JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No.

5 (604 - 610): Bone Formation and Reosseointegration in Peri-implantitis Def

Bone Formation and Reosseointegration in

Peri-implantitis Defects Following Surgical
Implantation of rhBMP-2
Oliver Hanisch, DMD, MS/Dimitris N. Tatakis , DDS, PhD/Milos M. Boskovic, DDS/Michael D.
Rohrer, DDS, MS/Ulf M. E. Wikesjö, DDS, PhD

This study was designed to evaluate bone formation and reosseointegration following surgical
implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) in
peri-implantitis defects. Hydroxyapatite-coated dental implants were placed bilaterally in the
mandibular and maxillary premolar area in four rhesus monkeys and were allowed to
osseointegrate for 1 year. Cotton ligatures were then placed around the healing abutments,
and plaque was allowed to accumulate for 11 months. Resulting circumferential
peri-implantitis defects exhibited a large intrabony and horizontal component. At
reconstructive surgery, peri-implantitis defects in contralateral jaw quadrants were randomly
assigned to receive rhBMP-2 (0.43 mg/mL implant volume) in an absorbable collagen sponge
carrier or a carrier control. The animals were sacrificed 4 months postsurgery, and block
sections were prepared for histometric analysis. Summary statistics included means calculated
per animal. Paired t tests were used to evaluate differences between experimental conditions (n
= 4). Defect depth amounted to 3.4 ± 0.9 mm and 3.2 ± 0.9 mm for rhBMP-2 and control
defects, respectively. Vertical bone gain in rhBMP-2 defects (2.6 ± 1.2 mm) was significantly
greater than in controls (0.8 ± 0.8 mm; P < .01). Reosseointegration within the confines of the
defect for rhBMP-2 defects (29.0 ± 10.5%) differed significantly from that in the control (3.5 ±
2.5%; P < .01). Reosseointegration within the extent of newly formed bone averaged 40.0 ±
11.0% in rhBMP-2 defects as compared to 8.9 ± 7.8% in the control (P < .01). Osseointegration
in resident bone amounted to 69.5 ± 6.9% and 72.6 ± 8.0% for rhBMP-2 and control defects,
respectively. There is significant evidence that rhBMP-2 has potential to promote bone
formation and reosseointegration in advanced peri-implantitis defects in a demanding
nonhuman primate model.
(INT J ORAL MAXILLOFAC IMPLANTS 1997;12:604–610)
Key words: bone formation, bone morphogenetic protein, dental implants, nonhuman primates, osseointegration,
peri-implantitis

I mplant dentistry has emerged to represent an alternative/supplement to conventional prosthetic

therapy in completely and partially edentulous patients.1-3 However, implant failures have also
been reported.4,5 Current hypothesis associates bacterial infection and/or biomechanical overload
with implant failures.5-11 For treatment of ailing implants, several procedures, including
antimicrobial, resective, and regenerative therapy, have been suggested. 12-21 Optimal treatment,
however, must include regeneration of lost alveolar support. Guided bone regeneration, when
applied to peri-implantitis defects, has resulted in some success; however, results of studies are
inconclusive.13,15,16,21

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An ideal method for replacing lost alveolar bone would be to stimulate endogenous bone growth.
Urist observed that demineralized bone matrix may induce de novo cartilage and bone formation when
implanted in extraskeletal sites.22 Further study identified a group of noncollagenous matrix proteins,
termed bone morphogenetic proteins (BMPs), that were thought to be responsible for observed cartilage
and bone induction.23 Since then, it has been demonstrated that BMPs promote bone formation in
several animal models.23
By means of molecular cloning and subsequent expression in recombinant systems, Wang et al
obtained a homogenous, recombinant human BMP (rhBMP-2).24 Implantation of rhBMP-2 in a rat
ectopic model induced new cartilage and/or bone formation.25 Furthermore, rhBMP-2 has been shown to
induce bone formation in rodent and ovine femur and in canine mandible segmental defects.26-28 It has
also been shown to support alveolar bone and cementum formation in periodontal models,29-31 and
alveolar bone formation and osseointegration in surgical supra-alveolar peri-implant defects.32 Possibly,
surgical implantation of rhBMP-2 may emerge as a treatment for peri-implantitis defects as well. Thus,
this study was designed to evaluate bone formation and reosseointegration following surgical
implantation of rhBMP-2 in peri-implantitis defects.
Materials and Methods
Animals and Anesthesia. Four systemically healthy, adult female rhesus monkeys (Macaca mulatta;
weight 9 to 11 kg) were used. Animal selection, management, and surgical protocol followed routines
approved by Loma Linda University Institutional Animal Care and Use Committee. Animals were
housed in standard cages with free access to water and were fed a standard soft diet. Ketamine HCl
anesthesia (Ketalar, Parke-Davis, Morris Plains, NJ; 10 mg/kg intramuscularly) was used for all
procedures. Routine dental infiltration anesthesia was used at the surgical sites.
Implant Placement. All premolar and first molar teeth were extracted in the maxilla and mandible.
Resulting alveolar ridges were allowed to heal for 3 months. Mucoperiosteal flaps were then raised to
expose the completely healed ridges. Implant sites were prepared, and two 10-mm hydroxyapatite- (HA)
coated cylindrical implants (Bio-Vent, Dentsply, Encino, CA) were placed in each jaw quadrant. The
flaps were repositioned and sutured.

Defect Induction. Defect induction has been recently described.33 Briefly, implants were uncovered,
and healing abutments were connected. Complete healing without peri-implant osseous defects was
confirmed by clinical examination. Four weeks following abutment connection, cotton ligatures were
placed immediately apical to the mucosal margin at the abutments, and plaque control measures were
abandoned to allow submucosal plaque accumulation. Ligatures were changed monthly for 10 months.
Plaque accumulation was then allowed to continue without ligatures for 1 more month. Submucosal
microbiota associated with defect induction was monitored by nonselective and selective culture
techniques and by DNA probe analysis.
Reconstructive Surgery. Following defect induction, the animals were placed in a plaque-control
program. Three times weekly, teeth and healing abutments were brushed with a soft toothbrush, and were
exposed to a 2% chlorhexidine solution (Chlor hexidine gluconate, ICI Pharmaceutical Group,
Wilmington, DE). Reconstructive surgery followed 4 weeks of plaque control. For defect access, buccal
and lingual mucoperiosteal flaps were raised after a midcrestal incision was made extending into
intrasulcular incisions around healing abutments and adjacent teeth. The epithelial lining facing the

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implants was excised. Healing abutments were removed and peri-implant defects were carefully debrided
using stainless steel curettes without touching the implant surface. Implant surfaces were treated with a
yarn-saturated citric acid solution for 60 seconds,34 and an air-powder abrasive (Prophy-Jet, Dentsply)
for 15 seconds, with the spray vector directed perpendicular to the implant surface (Fig 1).35
Peri-implant defects in contralateral jaw quadrants were randomly assigned to receive surgical
implants consisting of rhBMP-2 (> 98% purity, 0.43 mg/mL implant volume; Genetics Institute,
Andover, MA) in an absorbable type I collagen sponge carrier (Helistat, Integra Life Sciences,
Plainsboro, NJ), or the carrier alone (control). Several layers of the carrier were molded around the
implants (Fig 1). To achieve tension-free wound closure, the periostea were fenestrated at the base of the
flaps. The mucoperiosteal flaps were then adapted using horizontal mattress and single interrupted
sutures (Gore-Tex Suture CV5, W.L. Gore & Associates, Flagstaff, AZ) to submerge the
collagen-covered implants.
Buprenorphine hydrochloride (Buprenorphine HCl, Reckitt & Colman Pharmaceuticals, Richmond,
VA) was administered 0.01 mg/kg intramuscularly every 12 hours for 48 hours for immediate
postsurgery pain control. Cephazolin sodium (Ceph azolin, Apothecon, Princeton, NJ) was administered
50 mg/kg intramuscularly 3 times daily for 1 week for postsurgery infection control. Postsurgery plaque
control was provided by daily topical application of the 2% chlorhexidine solution for 2 weeks.
Recordings. Intrasurgery peri-implant defect morphology recorded to the nearest 0.5 mm at the
buccal, lingual, mesial, and distal aspect of the implants using a calibrated periodontal probe (CP 15
UNC, Hu Friedy, Chicago, IL) included defect depth (distance from the fundus of the defect to the
implant top surface), defect margin (distance from the fundus of the defect to the most coronal point of
the alveolar crest), and defect width (distance between the most coronal point of the alveolar crest and
the implant surface). All recordings were performed by investigator OH. Intraoral radiographs were
obtained to document peri-implant bone support immediately postsurgery and at 4, 8, 12, and 16 weeks
postsurgery. Postsurgery complications, including exposed implants and mucosal peri-implant
inflammation, were recorded.
Histologic Procedures. The animals were sacrificed 16 weeks postsurgery using intravenous
concentrated sodium pentobarbital. Implants were resected en block with the surrounding bone and soft
tissue. Block sections were fixed in 10% buffered formalin, dehydrated in alcohol, and embedded in
specialized resin. They were cut midaxially in mesiodistal sections of 200-µm thickness using the
cutting-grinding system devised by Donath.36 One section from each specimen was ground to 10 µm and
stained in 1% toluidine blue for histologic and histometric analysis. The other section was ground to 80
µm and used unstained for fluorescence microscopy evaluation.
Histometric Analysis. Undecalcified specimens were analyzed using a microcomputer-based image
analysis system (Image-Pro Plus, Media Cybernetics, Silver Spring, MD). The following measurements
were recorded for the mesial and distal surfaces for each implant:
• Defect depth: distance between the fundus of the defect and the implant top surface
• Vertical bone gain: distance between the fundus of the defect and the most coronal extension of bone
formation
• Reosseointegration within the defect: percent bone-implant contact between the fundus of the defect
and the implant top surface

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• Reosseointegration within newly formed bone: percent bone-implant contact between the fundus of the
defect and the most coronal extension of newly formed bone contacting the implant surface
• Osseointegration within resident bone: percent bone-implant contact within resident bone
Statistical Analysis. Summary statistics included means (±SD) calculated per implant for each
maxillary and mandibular jaw quadrant, and for each monkey. Paired t tests were used to evaluate
differences between experimental conditions, with the animal as the statistical unit (n = 4). A P value of
< .05 was chosen for statistical significance.
Results
Clinical Observations. At reconstructive surgery, 31 of 32 dental implants were immobile; one implant
was mobile and was removed. The ligature-induced circumferential peri-implant defects exhibited large
vertical and horizontal components without statistically significant differences between maxillary and
mandibular sites (Fig 1; see also ref 33).
Primary wound closure was achieved in all sites during reconstructive surgery. Seven of 31 implants
became exposed during the 16-week healing interval, and showed no or minor signs of mucosal
inflammation. Six of the exposed implants had received the carrier control, and one had received
rhBMP-2. The difference between treatments was statistically significant (Chi square test, P < .05). The
exposure of the rhBMP-2–treated implant regressed between week 1 and week 4 postsurgery and
remained stable with minimal exposure. For the control, the number of exposed implants, as well as the
amount of exposure, increased over time.
Radiographic Observations. Radiographic observations revealed initial radiopacity at week 4
postsurgery for rhBMP-2 defects. Eight-, 12-, and 16-week observations exhibited increasing radiopacity
(Fig 2). Control defects exhibited limited, if any, suggestion of mineralized tissue formation.
Histologic Observations. Bone formation following surgical implantation of rhBMP-2 varied
between animals. One animal exhibited limited bone formation in the rhBMP-2 defects. The remaining
three animals exhibited a clear distinction between rhBMP-2 and control defects (Figs 3 and 4). For these
animals, bone formation generally comprised 70% to 100% of the defect height in rhBMP-2–treated
defects. The newly formed bone exhibited a trabecular pattern and cortical condensation closely
resembling that of the resident bone (Fig 4). The newly formed bone was predominantly of lamellar
nature. Areas of reosseointegration to the previously plaque-exposed implant surface were evident;
however, the reosseointegration appeared to be reduced as compared to the osseointegration in the
resident bone (Fig 4). Bone formation in controls was limited except for one mandibular defect, which
exhibited complete regeneration of a dense trabecular nature. There were no appreciable differences in
extent and nature of bone formation between maxillary and mandibular defects.
The implant’s HA coating generally was absent within the defect area. In contrast, the part of the
implant that was integrated in resident bone commonly exhibited HA coating.
Histometric Observations. The peri-implant defects exhibited a depth of 3.4 ± 0.9 mm and 3.3 ± 0.9
mm for rhBMP-2 and control defects, respectively (Fig 5). Vertical bone gain was significantly enhanced
in rhBMP-2 defects (2.6 ± 1.2 mm) compared to control defects (0.8 ± 0.8 mm; P < .01; Fig 5). The
rhBMP-2 defects exhibited significantly higher reosseointegration within the confines of the defect and
within the extent of newly formed bone compared to the control (P < .01; Fig 6). Reosseointegration
within the confines of the defect was significantly lower than osseointegration in the resident alveolar

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bone for rhBMP-2 and control defects (P < .01). Reosseointegration within the extent of newly formed
bone also differed significantly from osseointegration in the resident alveolar bone for rhBMP-2 and
control defects (P < .01). There were no significant differences between maxillary and mandibular
defects for any histometric parameter.
Discussion
This study evaluated bone formation and reosseointegration following surgical implantation of rhBMP-2
in advanced peri-implantitis defects and a 16-week healing interval in nonhuman primates. Vertical bone
gain was three times greater in both the maxilla and the mandible in rhBMP-2–treated defects than in the
controls. The rhBMP-2–treated defects exhibited significantly higher reosseointegration within the
confines of the defect area and within the extent of newly formed bone as compared to the controls;
however, reosseointegration was significantly lower than the osseointegration in resident bone.
The present study used nonhuman primate peri-implantitis defects resulting from ligature-enhanced
plaque accumulation around HA-coated implants.33 The defects exhibited a submucosal microbiota
associated with peri-implantitis and advanced periodontal disease in humans, including Porphyromonas
gingivalis, Bacteroides forsythus, and Fusobacterium species. The resulting osseous defects exhibited
complex morphology, commonly combining large vertical and horizontal components. The implant
surfaces displayed calculus formation as a result of longstanding plaque accumulation.33 This preclinical
model features several characteristics of human peri-implantitis, and appears adequate to evaluate the
potential for bone regeneration and reosseointegration in peri-implantitis defects.
Considerable vertical bone gain and reosseointegration following surgical implantation of rhBMP-2
was shown in the present study. Previous studies have evaluated guided bone regeneration with or
without bone substitute implants in peri-implantitis defects in the micro pig21 and in beagle
dogs.13,15,16 Grunder et al could not demonstrate new bone formation following guided bone
regeneration around titanium implants in the beagle dog. However, the plaque-induced defects were
mainly horizontal and may not allow significant bone formation.13 Jovanovic et al16 reported histologic
evidence of bone formation and reosseointegration following guided bone regeneration in vertical,
plaque-compromised, surgical defects around uncoated titanium, titanium plasma-sprayed, and
HA-coated implants in dogs. The authors suggested that reosseointegration was enhanced at HA-coated
implants. Surgical reentry data from Hürzeler et al15 using guided bone regeneration in plaque-induced
intrabony peri-implantitis defects in the beagle dog around uncoated titanium implants appear to
corroborate the findings of Jovanovic et al.16 The present study presents histologic and histometric
evidence demonstrating that surgical implantation of rhBMP-2 has potential to support new bone
formation and reosseointegration in advanced peri-implantitis defects around HA-coated dental implants.
In the present study, reosseointegration within newly formed bone was significantly lower than
osseointegration within resident bone. Differences in osseointegration may relate to the observation
interval, and a longer healing period might allow bone remodeling with increased reosseointegration. The
reduced reosseointegration may also relate to the implant surface detoxification protocol. Noxious
residues remaining at the implant surface may potentially compromise reosseointegration. One may also
speculate that altered implant-surface characteristics following the citric acid and air-powder abrasive
detoxification protocol influenced reosseointegration. The HA coating appeared generally absent within
the defect area. The chemical-mechanical treatment may thus have modified the implant surface to a
lower osseointegration potential.37-39

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Seven of 31 implants became exposed over the healing interval in the present study. Six of the
exposures occurred in control defects. Only one exposure was observed in the rhBMP-2–treated defects.
The difference between treatments was statistically significant. Observed differences in mucosal healing
could be an effect, either directly or indirectly (because of the bone-inductive process), of rhBMP-2.
Conclusion
The present study presents evidence that rhBMP-2 has a strong potential to promote bone formation and
reosseointegration in advanced peri-implantitis defects in a demanding nonhuman primate model. These
observations suggest a clinical utility of rhBMP-2 in the rescue of the peri-implantitis–compromised,
implant-supported/-retained prosthesis, but also in less demanding maxillary or mandibular alveolar
defects, and in conjunction with surgical placement of dental implants in compromised bony sites.
Acknowledgments
The authors are indebted to Dr Pablo Peres and Dr Thorarinn Sigurdsson for surgical assistance, to
Ms Lisa Jin for technical support, and to Dr Paul McMillan for histometric analysis support. Technical
support and rhBMP-2 were provided by Genetics Institute, Andover, Massachusetts. Funding was
provided by Dentsply, Encino, California, and by Loma Linda University, Loma Linda, California.

Oliver Hanisch

Assistant Professor, Department of

Prosthodontics, University of Aachen, Aachen,
Germany. Center for Prosthodontics and Implant
Dentistry, Loma Linda University, Loma Linda,
California.

Dimitris N. Tatakis

Associate Professor, Department of Periodontics,

Loma Linda University, Loma Linda, California.

Milos M. Boskovic

Assistant Professor, Center for Prosthodontics and

Implant Dentistry, Loma Linda University, Loma
Linda, California.

Michael D. Rohrer

Footnotes 6
 Professor, Hard Tissue Research Laboratory,
University of Oklahoma, Oklahoma City, Oklahoma.

Ulf M. E. Wikesjö

Professor, Department of Periodontics, Loma

Linda University, Loma Linda, California.

FIGURES

Figure 1a

Fig. 1a Osseous morphology at reconstructive surgery for reentered defect.

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Figure 1b

Fig. 1b rhBMP-2 construct in situ; the implants are completely covered.

Figure 1c

Fig. 1c Reentry osseous morphology of defect shown in Fig 1a. Newly formed bone
approaches the top surface of the implants.

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Figure 2a-b

Figs. 2a and 2b Radiographs of implants shown in Fig 1 (left) prior to reconstructive surgery
and (right) 16 weeks postsurgery.

Figure 3

Fig. 3 Photomicrograph of control defect. New bone formation cannot be appreciated. The
arrows indicate the base of the induced defect (toluidine blue stain, original magnification ×1).

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Figure 4a

Fig. 4a Photomicrograph of the rhBMP-2–treated defect shown in Fig 2. The defect area
reveals new bone formation to the top surface of the implant. The trabecular and cortical
components of newly formed bone closely resemble that of the resident bone. The arrows
indicate the base of the defect (toluidine blue stain, original magnification ×1).

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Figure 4b

Fig. 4b Higher magnification of the defect shown in Fig 2. The arrows indicate the coronal and
apical extension of reosseointegration (toluidine blue stain, original magnification ×40).

Figure 5

Fig. 5 Mean (±SD) histometric defect depth and vertical bone gain following reconstructive
surgery of peri-implantitis defects, including an rhBMP-2 implant or a carrier control (**P ≤ .01;
n = 4).

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Figure 6

Fig. 6 Mean (±SD) reosseointegration within the confines of the defect (DROSS), within the
extent of newly formed bone (BROSS), and osseointegration in the resident bone (OSS)
following reconstructive surgery of peri-implantitis defects, including an rhBMP-2 implant or a
carrier control (**P ≤ .01; n = 4).

Bone Formation and Reosseointegration in Peri-implantitis Defects Following

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