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Regenerative Treatment of Peri-implantitis
A randomized clinical trail.
Catrine Isehed
Supervisor: Professor Stefan Renvert and
Anders Holmlund
1.1
Regenerative Treatment of Per-implantitis. A randomized
clinical trial.
1.2
Introduction
Biological complications in implant dentistry are referred to as peri-implant mucositis
and peri-implantitis. Peri-implantitis was defined as an inflammatory process
affecting the tissues around an osseointegrated implant in function, resulting in loss of
supporting bone and peri-implant mucositis was defined as reversible inflammatory
changes of the peri-implant soft tissues without any bone loss (1). The prevalence of
peri-implantitis seems to be between 28% and 56% of subjects and in 12% and 43%
of implants (2). Risk indicators for peri-implant diseases are poor oral hygiene, a
history f periodontitis and cigarette smoking (3).
Therapies proposed for the management of peri-implant diseases appear to be
based on the evidence available for treatment of periodontitis. Most publications on
treatment of peri-implant lesions in humans report individual cases treated by
combined procedures, aimed at reducing the bacterial load within the peri-implant
pocket . The concept that bacteria play a major role in the etiology of peri-implant
mucositis and peri-implantitis is well documented (4,5).
No single method to decontaminating implants mechanically was found to be
superior, and so far it is not known if the adjunctive use of antibiotics in surgical
therapy of peri-implantitis is required (7). In peri-implantitis lesions non-surgical
therapy was not found to be effective (8). Animal research has demonstrated that it
may be possible to regenerate bone and even to obtain re-osseointegration on a
previously infected implant surface. Different regenerative therapies have been
proposed for humans and many case reports are available in the literature (7).
Enamel matrix derivative (EMD) is a protein extract purified from porcine enamel
and has been introduced in clinical practice to promote periodontal tissue regeneration
(9). In a recent review it was concluded that “overall the data support the positive
effect of EMDs on osteoblastdifferentiation” (10). It was concluded 2004 a gain of
attachment with more than 4mm is twice as common in treatment of peridontal
defects with EMD compared with surgery alone (11).
Few studies are available evaluating the results of EMDs in conjunction with implant
treatment. An vitro study reported that EMD enhanced cell proliferation and viability
of human SaOs(2) osteoblasts on SLA titanium implants in a concentration-dependent
manner (12).
If the loss of osseointegration is more pronounced it is not possible to either treat the
infection or to accomplish new bone regeneration in the defects using a non-surgical
approach. Surgery may be needed to obtain access to the infected surface and to use a
regenerative approach. As the literature regarding treatment of peri-implantitis is
scarce, randomized clinical trails of peri-implantitis treatment are needed.
1.3
Aim
The aim with the proposed study is to determine whether healing of peri-implantitis
lesions using surgical debridement and detoxification of the implant surface is
affected by the use of enamel matrix derivate. Ho hypothesis .
1.4
Question at issue
We intend to assess:

the clinical effects of enamel matrix proteins on peri-implant defects.

the microbial changes after a regenerative surgical procedure
Outcome variables:

The primary outcome measures are;
o clinical probing pocket depth values (PPD)
o changes in “bone levels” (presence of mineralization in conjunction
with the implant measured at periapical radiograph)
o the extent of gingival inflammation (bleeding on probing- BOP)
o recession of the peri-implant mucosal

The secondary outcome measures are
o the presence and proportions of bacterial strains in peri-implant
pockets.

The third outcome measure is the prevalence of implant loss.
1.5
Method
Patient screening – selection
Patients will be recruited at a specialist clinic for Periodontology therapy. A
preliminary evaluation will identify patients with implants diagnosed as having periimplant infections.
Exclusion criteria

Subjects with uncontrolled diabetes mellitus (HbA1c > 7,0)

Subjects requiring antibiotic prophylaxis

Subjects taking prednisolone or other anti-inflammatory prescription drug

Subjects taking medications known to have effects on gingival growth

Subjects with a history of taking systemic antibiotics in the preceding 3
months
Inclusion criteria - Presence of peri-implantitis
Following a review of the medical history (see exclusion criteria) a full mouth routine
periodontal examination including analysis of available radiographs will be
performed.

Subjects who consent to participate and have a minimum of one
osseointegrated implant with angular peri-implant bone loss
o Peri-implant marginal bone loss≥ 2mm as determined from a
comparison of the bone level one
reconstruction
with
the
bone
level
year following implant
at
screeningradiograph,
or
o  3 mm in depth as determined from a periapical radiograph, which
includes the total loss of bone.
o In combination with probing pocket depth ≥5 mm together with
bleeding and/or pus on probing using 0.25 N probing force.
Any periodontal infection in the remaining dentition should be treated prior to
baseline measures.
Measurements
One and the same examiner, unaware of treatment group for the patient, will perform
all the measurements. An intraindividuell calibration study will be performed.
Clinical measurements at baseline(BL), 6 and 12months. At BL and end-point 12
months PPD measuring after removal of screw-retained superstructure.
a. Probing pocket depth (PPD) (4 sites/implant).
b. Recession of the mucosal margin (4 sites/implant)
c. Bleeding on probing (BOP) (4 sites/implant)
d. Presence/absence of plaque (4 sites/implant)
e. Presence/absence of suppuration (4 sites/implant)
f. Full mouth plaque score (FMPS) (4 sites per tooth/implant)
g. Full mouth bleeding score ( FMBS) (4 sites per tooth/implant)
BOP will be assessed dichotomously at a force of 0.25 N with a manual pressure
sensitive probe (Hawe Click probe) at 4 sites per tooth/implant. FMBS and FMPS will
be calculated as the percentage of total surfaces that bleed on probing/presence of
plaque.
Intraoral radiographs
Intraoral standardised radiographs of the implant site will be taken at BL and 12
months. A parallel technique will be used. Full set of intraoral radiographs of all
teeth/implants at BL (if radiographs not older than 3 months are not available).
Microbial analysis - Enumeration of organisms using DNA probes
Microbial sampling from the deepest site of each qualifying implant at BL, 2weeks, 3
month, 6 month and 12 month after treatment. Checkerboard DNA-DNA
hybridization, for bacterial species will be used. (13)
Treatment procedure – randomization.
One surgeon will proceed all surgery.

Intrasulcular incision and vertical releasing incisions when needed (at a
distance of about 10mm from the implant) to required adequate access.

Removal of chronic inflammatory tissue using titanium curettes.

Surface decontamination – by rubbing the implant surface with saline soaked
foam pellets, followed by extensive rinsing with saline 2 x 20 ml.
Now randomization is performed and depending on the result of the randomization,
application of EMD will be used or not. Random assignment will be performed
according to pre-defined randomisation.

The flaps are replaced and sutured with 5/0 polyamid non-resorbable sutures
without tension. If needed a periosteal releasing incision is made.
Intrasurgical measurements will be made following debridement of the defect at 4
aspects.

The distance from the restoration margin to the base of the defect (mm)

The distance from the alveolar bone crest to the base of the defect (mm)

Horizontal width of the defect i.e. the distance from the implant surface to the
bony wall (mm).

The defect morphology will be described (circumferential, crater, wide,
angular, narrow).
Post-operative pain will be controlled with paracetamol as required. All patients will
be instructed to rinse twice daily with chlorhexidine mouthrinse (0.12% or 0,2%) and
to use modified oral hygiene procedures for the first 6 postoperative weeks following
access flap surgery. Patients will be advised not to chew on the treated area during the
first two weeks post-operative. Post-operative follow up at 2, 3 and 6 weeks.
Maintenance care
During year 1 a maintenance care program will be provided every 3rd month. At each
maintenance care appointment FMPS will be recorded. Patients will receive
professional prophylaxis as required.
Subject protection – monitoring of adverse events
In case of any adverse events necessary treatment will be provided according to the
current standard of care.
Power
If a PPD reduction of 1mm is to be detected at  = 0.05 and a power of  = 0.2, the
appropriate number of subjects per group would be around n = 25. Hence, it is
foreseen to incorporate approximately 50 subjects in the study.
Statistics
Longitudinal study with repeated measures: numerical data: para t-test or ANOVA,
categorical data: Chi square test. (?)
1.6 Ethical consideration
Clinical data and testresults will be registered at the general procedure in the patient
journal. All scientific data will be identified by the code number. Individual data will
not be reported. General principle of secrecy will be applied. Whenever patient want
to leave the study it is her decision.
Reduction of pocket depth, bleeding at implantsites and a decreased risk of disease
progression are the expected due to earlier studies. The complications caused by the
treatment (a surgery procedure) may be tenderness, but does not differ from the
treatment of practice. After a risk-benefit analysis no ethichical problems have been
detected.
1.6
Importance
Surgical approach has been used in treatment of per-implantitis but todays
information of efficiency is unknown. It is necessary to improve treatments of periimplantitis due to the fact that at least 28-56% of patients with implants within 10
years show peri-implantitis, and some implants are lost.
1.7
Time plan
The study is a single-center, randomized, case-control study over 12 months. Patient
enrolment into the study will be completed within 18 months from the beginning of
the study.
1.8 Financial calculation
The treatment of peri-implantitis is time consuming and the additional cost for EMD
is expensive. It is of great importance that the healing outcome is predictable and
possible to communicate with the patient when therapy decision is decided.
One year of study is calculated to 300 000:-, to be compared with a cost of 7-9000:per treatment, EMD included.
1.8
References
(1) Albrektsson T. & Isidor F. Consensus report of session IV. In: Lang, N.P. &
Karring, T. (eds): Proceedings of the First European Workshop on
Periodontology,1994; 365-369. Quitessense
(2) Zitzmann N.U. and Berglundh T. Definition and prevalence of peri-implant
diseases. J Clin Periodontol 2008; 35 (Suppl. 8): 286-291.
(3) Heitz-Mayfield L.J.A. Peri.implant diseases: diagnosis and risk indicators. J
Clin Periodontol 2008; 35 (Suppl. 8):292-304.
(4) Berglundh T, Lindhe J, Marinello C, Ericsson I. and Liljenberg B. Soft tissue
reaction to de novo plaque formation on implants and teeth. An experimental
study in the dog. Clinical Oral Implants Research 1992; 3:1-8.
(5) Pontoriero, R., Tonetti, M.P., Carnevale, G., Mombelli, A., Nyman, S.R. and
Lang, N.P. (1994) Experimentally induced peri-implant mucositis. A clinical
study in humans. Clinical Oral Implants Research 1994; 5: 254-259.
(6) Leonardt Å, Renvert S, and Dahlén G. Microbial findings at failing implants.
Clinical Oral Implant Research;1999: 10:339-345.
(7) Claffey N, Clarke E, Polyzois I and Renvert S. Surgical treatmen of periimplantitis.J Clin Periodontol 2008; 35 (Suppl. 8): 316-332
(8) Renvert S, Roos-Jansåker A-M and Claffey N. Non-surgical treatment of periimplant mucositis and per-implantitis: a literaure review. J Clin Periodontol
2008; 35 (Suppl. 8): 305-315
(9) Bosshardt D.D. Biological mediators and periodontal regeneration: a review of
enamel matrix proteins at the cellular and molecular levels. J Clin Periodontol
2008; 35 (Suppl. 8): 87-105.
(10)
Jiang J, Goodarzi G, He J, Li H, Safavi KE, Spangberg LS, Zhu Q.
Emdogain-gel stimulates proliferation of odontoblasts and osteoblasts. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:698-702.
(11)
SBU-rapport Kronisk parodontit - prevention, diagnostik och
behandling. 2004 ISBN: 91-87890-96-8.
(12)
Schwarz F, Rothamel D, Herten M, Sculean A, Scherbaum W, Becker
J. Effect of enamel matrix protein derivative on the attachment, proliferation,
and viability of human SaOs(2) osteoblasts on titanium implants. Clin Oral
Investig. 2004; 8:165-71
(13)
Socransky, S,S., Haffajee, A,D., Smith, C., Martin, L., Haffajee, J.A.,
Uzel, N,G., and Goodson, J.M. Use of checkerboard DNA-DNA hybridization
to study complex microbial ecosystems. Oral Microbiology Immunology,
2004;19: 352-362.