Long-Term Results of GuidedTissue Regeneration Therapy WithNon-Resorbable and BioabsorbableBarriers. III. Class II Furcations After10 YearsPeter Eickholz,* Bernadette Pretzl,† Rolf Holle,‡ and Ti-Sun Kim†

Background: The aim of this 10-year follow-up was to eval-uate the long-term results after guided tissue regeneration (GTR)therapy of Class II furcation defects using non-resorbable andbioabsorbable barriers clinically.

Methods: In nine patients with advanced periodontitis, ninepairs of contralateral Class II furcation defects were treated.Within each patient, one defect received a non-resorbable ex-panded polytetrafluoroethylene barrier (ePTFE; C) and theother a bioabsorbable (polyglactin 910; T) barrier by randomassignment. At baseline and 12 and 120 – 6 months after sur-gery, clinical parameters were obtained.

Results: Twelve and 120 months after GTR therapy, statis-tically significant (P <0.05) horizontal clinical attachment level(CAL-H) gain was observed in both groups (C12: 1.9 – 0.5mm; C120: 1.1 – 1.3 mm; T12: 1.9 – 0.8 mm; T120: 1.7 –1.4 mm). However, one patient with furcations that had beenassessed as Class I 12 months after GTR therapy had losttwo teeth after 10 years, and another patient had lost morethan 2 mm CAL-H at one furcation from 12 to 120 – 6 monthspost-surgery 10 years after implantation of an ePTFE barrier.Horizontal bone sounding revealed similar bone gain in bothgroups 120 – 6 months post-surgery (C120: 0.8 – 1.0 mm;T120: 1.1 – 1.1 mm).

Conclusions: CAL-H gain achieved after GTR therapy inClass II furcations was stable after 10 years in 15 of 18 defects(83%). The study failed to show a statistically significant differ-ence in stability of CAL-H gain between group C and T 10 yearsafter GTR therapy. J Periodontol 2006;77:88-94.

KEY WORDS

Furcation defects/therapy; guided tissue regeneration;membranes, artificial; polytetrafluoroethylene/therapeuticuse.

Guided tissue regeneration (GTR)provides the potential for estab-lishing a new connective tissue

attachment after periodontal surgery us-ing non-resorbable membranes1-3 andbioabsorbable barriers4 in humans histo-logically. Several clinical studies com-pared therapy according to the GTRprinciple using non-resorbable expandedpolytetrafluoroethylene (ePTFE)§ as wellas bioabsorbable barriers and conven-tional periodontal surgery, revealing morefavorable results for GTR therapy in ClassII furcation defects, particularly in man-dibular molars,5-7 maxillary molars,8 andbuccal9 and mesiolingual10 maxillary fur-cations. The removal of non-resorbablebarriers requires a second surgical pro-cedure after 4 to 6 weeks. Clinical studiescomparing GTR therapy of Class II furca-tion lesions with non-resorbable and bio-absorbable barriers demonstrated similarresults for short-term periods: 5 to 6months,11,12 12 months,13-15 and 24months.16 Long-term results are scarce.17

To our knowledge, there have been nostudies comparing the results 10 yearsafter implantation of non-resorbable andbioabsorbable barriers.

The objective of this follow-up studywas to compare the results of periodontaltherapy, according to the GTR principle,

* Department of Periodontology,Center for Dental, Oral, and Maxillofacial Medicine,University Hospital Frankfurt, Frankfurt, Germany.

† Section of Periodontology, Department of Conservative Dentistry, Clinic for Oral, Dental,and Maxillofacial Diseases, University Hospital Heidelberg, Heidelberg, Germany.

‡ Institute of Health Economics and Health Care Management, GSF-National ResearchCenter for Environment and Health, Neuherberg, Germany.

§ Gore-Tex Periodontal Membrane, W.L. Gore, Flagstaff,AZ.

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with non-resorbable and bioabsorbable barriers clini-cally and radiographically over a 10-year period in theClass II furcation defect subgroup of a population thathad already been evaluated after 6,12 24,16 and 6017

months.

MATERIALS AND METHODS

PatientsNine patients (three males and six females), rangingin age from 34 to 58 years (46.9 – 9.3 years) and un-der treatment for advanced periodontal disease at theSection of Periodontology, Department of Conserva-tive Dentistry, Clinic for Oral, Dental, and Maxillofa-cial Diseases, University Hospital Heidelberg, tookpart in the present study. Each patient exhibited onepair of similar contralateral Class II furcation defects.After recruitment of the patients, the study, risks, be-nefits, and procedures were explained, and informedconsent was obtained. The study was approved bythe Institutional Review Board for Human Studies ofthe University of Heidelberg. Patients were enrolledin the study from October 1993 to October 1994.The patients investigated in this study were theClass II furcation subsample of a sample describedbefore.12,16,17

Clinical and Radiographic ExaminationsThe gingival index (GI) and plaque index (PI)18 wereassessed at six sites per tooth (mesiobuccal, midbuc-cal, distobuccal, distolingual, midlingual, and mesio-lingual). Probing depths (PD) and vertical probingclinical attachment levels (CAL-V) were measuredto the nearest 0.5 mm using a straight periodontalprobe.i As a reference for the CAL-V measurementsthe cemento-enamel junction (CEJ) was used. If theCEJ was destroyed by a restoration (filling or crown)the margin of this restoration served as reference.Further, the clinical horizontal probing attachmentlevels (CAL-H) were assessed to the nearest 0.5 mmat each furcation location using a color-coded, cali-brated Nabers probe, marked at 3-mm intervals.¶5,19

As a reference for this measurement, we used a tan-gent to the roots adjacent to the scored furcation.The degree of furcation involvement was calculatedfrom the CAL-H according to Hamp et al.20: degree0 = no furcation involvement; degree I = CAL-H £3mm; degree II = CAL-H >3 mm, but the defect doesnot encompass the whole furcation; degree III = com-plete furcation. At 12 and 120 – 6 months post-sur-gery, clinical parameters were assessed again (GI,PI, PD, CAL-V, and CAL-H). During the 120-monthexamination, the horizontal probing bone level(PBL-H) was assessed to the nearest 0.5 mm under lo-cal anesthesia at all but two furcations using a color-coded, calibrated Nabers probe that was marked at 3-mm intervals. All clinical parameters at the baseline

and at the 12-month examination were assessed byone examiner (PE). Examinations at 120 – 6 monthswere performed by another examiner blinded with re-gard to treatment assignment and previously as-sessed clinical parameters (BP). Patients whoreported smoking >10 cigarettes per day were classi-fied as smokers. Three smokers took part in the pres-ent study. In the course of a previous study all patientsin this analysis had been retrospectively tested for theinterleukin-1b polymorphism group using a commer-cially available test kit.#17 Therefore, a foam swab wasmoved over cheek mucosa for 20 seconds to samplecells that were then sent for analysis to the laboratory.

Periodontal SurgeryPeriodontal surgery was performed first on the defecton the patient’s left side. Treatment of the defect onthe right side was performed 1 to 3 weeks later. Foreach patient, treatment assignment was made ac-cording to a table of random digits;21 one side wouldreceive a non-resorbable barrier (control) and theother a bioabsorbable barrier (test).** The surgicalprocedure has been described in detail before.12,16

After reflection of a mucoperiosteal flap and removalof inflammatory granulation tissue, PBL-H was mea-sured to the nearest 0.5 mm at each furcation usinga color-coded, calibrated probe marked at 3-mm in-tervals. GTR surgery in all patients was performedby one author (PE).

To prevent post-surgical infection, 1 million IU ofpropicillin was prescribed 3 times daily for 1 week.The patients rinsed with a 0.2% chlorhexidine gluco-nate solution†† for 2 minutes, two times daily, for 5to 7 weeks after surgery. During this time, all patientswere seen at least every other week for the control andgentle cleaning of teeth under GTR therapy. If expo-sure of a barrier was noted, the patient was advisedto use a 1% chlorhexidine gluconate gel‡‡ once daily.Four to 6 weeks after temporary implantation, non-resorbable barriers were removed in a second surgicalprocedure. Thereafter, patients were placed on amaintenance program that included oral hygiene in-struction and professional tooth cleaning once every3 months for the first 2 years. Later on, most patientswere seen for supportive maintenance every 4 to 6months. Each supportive-maintenance visit includedthe assessment of a full-mouth bleeding (gingivalbleeding index, or GBI)22 and plaque score (plaquecontrol record, or PCR).23 A patient who compliedto at least one supportive-maintenance visit per yearat the Section of Periodontology, Department of

i PCPUNC 15, Hu-Friedy, Chicago, IL.¶ PQ2N, Hu-Friedy.# GenoType PRT Parodontitis-Risiko-Test, Advanced Diagnostic Systems

GmbH, Nehren, Germany.** Vicryl Membrane, Ethicon GmbH & Co. KG, Norderstedt, Germany.†† Corsodyl, Fink GmbH, Herrenberg, Germany.‡‡ Corsodyl Gel, Fink GmbH.

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Conservative Dentistry, Clinic for Oral, Dental, andMaxillofacial Diseases, University Hospital, Heidelberg,was classified as having regular recalls. Four patientsdid not comply with this regimen.

Statistical AnalysisThe main outcome variable for the comparison of thetherapeutic effects of test and control treatments wasthe change of CAL-H. CAL-V and PBL-H change wereconsidered secondary endpoints. All other clinical(GI, PI, and PD) parameters were considered controlvariables. The patient was defined as the statisticalunit. Hence, for each patient and barrier material,measurements at the furcation site were used for anal-ysis. If more than one pair of Class II furcation defectshad been treated within one patient, the defect pairwith the more pronounced horizontal attachment losswas selected for analysis. All clinical parameters weretested for normal distribution using the Kolmogorov-Smirnov-Lilliefors test. For the comparison of testand control treatments, the changes from baseline to12- and 120-months later were calculated as differ-ences. Due to the small sample size and the high var-iability of results, these differences for test and controlgroups were compared using the non-parametricWilcoxon test. To check whether the study had ade-quate statistical power, we calculated the test powerfor a type I error probability of a <0.05, a clinically rel-evant difference between test and control d = 1 mm,and the observed standard deviation of the differencesbetween test and control for the main outcome vari-able.24 Statistical analysis was performed using a per-sonal computer program.§§

RESULTS

Clinical ParametersNine patients, contributing nine pairs of similar con-tralateral Class II furcation defects, were investigated inthis study. The characteristics of these patients (age,number of recall visits, mean full-mouth bleedingscore, mean full-mouth plaque score of all recall vis-its, and interleukin-1b polymorphism) and the loca-tion of Class II furcation defects are given in Table1. Three patients were classified as smokers, andone had type II diabetes mellitus (Table 1). Four pa-tients failed to comply with regular supportive main-tenance visits (Table 1).

From the 5-17 to the 10-year examination,patient 2 had lost all teeth. Thus, both Class II furca-tion defects that had been contributed by this patientwere lost for the 10-year analysis. All 10-year com-parisons are based on eight pairs of defects. Meanand standard deviation of PI, GI, and PD at baseline,12, and 120 months after surgery are shown in Table2. There are small mean vertical attachment gains inboth groups at 12 months after surgery that are statis-tically significant for the test group (Table 3). Tenyears post-surgery in the polyglactin 910 group, morethan half of the mean CAL-V gain was lost again(Table 3). The ePTFE group lost all mean CAL-V gainafter 10 years, with a singular severe vertical attach-ment loss in patient 1 (Table 3). The study failed toshow statistically significant differences between the

Table 1.

Patient Characteristics

Patient Age

Teeth

Defect Site

Regular

Recalls

Number of

Recalls

Mean – SD

GBI*

Mean – SD

PCR† Smoking

Interleukin-1b

Polymorphism OtherTest Control

1 34 18 31 Lingual + 21 1.4 – 2.4 4.1 – 3.3 + — —

2 39 14 3 Distolingual — 14 10.9 – 8.7 44.4 – 17.3 + + —

3 40 31 18 Buccal — 11 4.5 – 4.3 18.5 – 5.0 — — —

4 37 3 14 Distolingual + 23 6.5 – 9.2 23.7 – 15.5 + — —

5 54 30 19 Lingual + 21 1.5 – 2.0 12.6 – 10.2 — — —

6 58 15 2 Buccal — 13 3.2 – 9.2 24.9 – 9.2 — — —

7 53 3 14 Distolingual + 18 5.3 – 5.5 27.1 – 12.5 — + —

8 57 19 30 Lingual — 15 6.5 – 5.6 39.1 – 19.4 — + Type II diabetes

9 50 3 14 Mesio/distolingual + 16 1.6 – 2.2 12.9 – 9.5 — + —

* Mean – SD of full-mouth bleeding scores of all recall visits.† Mean – SD of full-mouth plaque scores of all recall visits.

§§ Systat for Windows, version 10, Systat, Evanston, IL.

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test and control groups regarding CAL-V gain at 12 or120 months after surgery.

Statistically significant CAL-H gains were observedat 12 and 120 months after the use of polyglactin 910barriers and ePTFE membranes (Table 4). In bothgroups there was a small, but statistically insignificantmean CAL-H loss from month 12 to 120 (Table 4). Nostatistically significant differences could be found forCAL-H gain between both barrier materials 12 months

post-surgery with a test power of5% and 120 months after surgerywith a test power of 39%. How-ever, two teeth (one test and onecontrol) in one patient had beenlost from the 5- to 10-year ex-amination. In another patient,10 years after implantation of aePTFE barrier, one furcation hadlost more than 2 mm CAL-Hfrom 12 to 120 – 6 months post-surgery.

Bone ParametersPBL-H measured intrasurgically(baseline) and obtained by bonesounding under local anesthesiawithout reflection of a mucoper-iosteal flap (120 months) areshown in Table 5. A PBL-H gainof 1.1 mm was observed in thetest group and a gain of 0.8 mmin the ePTFE group. PBL-H gainin the test group was statisticallysignificant (P <0.05) (Table 5).Regarding PBL-H gain, the studyfailed to show statistically signifi-cant differences between poly-glactin 910 and ePTFE (Table 5).

DISCUSSION

Several studies have revealed more favorable clinicalresults after GTR therapy of Class II furcation defectswith non-resorbable or bioabsorbable membranesthan after conventional surgery.5-10 Most studiescomparing clinical results after GTR therapy of ClassII furcations with non-resorbable and bioabsorbablebarriers failed to observe statistically significant orclinically relevant differences for observation periods

Table 2.

Plaque Index, Gingival Index, and Probing Depth*

Plaque Index Gingival Index Probing Depth

Polyglactin 910 ePTFE Polyglactin 910 ePTFE Polyglactin 910 ePTFE

Baseline 0.9 – 0.9 1.1 – 0.9 1.9 – 0.3 1.8 – 0.4 5.4 – 1.5 4.9 – 1.6

12 months 0.9 – 0.9 0.7 – 0.9 0.6 – 0.9 0.6 – 0.9 2.8 – 0.7 2.6 – 0.6

Change 0.0 – 1.0 -0.4 – 1.4 -1.3 – 1.1 -1.2 – 0.8 -2.6 – 1.5 -2.3 – 1.5

120 months 0.5 – 0.9 0.3 – 0.7 0.5 – 0.9 0.9 – 1.0 3.5 – 0.4 3.9 – 1.8

Change -0.4 – 1.8 -0.8 – 1.2 -1.4 – 0.9 -0.9 – 1.2 -1.9 – 1.3 -1.0 – 2.6

* Mean – SD.

Table 3.

Vertical Attachment Levels (mm)

Polyglactin 910 ePTFE

Patient Baseline 12 Months 120 Months Baseline 12 Months 120 Months

1 8.5 6.0 8.5 5.0 4.5 9.5

2 7.5 6.5 * 5.5 5.0 *

3 5.0 4.0 4.5 2.5 2.5 4.0

4 7.0 3.5 5.5 6.0 3.0 3.5

5 4.0 4.0 5.0 3.5 4.5 4.5

6 7.0 5.0 5.0 9.0 5.0 6.0

7 4.0 4.0 6.0 6.0 6.0 6.0

8 6.0 5.0 4.5 6.0 5.5 3.5

9 7.0 4.5 5.0 5.0 3.5 5.5

Mean – SD 6.2 – 1.6 4.7 – 1.0 5.5 – 1.3 5.4 – 1.8 4.4 – 1.2 5.3 – 2.0

Change to baseline 1.5 – 1.2† 0.7 – 1.5 1.0 – 1.6 0.1 – 2.5

Change 12 to 120months

-0.8 – 1.1 -0.9 – 2.0

* Tooth lost.† P <0.05.

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up to 24 months.11-16 To our knowledge, only onestudy has reported long-term results (5 years)after GTR therapy of Class II furcation defects withnon-resorbable or bioabsorbable membranes.17 Thisfollow-up study was undertaken to go beyond the ob-servation period of 5 years and to examine the long-term results of the Class II furcation subsample ofa previously published 24-month longitudinal study,which compared the results of GTR therapy usingnon-resorbable or bioabsorbable barriers in infrabonyClass II and III furcations.12,16 We did not follow up theClass III furcations because most of them failed to beclosed and some required further surgical interventionbecause of recurrent periodontitis.

The present study revealed less CAL-H gain in de-gree II furcations (12 months: 1.9 mm [test], 1.9 mm[control]; 120 months: 1.7 mm [test], 1.1 mm [con-trol]) than in results reported by Pontoriero et al. 5 6months after use of ePTFE membranes at buccal(4.1 mm) and at lingual (3.3 mm) furcations of man-dibular molars. However, our results are similar tothose reported by Hugoson et al. 13 (1.4 mm [ePTFE]and 2.2 mm [polylactic-acetyltributylcitrate]) andCaffesse et al. 14 (2.3 mm [ePTFE] and 1.8 mm

[polyglycolide/poly-D,L-lac-tide-coglycolide]) at12 monthspost-surgery.CAL-Hgain, frombaseline to 120 months, of 1.7mm in the test group and 1.1mm in the control group werestatistically significant. How-ever, are these small meanlong-term gains clinically rele-vant as well? From a total of18 Class II furcation defects atbaseline, nine (50%) were stillreduced to Class I furcation de-fects 10 years after therapy.Class I furcation defects are as-sociated with a lower risk fortooth loss than Class II furca-tions.25 Although some molarshad returned to Class II furca-tion involvement from 12 to120 months, 16 of the original18 molars were still in function.Taken together, this may beinterpreted as a clinically rele-vant improvement by GTRtherapy.

No statistically significantdifferences could be found forCAL-H gain between both bar-rier materials 12 months post-surgery with a difference of0.06 mm and a test power of

5%, and at 120 months after surgery with a differenceof 0.6 mm and a test power of 39%. This is well belowthe required test power to conclude equivalence.However, the respective differences between testand control are also far below clinical significance.The sample size of this study is small, and it was per-formed at only one center. Thus, the results are diffi-cult to generalize.

The horizontal attachment gain was found to be sta-ble after test and control treatments up to 10 yearspost-surgery. However, two furcations that had beenassessed for Class I furcation involvement 12 monthsafter GTR therapy were lost between the 5- and 10-year examination because the patient lost all teeth(patient 2). In another patient, 10 years after implan-tation of an ePTFE barrier, one furcation had lost 2.5mm of the CAL-H gain that had been observed 12months after therapy (patient 1). Patient 2 exhibitedcertain risk factors for impaired stability of attach-ment gain after GTR therapy.26,27 She was an activecigarette smoker, did not attend regular maintenancevisits, exhibited hyperreactive interleukin-1b polymor-phism, and demonstrated relatively unstable plaquecontrol. However, patient 1 showed mainly favorable

Table 4.

Horizontal Attachment Levels (mm) and Class ofFurcation Involvement

Polyglactin 910 ePTFE

Patient Baseline 12 Months 120 Months Baseline 12 Months 120 Months

1 4.0 3.0 I 3.0 I 4.0 2.5 I 5.0 II

2 4.5 2.5 I * 5.0 3.0 I *

3 5.0 2.5 I 4.0 II 5.0 3.0 I 4.0 II

4 5.0 2.5 I 3.0 I 4.5 2.5 I 3.0 I

5 4.0 3.0 I 2.5 I 4.0 3.0 I 3.0 I

6 5.0 3.0 I 1.0 I 5.5 3.0 I 3.0 I

7 6.0 2.5 I 2.5 I 4.0 2.0 I 1.0 I

8 5.0 3.5 II 4.0 II 5.5 4.0 II 5.5 II

9 4.0 2.5 I 4.0 II 5.0 2.5 I 4.0 II

Mean – SD 4.7 – 0.7 2.8 – 0.4 3.0 – 1.0 4.7 – 0.6 2.8 – 0.6 3.6 – 1.4

Change tobaseline

1.9 – 0.8† 1.7 – 1.4‡ 1.9 – 0.5† 1.1 – 1.3‡

Change 12 to120 months

-0.2 – 1.1 -0.8 – 1.1

* Tooth lost.† P <0.01.‡ P <0.05.

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conditions for GTR therapy with the exception that shewas an active smoker. Although patient 2 lostboth Class II furcation defects, in patient 1, the test de-fect contralateral to the ‘‘losing’’ defect was stable andshowed improved CAL-H at both 12 and 120 monthsafter surgery. It seems that besides patient char-acteristics like smoking, compliance to supportivemaintenance visits, general oral hygiene, geneticcharacteristics, and diabetes site specific factors playa further role in influencing stability.17

Despite some losses, CAL-H gain achieved afterGTR therapy in Class II furcations was stable after10 years in 15 out of 18 defects (83%). Loss of hori-zontal or vertical attachment levels could be attributedto neither barrier material. Concerning stability ofCAL-H gain from 12 to 120 months, the study failedto show a statistically significant difference betweentest and control cases. However, from 12 to 120months, two molars in the test and three molars inthe control group changed from Class I to II furcationinvolvement. Class II furcation defects are associatedwith a higher risk for tooth loss.25 Thus, prognosis ofthese molars has deteriorated.

A statistically significant PBL-H gain of 1.1 mm wasobserved in the test group after 10 years, whereas thePBL-H gain of 0.8 mm that was measured for the con-

trol group failed to reach statistical significance. How-ever, the study failed to show a statistically significantdifference between test and control groups regardingPBL-H gain. Generally, horizontal bone gain was lesspronounced than CAL-H gain. Earlier studies haddemonstrated that attachment and bone levels aretwo different aspects of periodontal healing.28,29

Collection of the clinical parameters at baselineand after 12 months, as well as periodontal surgery,were performed in all patients by the same examiner(PE). This might have introduced some bias. How-ever, the surgical treatment of all patients was spreadover 1 year, and the reexaminations at 12 monthspost-surgery were performed without knowing whichside had been treated with which material. The datawere attributed to test or control after assessment.This and the long intervals between surgery and re-examinations should have eliminated operator bias.Furthermore, bias regarding 10 years of data maybe ruled out because all clinical assessments hadbeen performed by another examiner (BP) blinded totreatment assignments and previous clinical data.

CONCLUSIONS

Under the limitations of the present study, we maydraw the following conclusions: The use of polyglactin910 as a bioabsorbable barrier material may be rec-ommended for use in regenerative periodontal sur-gery of Class II furcation defects to avoid the secondsurgical procedure required to remove non-resorbablemembranes. The horizontal attachment gains achievedafter GTR therapy using non-resorbable and bioab-sorbable barriers can be maintained for 10 years aftersurgery in most Class II furcation defects. Besidespatient characteristics like smoking, interleukin-1bpolymorphism, or diabetes, site-specific factors seemto influence the stability of attachment gains.

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Table 5.

Horizontal Bone Levels (mm)

Polyglactin 910

PBL-H

ePTFE

PBL-H

Patient Baseline

120

Months Baseline

120

Months

1 3.0 3.0 4.0 3.5

2 3.5 * 3.5 *

3 5.5 4.0 4.0 4.5

4 4.0 2.0 4.5 2.0

5 4.0 3.0 4.0 4.5

6 4.5 1.5 5.5 4.0

7 4.5 3.0 6.0 2.0

8 5.0 4.0 5.0 5.5

9 3.5 4.0 4.5 5.0

Mean – SD 4.1 – 0.8 3.0 – 0.6 4.4 – 0.6 3.6 – 1.1

Change to baseline/12 months

1.1 – 1.1† 0.8 – 1.0

* Tooth lost.† P <0.05.

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27. Machtei EE, Grossi SG, Dunford R, Zambon JJ, GencoRJ. Long-term stability of Class II furcation defectstreated with barrier membranes. J Periodontol 1996;67:523-527.

28. Eickholz P, Hausmann E. Evidence for healing ofinterproximal intrabony defects after conventionaland regenerative therapy: Digital radiography andclinical measurements. J Periodontal Res 1998;33:156-165.

29. Eickholz P, Hausmann E. Evidence for healing of ClassII and III furcations 24 months after GTR therapy:Digital subtraction and clinical measurements. J Peri-odontol 1999;70:1490-1500.

Correspondence: Dr. Peter Eickholz, Poliklinik fur Paro-dontologie, Theodor-Stern-Kai 7, D-60590 Frankfurt,Germany. E-mail: eickholz@med.uni-frankfurt.de.

Accepted for publication June 8, 2005.

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