Shanbhag et al.

International Journal of Implant Dentistry (2024) 10:55 International Journal of

https://doi.org/10.1186/s40729-024-00572-9
Implant Dentistry

REVIEW Open Access

Peri-implant bone regeneration in pigs

Siddharth Shanbhag1,2,3*, Javier Sanz-Esporrin4, Carina Kampleitner5,6,7, Stein-Atle Lie2, Reinhard Gruber7,8,9,
Kamal Mustafa2 and Mariano Sanz3,4

Abstract
Purpose To review the current literature to answer the focused question: in the experimental pig model (population),
which types of peri-implant bone defects (exposure) have been used evaluate different modes of therapy and what is
their capacity for spontaneous healing and regeneration (outcome)?
Methods Following PRISMA guidelines, electronic databases were searched for studies reporting peri-implant bone
defects in the maxillae or mandibles of pigs. Those studies which reported a control group of untreated defects with
assessment of spontaneous regeneration [new bone area (BA)] and/or re-osseointegration [new bone-to-implant
contact (BIC)] via quantitative radiography or histomorphometry were included in a random effects meta-analysis for
the outcomes BA and BIC.
Results Overall, 21 studies, mostly performed in the mandibles of minipigs, were included. Most studies reported
‘acute’ intrabony (circumferential and/or dehiscence; n = 12) or supra-alveolar defects (horizontal; n = 4). Five studies
attempted to induce ‘chronic’ peri-implantitis lesions using ligatures with conflicting results. Meta-analyses revealed
pooled estimates (with 95% confidence intervals) of 48.07% BIC (30.14–66%) and 64.31% BA (42.71–85.91%)
in intrabony defects, and 52.09% BIC (41.83–62.35%) and 28.62% BA (12.97–44.28%) in supra-alveolar defects.
Heterogeneity in the meta-analysis was high (I2 > 90%).
Conclusion Current evidence for peri-implant bone regeneration in pigs is mainly based on acute intrabony defects,
which demonstrate a high capacity for spontaneous regeneration and re-osseointegration. The evidence for chronic
peri-implantitis is limited and does not clearly indicate a spontaneous progression of the disease in this animal model.
Keywords Bone regeneration, Peri-implantitis, Animal models, Systematic reviews

5
*Correspondence: Karl Donath Laboratory for Hard Tissue and Biomaterial Research,
Siddharth Shanbhag Division of Oral Surgery, University Clinic of Dentistry, Medical University
[email protected] of Vienna, Vienna, Austria
1 6
Department of Immunology and Transfusion Medicine, Haukeland Ludwig Boltzmann Institute for Experimental and Clinical Traumatology,
University Hospital, Bergen, Norway The Research Center in Cooperation with AUVA, Vienna, Austria
2 7
Center for Translational Oral Research (TOR), Department of Clinical Austrian Cluster for Tissue Regeneration, Vienna, Austria
8
Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway Department of Oral Biology, University Clinic of Dentistry, Medical
3
Department of Periodontology, Faculty of Dentistry, University of Oslo, University of Vienna, Vienna, Austria
9
Oslo, Norway Department of Periodontology, School of Dental Medicine, University of
4
ETEP Research Group, Faculty of Odontology, University Complutense of Bern, Bern, Switzerland
Madrid, Madrid, Spain

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Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 2 of 12

Background society as companion animals. Therefore, there is a grow-

Bone regeneration around dental implants as a result of ing trend towards the ‘phasing out’ of dog models and the
insufficient bony volume or as a treatment of the sequelae promotion of other animals (e.g. pigs) as the preclinical
from peri-implantitis presents a clinical challenge. These model of choice in bone regenerative studies.
bone defects present a net loss of osseointegration, i.e., Conversely to dogs, pigs are considered to be food pro-
diminished direct bone-to-implant contact (BIC), poten- ducing animals, and therefore, their use in experimental
tially compromising short- and long-term treatment in vivo investigations may have the advantage of a rela-
outcomes [1, 2]. The treatment objective herein, beyond tively less critical public perception. In fact, a recent sur-
the arrest of the inflammation by infection control mea- vey showed that there is a perceived difference in moral
sures, is to reconstruct the bone architecture around the status between companion animals and farm animals,
implant and reestablish the lost BIC [3]. Results from such as pigs [20]. The advent of miniature pigs or mini-
clinical studies have recommended different regenera- pigs, being smaller and easier to manage than domestic
tive therapies for the different peri-implant defects, usu- breeds, has further contributed to their preference as
ally following the principles of guided bone regeneration experimental animals. Additional advantages in their use
(GBR), using barrier membranes in combination with are their easy availability, relatively low cost, ability to
bone grafts and/or bone substitute materials [4, 5]. Simi- produce large litters, and the possibility to obtain a larger
larly, there is evidence from preclinical studies on the volume of tissue biopsies [21–24]. Furthermore, pigs
achieved regenerative outcomes, including the re-estab- are closely related to humans in terms of bone anatomy,
lishment of ‘osseointegration’, with the concomitant rise composition, and metabolism [25–27].
in BIC percentages, even in cases of previously contami- While the possibility of inducing chronic peri-implanti-
nated implant surfaces [6, 7]. Although these regenera- tis in pig models has been suggested from as early as 1991
tive surgical procedures have shown a certain degree of [28], compared to dogs, there is relatively less informa-
efficacy depending on the defect architecture, there is no tion on the characteristics of experimental peri-implant
consensus on the effectiveness of one technique over the bone defects in pigs. It is also presently unclear which
other [8–12]. defect designs and dimensions in pigs most accurately
Preclinical testing of new regenerative therapies in clin- represent a critical-size defect (CSD) around implants,
ically relevant animal models is an important aspect of i.e., the smallest-size experimental defect that will not
translational research and, in most cases, a requirement spontaneously and completely regenerate with bone
of regulatory health agencies before initiating human in a defined timeframe without intervention [29, 30].
clinical trials [13, 14]. In particular, large-animal models In context, we have recently demonstrated through a
(dogs, pigs, sheep, and non-human primates) are used meta-analysis the relatively high capacity for spontane-
to simulate clinical conditions, and hence, predict thera- ous regeneration (~ 40–50%) in experimental alveolar
peutic efficacy and foster human clinical research [14]. bone defects of pigs [31]. Systematic reviews and meta-
Although non-human primates (NHPs) represent the analyses of animal studies can be useful for detecting
closest animal model to humans, based on genetic back- heterogeneity and improving the methodological quality
ground and biological similarity, the economic and ethi- of future studies, allowing for reliable comparisons and
cal concerns surrounding their use have made this model more accurate clinical translation [32]. Therefore, our
almost completely non-viable in several countries [15]. present objective was to systematically review the litera-
Hence, dog, sheep, goat, and pig models are the preferred ture to answer the focused PEO (population, exposure,
alternatives since their bone composition and biology are outcome) question: in the pig model (P), what are the
similar to those of humans. characteristics of experimental peri-implant bone defects
From these, dog models are arguably the most fre- (E) in terms of their three-dimensional configuration and
quently used in peri-implantitis research [16, 17]. Pre- capacity for spontaneous regeneration, i.e., new bone for-
clinical dog models of peri-implantitis are broadly mation and new BIC or re-osseointegration (O)?
categorized as either the experimental model of ligature-
induced “chronic” peri-implantitis (LIPI), or “acute” sur- Methods
gically developed bone defects around implants. Since Study design
dogs have a natural susceptibility to periodontal (and The review protocol was based on the Preferred Report-
peri-implant) diseases, the chronic LIPI model represents ing Items for Systematic reviews and Meta-Analyses
the ‘gold standard’ to investigate both the pathogenesis of (PRISMA) [33] and Systematic Review Centre for Labo-
peri-implant diseases and the efficacy of bone regenera- ratory Animal Experimentation (SYRCLE) guidelines
tive therapies around implants [18, 19]. However, as for [34], and registered on the database PROSPERO: Inter-
NHPs, the use of dogs in experimental in vivo investiga- national Prospective Register of Systematic Reviews
tions has raised significant criticisms given their role in (CRD42023450700). The results of studies reporting on
Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 3 of 12

alveolar bone defects (without implants) are published Inter-rater reliability was measured using the Cohen’s
elsewhere [31]. kappa statistic. A summary of the study selection process
Inclusion criteria: is presented in Supplementary Fig. 1.

1. Experimental in vivo studies in pigs, including Data extraction

minipigs. Based on full-text screening of the selected studies, the
2. Creation of experimental peri-implant bone defects, following data was extracted using a standardized, pre-
either chronic (LIPI) or acute (surgically created), in piloted form: author(s), study design, animal character-
the maxilla or mandible. istics, model type, number of animals/defects, number
3. Quantitative assessment of new bone formation of procedures, intervention(s), observation time(s),
and/or re-osseointegration (new BIC) using clinical outcome(s), method(s) of outcome evaluation, main find-
measurements, three-dimensional (3D) radiography/ ings, and conclusions. Missing data was requested from
tomography [computerized tomography (CT), the authors. Descriptive summaries of studies included
cone-beam CT (CBCT), micro-CT] and/or 2D were entered into tables. Quantitative radiographic
histomorphometry. and histomorphometric data was extracted for pos-
sible meta-analysis; data were recorded as (or converted
Exclusion criteria: into) means and standard deviations (SD) for analysis. If
data were only expressed graphically, numerical values
1. In vivo studies in other animal species. were requested from the authors, and if no response was
2. In vivo studies reporting defects in other anatomical received, a digital ruler software was used to measure
sites (calvarial or non-maxillofacial) and ectopic graphical data (ImageJ; National Institutes of Health,
(subcutaneous or intramuscular implantation) Bethesda, MD, USA).
models.
3. Reporting of only qualitative or semiquantitative Quality assessment and risk of bias
radiographic and/or histological analyses. Reporting quality assessment of all studies will be per-
4. In vitro and in silico studies. formed based on a modification of the ARRIVE (Animal
5. Clinical studies. Research: Reporting In Vivo Experiments) guidelines
[35], regarding relevant items [36]. Compliance with the
Outcome: The primary outcome of interest was char- guidelines was evaluated using a predefined grading sys-
acterizing the different types of peri-implant defects tem applied to each of the 20 items [37] (Supplementary
reported in minipigs. The secondary outcome of interest Table 2). Reporting quality was judged as ‘high’, ‘moder-
was the amount of unassisted or spontaneous regenera- ate’ or ‘low’. Risk of bias (RoB) assessment is performed
tion (new bone formation) and reosseointegration (BIC) using a modification of SYstematic Review Centre for
in untreated control defects assessed by 3D tomography Laboratory animal Experimentation (SYRCLE) RoB tool
or 2D histomorphometry. for animal studies, and judged as ‘high’, ‘low’ or ‘unclear’
[38] (Supplementary Table 3). Any disagreement between
Search strategy, screening, and study selection the reviewers during study selection, data extraction,
A search strategy was developed with assistance from and quality assessment was resolved by discussion and
the University of Bergen library in accordance with the consensus.
SYRCLE guidelines [34]. Electronic databases of MED-
LINE (via PubMed), EMBASE and Web of Science were Meta-analysis
searched for relevant literature up to and including A meta-analysis was performed to determine the degree
December 2023; the search strategy for MEDLINE is pre- of spontaneous regeneration in acute peri-implant
sented in Supplementary Table 1. Bibliographies of the defects of minipigs using STATA Statistical Software 12
selected studies and relevant review articles were checked (StataCorp LP, College Station, TX, USA) and the Der-
for cross-references, and additional relevant studies were Simonian and Laird random effects model, assuming
obtained using the Google and Google Scholar search a degree of heterogeneity between the individual stud-
engines. Titles and abstracts of the search-identified ies [39]. Only studies which included a control group
studies were screened by two authors (S.S. and C.K.) receiving no treatment, i.e., “sham” or “empty defect”
and full texts of all eligible studies were obtained. Uncer- group, and reporting quantitative tomographic or his-
tainty in the determination of eligibility was resolved by tomorphometric outcomes (BA and BIC) were included
discussion with the other authors. Two authors (S.S. and in the meta-analysis. Separate analyses were performed
C.K.) reviewed the selected full texts independently and for the outcomes BA and BIC in intrabony and supra-
final inclusion was based on the aforementioned criteria. alveolar defects. Pooled estimates [effect sizes (ES)] were
Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 4 of 12

calculated along with 95% confidence intervals (CI). The •  intrabony defects (n = 12 studies, observation
I2 statistic was used as a measure of heterogeneity across time 4–24 weeks) [43–54], where implants
studies, with I2 > 75% indicating substantial heterogene- were placed at the level of the alveolar crest and
ity [39]. A univariate meta-regression analysis was per- defects were surgically created to simulate Class I
formed to test the effects of different variables on pooled defects with “well-defined intrabony components”
ES for each outcome. Publication bias was assessed via (circumferential and/or dehiscence).
funnel plot asymmetry and Egger’s regression test. •  supra-alveolar defects (n = 4 studies, observation
time 2–48 weeks) [55–58], where implants were
Results placed supra-crestally, leaving the coronal 2–5 mm of
Search results the implant exposed to simulate Class II defects with
The initial search yielded 96 publications (after removing “horizontal bone loss” [42].
duplicates) studying bone regeneration around implants
in pigs. To limit the search to the focused question,
only those studies reporting experimental peri-implant Chronic (ligature induced) defects
bone defects were considered for inclusion [Cohen’s Five studies assessed the development of chronic peri-
kappa = 0.857 (95% CI 0.811–0.903)]. Based on further implant disease by means of submarginal placement
eligibility criteria and full-text review, 21 studies report- of ligatures in minipigs [28, 40, 59, 60]. One study was
ing on acute defects (n = 16) and chronic ligature induced in progress at the time of review, but relevant data was
defects (n = 5) were included in the review. Among the directly obtained from the authors [41] (Table 2). All four
latter, two publications were possibly different reports studies evaluated the etiopathogenesis of experimentally
from the same experiment [28, 40], while one study was induced peri-implantitis, and three studies additionally
still in progress at the time of this review, but relevant evaluated the efficacy of different therapies. Considerable
data was obtained directly from the authors [41]. The heterogeneity was observed between studies with regards
primary reason for exclusion was assessment of implant to the induction protocol. Most studies used silk ligatures
osseointegration rather than peri-implant bone regenera- around osseointegrated implants (8–12 weeks healing) to
tion (Supplementary Table 4). accumulate plaque and induce disease; in one study, liga-
tures were placed simultaneously with the implants, i.e.,
Study characteristics prior to implant osseointegration [59]. Differences were
All studies reported the use of minipigs, mostly of the also found with regards to the length of the “active induc-
Göttingen type. On average, the animals were mostly tion phase”, i.e., duration of ligature placement, ranging
females, aged 20.38 ± 4.5 months. The most common from 6 weeks [28, 40] up to 12 [60] or even 14 weeks [41].
anatomical site for defects was the mandibular or maxil- The duration of the “chronification phase”, i.e., disease
lary alveolar ridge (premolar-molar region) with a “split- progression after ligature removal, which ranged from
mouth” design (bilateral defects); other sites included the 0, i.e., no waiting period between ligature removal and
mandibular inferior body. Most studies reported an intra- assessment [28, 40, 59] to 4 weeks [41, 60].
oral surgical approach whereby molar and/or premolar
teeth were first extracted, followed by a healing phase, Defect/disease development and spontaneous healing
after which standard implants were inserted (mean diam- In eight studies reporting acute defects, a control group
eter 3.78 ± 0.42 mm, mean height 9.55 ± 1.86 mm). All but of “empty” defects receiving no treatment was included
two studies [28, 40] reported the use of implants with and therefore, spontaneous bone regeneration could
modified/rough surfaces, most commonly sand-blasted be assessed. Outcome assessment was performed via
and acid-etched. Based on defect type, the included stud- micro-CT and/or histology with histomorphometry.
ies were categorized under ‘acute’ and ‘chronic’ defects Among the studies using ligature models, most studies
(Tables 1 and 2). reported radiographic bone loss, usually based on a non-
quantitative description of “implant thread exposure”
Acute defects (Supplementary Table 5). According to studies, bone
Most studies reported the use of acute type defects, loss obtained after the induction period is around 2–3
where defects were created at the time of implant place- threads, however some of the studies report a rather ran-
ment and the regenerative intervention was immediately dom distribution of that bone loss (where some implants
applied (Table 1). These defects could be further classi- developed complete loss of support and others did not
fied, according to the classification by Schwarz et al. [42], experience bone loss) [41]. Three studies used histologi-
as: cal analysis to report differences between the treatment
groups but without characterizing the defect/disease
development, while in two studies, defect development
Table 1 Summary of studies reporting acute peri-implant defects
Year Study N Age (m) Site n Uni Implant size (mm) Implant surface (manufacturer) Defects Class# Time Methods Outcomes
/side / Bi - type, size (mm)
- Intrabony defects
2009 Neugebauer et al. ** (43) 6 18–21 P 5 ? 3.8 × 5 SA (Dentsply) D, 4.2 × 3.5 I-a 4m Hm BA, BIC
2012 Zambon et al. (44) 12 20 P, M1 2 B 4.1 × 8 SA-A (Straumann) D, 12 × 6 × 2 I-a/b 5m Hm BIC
2014 Friedmann et al. (45) 6 18 P, M1 2 B 4.1 × 8 SA/SA-A (Straumann) C-D, 5 × 5 I-a/b 4w Hm BA, BIC
2015 Kim et al. (46) 6 24 P 4 B 3 × 10 SA (Osstem) C, 2 (depth) I-e 4–12 w Hm BA, BIC
2016 Verket et al. (47) 5 20 P 2 B 3.3 × 8 SA-A (Straumann) D, 6 × 10 I-a 3m Hm BA, BIC
Shanbhag et al. International Journal of Implant Dentistry

2016 von Wilmowsky et al.* (48) 6T 18 ± 4 - 4 U 4.1 × 12 SA (Straumann) C-D, 4 × 3 × 3 I-b 90 d Hm BA, BIC
2017 Kämmerer et al. (49) 15 22 P 1–2 B 4.3 × 12 SA + CaP (Bonit-ex) C, 7 × 5 I-e 120 d Hm BIC
2018 Verket et al. (50) 6 17–19 P 3 B 3.25 × 11.5 SA (Biomet-3i) C, 6 × 5 I-e 6w mCT, Hm BA, BIC
2019 Wang et al. (51) 14 12 P, M1 3 B 4.1 × 10 NR D, 12 × 6 × 2 I-a 3, 6 m mCT BA
2020 Tan et al. (52) 5 24 P4 1 ? 4.1 × 12 SA (Straumann) C-D, 10 × 12 I-b 6m Hm BA, BIC
2021 Almansoori et al.* (53) 5 12–18 - 3 B 4 × 8.5 SA (Osstem) C-D, 8 × 2 × 4 I-b 12 w mCT, Hm BA, BIC
(2024) 10:55

2021 Thieu et al. (54) 6 27–32 P 2 B 3 × 11 SA + F (Dentsply) C-D, 8 × 5 × 6 I-c 12 w mCT, Hm BA, BIC
- Supra-alveolar defects
2009 Fenner et al. ** (55) 8 NR P, M 6 U NR SA (Dentsply) CE, 2–8 II 12 m Hm BA, BIC
2012 Freilich et al. S (56) 8 24 P, M1 2 B 4.1 × 9 SA/SA-A (Straumann) CE, 2.5 II 9w Hm BIC
2013 Catros et al. S (57) 6 NR P, M1 2 B 4.1 × 9 SA/SA-A (Straumann) CE, 2.5 II 8w mCT, Hm BIC
2017 Schorn et al. (58) 12 NR P, M1 3 B 3.5 × 11 TO (Nobel Biocare) CE, 5 II 2–12 w Hm BA, BIC
N, number of animals, n, number of implants per side, Uni/Bi, unilateral or bilateral (split-mouth), m, months, w, weeks, NR, not reported; BA, bone area, BIC, bone-to-implant contact
All studies performed in the mandibular ridge except (*) mandibular inferior border and (**) maxilla
SA, sand-blasted acid-etched; SA-A, sand-blasted and chemically treated; TO, titanium oxide blasted; CaP, calcium phosphate; F, fluoride; P, proprietary surface treatment
C, circumferential, D, dehiscence, CE, coronal exposure of implant, P, premolars, M, molars
#
Classification according to Schwarz et al. [53]
T
3 diabetic and 3 healthy animals
S
Modified abutment design to provide “space maintenance”
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Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 6 of 12

was described based on clinical parameters, mainly prob- II peri-implantitis defects [42], respectively. Based on our
ing depth [28, 59]. Two studies provided microbiological meta-analysis, this experimental model demonstrated
data reporting either a shift in the microbiological profile a high capacity for spontaneous bone regeneration
[28] or a significant increase in non-periodontitis related (BA) and re-osseointegration (BIC) in both intrabony
bacteria which was not correlated to the clinical findings and supra-alveolar defects. The evidence on the use of
[41]. chronic ligature induced peri-implantitis (LIPI) in mini-
pigs is limited and does not clearly indicate a natural pro-
Meta-analysis gression of peri-implantitis in this animal model.
A meta-analysis was separately performed for the histo- The optimal animal model for evaluating bone regen-
morphometric outcomes BIC (n = 9 studies) and BA (n = 5 erative therapies should simulate the clinical scenario by
studies); in each case, sub-groups were defined based providing a disease profile that is comparable to humans,
on defect type, i.e., intrabony and supra-alveolar (Figs. 1 and allow the use of similar therapies as would be used
and 2). No meta-analysis could be performed for ligature clinically [61]. Indeed, pigs fulfil these criteria and repre-
studies. Overall, the pooled estimates of spontaneous sent an adequate model of bone regeneration, since they
regeneration [ES (95% CI)] were as follows: 48.07% BIC are closely related to humans in terms of bone anatomy,
(30.14–66%) and 64.31% BA (42.71–85.91%) in intrabony composition, and metabolism, and allow for the use of
defects, and 52.09% BIC (41.83–62.35%) and 28.62% BA dental implants and biomaterial scaffolds of clinically
(12.97–44.28%) in supra-alveolar defects. A univari- relevant dimensions [62]. The studies included in this
ate meta-regression analysis was performed within each report have used minipigs, particularly Göttingen mini-
outcome group to test the effect of healing time, but no pigs, on average 20 months old, resulting in bone defects
significant effect was observed (data not shown). All morphologically similar to humans. However, in the case
meta-analyses revealed high heterogeneity (I2 > 90%), of periodontitis and peri-implantitis, an additional rel-
while funnel plot asymmetry and Egger’s tests revealed evant criterion for selecting the optimal animal model is
potentially high publication bias (Supplementary Fig. 2), the “natural” occurrence of the disease or the possibility
indicating that the results must be interpreted with to induce the disease, e.g. via placement of ligatures and
caution. plaque accumulation, which will “chronically progress”
(in terms of continuing bone loss) after removal of the
Quality assessment and risk of bias infectious stimulus (ligatures). The LIPI model in dogs
The overall quality of the included studies was judged to [19] is considered as the ‘gold standard’ for investigating
be average and the RoB was judged to be moderate (Sup- both the pathogenesis and therapy of peri-implantitis,
plementary Tables 6–7). For RoB, the items which most given their natural tendency to develop periodontitis and
often scored poorly were related to baseline data, hous- the possibility to induce peri-implantitis with a tendency
ing, blinding of operators, and blinding of assessors. It for natural progression [18, 63]. In contrast, only a few
must be noted that the included studies covered a wide studies have reported the experimental induction of peri-
span of publication dates, with many studies being pub- odontitis using ligatures in pigs [64, 65]. Similarly, only
lished before the ARRIVE and SYRCLE guidelines. Nev- four studies reporting LIPI in pig models were identified
ertheless, a clear need for better quality reporting and in the present review. Considerable heterogeneity was
compliance with these guidelines was identified herein. observed among these studies in terms of the experimen-
tal protocols used, specifically on the use of different liga-
Discussion ture placement and disease induction protocols. Despite
The aim of this study was to systematically review the differences in the length of the active ligature induced
available evidence to identify the most pertinent experi- disease period (ranging from 6 to 14 weeks), the degree
mental design using the pig as the experimental ani- of bone loss achieved did not vary remarkably between
mal, for studying the regeneration of peri-implant bone the studies. Moreover, unlike in dogs, the configurations
defects. Overall, a modest number of relevant studies of resulting bone defects did not frequently resemble
(n = 21) were identified, mostly with acutely developed naturally occurring lesions in humans. Despite differ-
defects, demonstrating large heterogeneity in terms of ences in the radiographic assessment methods among
the characteristics of the experimental model used. Most the studies, the attained bone loss was often restricted
of the experimental defects were created in the man- to the first 2 or 3 threads and its occurrence was unpre-
dibular alveolar ridge following extraction of premo- dictable. Indeed, in some studies there was no consistent
lars and first molars and after placing standard dental bone loss pattern (some of the implants had exhibited
implants. These acute defects could be broadly classi- complete supporting bone loss, while others in the same
fied as intrabony (circumferential and/or dehiscence) or study or animal showed absence of bone loss after 14
supra-alveolar, somewhat simulating human Class I and weeks of active induction period) [60]. Therefore, based
Table 2 Summary of studies reporting ligature-induced peri-implant defects
Year Study Type N Age Site n Uni Im- Implant surface Healing Ligatures Active Post Methods Defect
(m) /side / Bi plant induction induction description
size
(mm)
1991 Hickey et al. E 2 NR P 3 B NR M (Nobel-pharma) 8w 4-0 silk 6w NR Clin, XR, NR
* (28) Micro
Shanbhag et al. International Journal of Implant Dentistry

1993 Singh et al. T 2 NR P 3 B NR M (Nobel-pharma) NR 4-0 silk 6w NR Clin, XR, ≥ 2 threads

* (40) Histo exposed
2016 Stubinger et E 6 16–17 P 4 B 4×8 SA + P (Thommen 0 4-0 silk 6w 0 Clin, mCT 1 (lingual) to 3
al. (59) Medical) (buccal) threads
exposed
2018 Rodriguez E, T 6 NR P 3 B 3.4 × 9 LM/RBT 12 w Metal 12 w 4 w (only in T Clin, Histo NR
(2024) 10:55

et al. (60) (Biohorizons) group)

2019 Ramos et al. E, T 8 NR P, M1 4 B 4 × 10 SLA + CaP 8w 3-0 silk 14 w 4 Clin, XR, Wide range (com-
** (41) (Intra-lock) (surgical) Micro, mCT plete to no bone
loss); mean defect
size after 18 w:
3.15 ± 2.42 mm
N, number of animals, n, number of implants per side, Uni/Bi, unilateral or bilateral (split-mouth), m, months; w, weeks; E, etiopathogenesis; T, treatment, NR, not reported; Clin, clinical; XR, radiography; Histo, histology;
mCt, micro-CT; Micro, microbiological
* Possibly different publications from the same experiment
** Study in progress, data obtained directly from authors
All studies performed in the mandibular ridge
M, machined surface; SA, sand-blasted acid-etched; P, proprietary surface treatment; LM, laser microtextured; RBT, resorbable blast textured; CaP, calcium phosphate coating
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Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 8 of 12

Fig. 1 Meta-analysis of studies reporting histomorphometric bone-to-implant-contact (1 = intrabony, 2 = supra-alveolar defects). Results are presented
as effect sizes with 95% confidence intervals (CI)

on limited evidence, it appears that bone defects from commonly dogs, and in humans. The induction of experi-
ligature placement in pigs occur as a result of mechanical mental chronic peri-implantitis lesions, via the place-
trauma rather than infectious disease progression. ment of ligatures (LIPI), is well established in the dog
It is of relevance to discuss the nature of peri-implant model. Several studies have demonstrated that the ini-
bone defects in pigs in the context of correspond- tiation and progression of LIPI in dogs follows a similar
ing defects observed in other animal models, most pattern as in humans, as evidenced by a “spontaneous
Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 9 of 12

Fig. 2 Meta-analysis of studies reporting histomorphometric bone area (1 = intrabony, 2 = supra-alveolar defects). Results are presented as effect sizes
with 95% confidence intervals (CI)

progression” phase following the removal of ligatures loss (22%). Other studies have reported predominantly
(“active breakdown” phase) [18, 63]. Moreover, Schwarz non-circumferential buccal dehiscence (34%) [67] or
et al. [42] reported that the configurations and sizes of circumferential bone loss with or without buccal dehis-
LIPI bone defects in dogs resemble naturally occur- cence (25–30%) [68] in human peri-implantitis lesions.
ring peri-implantitis lesions in humans; circumferential In context, LIPI bone defects in pigs do not seem to
defects associated with a horizontal alveolar bone loss, demonstrate any predictable patterns or resemble those
were most frequently observed in both dogs (86.6%) and configurations frequently encountered in human peri-
humans (55.3%). However, in a recent systematic review implantitis lesions. Given that bone defects from liga-
of canine LIPI models (n = 36 studies), Solderer et al. [66] ture placement seemed to occur as a result of mechanical
reported large variations in defect ‘depth’ measurements trauma rather than infectious disease progression, even
across studies and over time (defect ‘morphologies’ were the LIPI in pigs can be considered as “acute” defects. Fur-
not considered in this review). More recently, a classifica- ther well-designed studies are needed to characterize and
tion of peri-implantitis defects was presented by Monje compare the morphologies of LIPI bone defects in pigs.
et al. [4] based on CBCT data from human implant sites. In light of the difficulties associated with the use of the
Contrary to previous reports, the authors found that the chronic LIPI model, in addition to the extended time and
most common defect morphology at the patient- (87%) high costs, most of the included studies used acute bone
and implant-level (55%) was an “infraosseous 2–3 wall defects, surgically created around implants to mimic
defect”, frequently including a component of buccal bone defect configurations naturally occurring peri-implantitis
Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 10 of 12

lesions; the regenerative intervention is then applied in was reflected in the meta-analyses and which affects the
the same surgical session. In a majority of the identified overall quality of the synthesized evidence. Secondly, a
studies the resulting bone defects are either Class I or wide range of observation (and ‘disease induction’) times
intrabony or defects, most frequently with a combined for both acute and chronic type defects was observed
circumferential-dehiscence configuration (Class I-c/d) across the included studies. Indeed, longer observation
according to Schwarz et al. [42]. While acute type defects times may reveal greater BA and BIC values. Although
may be less time consuming and easier to implement than a univariate regression analysis revealed no significant
LIPI, major limitations of this approach are as follows. effect of time on BA or BIC in acute defects, possibly
Firstly, the absence of a microbial/infectious component, due to heterogeneous data, the ‘time’ variable may have
which is the primary challenge in peri-implantitis pro- introduced some bias in the analysis. Finally, the influ-
gression and treatment, and secondly, the potential bias ence of implant properties (macro-/micro-geometry,
introduced by spontaneous regeneration of these defects surface characteristics, coatings, etc.), known to influ-
depending on the animal model; a high degree of sponta- ence the progression/ outcomes of peri-implantitis and
neous regeneration may confound the detection of clini- capacity for re-osseointegration [69, 70], were rarely con-
cally meaningful effects of the tested therapy. Indeed, a sidered among the included studies and might have influ-
high degree of spontaneous regeneration was observed enced the results. Nevertheless, based on the reviewed
in our meta-analysis in terms of histomorphometric BIC literature, the following factors may be considered when
and BA (~ 50%), especially in intrabony defects. Even in selecting an experimental peri-implantitis animal model;
supra-alveolar defects, i.e., when the coronal portion of
the implant was left exposed/unsubmerged, the pooled •  In pigs, the use of acute peri-implant defects may be
BIC was 52.09% (95% CI: 41.83–62.35%), suggesting questioned due to the limited clinical relevance of
that there was substantial new bone growth along the the method (absence of microbial insult) and high
exposed implant surface outside the original bony enve- capacity for spontaneous regeneration.
lope [it must be noted that in two studies of supra-alve- •  The feasibility of inducing peri-implantitis via
olar implant placement, a modified “umbrella” abutment ligatures is also questionable due to the lack of
design was used to function as a “scaffold retainer”, which convincing data demonstrating establishment of
provided some degree of space maintenance and pos- a pathological microbial milieu (correlated with
sibly primary clot stability to facilitate healing [56, 57]]. clinical findings), and evidence of continual disease
Not surprisingly, these values correlate closely with our progression after ligature removal, as has been
recent meta-analysis of spontaneous bone regeneration described in dogs.
in experimental alveolar defects in pigs, which was also •  Consequently, dogs may still represent the preferred
found to be ~ 40–50% [31]. Even critical-sized defects animal model for experimental peri-implantitis
that were allowed to become chronic in minipigs showed pathogenesis and therapy.
a higher degree of spontaneous regeneration compared
to similar defects in dogs [31]. This may be attributed to
differences in bone metabolism/healing rates between Conclusions
species [26]. The spontaneous regeneration phenomenon Based on our inclusion criteria, we identified 21 stud-
is not unique to minipigs. Indeed, even in ‘gold stan- ies evaluating bone regeneration in experimental peri-
dard’ canine LIPI defects, a ‘self-arresting’ phase often implant defects in pigs. The results are derived mainly
occurs after the active breakdown phase, i.e., removal of from acute defects in adult female Göttingen minipigs,
ligatures, and may even result in some ‘recovery’ (bone which could be broadly classified as intrabony (combined
regeneration) before further disease progression [63]. circumferential and dehiscence defects) or supra-alveolar
However, in minipigs, this innate healing capacity may (horizontal) defects. Evidence for chronic LIPI in this
be especially high, which further limits the feasibility of animal model is inconclusive; bone defects from ligature
LIPI since, as previously mentioned, if the lesions were placement occur most likely as a result of mechanical
allowed to become chronic, the defects would likely trauma rather than infectious disease progression. Until
self-resolve. Thus, given the limitations of acute defects further well-designed studies demonstrate the feasibility
and the challenges associated with establishing LIPI, the of inducing LIPI with spontaneous progression in pigs,
appropriateness of the minipig model for peri-implantitis dogs represent the preferred animal model for experi-
research may be questioned. mental peri-implantitis.
Some limitations of the present review must be
acknowledged. Firstly, the quality of the included studies Supplementary Information
was judged to be moderate and a large heterogeneity was The online version contains supplementary material available at ​h​t​t​​p​s​:​/​​/​d​o​​i​.​​o​r​
g​/​1​0​.​1​1​8​6​/​s​4​0​7​2​9​-​0​2​4​-​0​0​5​7​2​-​9​​​​.​ ​​
observed in terms of the experimental settings, which
Shanbhag et al. International Journal of Implant Dentistry (2024) 10:55 Page 11 of 12

Summary and consensus statements. The 4th EAO Consensus Conference

Supplementary Material 1 2015. Clin Oral Implants Res. 2015;26 Suppl 11:202-6.
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upon request. We also thank Regina Kufner Lein fromthe University of Bergen of bone reconstructive therapies in the management of peri-implantitis.
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and approved the final manuscript. tissue engineering in oral peri-implant defects in preclinical in vivo
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Funding 2018;12(1):e336–49.
This work was partially supported by the International Team of Implantology 13. Pellegrini G, Seol YJ, Gruber R, Giannobile WV. Pre-clinical models for oral and
(ITI Research Grant 1712–2022), the ICOI Implant Dentistry Research and periodontal reconstructive therapies. J Dent Res. 2009;88(1065).
Education Foundation (IDREF Grant 2023) and Helse Vest Norway (F-12124). 14. Stavropoulos A, Sculean A, Bosshardt DD, Buser D, Klinge B. Pre-clinical in vivo
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Declarations
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Consent for publication
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Not applicable.
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The authors declare no competing interests.
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Not applicable.
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