Periodontology 2000, Vol. 68, 2015, 168–181 © 2015 John Wiley & Sons A/S.
amp; Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Animal models for peri-implant
mucositis and peri-implantitis
F R A N K S C H W A R Z , A N T O N S C U L E A N , S T E V E N P. E N G E B R E T S O N , J UR
& MARTIN SAGER
Peri-implant mucositis describes an inflammatory
lesion that is found in the mucosa and represents the
host response of the peri-implant soft tissues to bac-
terial challenge. At peri-implantitis sites, the lesion
also affects the supporting bone (39). The key charac-
teristic in the diagnosis of peri-implant mucositis is
bleeding upon gentle probing. In contrast, peri-im-
plantitis is characterized by changes in the crestal
bone level in conjunction with bleeding on probing
and pus formation, with or without concomitant
deepening of peri-implant pockets (39).
The results of animal experiments suggest a
cause-and-effect relationship between microbial
plaque colonization and the pathogenesis of peri-
implant disease by means of an experimental
breakdown of the supporting soft and hard tissues
(40, 43). In this experimental model, peri-implant
mucositis is established using varying periods of
undisturbed plaque accumulation (9, 16), and peri-
implantitis lesions are initiated by the additional
placement of ligatures around the implant neck in
a submucosal position. This resulted in a plaque-
associated progressive inflammation and subse-
quent rapid breakdown of the peri-implant soft
and hard tissues (40, 43).
This specific defect model was originally described
by Rovin et al. in 1966 (67), and was proven to cause
microorganism-associated, progressive periodontal
lesions in rats. In the following years, this principle
has been successfully adopted to investigate the path-
ogenesis of periodontal diseases in larger animals,
such as monkeys (35) and dogs (17). Since the early
1990s, the “ligature-induced” defect model has also
became a standard experimental model to investigate
both the pathogenesis and the therapy of peri-
implantitis (77) (Table 1).
168
PERIODONTOLOGY 2000
€ GEN BECKER
Animal selection
The available literature reporting on experimental
studies aimed at investigating the pathogenesis and
therapy of both peri-implant mucositis and peri-im-
plantitis commonly employ large animal models.
These mainly include canine models, but also include
nonhuman primate and swine (mini pig) models
(Table 1).
Dogs
Most breeds of dog (e.g. Beagles, Foxhounds, or
Labradors), exhibit a natural susceptibility to peri-
odontitis (98). Whilst periodontal health can be main-
tained with meticulous plaque control, the induction
of progressive inflammatory reactions in the peri-
odontal tissues correlates with undisturbed plaque
accumulation, which may be accelerated by a soft-
food diet and the submarginal placement of ligatures
(17, 44). These findings have been successfully trans-
ferred to the study of peri-implant tissues (9, 16, 43).
Accordingly, the canine model is the large-animal
model most frequently used to investigate either the
pathogenesis or treatment of peri-implant disease
(20, 66). Probably because of their docile character,
convenient size and ease of maintenance, Beagle
dogs are most commonly employed in dental studies
(Table 1). The macro- and microstructure of canine
bone is moderately similar to that of human bone;
however, bone composition (i.e. the water, organic,
volatile inorganic and ash fractions) of dogs (and pigs;
discussed later) is very similar to that of humans. It is
important to emphasize that bone remodeling in the
canine mandible has been reported to be twofold
greater than that in the maxilla (51% per year vs.
 Animal models for peri-implant disease

25.5% per year, respectively), and remains elevated

mucositis to peri-implantitis lesions

with animal age (28), whilst still being moderately

Does not closely resemble naturally

similar to that of human bone (1.5–2.0 lm/day for

Tendency toward spontaneous

dog vs. 1.0–1.5 lm/day for human) (60). The specific

occurring lesions in humans

anatomic characteristics of the canine jaw bone usu-

configuration and sizes

Nonstandardized defect
ally facilitate the insertion of common dental

Technically demanding
Rapid conversion from
implants (e.g. length = 10 mm; diameter = 3–4 mm).

Time consuming
In addition, a potential advantage of most dogs is
Disadvantages

regeneration
their ease of management during postoperative oral
hygiene procedures, thus facilitating infection con-
trol. This issue is particularly relevant in the ligature-
induced peri-implantitis defect model (78).
naturally occurring lesions in
peri-implantitis Bone defects

Nonhuman primates
(dogs) seemed to resemble

spontaneous regeneration
Less time consuming than
Configuration and sizes of

Standardization of defect
configuration and sizes
It is well known that nonhuman primates possess sim-
No tendency toward

ilar oral structures to humans and also exhibit natu-

ligature induction

rally occurring bacterial plaque biofilms and a

humans (76)

susceptibility to develop gingivitis. Interestingly, in the

Advantages

case of undisturbed accumulation of plaque, sponta-

neous progression of the inflammatory cell infiltrate
N/A

and subsequent ongoing attachment loss was found

to be limited to implants and ankylosed teeth and did
not occur in relation to control teeth exhibiting an
Animal species
Table 1. Pre-clinical large-animal peri-implant mucositis and peri-implantitis defect models

intact periodontal ligament (71, 72, 74). Accordingly,

Nonhuman

Nonhuman
primate

primate

nonhuman primates (i.e. macaque, baboon and cyno-

Mini pig
Canine

Canine

Canine

molgus macaque) have been frequently employed for

studies on the pathogenesis and treatment of peri-
implant disease. However, the specific anatomic char-
(mainly circumferential)

defect components (76)

acteristics of the nonhuman primate jaw bone do

Circumferential (33, 34)

require the insertion of diameter-reduced dental

implants. As a result of strict regulatory requirements,
+ Supracrestal

Dehiscence (89)

demanding acquisition and maintenance costs as well

Defect type

as difficulties in controlling postsurgical infections

Intrabony

and trauma (98), nonhuman primates are nowadays

rarely used in dental research (78).
N/A

Surgically created acute defects

Mini pigs
Acute/chronic disease model

Secondary plaque infection

The development of miniature pigs and micro pigs

Ligature-induced lesions

Ligature-induced lesions
Chronic disease model

Chronic disease model

has overcome some potential disadvantages com-

at titanium implants

monly encountered with domestic pigs (i.e. rapid

Plaque formation

growth rate, excessive body weight and demanding

Characteristics

manageability). Both the macro- and microstructure

of pig bone are moderately similar to those of human
bone. Most similarities between pig and human bone
were observed for either bone composition or bone
remodeling (1.2–1.5 lm/day for pig vs. 1.0–1.5 lm/
Peri-implantitis

Peri-implantitis

day for human) (60). Accordingly, miniature pig

Peri-implant

and micro pig animal models are frequently used to

mucositis

evaluate the safety and efficacy of biomaterials related

Model

to implant dentistry. At the current time, the ligature-

induced peri-implantitis defect model has only been

169
 Table 3. Pre-clinical ligature-induced peri-implantitis defect models

Model Objectives Methodology Healing Healing period II Active breakdown Progression Bone loss
period I period period

Canine Pathogenesis* (3, 4, 8, 12, Clinical observations, histological 13.2  7.7 Two-part implant: 12.0  5.0 weeks 21.1  19.9 41.6  16.1%†
22, 24, 38, 41–43, 50–52, observations, immunological weeks Submerged = 13.4  Ligature exchange: weeks†
56, 76, 80, 81, 85, 90, 91, analysis, microbiological analysis, 2.8 weeks 3.6  1.5
97, 100, 102) radiological analysis Abutment = 8.6 
6.5 weeks
One-part implant:
13.2  4.0 weeks
Therapy‡ (5, 13, 14, 18, 23, Clinical observations, histological 13.2  7.7 Two-part implant: 14.4  6.2 weeks 2.3  3.1 41.1  14.4%†
26, 30, 31, 34, 46, 47, 49, observations, microbiological weeks Submerged = Ligature exchange: weeks†
55, 57, 59, 61–64, 75, 79, analysis, radiological analysis 13.2  2.7 weeks 2.4  2.5
82–84, 88, 99) Abutment = 8.8 
6.3 weeks
One-part implant:
13.2  4.0 weeks
Nonhuman Pathogenesis* (2, 15, 25, Clinical observations, histological 3.0  0.0 Two-part implant: (96) 30.0  13.2 weeks† 0.7  1.5 27.0  16.3%†
primate 29, 40, 71–74, 96) observations, microbiological weeks† Submerged = 12 weeks Ligature exchange: weeks†
analysis, radiological analysis Abutment = 2.8  3.3†
20 weeks
Therapy‡ (21, 25, 68–70) Clinical observations, histological 59.0  19.0 weeks† 3.5  0.5 37.5  12.5%†
One-part implant:
observations, microbiological Ligature exchange: weeks†
11.4  5.4 weeks†
analysis, radiological analysis 16.0  6.0†
Swine Pathogenesis* Clinical observations, 3.5  0.5 Two-part implant: 45 days No Not indicated
(27) microbiological analysis, weeks† Submerged = 8 weeks Singular ligature
radiological analysis Abutment = 2 weeks application
Therapy‡ Clinical observations, 6 weeks No Not indicated
(86) histological observations Singular ligature
application
Values are given as n or mean  standard deviation.
*Available studies assessing the pathogenesis of peri-implantitis.
†Calculated from the data provided in the original papers.
‡Available studies assessing treatment of peri-implantitis.

173
Animal models for peri-implant disease
 Animal models for peri-implant disease

to 2.3  0.8 volume%), leukocytes (0.6  0.4 volume

% to 7.7  2.6 volume%) and residual tissue

Bone
loss

No

No
(4.9  1.5 volume% to 35.7  4.3 volume%) (9). The
effects of long-standing plaque accumulation at

Progression
90 days were assessed by Ericsson et al. (16). In com-
parison with gingivitis lesions established at natural

period
teeth, the apical extension of the inflammatory cell

No

No
infiltrate was observed to be more pronounced in the
peri-implant mucosa, but was still separated from the

period of 6 weeks, 29 silk ligatures for 4 weeks

adjacent bone by an intact subepithelial connective
tissue (19). Despite many similarities, the composi-

Undisturbed plaque formation during a

tion of the inflammatory cell infiltrate at teeth and

during a period of 17.2  11.0 weeks†

implants differed in regard to the percentage of fibro-
blasts (7.3% > 3.4%), lymphocytes (1.2% > 0.5%),

Silk ligatures for 4 months (41)

Undisturbed plaque formation
polymorphonuclear leukocytes (1.6% > 1.1%) and
residual tissue (33.4% > 42.5%) (16). At 9 months, the

Active breakdown period

height of the peri-implant mucosa was reduced at
inflamed sites compared with healthy sites (3.5 mm
vs. 4.1 mm, respectively), whereas the length of the
junctional epithelium was almost the same in both
groups (2.3 mm vs. 2.4 mm, respectively). The exten-
sion of the inflammatory cell infiltrate was about
0.9 mm and was still separated from the implant-sup-
porting alveolar bone (19). After 5 and 6 months of

22.0  10.3 weeks†

undisturbed plaque accumulation, these histopatho-
logical characteristics did not differ between one- and Healing period II
two-part implant systems or abutments exhibiting
Table 2. Pre-clinical peri-implant mucositis model: canine and nonhuman primate

different surface roughnesses (1, 101).

90 days
Only one animal study has focused on the therapy
of peri-implant mucositis. Peri-implant mucositis
lesions were induced in nonhuman primates by stop-
12.7  1.5 weeks†
Healing period I

ping the plaque-control regimen, which was followed

by an interrupted application of silk ligatures over a
period of 4 weeks (92). This was associated with a sig-
12 weeks

nificant increase in mean probing pocket depths and

clinical attachment levels. Histomorphometrical mea-
surements revealed a distance between the apical
*Available studies assessing the pathogenesis of peri-implant mucositis.
observations/analysis,

extension of the junctional epthelium and the bone

observations/analysis
Clinical observations/

Clinical observations/
analysis, histological

analysis, histological
radiological analysis

‡Available studies assessing treatment of peri-implant mucositis.

crest of 0.73  0.38 mm. This area was mainly char-

acterized by inflammatory cells (57.4  7.74 volume
†Calculated from the data provided in the original papers.
Methodology

%), but also by a noninfiltrated connective tissue

(38.7  59.3 volume%) (92).
Values are given as n or meanstandard deviation.

At the current time, studies on how well-established

experimental mucositis lesions in animals may mimic
the histopathological characteristics of naturally
(1, 9, 16, 19, 41, 73, 101)

occurring lesions in humans are lacking (39) (Table 2).

Animal models for peri-implantitis

Pathogenesis*
Objectives

Therapy‡

The vast majority of pre-clinical data reporting

(92)

on either the pathogenesis or the therapy of

peri-implantitis are based on the ligature-induced

171
Schwarz et al.
defect model (77). Most research studies on the patho-
genesis of ligature-induced peri-implantitis (n = 22)
used the dog as the experimental animal of choice (3,
4, 8, 12, 22, 24, 38, 41–43, 50–52, 56, 76, 80, 81, 85, 90,
91, 97, 100, 102). Although nonhuman primates were
employed in 10 studies (2, 15, 25, 29, 40, 71–74, 96),
only one publication has reported on a micro-pig
model (27) (Table 3). Similarly, most studies (n = 28)
have employed the dog for research on the treatment
of peri-implantitis (5, 13, 14, 18, 23, 26, 30, 31, 34, 46,
47, 49, 55, 57, 59, 61–64, 75, 79, 82–84, 88, 99). Nonhu-
man primates have been used in four studies (21, 25,
68–70), and one publication has reported on micro
pigs (86) (Table 3).
Only one publication reported on the use of surgi-
cally created buccal dehiscence-type defects at tita-
nium implants, which were subsequently infected with
plaque by the application of a stainless-steel mesh (89).
Even though this disease model is less time consuming
than a ligature-induced bone resorption around tita-
nium implants, these specific defects do not closely
resemble naturally occurring lesions in humans
(Table 1). In contrast, the configurations and sizes of
ligature-induced peri-implantitis bone defects (76), as
well as the associated microflora in dogs (56), seemed
to closely resemble naturally occurring lesions in
humans. Accordingly, this pre-clinical model may be
indicated until more definitive studies in humans are
ethically justified. In this context, one must keep in
mind the potential clinical relevance of experimentally
induced chronic-defect models as they feature no ten-
dency toward spontaneous regeneration (102) and
therefore possess similarities to the biological environ-
ment of a true peri-implantitis lesion. However, a
potential disadvantage is related to difficulties in stan-
dardizing the configuration and size of the defects (i.e.
Class I and Class II defect components) subsequent to
the chronification period (76) (Table 1). This may be
particularly true for the horizontal dimension of the
adjacent alveolar bone, which has been reported to be
an important determinant of bone regeneration (65).
An evaluation of the available literature on animal
studies of the pathogenesis and treatment of peri-im-
plantitis clearly revealed that the methodological
approaches varied considerably among these publica-
tions, thus implying that a standardized protocol is still
lacking (Table 3) (78).
Surgical procedure
The basic methodological procedure of the ligature-
induced peri-implantitis defect model includes the
following phases:
172
 tooth extraction.
 healing period I.
 placement of endosseous implants.
 healing period II (plaque control).
 implant uncovering + healing period III (plaque
control) for two-part implants and a submerged
healing procedure.
 active breakdown period: ligature placement
(undisturbed plaque accumulation).
 progression period: after ligature removal (plaque
control).
Tooth extraction
Dogs commonly exhibit a permanent dentition
including three incisors, one canine tooth, four pre-
molars and three molars in the mandible (two molars
in the maxilla). In most studies, the mandibular pre-
molar (P1-P4) and molar (M1) regions were defined
as the primary experimental units. As the alveolar
bone height and width in the upper jaw is usually
under-dimensioned in the molar region (M1–M2),
these areas were usually not considered for this
experimental model.
Nonhuman primates exhibit deciduous and perma-
nent dentitions similar to those of humans. However,
the tooth size of nonhuman primates is considerably
smaller than the tooth size of humans and therefore
most authors also defined the mandibular premolar
(P1-P2) and molar (M1-M2) regions as primary exper-
imental units.
The pig dentition includes three incisors, one
canine tooth (without the root), four premolars and
three molars in both the mandible and maxilla. Simi-
larly to studies in nonhuman primates, the available
studies in pig also defined the mandibular premolar
region as the primary experimental unit (78) .
Healing period I (following tooth extraction)
The mean healing period following tooth extraction
was 13.2  7.7 weeks in the canine model, 3.0 
0.0 months in the nonhuman primate model and
3.5  0.5 months in the mini-pig model (Table 3).
During this healing period, a meticulous plaque-
control program, including tooth and implant clea-
ning, is usually provided two to four times per week.
Although this procedure can easily be performed
without sedation/anesthesia in dogs, postsurgical
infection control is obviously more demanding in
nonhuman primates and mini pigs (78).
Implant placement
In the canine model the mean implant diameter and
length were 4.1  1.4 mm and 8.8  1.6 mm, respec-
 Table 3. Pre-clinical ligature-induced peri-implantitis defect models

Model Objectives Methodology Healing Healing period II Active breakdown Progression Bone loss
period I period period

Canine Pathogenesis* (3, 4, 8, 12, Clinical observations, histological 13.2  7.7 Two-part implant: 12.0  5.0 weeks 21.1  19.9 41.6  16.1%†
22, 24, 38, 41–43, 50–52, observations, immunological weeks Submerged = 13.4  Ligature exchange: weeks†
56, 76, 80, 81, 85, 90, 91, analysis, microbiological analysis, 2.8 weeks 3.6  1.5
97, 100, 102) radiological analysis Abutment = 8.6 
6.5 weeks
One-part implant:
13.2  4.0 weeks
Therapy‡ (5, 13, 14, 18, 23, Clinical observations, histological 13.2  7.7 Two-part implant: 14.4  6.2 weeks 2.3  3.1 41.1  14.4%†
26, 30, 31, 34, 46, 47, 49, observations, microbiological weeks Submerged = Ligature exchange: weeks†
55, 57, 59, 61–64, 75, 79, analysis, radiological analysis 13.2  2.7 weeks 2.4  2.5
82–84, 88, 99) Abutment = 8.8 
6.3 weeks
One-part implant:
13.2  4.0 weeks
Nonhuman Pathogenesis* (2, 15, 25, Clinical observations, histological 3.0  0.0 Two-part implant: (96) 30.0  13.2 weeks† 0.7  1.5 27.0  16.3%†
primate 29, 40, 71–74, 96) observations, microbiological weeks† Submerged = 12 weeks Ligature exchange: weeks†
analysis, radiological analysis Abutment = 2.8  3.3†
20 weeks
Therapy‡ (21, 25, 68–70) Clinical observations, histological 59.0  19.0 weeks† 3.5  0.5 37.5  12.5%†
One-part implant:
observations, microbiological Ligature exchange: weeks†
11.4  5.4 weeks†
analysis, radiological analysis 16.0  6.0†
Swine Pathogenesis* Clinical observations, 3.5  0.5 Two-part implant: 45 days No Not indicated
(27) microbiological analysis, weeks† Submerged = 8 weeks Singular ligature
radiological analysis Abutment = 2 weeks application
Therapy‡ Clinical observations, 6 weeks No Not indicated
(86) histological observations Singular ligature
application
Values are given as n or mean  standard deviation.
*Available studies assessing the pathogenesis of peri-implantitis.
†Calculated from the data provided in the original papers.
‡Available studies assessing treatment of peri-implantitis.

173
Animal models for peri-implant disease
Schwarz et al.

tively, and in nonhuman primates were
2.8  0.2 mm and 8.0  1.4 mm, respectively. How-
ever, similar data on implant diameter and length
have not been reported in publications employing a
mini-pig model.
Healing period II (following implant placement)
A thorough analysis of the available literature
revealed that most authors favored a submerged
healing procedure in the canine model. The mean
healing period following implant placement was
13.4  2.8 weeks for submerged implants and
13.2  4.0 weeks for nonsubmerged implants. In
contrast, a nonsubmerged healing procedure was
commonly favoured in nonhuman primates, with a
mean healing period of 11.4  5.4 weeks being
employed. Both available studies performed in mini
pigs employed a submerged healing procedure with a
healing period of 8 weeks (78) (Table 3).
Implant uncovering + healing period III (two-part
implants)
In the canine model, the mean healing period follow-
ing implant uncovering was 8.6  6.5 weeks. The
only study employing a submerged healing procedure
in nonhuman primates reported that a 3-month
plaque-control regimen was initiated 2 months after
abutment connection (24, 25). Only one study
reported on a 2-week healing period following
implant uncovering in a mini-pig model (86).
Active breakdown and spontaneous progression
period
In the original protocols (43), the active breakdown
period was initiated by terminating plaque-control
regimens and placement of cotton ligatures in a posi-
tion immediately apical of the perimucosal margin in
Beagle dogs. These ligatures were exchanged after
3 weeks in the pocket of a receded mucosal margin. A
second set of ligatures was removed after a further
3 weeks. This active breakdown period was followed
by a spontaneous progression period of 4 weeks. Du-
ring that period, renewal of the plaque-control regimen
was initiated (i.e. teeth and abutments were cleaned
with a toothbrush and dentifrice) (43) (Fig. 2A).
In an experimental study employing a progression
period of 12 months without plaque control, it was
observed that 16 of 21 implants revealed varying
amounts of additional radiographic bone loss, thus
pointing to the spontaneous progression of ligature-
induced peri-implantitis in dogs (102). In some speci-
mens, and after 2 months of plaque control, the
inflammatory cell infiltrate was separated from the
adjacent alveolar bone by a noninfiltrated connective
tissue. However, the majority of sites were characte-
rized by an ongoing disease progression (102). Similar
findings were also reported by other authors employ-
ing the same animal model (3, 4, 49).
Accordingly, it may be assumed that a ‘‘self- limi-
ting’’ process following ligature removal, as noted for
natural teeth, may not occur in peri-implant tissues
(10).
Ligatures and modes of application
Cotton and silk ligatures (4–0) were those most com-
monly used to establish a peri-implant pocket during
the active breakdown period. However, the specific
mode of ligature application was rarely reported. This
rudimentary information ranged from a “supramuco-
sal” to a “submucosal” application in either a mono
or layered mode (Fig. 2A). Distinct heterogeneity was
also noted with respect to ligature exchange. While
most authors preferred a single application, the
minority of the available publications performed liga-
ture exchange at individual time points, or just a
renewal if the ligature was lost (78) (Table 3).
Characteristics of the ligature-
induced peri-implantitis defect
model
Spontaneous progression of ligature-induced peri-
implantitis in dogs occurred at implants with diffe-
rent geometry and surface characteristics (3, 4, 51, 52,
81, 90, 91). However, limited evidence suggests that
progression of untreated lesions in dogs may be more
pronounced at moderately rough surfaces compared
with polished titanium implant surfaces (3, 4, 8). In
addition, one study has pointed to increased bone
loss at two-part implants compared with one-part
implants (100). Lateral static loading using controlled
forces did not enhance disease progression at either
mucositis or peri-implantitis sites (22).
In studies aimed at investigating the pathogenesis
of peri-implantitis in dogs, the mean active
breakdown and progression period (mean ligature
application/exchange = 3.6  1.5 weeks) was 12.0 
5.0 weeks and 21.1  19.9 weeks, respectively. This
resulted in a calculated mean bone loss of 41.6 
16.1% relative to the original implant length. The
mean active breakdown period in therapeutic studies
was 14.4  6.2 weeks (mean ligature application/
exchange = 2.4  2.5), which was followed by a mean
progression period of 2.3  3.1 weeks. This resulted

174

A C
B D
Fig. 2. (A) Active breakdown period of the ligature-induced
peri-implantitis defect model in the canine model. Peri-
implantitis lesions are initially induced by ligature place-
ment in a submarginal position in the absence of oral
hygiene procedures. (B) Clinical situation at the end of the
progression period showing an established peri-implantitis
in a calculated mean bone loss of 41.1  14.4% rela-
tive to the original implant length (Fig. 2B–D).
Microbiological analysis revealed an increased level
of Porphyromonas gingivalis, Prevotella intermedia
and Tannerella forsythia (42, 56, 91). Campylobacter
spp. and Candida spp. were detected only occasion-
ally (81).
Histologically, peri-implantitis lesions in dogs were
characterized by the presence of a large inflamma-
tory cell infiltrate residing in the peri-implant
mucosa, but also extending into the alveolar bone
(Fig. 3A). This was associated with ulceration of the
pocket epithelium and loss of implant-supporting
alveolar bone (Fig. 3B and C). In comparison with
experimental periodontitis lesions, the inflammatory
cell infiltrate at implants revealed small amounts of
collagen, but a proportionally higher vasculature
and larger volumes of polymorphonuclear leukocytes
and plasma cells (Fig. 3D). In particular, the per-
centage volume of the inflammatory cell infiltrate
revealed the following major components: collagen
(25.9  11.1 volume%), vascular structures (8.7 
2.1 volume%), fibroblasts (1.4  0.9 volume%), mac-
rophages (1.3  0.3 volume%), lymphocytes (1.3 
0.3 volume%), plasma cells (20.3  3.7 volume%),
polymorphonuclear leukocytes (4.1  2.1 volume%)
and residual tissue (37.1  11.8 volume%) (43)
(Fig. 3E).
Animal models for peri-implant disease
lesion as defined by: positive bleeding on probing, suppura-
tion and deepening of the peri-implant pockets. (C) Intraope-
rative view indicating that the peri-implantitis bone defects
are filled with granulation tissue. (D) Granulation tissue
removal revealed the most common defect configuration:
circumferential-type intrabony + supracrestal bone loss.
These ligature-induced peri-implantitis lesions in
dogs seem to have many features in common with
naturally occurring lesions, as presented in human
biopsy material (10, 39). Moreover, it was demon-
strated that the configurations and sizes of ligature-
induced peri-implantitis bone defects in dogs seemed
to resemble naturally occurring lesions in humans
(76). In particular, both naturally occurring and liga-
ture-induced peri-implantitis lesions most commonly
featured a combined defect configuration including a
supracrestal (Class II) defect (prevalence: 79% in
humans and 53.3% in dogs) as well as an intrabony
aspect. The latter could be differentiated into five
characteristic defect classes (76). In particular, defects
most frequently (55.3% in humans and 86.6% in dogs)
exhibited a circular bone resorption under mainte-
nance of the buccal and oral contours of the support-
ing alveolar bone (i.e. Class Ie). This was followed by
buccal dehiscence defects revealing a semicircular
bone resorption to the middle of the implant body
(i.e. Class Ib) (humans, 5.8%; dogs, 0%), and buccal
dehiscence defects with a circular bone resorption
under either maintenance (i.e. Class Ic) (humans,
13.3%; dogs, 6.7%) or loss (i.e. Class Id) (humans,
10.2%; dogs, 0%) of the lingual cortical bone. The lo-
west frequency featured conventional buccal dehis-
cence defects (i.e. Class Ia) (humans, 5.4%; dogs,
6.7%) (76) (Figs 2D and 3A).
175
Schwarz et al.
A D
C magnification 340). (C) The liga-
In studies aimed at investigating the pathogenesis
of peri-implantitis in nonhuman primates, the
mean active breakdown (mean ligature application/
exchange = 2.8  3.3 weeks) and progression periods
were 30.0  13.2 weeks and 0.7  1.5 weeks, respec-
tively. This resulted in a calculated mean bone loss of
27.0  16.3% relative to the original implant
length. The mean active breakdown (mean ligature
176
Fig. 3. (A) Histological view of a liga-
ture-induced peri-implantitis defect
in the canine model (vestibulo-oral
section; toluidine blue stain; original
magnification 312.5) showing a
combined (i.e. supra- and intrabony)
defect component. (B) The amount
of mineralized and nonmineralized
plaque biofilms increased in both
supra- and submucosal compart-
ments (toluidine blue stain; original
ture-induced peri-implantitis lesion
is characterized by an ulcerated
pocket epithelium and massive
degeneration of the subepithelial
connective tissue with a loss of colla-
gen structures (canine model, tolui-
dine blue stain; original
magnification 340). (D) The inflam-
matory cell infiltrate is dominated
by plasma cells (canine model, tolui-
dine blue stain; original magnifica-
tion 3200). (E) The apical extension
of the inflammatory cell infiltrate is
associated with a resorption of the
implant-supporting alveolar bone
(canine model, toluidine blue stain;
original magnification 3100).
application/exchange = 16.0  6.0 weeks) period in
therapeutic studies was 59.0  19.0 weeks, which
was followed by a mean progression period of
3.5  0.5 weeks. This resulted in a calculated mean
bone loss of 37.5  12.5% relative to the original
implant length.
One group of authors inoculated a monkey with
pathogenic P. gingivalis three times weekly for

2 weeks at 1 month after ligature placement (68). The
potential influence of this methodological approach
to increase disease progression is currently unknown.
However, plaque accumulation was obviously
enhanced in the absence of a keratinized mucosa,
thus accelerating attachment loss (96). Microbiologi-
cal analysis revealed that ligature-induced peri-im-
plantitis lesions in nonhuman primates were
associated with increased proportions of motile
rods, spirochetes, P. gingivalis, P. intermedia, Fuso-
bacterium spp. and beta-hemolytic streptococci (2,
24, 71). The spirochete levels were significantly corre-
lated with probing pocket depths and bone loss at
peri-implantitis sites (15). At the present time, the his-
topathological characteristics of ligature-induced
peri-implantitis lesions in nonhuman primates have
not been investigated.
In both canine and nonhuman primate models,
histological data provide some evidence that probe
penetration depth increases with the level of inflam-
mation, thus probe penetration extends deeper than
the connective tissue level at peri-implantitis sites
(41, 73).
The two studies reporting on the pathogenesis and
therapy of peri-implantitis in a mini-pig model
employed different lengths of active breakdown pe-
riods (following application of a single ligature) – in
one study it was 45 days and in the other it was
6 weeks. Although the microbiological analysis
pointed to an increase in the numbers of gram-nega-
tive obligate anaerobes (27), the histopathological
characteristics of ligature-induced peri-implantitis
lesions in mini pigs have not been investigated
(Table 3).
A recent systematic review and consensus state-
ment on the quality of reporting of animal studies on
the pathogenesis and treatment of peri-implant mu-
cositis and peri-implantitis has identified missing
information in these publications and may encourage
authors to consider the checklist as proposed by the
Animal Research: Reporting of in-vivo experiments
(ARRIVE) to further improve the quality of reporting
in this field of research (77).
Future directions
In addition to advances in the development of preclin-
ical animal models for the study of peri-implantitis in
systemically healthy animal models, as the health of
the population changes, there will be an increasing
need to study peri-implantitis in systemically com-
promised situations. Diabetes and obesity are each
independently associated with increased risk for perio-
Animal models for peri-implant disease
dontitis and tooth loss (32). The best available evi-
dence indicates that individuals with diabetes also
have less favorable dental implant outcomes (48, 58,
93, 95) and are at increased risk for peri-implantitis
(11, 54). Thus, it is anticipated that individuals with
systemic conditions such as obesity/metabolic syn-
drome and diabetes (currently >35% and >8% of the
US adult population, respectively, and even higher in
many other regions of the world) will experience lar-
ger-than-anticipated implant complications (53).
Novel pre-clinical models are needed to investigate
the effects of systemic disease on peri-implantitis.
Until recently, large-animal models of type 2 diabe-
tes have been extremely costly and impractical for the
study of peri-implantitis (95). Consequently, to date
there are no large-animal models for investigating the
effect of systemic disease on peri-implantitis.
Advances in veterinary medicine have led to the
development of models for metabolic syndrome and
diabetes in the miniature-pig model (37). Miniature
pigs subjected to ad-libitum feeding of a high-calorie,
high-sugar/fat diet develop obesity within 6 months.
The phenotype of these obese miniature pigs is
defined by abnormalities such as visceral obesity, glu-
cose intolerance, insulin resistance, hypertension,
dyslipidemia, a prothrombotic state (i.e. an increased
number of thrombocytes) (94), elevated levels of
tumor necrosis factor-alpha and abnormalities
related to immune-system regulation and inflamma-
tion. Moreover, known abnormalities related to
structural and extracellular matrix proteins, such as
serum amyloid-P component, as well as abnormali-
ties related to the coagulation cascade, have been
reported (6).
A type 2 diabetic state has also been successfully
induced in miniature pigs with metabolic syndrome
by injection with streptozotocin (36). These minia-
ture pigs share substantial similarities with obese/
diabetic humans, such as hyperglycemia, hyperlip-
idemia, insulin resistance, a pro-inflammatory
phenotype, high blood pressure and atherosclerosis
(7, 45, 87).
Future studies should attempt to systematically
establish baseline bone and soft-tissue healing kinet-
ics and peri-implant disease progress in the meta-
bolic syndrome and diabetic miniature pig models.
Efforts in this direction will help to address peri-im-
plantitis issues in this increasingly large segment of
the population that represents a significant public
health concern. Establishment of translational sys-
temically compromised large-animal models for the
study of peri-implantitis will allow for future investi-
gations of treatment and prevention.
177
Schwarz et al.
Conclusions/relevance to human
biology
It is important to recognize that ethical concerns limit
any systematic investigation of the pathogenesis on
peri-implant diseases in humans. Data from animal
studies on peri-implant disease may provide impor-
tant insights into the pathogenesis of these lesions
and provide the rationale for further evaluation of
treatment strategies in carefully designed and con-
trolled clinical trials.
The current review has focused on animal studies
employing different models to induce peri-implant
disease. Studies on mucositis have used varying pe-
riods of undisturbed plaque accumulation, whereas
studies on peri-implantitis have commonly employed
the “ligature model”.
The available evidence indicates that peri-implanti-
tis lesions were most frequently induced in dogs and
were found to have many clinical and histological fea-
tures in common with naturally occurring lesions
observed in humans.
Acknowledgments
The review was self-funded by the authors’ own
departments. The authors declare that they have no
conflict of interests related to this article.
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