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JDRXXX10.1177/0022034517740560Journal of Dental ResearchMetal Particle Release and Peri-implant Bone Destruction

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Is Metal Particle Release Associated © International & American Associations
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An Emerging Concept DOI: 10.1177/0022034517740560

https://doi.org/10.1177/0022034517740560
journals.sagepub.com/home/jdr

T. Fretwurst1,2, K. Nelson2, D.P. Tarnow3, H.-L. Wang1,

and W.V. Giannobile1,4

Abstract
Peri-implant diseases affecting the surrounding structures of endosseous dental implants include peri-implant mucositis and peri-
implantitis. The prevalence of peri-implantitis ranges between 15% and 20% after 10 y, highlighting the major challenge in clinical practice
in the rehabilitation of dental implant patients. The widespread nature of peri-implant bone loss poses difficulties in the management of
biological complications affecting the long-term success of osseointegrated implant reconstructions. Metal and titanium particles have
been detected in peri-implant supporting tissues. However, it remains unclear what mechanisms could be responsible for the elicitation
of particle and ion release and whether these released implant-associated materials have a local and/or systemic impact on the peri-
implant soft and hard tissues. Metal particle release as a potential etiologic factor has been intensively studied in the field of orthopedics
and is known to provoke aseptic loosening around arthroplasties and is associated with implant failures. In dental medicine, emerging
information about metal/titanium particle release suggests that the potential impact of biomaterials at the abutment or bone interfaces
may have an influence on the pathogenesis of peri-implant bone loss. This mini-review highlights current evidence of metal particle
release around dental implants and future areas for research.

Keywords: peri-implantitis, dental implants, titanium, nanoparticles, prosthesis failure, dental abutments

Peri-implantitis and Peri-implant conversion nor the onset of peri-implantitis is well clarified,
Bone Loss but it is suspected that the onset occurs within 2 to 3 y of
implant functional loading (Derks et al. 2016). The American
Dental implant reconstructions have proven to be a successful Academy of Periodontology states that mucositis does not nec-
treatment modality, yielding a beneficial clinical outcome for a essarily lead to peri-implantitis; however, peri-implantitis sus-
large number of patients. Implant survival rates exceed approxi- ceptibility is associated with all dental implant systems,
mately 94%, as reported in systematic reviews with at least 10 y jeopardizing implant survival and potentially leading to
of follow-up (Moraschini et al. 2015). However, high rates of implant loss (American Academy of Periodontology 2013).
peri-implantitis demand further investigation of its pathogenic Implant failures are classified as early failures if they occur
mechanisms (Derks and Tomasi 2015). A recent epidemiologic before or at prosthetic restoration, while late failures occur
review reported that every fifth inserted implant eventually after prosthetic rehabilitation (Derks et al. 2016). Others distin-
develops peri-implantitis during a mean functional loading time guish implant failure after osseointegration is initially achieved
of 3.4 to 11 y (Derks and Tomasi 2015). This wide range of peri- (late failure) or not at all (early failure; Al-Sabbagh and Bhavsar
implantitis prevalence is attributed to different case definitions 2015). Existing protocols for treatment of peri-implantitis have
(Derks and Tomasi 2015; Renvert and Quirynen 2015).
Consensus criteria for peri-implant disease include bleeding
1
and/or suppuration on gentle probing, increased probing pocket Department of Periodontics and Oral Medicine, School of Dentistry,
depths, and marginal alveolar bone loss (Lang and Berglundh University of Michigan, Ann Arbor, MI, USA
2
Department of Oral and Craniomaxillofacial Surgery, Center for Dental
2011). However, a recent consensus conference concluded that
Medicine, University Medical Center Freiburg, Freiburg, Germany
in the absence of radiographs, neither bleeding on probing nor 3
College of Dental Medicine, Columbia University, New York, NY, USA
probing pocket depth is a reliable diagnostic tool for confirma- 4
Department of Biomedical Engineering, College of Engineering,
tion of peri-implantitis (Albrektsson et al. 2016). University of Michigan, Ann Arbor, MI, USA
A reversible inflammatory process similar to gingivitis,
Corresponding Author:
termed mucositis, occurs in the peri-implant soft tissue, fol- T. Fretwurst, Department of Oral and Craniomaxillofacial Surgery,
lowed by marginal bone loss beyond physiologic bone remodel- Center for Dental Medicine, University Medical Center Freiburg,
ing designated as peri-implantitis (Lang and Berglundh 2011). Hugstetter Straße 55, D-79106 Freiburg, Germany.
Neither the direct mechanisms of mucositis-to-peri-implantitis Email: [email protected]
2 Journal of Dental Research 00(0)

2004). In contrast, others demonstrated a relationship between

surface roughness and titanium abrasion in an animal model
and found particles up to 20 nm within the peri-implant tissues.
These particles were mainly detected at the crestal region
(Meyer et al. 2006). Interestingly, in some preclinical studies,
the titanium content increases in the peri-implant tissue with
time following implant installation. The titanium content is
slightly higher after a year versus the first few weeks after
implant placement (Bianco et al. 1996; Wennerberg et al.
2004). Biocorrosion, influenced by purported implant micro-
motion, in combination with the microbial biofilm on the
implant surface seems probable, but the particle release mech-
anism remains unknown (Sridhar, Wilson, et al. 2016). A cur-
rent finding promotes the hypothesis that implant placement
alone is insufficient to trigger titanium abrasion. A simulated
surgical implant insertion could not show evidence of titanium
particles even at high torque values (>60 N·cm; Sridhar,
Wilson, et al. 2016). Conversely, an in vitro study demon-
strated damage of the titanium implant surface during implant
placement based on the recommended torque values, with cor-
responding particles of titanium (10 nm to 20 μm) in the bone
of the implantation sites (Senna et al. 2015).
A recent study demonstrated that titanium particles derived
from dental implants could activate the DNA damage response
pathway in oral epithelial cells (Suárez-López del Amo et al.
Figure 1. Potential mechanisms of peri-implant bone loss, including the
microbial biofilm, cement excess, implant malposition, and metal ion/ 2017). Also, 2 in vitro model systems showed that titanium
particle release. particles released by ultrasonic scaling of SLA surfaces can
activate the inflammatory response, resulting in an increased
secretion of IL-1β, IL-6, and TNF-α in cultured human macro-
not been standardized and are associated with high recurrence phages (Eger et al. 2017; Pettersson et al. 2017). Note that dif-
rates (Esposito et al. 2012). fering particle compositions (titanium grades 4 and 5) could be
In addition to the concept of microbial biofilm–related peri- released into the peri-implant tissues, depending location of
implantitis within a susceptible host, prosthetic, surgical, and the biomaterial origin.
biomechanical factors are considered additional trigger mecha-
nisms for peri-implant bone loss, with varying degrees of
available evidence (Canullo et al. 2015; Albrektsson et al. Human Biopsy Studies
2016; Fig. 1). The present article investigates in greater detail
Recent data regarding the biological influence of metal ions or
the potential influence of metal particle (or ion) release on peri-
particle release into peri-implant human tissue are available in
implant bone loss beyond physiologic bone remodeling, offering
dentistry. Metal-like particles have been detected in smears of
a biological perspective on a potential contributor to peri-
peri-implant mucosa from clinical samples afflicted with and
implant complications.
without peri-implantitis by using exfoliative cytology of epi-
thelial cells and macrophages, with a higher titanium concen-
tration found in peri-implantitis tissues (Olmedo et al. 2013;
Preclinical and In Vitro Findings Table 2). Two independent studies analyzed soft tissue samples
Preclinical animal studies have demonstrated that a release of from peri-implantitis subjects via SEM (scanning electron
titanium particles into the surrounding tissue, regional lymph microscopy), EDS (energy dispersive X-ray spectrometry),
nodes, and internal organs can occur during or after implant SRXRF, and PLM (polarized light microscopy) and detected
placement (Table 1; Schliephake et al. 1993; Bianco et al. metal particles (Wilson et al. 2015; Fretwurst et al. 2016; Fig.
1996; Wennerberg et al. 2004). Titanium ions were detected in 2). Titanium and metal particles were also measurable in peri-
bony tissues 12 wk and 1 y after implant placement in a rabbit implantitis bone tissues (Fretwurst et al. 2016). Pettersson et al.
model based on SRXRF (synchrotron radiation X-ray fluores- (2017) demonstrated, in human peri-implant soft tissue biop-
cence; Wennerberg et al. 2004). Other authors detected tita- sies of healthy regions and regions with mucositis and peri-
nium after initial implant placement but did not verify titanium implantitis, a titanium concentration of 7.3 to 38.9 µm with
particles in peri-implant tissue after 5 mo (Schliephake et al. ICP-MS (inductively coupled plasma mass spectrometry).
1993). A correlation between the increasing titanium surface However, the analysis did not conclude if a relationship exists
roughness and ion release from implants could not be demon- between titanium content and peri-implant inflammation. In
strated in either in vitro or in vivo studies (Wennerberg et al. implant dentistry, micrometer-sized metal particles have been
Metal Particle Release and Peri-implant Bone Destruction 3

Table 1. Preclinical and In Vitro Findings.

Implant: Location,
Test:Control Loading, Duration,
Study, Type (n) Animal Model Type Sample Type Methods Results Particle Size Ti Concentration

Schliephake 4:2 Gottinger Mandible; none; Lung, liver, SEM, BSD, Significantly higher contents Rounded solid Lungs:
et al. 1993, minipig immediate kidney, and EDX, of Ti within all the particles, 135.7 ng/mg,
in vivo specimen peri-implant GF-AAS examined organs in 15 × 30 µm; liver:
harvesting, 5 mo; bone tissue the test group; various flat particles, 11.5 ng/mg,
Ti screw tabs and sizes of Ti particles 10 × 10 × kidneys:
fixtures were detected within 0.5 µm 2.92 ng/mg
the bone samples
obtained immediately
after implantation; no Ti
particles detection 5 mo
after implant placement.
Bianco et al. 21:5 New Zealand Tibia; none; 1, 4, 12 Muscle and bone GF-AAS Significantly higher Ti N/A Local muscle:
1996, in white mo; Ti fiber felt tissue from in concentrations measured 27.5 to
vivo rabbit (Tifelt) the vicinity of in the local tissues 31.4 ng/g;
the implant of the test group; Ti local bone:
concentration increase 485 to
with time after implant 742 ng/g
placement.
Frisken et al. 12:4 Sheep Mandible; none; 1, Lymph node, AAS No significant differences of N/A Failed implants:
2002, in 4, 8, to 12 wk; lung, spleen, Ti content in comparison 1719 ng/gm at
vivo single self-tap and liver test versus control group 4 wk
Mark II implants tissue in any organ; significantly 2882 ng/gm
(10 × 3.75 mm; higher contents of Ti in at 8 to
Nobel Biocare) lymph nodes and lungs 12 wk (lymph
of 2 sheep with failed nodes)
implants.
Franchi et 2 sheep, 28 Sheep Femur and tibia; Bone tissue SEM, BSD, Detachment of wear debris 30 to 60 µm N/A
al. 2004, implants, none; immediate adjacent to SE from TPS implants (TPS)
in vivo no specimen the implant occurred immediately
control harvesting, 14 d; after insertion.
Conic Ti implant
screws (3.8 × 8
mm), 4 surface
topographies
Wennerberg 16 (in vivo), New Zealand Tibia; none; 3, Bone tissue SRXRF, SIMS Tissue concentrations of N/A Ion relesae: 20
et al. 2004, 6 (in white 12 mo; Ti adjacent to titanium decrease with to 100 ppmw
in vivo, vitro) rabbit screws (grade the implant increasing distance to
in vitro I) 4 surface the implant surface;
topographies differences in surface
topography do not
correlate with release of
titanium.
Meyer et al. 2 Gottinger Mandible; none; Bone tissue SEM-EDS Overall amount of Ti Small angular N/A
2006, minipig 1 d; cylindrical adjacent to contamination in peri- or round
in vivo screw-type ITI- the implant implant bone was highest elongated
SLA; cylindrical near TPS implants, particles near
ITI-TPS implant; followed by SLA and ILI SLA or ILI,
conical-type implants. Ti particles large and
implant (ILI) were located more oval shaped;
crestal and less in the particles near
apical region. TPS
Sridhar, 16 implants/ N/A N/A; None; Sawbone blocks Digital optical Exfoliated materials N/A N/A
Wilson, control immediate (polyurethane microscopy, deposited on the
et al. blocks removal; foam) XRD osteotomy walls, but
2016, Straumann SLA XRD did not show
in vitro (4.8 × 7.0 mm any presence of metal,
and 4.1 × 6 mm) specifically Ti or other
alloys. Different sawbone
densities showed similar
diffraction patterns.

AAS, atomic absorption spectroscopy; BSD, back-scattered electron detector; EDS, energy-dispersive spectroscopy; EDX, energy-dispersive X-ray
spectroscopy; GF, graphite furnace; SE, secondary electron detector; SEM, scanning electron microscope; N/A, not available; SIMS, secondary ion mass
spectroscopy; SRXRF, synchrotron radiation X-ray fluorescence; TPS, titanium plasma sprayed; XRD, powder X-ray diffraction; Ti, titanium.

identified within or near macrophages, but no correlation The source of the metal particles or ions has not yet been
between the amount of titanium/metal content and the specific- fully elucidated; however, there are several potential release
ity of the immune reaction has been shown (Olmedo et al. mechanisms under consideration. Plausible causes for metal
2013; Fretwurst et al. 2016). ion and particle release are mainly mechanical: wear debris
4 Journal of Dental Research 00(0)

Table 2. Analysis of Human Peri-implant Biopsies.

Particle
Test: Peri- Implant Type Location of Location? /
Control Sex/Age implantitis Implant and Quality the Implant Particle Titanium Localization
Study, Type (n) Stated? Present? Duration of Ti Stated? Stated? Sample Type Methods Particle Size Composition Concentration Possible?

Safioti 20:20 Yes/yes Yes 7.95 ± 4.59 y No N/A Submucosal ICP-MS — — 48.73 ng/µL No/no
et al. 2017, plaque
retrospective (human)
cohort study
Fretwurst 12:1 Yes/yes Yes N/A Yes Yes Bone, PLM, SRXRF — — — Yes/yes
et al. 2016, soft tissue
retrospective (human)
cohort study
He et al. 2016, 7:6 Yes/yes N/A N/A No Yes Bone ICP-OES, 0.5 to 40 µm — 1,940 µg/kg Yes/yes
postmortem (human) LA-ICP-MS,
study SEM, EDX
Wilson 36:N/A N/A Yes N/A N/A N/A Soft tissue LM, SEM, 9 to 54 µm 2% to 43% Ti — Yes/yes
et al. 2015, (human) EDX
retrospective
cohort study
Olmedo 153:N/A Yes/yes No 6 mo Yes N/A Soft tissue LM, SEM, 0.9 to 3 µm2 — — Yes/yes
et al. 2012, (human) EDX
retrospective
cohort study
Olmedo 15:15 Yes/yes Yes N/A Yes N/A Gingival LM, ICP-MS — — 2.02 to 2.44 Yes/no
et al. 2013, smear ppb
retrospective (human)
cohort study
Olmedo 10:0 N/A No N/A N/A N/A Bone, LM, EDX 1 to 3 µm — — Yes/yes
et al. 2003, soft tissue
retrospective (human)
cohort study

EDX, energy-dispersive X-ray spectroscopy; ICP, inductively coupled plasma; LA, laser ablation; LM, light microscopy; MS, mass spectrometry; N/A,
not available; OES, optical emission spectrometry; PLM, polarized light microscopy; SEM, scanning electron microscope; SRXRF, synchrotron radiation
X-ray fluorescence; Ti, titanium.

from the implant-abutment connection, the initial implant implant-abutment interface and widens the microgap, allowing
placement by mechanically stripping off from the implant sur- dislocation of wear particles into the peri-implant tissue. Based
face, particle release from dental restorations, or manipulations on energy-dispersive X-ray spectroscopy analysis, metal par-
during peri-implant surface treatment (Olmedo et al. 2013; ticles identified in the peri-implant tissues were discovered to
Blum et al. 2015; Fretwurst et al. 2016; Sridhar, Abidi, et al. be the same composition as the actual dental implant (Rack et
2016). Besides mechanical sources, biocorrosion, defined as al. 2010; Blum et al. 2015; Fretwurst et al. 2016). These find-
electrochemical deterioration of the implant surface, has been ings suggest a continuous particle release under force transmis-
thought to be a possible source of particle release (Bianco et al. sion at the implant-abutment connection, in contrast to the
1996). Although titanium is highly resistant to corrosion due to wear particles generated during implant installation. The local-
its oxidization potential, the acidic environment within the oral ization of the implant-abutment connection within the peri-
cavity increases corrosion susceptibility (Ishii et al. 2002). implant tissues (i.e., the implant insertion depth) may influence
the impact of the particle release into the surrounding peri-
implant structures. Finally, it remains uncertain whether the
Implant-Abutment Connection metal ions or particles released from fatigue-loaded dental
Hypothesis implants have a local and/or systemic impact in the peri-
A present hypothesis assumes that wear particles are formed at implant tissue, since a recent human cadaver study found tita-
the implant-abutment interface and subsequently released into nium particles around osseointegrated unaffected implants (He
the peri-implant tissue by infiltrating the microgap between the et al. 2016).
implant and abutment. Whether these particles can induce a spe-
cific cellular response remains unclear (Fig. 2; Fretwurst et al. Aseptic Loosening in Orthopedics:
2016).
Relevance to Dental Implants?
Several reports demonstrate that wear debris is formed due
to mechanical stress at the implant-abutment interface (Klotz Total joint replacements are a predictable rehabilitation method
et al. 2011; Stimmelmayr et al. 2012; Blum et al. 2015). Blum with favorable long-term success (Holt et al. 2007). The sur-
et al. (2015) showed that micromovement of the abutment dur- vival rates are 85% after 25 y of follow-up, with only 7% of all
ing mastication (force application) generates wear debris at the revisions in orthopedics caused by infection (Bitar and Parvizi
Metal Particle Release and Peri-implant Bone Destruction 5

2015; Magone et al. 2015). The most common reason for revi-
sion is aseptic loosening, a local periprosthetic osteolysis
around joint replacements triggered by wear debris in the
absence of bacteria, an inherently mechanical problem
(Marshall et al. 2008). The onset of osteolysis generally occurs
5 y after orthopedic implantation (Harris 2001; Hallab and
Jacobs 2009; Lohmann et al. 2014). Released elements consist
of titanium or other metals (e.g., Fe, Cr, Mo), ceramics (e.g.,
Al2O3, ZrO2), or polyethylene (e.g., HCLPE, XL-PE), since
hard-on-hard surfaces (e.g., metal on metal, ceramic on
ceramic) and hard-on-soft surfaces (e.g., metal on polyethyl-
ene, ceramic on polyethylene) are primarily used for total hip
replacements (Hjorth et al. 2014; Bitar and Parvizi 2015). In
this context, various modifications of endoprostheses and sur-
gical techniques have been established to reduce wear (Holt
et al. 2007). Wear debris occurs at the articulating region,
either at the bone-implant interface or the bone-cement inter-
face, with particle sizes ranging between nanometers and mil-
limeters depending on implant design and material (Holt et al.
2007; Hallab and Jacobs 2009; Bitar and Parvizi 2015). Grosse
et al. (2015) demonstrated particle sizes of 0.1 to 6.4 μm for
uncemented prostheses. The authors also demonstrated that the
number of particles was correlated with the cell composition
and grade of inflammation. It is assumed that next to metal
particle size, shape, concentration, and composition, the corro-
sion properties, chemical reactivity, and host response all affect
the local immune response (Lohmann et al. 2014; Bitar and
Parvizi 2015). Although all released particles and particle mix-
tures are able to stimulate an immune response, there is insuf-
ficient evidence to support whether particle composition has a
significant impact or not (Holt et al. 2007; Obando-Pereda
et al. 2014; Bitar and Parvizi 2015). Currently, the pathologic
mechanisms on how the body responds to these particles are
not fully understood. The immune response is largely influ-
enced by cytokines, chemokines, growth factors, and/or cell
types (e.g., macrophages, fibroblasts, foreign body giant cells,
lymphocytes) associated with local tissue destruction (Holt et al.
2007). Essentially, macrophage- and lymphocyte-dominated
and mixed immune reactions of aseptic loosening are differen-
tiated states (Lohmann et al. 2014). Phagocytic cells, such as
macrophages and multinucleated giant cells, phagocytize par-
ticles size dependently such that multinucleated giant cells
occur in the vicinity of metal particles ≥10 μm (Holt et al.
2007; Grosse et al. 2015). Macrophages however, are known to Figure 2. Proposal of a metal particle release hypothesis for peri-
be sensitive to submicron-sized particles (Holt et al. 2007; implant disease initiation and progression. (A) Model of mechanism
Obando-Pereda et al. 2014). Macrophages in contact with of metal particle release and elicitation of reaction to debris and
stimulation of soft and hard tissue destruction. (1) Occlusal loading.
orthopedic titanium wear particles express increased levels of (2) Micromovement of the abutment. (3) Wear particles formation
mRNA for toll-like receptors (especially TLR4) and their intra- at the implant-abutment interface. (4) Wear particle release into the
cellular adaptors (MyD88, TRIF, NF-κB), proinflammatory peri-implant tissue by infiltrating the microgap between the implant and
cytokines (TNF-α, IL-1β, IL-6), and growth factors (M-CSF, abutment. (B) Polarized light microscopy of harvested peri-implantitis
tissue in close proximity of the implant-abutment connection. Several
GM-CSF, VEGF; Holt et al. 2007; Pajarinen et al. 2013; configured and sized metal particles are detectable (arrows). Staining:
Obando-Pereda et al. 2014). The proinflammatory cytokines CD 68, clone PGM1. Reprinted with permission from Fretwurst et
TNF-α, IL-1β, and IL-6 induce osteoclastogenesis and inhibit al (2016). (C) Corresponding SRXRF (synchrotron radiation X-ray
fluorescence) line scans for titanium of the same sample. The spot size
osteoblastogenesis through the RANK-RANKL pathway and (resolution) is 100.0 × 100.0 μm2. The y-axis shows different gradings
consequently lead to bone resorption around joint replace- (counts norm). The blue line marks titanium peaks above the 400-count
ments (Obando-Pereda et al. 2014). Bitar and Parvizi (2015) threshold; high titanium content is marked in red.
6 Journal of Dental Research 00(0)

addressed cytokine-mediated osteolytic changes elicited by implant surfaces, is not fully understood and requires further
macrophages and reactive oxygen intermediates (peroxide and investigation. Future studies should seek a better understand-
nitric oxide), lysosomal enzymes (matrix metalloproteinases ing of the influence of metal particle release on peri-implant
and collagenases), and activation of the complement cascade bone destruction.
as factors affecting bone metabolism around endoprostheses.
Hence, the findings at the implant-abutment interface of dental Author Contributions
implants suggest similarities to metal-on-metal contacts asso- T. Fretwurst, W.V. Giannobile, contributed to conception, design,
ciated with aseptic implant loosening in orthopedics. However, data acquisition, analysis, and interpretation, drafted and critically
dental implants are within a transmucosal environment con- revised the manuscript; K. Nelson, contributed to conception,
nected with the oral cavity via the peri-implant sulcus. Hence, design, and data acquisition, critically revised the manuscript;
dental implants cannot be directly compared with a “closed D.P. Tarnow, H.-L. Wang, contributed to conception, critically
system” in with orthopedic metallic implants. revised the manuscript. All authors gave final approval and agree
to be accountable for all aspects of the work.
Metal Particles and Microbial Biofilms
Acknowledgments
Peri-implantitis is seen primarily as a polymicrobial disease
with a mixed flora and high proportions of gram-negative This work was supported by a research fellowship to T.F. by the
Osteology Foundation, Lucerne, Switzerland. The authors declare
anaerobes (Belibasakis 2014). Bacteria are detectable within
no potential conflicts of interest with respect to the authorship and/
30 min after implant placement at the implant surfaces. The
or publication of this article.
bacterial composition and profile of peri-implantitis lesions
remain inconsistent, and recent studies indicate mixed micro-
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