internal implant surface
implants (p  =  0.016) and on PEEK caps placed on Zr  +  Al implants
(p = 0.003), respectively (Figure 3). In PEEK closure caps, a fibrous No significant effect was noted regarding “implant type,” “cell size”
layer was always observed between the biomaterial and the bone. or the interaction amongst them. Although none of the effects were
In contrast, the bone was in direct contact with the Ti closure cap. significant, post hoc tests were performed for explorative reasons.
CABALLÉ‐SERRANO et al. |
      5

F I G U R E 3   Boxplots displaying the


normalized numbers of multinucleated
giant cells in contact with the closure caps
made of Ti and polyetheretherketone
placed on either Zr or Zr+Al in the bone
region of the external compartment

F I G U R E 4   Boxplot presenting the


normalized numbers of multinucleated
giant cells at the soft tissue region in the
external compartment for the closure
caps made of Ti and polyetheretherketone
placed on either Zr or Zr+Al

F I G U R E 5   Boxplots displaying the


normalized numbers of multinucleated
giant cells on the closure caps in the
internal compartment for the closure caps
made of Ti and polyetheretherketone
placed on either Zr or Zr+Al

Because the comparison of the “implant type” was insignificant, the 4 | D I S CU S S I O N
mean values of small and large cells were considered. Because the
samples were not paired, Mann–Whitney–Wilcoxon tests were per‐ An increasing number of reports are published on the mechanical
formed. None of the p‐values for group comparisons reached signifi‐ and adhesive properties of PEEK (Uhrenbacher et al., 2014; Zoidis,
cance at the 5% level (Figure 6). Bakiri, & Polyzois, 2016; Zoidis & Papathanasiou, 2016). However,
|
6       CABALLÉ‐SERRANO et al.

F I G U R E 6   Boxplots displaying the normalized numbers of multinucleated giant cells in contact with the three implant fixtures in the
internal compartment

not much studies addressed the tissue integration or tissue response fuse between them adopting a bigger size with greater number of
to this biomaterial, especially in the dental field. To the best of our nuclei. Bigger cells exhibit, for example, a greater capacity of phago‐
knowledge, up to date there is no study reporting the interaction of cytosis possibly meaning a stronger foreign body reaction (McNally
soft tissues with PEEK utilizing quantitative and qualitative meth‐ & Anderson, 2011). Whether the higher number or size of MNGCs
ods. The present preclinical study demonstrates that MNGCs were in contact with the PEEK closure caps has a negative effect on the
present on all investigated surfaces, but in different numbers. The surrounding tissues needs to be determined. Other preclinical (Rea
results demonstrate that significantly lower numbers of MNGCs et al., 2017) and clinical (Koutouzis et al., 2011) data, however, docu‐
were found on closure caps made of Ti than on closure caps made mented no adverse effects.
of PEEK, and this was true in the external compartment facing both Polyetheretherketone is increasingly used as an implant prosthetic
soft and hard tissues as well as in the internal compartment. These hardware (Koutouzis et al., 2011; Neumann et al., 2014; Stawarczyk et
data demonstrate that the closure cap material has an influence on al., 2013, 2014; Tetelman & Babbush, 2008). In this context, another
the number of MNGCs. interesting finding in the present study was the misfit of the PEEK clo‐
The chemical and physical characteristics of an implanted bio‐ sure caps. However, this unfortunate event was rarely observed for
material have been shown to influence the tissue response, thereby the Ti closure caps. It must be taken into consideration that closure
triggering inflammation, immune response, healing, fibrous encap‐ caps made of PEEK were press‐fit and not screwed, possibly playing
sulation and, ultimately, osseointegration (Kasemo, 2002; Sridharan, a role in the poor adaptation and sealing. Dental implant abutments
Cameron, Kelly, Kearney, & O'Brien, 2015). In a recent publication, it made of PEEK reinforced with Ti have shown good in vivo results with
was shown that the surface characteristics of PEEK can modulate the adequate maintenance of crestal bone height (Mate Sanchez de Val et
bioactivity of PEEK (Ma & Tang, 2014). In vivo studies have identified al., 2016). Future studies should specifically compare misfit between
that surface topography of PEEK implants influences osseointegra‐ PEEK and Ti abutments, as misfit and leakage of prosthetic abutments
tion (Poulsson et al., 2014) and that a rough PEEK surface—as is the can negatively affect soft and hard tissues around implants (Assenza
case with Ti surfaces—favours cell attachment compared to a smooth et al., 2012; Canullo et al., 2015; Jansen, Conrads, & Richter, 1997). A
PEEK surface (Wu et al., 2012). It has been speculated that the per‐ suboptimal fitting of PEEK abutments might then lead to an accumu‐
sistence of MNGCs surrounding biomaterials at healed sites could lation of MNGCs inside the implant structure, as shown in the pres‐
be triggered by the chemical composition of the material or by its ent study, and possibly lead to the release of inflammatory molecules
surface characteristics (Kasemo, 2002; Petillo et al., 1994; Sridharan around the implant, which eventually may lead to bone resorption.
et al., 2015). Along these lines, it must be known that MNGCs can be Clinically, radiographic analysis of the fitting of prosthetic components
indicators of an inflammatory or a foreign body response to the im‐ is important to ensure a correct adaptation. The fact that PEEK is ra‐
planted biomaterial (Butterfield et al., 2006; Fujiwara & Kobayashi, diolucent (Kurtz & Devine, 2007) might represent a disadvantage in
2005). Indeed, another study found inflammatory cells in soft tis‐ implant dentistry, since it does not allow to be radiographically anal‐
sues around PEEK implants (Nieminen et al., 2008; Toth et al., 2006). ysed. In this sense, prosthetic abutments made of a composite of PEEK
In contrast, no inflammatory cells were found in the present study. with a radiopaque material could eliminate this matter.
In the present study, we have also analysed the size of the MNGCs A large number of PEEK dental products have recently been
having significant differences between groups. Under special condi‐ released without adequate biocompatibility testing. Furthermore,
tions that require a greater action by macrophages, these cells can PEEK has also gained popularity as a material for the fabrication of
CABALLÉ‐SERRANO et al. |
      7

prosthetic hardware such as CAD/CAM components, implant abut‐ AU T H O R C O N T R I B U T I O N S


ments and removable dentures. To date, the influence of this ma‐
JCS and DDB conceived the idea; VC performed the surgeries; VC,
terial on soft and hard tissues has not been fully addressed in the
DB and DDB conceived and prepared the protocol of the study.
literature. Our study presents novel data on the soft tissue integra‐
JCS collected the data and together with AM analysed it. JCS and
tion around PEEK components. The finding that higher numbers of
DDB wrote the manuscript. All authors revised and approved the
MNGCs are found on PEEK than on Ti closure caps might be the
manuscript.
primer for future research and development of new biomaterials in
dentistry with improved tissue integration. So far, an extrapolation
of these short‐term preclinical data to the human situation cannot ORCID
be made. MNGCs on dental biomaterials may be part of the nor‐
Jordi Caballé‐Serrano  https://orcid.org/0000-0003-4684-4770
mal wound healing process and therefore a transient phenomenon
(Miron & Bosshardt, 2018). In contrast to this view, MNGCs are impli‐ Vivianne Chappuis  https://orcid.org/0000-0003-1227-7587
cated in playing a role in the development of biological complications Alberto Monje  https://orcid.org/0000-0001-8292-1927
that could lead to loss of osseointegration (Trindade, Albrektsson,
Tengvall, & Wennerberg, 2016).
The present study faces some limitations. First, preclinical re‐ REFERENCES
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