Peri-implantitis is defined as an inflammatory disease affecting the tissues around osseointegrated functioning implants. Unfortunately, detailed peri-implantitis pathogenesis is not well understood and current treatments lack predictability. Compare the healing potential of late-stage ligature-induced periodontitis and peri-implantitis after ligature removal. Four-week-old C57BL/6J male mice had their left maxillary molars extracted. After 8 weeks, implants were placed in healed sockets and allowed to osseointegrate. Mice were separated into control (no ligature) and experimental (ligature) groups. In the experimental group, ligatures were placed around the implant and the contralateral second molar. Four weeks later, the ligature group was randomly divided into ligature-retained and ligature-removed groups. Mice were sacrificed at 2 time points: 1 and 2 weeks after ligature removal. The samples were analyzed by microcomputed tomography (micro-CT) and histology. Ligature-induced significant bone loss in peri-implantitis and periodontitis were compared with respective controls. At the 2-week time point, bone formation was observed in the ligature-removed groups compared with respective controls; however, more bone was regained in periodontitis ligature-removed compared with the peri-implantitis ligature-removed group. Histologically, the peri-implantitis ligature-retained group had higher inflammatory levels and a higher number of osteoclasts compared with the periodontitis ligature-retained group. Moreover, in the peri-implantitis ligature-retained group, collagen appeared less organized compared with the periodontitis ligature-retained group at both time points; although collagen tended to reorganize following ligature removal in both conditions. Peri-implantitis does not respond to treatment as well as periodontitis. Future work includes understanding peri-implantitis pathogenesis and developing predictable treatment protocols.

Introduction

Peri-implantitis and periodontitis are defined as inflammatory diseases affecting the soft and hard tissues around osseointegrated functioning implants and teeth.1  Peri-implantitis is a growing concern because it affects ∼45% of all patients with implants and ∼14% present with moderate to severe disease.2  Moreover, current treatment modalities for peri-implantitis, which are derived from therapeutical options for treating periodontitis,35  are unpredictable.68 

The etiology of peri-implantitis is multifactorial, resembling periodontitis,9  and includes a complex interaction between the bacterial biofilm and the host's protective immune response. In addition, risk factors associated with peri-implantitis have also been associated with periodontitis, including poor oral hygiene, tobacco use, diabetes, and genetic factors.9  Moreover, history or current periodontitis status has been reported as a predictive risk factor for peri-implantitis.914  Although peri-implantitis and periodontitis have pathophysiologic similarities, several studies have suggested pathophysiologic differences between the 2 conditions.1517 

Considering the current knowledge, we hypothesize that peri-implantitis is a more aggressive disease and does not respond as well to treatment when compared to periodontitis. To address this question, we used an established murine model of experimental peri-implantitis and periodontitis18,19  that resembles late-stage conditions to compare how peri-implantitis and periodontitis respond after the elimination of the insult (ligature).

Materials and Methods

Mice

Thirty-five C57BL/6J 4-week-old male mice (at least [n ≥ 3] mice/group/time point) (The Jackson Laboratory, Bar Harbor, Maine) were used according to the Chancellor's Animal Research Committee of the University of California, Los Angeles guidelines for all the experiments. In addition, the Animal Research: Reporting in Vivo Experiments guidelines were followed.20  Mice were fed a soft diet (Bio-Serv; Frenchtown, NJ) ad libitum for the duration of the experiment.

Tooth extraction, implant placement, and induction of periodontitis and peri-implantitis

Left maxillary molars were extracted from 35 one-month-old C57BL/6J male mice. Eight weeks after extraction, 1 mm × 0.5 mm titanium implants (DP Machining Inc, La Verne, Calif) were placed in the edentulous socket. The implants were allowed to osseointegrate for 4 weeks.18,21  Following implant osseointegration (28 implants osseointegrated), mice were randomly separated into control (no ligature) and experimental (ligature) groups. In the experimental group, mice received 6-0 silk ligatures (P.B.N. Medicals, Stenløse, Demark) placed immediately apical to the implant head and on the contralateral second molar, in a split mouth design. To resemble late-stage disease, ligatures were kept for 4 weeks without intervention. After 4 weeks, the experimental group was randomly divided into ligature-retained and ligature-removed groups. The ligature-retained group kept the ligatures for the duration of the whole experiment, and the ligature-removed group had their ligatures removed. All mice were sacrificed at 2 time points: 1 and 2 weeks from the date of ligature removal (Figure 1a and b). Maxillae were harvested and imaged using a digital optical microscope (VHX-1000; Keyence, Osaka, Japan), fixed in 4% formalin for 24 hours, and stored in 70% ethanol.

Figure 1

Schematic diagrams. (a) Schematic diagram depicting the timing of the experimental design. (b) Schematic diagram specifying the number of samples that were used for the study.

Figure 1

Schematic diagrams. (a) Schematic diagram depicting the timing of the experimental design. (b) Schematic diagram specifying the number of samples that were used for the study.

Micro-computed tomography scanning

Maxillae were imaged using micro-computed tomography (micro-CT; Model 1172; SkyScan, Kontich, Belgium) at 10 μm resolution.18,21  Linear bone loss measurements were performed using Dolphin software (Navantis, Toronto, Canada). In brief, the second molars were oriented such that the cementoenamel junction (CEJ) was parallel in the coronal plane. The axial plane represented the middle of the second molar crown. Measurements were taken from the CEJ to the alveolar bone crest (ABC).18,21  Implants were oriented such that the head and the shaft of the implant were perpendicular to each other in the sagittal plane.18  A single blind examiner recorded measurements in the mesial, distal, buccal, and palatal locations for both teeth and implants. Measurements were averaged per mouse to create a mean bone loss value for each implant or tooth.

Histology

Samples were decalcified in 15% EDTA for 4 weeks.18,21  Samples were stained with hematoxylin and eosin (H&E), picrosirius red (Polysciences, Inc, Warrington, Pa), and tartrate-resistant acid phosphatase (TRAP; Sigma-Aldrich, St Louis, Mo), according to the manufacturer's protocol. Osteoclasts, TRAP+ cells with ≥2 nuclei in contact with the bone,22  were counted in the area immediately adjacent to the teeth and implants along the ABC (n = 3/group/time point).

Statistical analysis

Thirty-five mice were included in the study. Each mouse had an implant placed in the left maxilla and the teeth on the contralateral right side were used for the experiments performed on the groups with teeth. However, prior to the ligature placement 7 implants were lost; therefore, those implant samples could not be used in the study. Figure 1b depicts the numbers of samples that were used for each experimental group.

Bone loss measurements were represented as mean ± SEM. Osteoclast numbers were normalized to their respective controls (tooth experimental to tooth control groups, implant experimental to implant control groups). Significance between groups was compared using 2-way analysis of variance (ANOVA) and a Bonferroni correction post-test (Prism 5; GraphPad Software, La Jolla, Calif). Levels of significance were as follows: P < .05*, P ≤ .01**, P ≤ .001***.

Results

Clinical assessment of periodontitis and peri-implantitis, ligature-retained and ligature-removed groups

Clinically, peri-implantitis and periodontitis ligature groups presented with generalized soft tissue edema in comparison with the respective control groups at the 1- and 2-week time points. Gingival edema decreased following ligature removal for peri-implantitis and periodontitis, at both time points (Figure 2a). However, the peri-implantitis ligature-removed groups appeared to still have some edema compared with the periodontitis ligature-removed groups at both time points.

Figure 2

Representative clinical images and micro-computerized tomography (micro-CT) analysis of periodontitis and peri-implantitis after insult removal. (a) Representative clinical images of control (no ligature), ligature-retained, and ligature-removed groups of teeth (periodontitist) and implants (perio-implantitis) at magnification ×50. Images were taken after 1 (top row) and 2 (bottom row) weeks of insult removal. Soft tissue edema present in periodontitis and peri-implantitis ligature-retained groups subsided following ligature removal for both conditions. (b) Representative sagittal micro-CT images of control (C), ligature-retained (L), and ligature-removed (Rx) groups of teeth (periodontitis) and implants (peri-implantitis) 1 and 2 weeks after insult removal. (b) Graphs represent the averaged distance from the cementoenamel junction to the alveolar bone crest in teeth and from the implant head to the alveolar bone. Data are mean ± SEM. *P < .05, **P < .01, ***P < .001 (n ≥ 3 for all groups/time points). Note that once ligature was removed, the teeth regained more bone compared with the implant ligature-removed group.

Figure 2

Representative clinical images and micro-computerized tomography (micro-CT) analysis of periodontitis and peri-implantitis after insult removal. (a) Representative clinical images of control (no ligature), ligature-retained, and ligature-removed groups of teeth (periodontitist) and implants (perio-implantitis) at magnification ×50. Images were taken after 1 (top row) and 2 (bottom row) weeks of insult removal. Soft tissue edema present in periodontitis and peri-implantitis ligature-retained groups subsided following ligature removal for both conditions. (b) Representative sagittal micro-CT images of control (C), ligature-retained (L), and ligature-removed (Rx) groups of teeth (periodontitis) and implants (peri-implantitis) 1 and 2 weeks after insult removal. (b) Graphs represent the averaged distance from the cementoenamel junction to the alveolar bone crest in teeth and from the implant head to the alveolar bone. Data are mean ± SEM. *P < .05, **P < .01, ***P < .001 (n ≥ 3 for all groups/time points). Note that once ligature was removed, the teeth regained more bone compared with the implant ligature-removed group.

Radiographic assessment of periodontitis and peri-implantitis, ligature-retained and ligature-removed groups

There was statistically significant linear bone loss in the peri-implantitis and periodontitis ligature-retained and ligature-removed groups compared with their respective controls at both time points (Figure 2b and c). For the 2-week time point, the linear bone height for peri-implantitis and periodontitis were 0.431 ± 0.019 mm and 0.377 ± 0.027 mm, respectively, whereas the bone height for the controls were 0.218 ± 0.012 mm and 0.181 ± 0.005 mm. For the 1-week time points, the numbers were not too far different. Two weeks after ligature removal, there was statistically significant bone gain in the periodontitis and peri-implantitis ligature-removed groups compared with their respective controls. The linear bone heights measured 0.261 ± 0.013 mm for teeth and 0.375 ± 0.014 mm for implants (Figure 2c). However, the peri-implantitis ligature-removed group had less changes in bone height compared with the periodontitis ligature-removed group.

Histologic assessment of periodontitis and peri-implantitis, ligature-retained and ligature-removed groups

The tissues surrounding the implants were associated with higher levels of inflammation with or without the ligatures (Figure 3). Ligature-induced inflammation and bone resorption was observed in teeth and implants. However, peri-implantitis developed higher levels of inflammation and bone resorption compared with periodontitis. Closer examination also showed that new bone accumulated during active periodontitis (ligature-retained group), but not in peri-implantitis. In both diseases, removal of the ligature allowed new bone formation; nonetheless, this phenomenon was far more evident in the periodontitis ligature-removed group compared with the peri-implantitis ligature-removed group. New bone formation during active and recovering periodontitis was notably concentrated around the periodontal ligament (PDL) area, and the direction of the early bone formation appeared to be parallel with that of the PDL.

Figure 3

Histologic evaluation after insult removal in periodontitis and peri-implantitis. Representative sagittal hematoxylin and eosin (H&E) images of control (C), ligature-retained (L), and ligature-removed (Rx) groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis. (a, b) 1-week time point of periodontitis and peri-implantitis at magnifications ×100 and ×200 (c, d) 2-week time point of periodontitis and peri-implantitis at magnifications ×100 and ×200. Note higher levels of inflammation in peri-implantitis control, ligature-retained, and ligature-removed groups as compared with the respective periodontitis groups. Also note new bone formation in periodontitis, which is concentrated around the periodontal ligament area. New bone formation was minimal in peri-implantitis groups. Yellow arrows point at bone formation sites, evident by reversal lines.

Figure 3

Histologic evaluation after insult removal in periodontitis and peri-implantitis. Representative sagittal hematoxylin and eosin (H&E) images of control (C), ligature-retained (L), and ligature-removed (Rx) groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis. (a, b) 1-week time point of periodontitis and peri-implantitis at magnifications ×100 and ×200 (c, d) 2-week time point of periodontitis and peri-implantitis at magnifications ×100 and ×200. Note higher levels of inflammation in peri-implantitis control, ligature-retained, and ligature-removed groups as compared with the respective periodontitis groups. Also note new bone formation in periodontitis, which is concentrated around the periodontal ligament area. New bone formation was minimal in peri-implantitis groups. Yellow arrows point at bone formation sites, evident by reversal lines.

Osteoclasts assessment of periodontitis and peri-implantitis, ligature-retained and ligature-removed groups

For both time points, the peri-implantitis ligature-retained groups presented with a statistically significantly greater osteoclast fold difference compared with their respective controls and ligature-removed groups (Figure 4a and b). Moreover, the peri-implantitis ligature-retained and ligature-removed groups presented with a greater osteoclast fold difference compared with the periodontitis ligature-retained and ligature-removed groups.

Figure 4

Osteoclast numbers after insult removal in periodontitis and peri-implantitis. (a) Representative sagittal of tartrate-resistant acid phosphatase (TRAP) stained images of control, ligature-retained, and ligature-removed groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis at magnification ×10. (b) Graphs represent the averaged number of osteoclasts at 1 and 2 weeks after insult removal in periodontitis and peri-implantitis groups normalized to their respective controls (n = 3/group/time point). *P < .05, **P < .01 (n ≥ 3 for all groups/time points).

Figure 4

Osteoclast numbers after insult removal in periodontitis and peri-implantitis. (a) Representative sagittal of tartrate-resistant acid phosphatase (TRAP) stained images of control, ligature-retained, and ligature-removed groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis at magnification ×10. (b) Graphs represent the averaged number of osteoclasts at 1 and 2 weeks after insult removal in periodontitis and peri-implantitis groups normalized to their respective controls (n = 3/group/time point). *P < .05, **P < .01 (n ≥ 3 for all groups/time points).

Collagen assessment of periodontitis and peri-implantitis, ligature-retained and ligature-removed groups

The collagen matrix around teeth and implants was assessed through picrosirius red staining under polarized light (Figure 5). For all groups, at all time points, the soft tissues around teeth presented with greater yellow birefringence than the soft tissues around implants. These signals are suggestive of type 1 collagen, which predominates around teeth. Control teeth, periodontitis ligature-retained, and periodontitis ligature-removed groups presented with collagen fibers organized parallel in between the molars and inserting into the cementum. In contrast, the peri-implantitis control groups presented with less type 1 collagen, and the collagen was loosely organized in a parallel manner. After the addition of ligatures, collagen integrity and organization further decreased in the peri-implantitis group. By the second week after ligature removal, collagen regained some organization in the peri-implantitis ligature-removed group by the second week, but was still not as organized as the periodontitis ligature-removed group.

Figure 5

Collagen organization after insult removal in periodontitis and peri-implantitis. Representative sagittal images of picrosirius red staining under polarized light of control, ligature-retained, and ligature-removed groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis at magnification ×10. Note greater and more organized type 1 collagen (yellow birefringence) in periodontitis vs peri-implantitis across all groups and time points.

Figure 5

Collagen organization after insult removal in periodontitis and peri-implantitis. Representative sagittal images of picrosirius red staining under polarized light of control, ligature-retained, and ligature-removed groups 1 and 2 weeks after insult removal in periodontitis and peri-implantitis at magnification ×10. Note greater and more organized type 1 collagen (yellow birefringence) in periodontitis vs peri-implantitis across all groups and time points.

Discussion

As mentioned already, peri-implantitis is a growing concern because it affects approximately half of the patients with dental implants2  and current treatment modalities are unpredictable.35  Therefore, to further our understanding of peri-implantitis, we evaluated treatment of late-stage peri-implantitis and compared it with periodontitis utilizing a murine model of ligature-induced peri-implantitis and periodontitis.

An animal model was chosen given the limitations of studying the pathophysiology of peri-implantitis in humans, such as lack of controlled environment, unknown disease onset,23  and ethical dilemmas.24,25  Among the animal models available to study peri-implantitis and periodontitis, the use of ligatures to induce disease has been widely accepted model.26  The ligature model was first described by Rovin et al using rats,27  and has since been used to successfully induce and study periodontitis in larger animals such as dogs and non-human primates.2832  Among the murine models of peri-implantitis, there are 2 models available, a ligature-induced peri-implantitis and P. gingivalis (P.g.)-induced model.33  We elected to use the ligature-induced because it is more widely accepted and bypasses differences in colonization. To assess how late-stage peri-implantitis lesions respond to treatment, linear bone loss, inflammation level, osteoclasts, and collagen distribution/type were monitored at 1 and 2 weeks from ligature removal.

Bone loss is one of the characteristic features of peri-implantitis and periodontitis. Based on the micro-CT analysis and histologic data, striking differences were observed between the responses of peri-implantitis and periodontitis to treatment (ligature removal). Insult removal led to significant new bone formation in periodontitis, and minimal bone formation in peri-implantitis. However, even the ligature-retained periodontitis group appeared to have bone formation, suggesting that periodontitis has bone formation even in the presence of ligature-induced inflammation. The bone formation in the periodontitis ligature-retained and periodontitis ligature-removed groups was adjacent to the PDL cells, suggesting that the reduced bone formation potential in the peri-implantitis groups could potentially be explained due to the lack of PDL around implants. The PDL not only possesses cells that can readily differentiate and assist in bone formation, but these cells are ready to produce bone when proper signals are present.34 

Bone formation and resorption involves an intimate interaction between osteoblasts and osteoclasts (OCs).35  Given that OCs are responsible for bone resorption, we assessed OCs numbers through histologic staining. The peri-implantitis lesions contained a higher number of OCs compared to periodontitis, which is in line with previously published research.36  The ligature-retained periodontitis lesions, however, did not reflect a fold increase of osteoclasts when compared with their respective control groups. This could partially be attributed to the length of the experiment, since these lesions resembled more of a chronic condition and less cells were present to induce osteoclasts. In terms of peri-implantitis treatment (peri-implantitis-ligature removal), there was a decrease in OC at both time points; however, the fold difference was still statistically greater than the control implant group after 1 week. This finding was not observed in the periodontitis ligature-removed group, as compared with the periodontitis with ligature-retained, suggesting that peri-implantitis experiences a delay in the signals to halt osteoclast differentiation when compared with periodontitis, which could partially explain the pathophysiologic differences between the 2 conditions.

The evaluation of soft tissue inflammation in our study demonstrated that the composition of the inflammatory infiltrate between peri-implantitis and periodontitis differs, which is in agreement with previously published research.37  To further characterize disease resolution after treatment of late-stage disease, extracellular matrix differences, collagen composition, and organization were evaluated with picrosirius red. Picrosirius red staining allows for the visualization of collagen fibers under polarized light38  and key differences between peri-implantitis and periodontitis were noted. The control peri-implantitis group showed less collagen fibers compared with the control periodontitis group, which correlates with previous studies,37  and corroborates with the notion that, in health, the absence of the PDL and transseptal fibers leads to a weaker biologic barrier. Furthermore, the peri-implantitis ligature-retained group presented critical structural differences. The collagen bundles appeared thinner and fiber distribution was highly affected by inflammation, evident by a weaker and more disorganized birefringence. On the other hand, thick collagen fibers were produced supracrestally around teeth, separating the area of ligature insult from the bone, which could potentially play a protective feature that is absent around implants. After insult removal, collagen remained largely disorganized by the first week, but somewhat reorganized by the second week in both groups; however, collagen organization in the peri-implantitis ligature-removed group remained less prominent. Our data, in conjunction with previously published work, support the idea that implant connective tissue adhesion has poorer mechanical resistance compared with natural teeth.15 

In conclusion, late-stage peri-implantitis treatment does not respond as well compared with periodontitis as seen by less bone formation, higher inflammation levels, delay in the reduction of OC numbers, and less organized type 1 collagen. Though peri-implantitis and periodontitis share some etiologic and clinical characteristics, our data showed that higher levels of inflammation/bone resorption associated with peri-implantitis and the intrinsic ability of the PDL to repair bone around the teeth are some of the main features of why periodontitis responds significantly better than peri-implantitis to treatment. These differences should be taken into consideration when designing a treatment protocol for peri-implantitis. This model should allow for future investigation to evaluate disease progression and healing, as well as aid in developing therapeutic approaches.

Abbreviations

    Abbreviations
     
  • ANOVA

    analysis of variance

  •  
  • ABC

    alveolar bone crest

  •  
  • C

    control

  •  
  • CEJ

    cementoenamel junction

  •  
  • H&E

    hematoxylin and eosin

  •  
  • L

    ligature-retained

  •  
  • micro-CT

    micro-computerized tomography

  •  
  • OCs

    osteoclasts

  •  
  • PDL

    periodontal ligament

  •  
  • Rx

    ligature-removed

  •  
  • TRAP

    tartrate-resistant acid phosphatase

Acknowledgments

This work was supported by the University of California-Los Angeles School of Dentistry Seed Grant. RW was supported by the American Academy of Implant Dentistry and the UCLA Clinical and Translational Science Institute, NIH 5TL1TR000121-05. SH was supported by NIH/NIDCR T90 DE022734-01. We would like to thank the Translational Pathology Core Laboratory from the UCLA David Geffen School of Medicine for assistance with preparing the decalcified histologic sections.

Note

The author(s) declare no potential conflicts of interest with respect to the authorship and or publication of this article.

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