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Periodontal Regeneration – Intrabony
Defects: A Systematic Review From the
AAP Regeneration Workshop
Richard T. Kao,*
†
Salvador Nares,
‡
and Mark A. Reynolds
§
Background: Previous systematic reviews of periodontal regeneration with bone replacement grafts
and guided tissue regeneration (GTR) were defined as state of the art for clinical periodontal regeneration
as of 2002.
Methods: The purpose of this systematic review is to update those consensus reports by reviewing
periodontal regeneration approaches developed for the correction of intrabony defects with the focus
on patient-, tooth-, and site-centered factors, surgical approaches, surgical determinants, and biologics.
This review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)
guidelines for systematic reviews.
A computerized search of the PubMed and Cochrane databases was performed to evaluate the clinically
available regenerative approaches for intrabony defects. The search included screening of original reports,
review articles, and reference lists of retrieved articles and hand searches of selected journals.
All searches were focused on clinically available regenerative approaches with histologic evidence of
periodontal regeneration in humans published in English. For topics in which the literature is lacking,
non-randomized observational and experimental animal model studies were used.
Therapeutic endpoints examined included changes in clinical attachment level, changes in bone
level/fill, and probing depth. For purposes of analysis, change in bone fill was used as the primary out-
come measure, except in cases in which this information was not available. The SORT (Strength of Rec-
ommendation Taxonomy) grading scale was used in evaluating the body of knowledge.
Results: 1) Fifty-eight studies provided data on patient, tooth, and surgical-site considerations in the
treatment of intrabony defects. 2) Forty-five controlled studies provided outcome analysis on the use of
biologics for the treatment of intrabony defects.
Conclusions: 1) Biologics (enamel matrix derivative and recombinant human platelet-derived
growth factor-BB plus b-tricalcium phosphate) are generally comparable with demineralized freeze-
driedboneallograftandGTRandsuperiortoopenflap debridement procedures in improving clinical
parameters in the treatment of intrabony defects. 2) Histologic evidence of regeneration has been dem-
onstrated with laser therapy; however, data are limited on clinical predictability and effectiveness. 3)
Clinical outcomes appear most appreciably influenced by patient behaviors and surgical approach
rather than by tooth and defect characteristics. 4) Long-term studies indicate that improvements in
clinical parameters are maintainable up to 10 years, even in severely compromised teeth, consistent
with a favorable/good long-term prognosis. J Periodontol 2015;86(Suppl.):S77-S104.
KEY WORDS
Controlled clinical trial; patient outcome assessment; periodontal diseases; tissue engineering; reviews.
doi: 10.1902/jop.2015.130685
* Private practice, Cupertino, CA.
† Division of Periodontology, School of Dentistry, University of California at San Francisco, San Francisco, CA.
‡ Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL.
§ Department of Periodontics, School of Dentistry, University of Maryland, Baltimore, MD.
See related practical applications paper in Clinical Advances in Periodontics (February 2015, Vol. 5, No. 1) at www.clinicalperio.org.
J Periodontol • February 2015 (Suppl.)
S77
Periodontitis is commonly characterized by the
formation of intrabony defects. Multiple surgical
approaches for treating intrabony defects have
shown effectiveness in improving clinical and radio-
graphic parameters, such as clinical attachment level
(CAL) and defect depth. Moreover, histologic evidence
demonstrates the potential to achieve regeneration of
the periodontal attachment apparatus—including new
bone, cementum, and periodontal ligament (PDL)—
using different therapeutic approaches.
1-14
However,
limitations in the predictability and effectiveness of re-
generative therapy, including bone replacement grafts
and guided tissue regeneration (GTR), are well docu-
mented in the literature.
15-24
A combination of factors
related to the patient, defect morphology, and surgical
procedure appear to influence the overall predictability
and effectiveness of periodontal regenerative ap-
proaches.
25
Although some of these factors, such as
defect morphology, provide insight into the selection
and treatment strategy for optimizing regenerative
outcome, a clinical need remains for more accurate
predictive models and more robust reconstructive
and regenerative strategies.
This systematic review examines available pub-
lished evidence to address focused questions related
to the predictability and effectiveness of regen-
erative therapies in the treatment of intrabony de-
fects. Case-based scenarios are used to develop
evidence-based recommendations for the use of
regenerative therapy in the management of peri-
odontal intrabony defects in daily clinical practice.
This review is a continuing effort to develop treat-
ment options for optimizing periodontal regenerative
strategies.
SEARCH PROTOCOL
PRISMA Compliance
This review adheres to the 2009 PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-
Analyses) guidelines for systematic reviews.
26
Focused Questions
Focused questions included the following. 1) What is
the evidence for periodontal regeneration in in-
trabony defects related to the following: a) patient-
centered behavioral and systemic considerations; b)
what is achievable and maintainable; c) the in-
fluence of tooth mobility; d) surgical considerations
(flap design); e) surgical considerations (defect
morphology, including width, depth, and contain-
ment); and f) surgical complications, factors to in-
crease stability, and stability relapse management?
2)Whatistheevidenceforthefollowingre-
generative procedures: a) updated classic re-
generative approach (demineralized freeze-dried
bone allograft [DFDBA]; GTR, and GTR combined
with graft materials); b) laser-assisted regeneration
(LAR)
i
; c) enamel matrix derivative
¶
(EMD) (EMD
alone, EMD versus GTR, and EMD combination);
and d) recombinant human platelet-derived growth
factor BB
#
(rhPDGF-BB)? 3) What is the optimal
timing of regenerative treatment of intrabony de-
fects in relation to orthodontic and endodontic
therapy?
Data Sources and Search Strategies
The screening process is outlined in Figure 1, and
search strategies, search words, time frame of the
search, and total number of references identified from
PubMed and Cochrane databases are described in
Table 1. The search strategy attempted to directly
identify the following: 1) new reports of bone graft
and GTR in clinical periodontal regeneration since
October 2002; 2) the role of biologics and laser; 3)
patient, tooth, and surgical considerations for im-
proved regeneration outcome; 4) the relationship of
regenerative therapy outcomes with endodontic and
orthodontic therapy; and 5) short- and long-term (>5
years) regenerative outcomes. For purposes of
analysis, change in bone fill was used as the primary
outcome measure, except in cases in which this in-
formation was not available.
These searches were supplemented by screening
review articles and reference lists of retrieved articles
and preprint online publications of Journal of Peri-
odontology,Journal of Clinical Periodontology, and
Journal of Periodontal Research. In situations in
which the same findings were reported in two sepa-
rate journals, only the most detailed reports were
included, and the secondary report was rejected. All
abstracts were read by two authors (RTK and SN),
and disagreements were resolved by consensus after
discussion with the third author (MAR).
Inclusion criteria. All searches were limited to
regenerative approaches with histologic ‘‘proof of
principle’’ that the periodontal apparatus can be re-
generated in human studies. Evidence from early
studies and approaches have been summarized in
several systematic reviews.
15,16
New regenerative
approaches discussed in this review have provided
similar histologic proof of principle
4,27-32
The search
parameters were limited to studies published in
English using autogenous bone, DFDBA, GTR,
EMD, rhPDGF-BB, and LAR with the neodymium:
yttrium-aluminum-garnet (Nd:YAG) laser. Studies
included randomized clinical trials (RCTs), cohort
studies, and selected case controlled studies. For topics
in which the literature is lacking, non-randomized
iLaser-Assisted New Attachment Procedure (LANAP), Millennium Dental
Technologies, Cerritos, CA.
¶ Emdogain, Institute Straumann, Andover, MA.
# GEM 21S, Osteohealth, Shirley, NY.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
S78
observational and experimental animal model stud-
ies were used.
Exclusion criteria. Exclusion criteria included non-
randomized (e.g., case series and case reports) and
experimental animal model studies in situations
in which there is an inadequate number of RCTs.
In certain new areas of regeneration, case series
were used to supplement and support findings
from RCTs.
Although there are extensive studies on various
bone replacement grafts and platelet-rich plasma
(PRP) preparations, such healing occurs by the for-
mation of long junctional epithelium. Furthermore,
although clinical stability was observed with grafting
strategies, it was not in the scope of this review
because of the lack of human histologic evidence of
periodontal regeneration as reported in a previous
systematic review.
15
Translation for evidence-based recommendations.
The grading system and recommendations were
made based on the SORT (Strength of Recommen-
dation Taxonomy) grading system. The quality and
consistency of evidence were used to define the
strength of recommendation. The quality rating score
system is a three-tier grade that deemphasizes ob-
servational studies, with RCTs receiving highest
score: A) consistent good-quality patient-oriented
evidence; B) inconsistent or limited-quality patient-
oriented evidence; and C) consensus, disease-oriented
evidence, usual practice, expert
opinion, or case series.
33
VARIABLES INFLUENCING
PERIODONTAL
REGENERATION
Patient-Centered
Considerations
Patient-centered variables are
modifiable factors that have
the potential to significantly in-
fluence regenerative outcomes
even under the most ideal sur-
gical conditions. Control of these
variables should be achieved
before initiating regenerative
procedures.
Diabetes mellitus. Studies ex-
amining the physiologic effect of
diabetes mellitus on regenerative
outcomes are lacking, given the
ethical considerations of con-
ducting prospective clinical trials
when comparing regenerative
outcomes in uncontrolled pa-
tients with diabetes with in-
dividuals with well-controlled or
no diabetes. Even with the lack of direct evidence in
humans, recent animal studies confirm the detri-
mental effects on periodontal tissues and the poor
regenerative capacity of animals with diabetes com-
pared with animals without it.
34-36
Moreover, the use of
biomimetic agents, such as EMD, did not improve
the compromised healing response of animals with
diabetes
35
(SORT level C).
Smoking. Smoking is a modifiable factor that is
clearly associated with compromised regenerative
outcomes.
10-12,37
The detrimental effects on oral
tissues appear multifactorial in nature, affecting nu-
merous aspects of the inflammatory and immune
responses.
13
Recent studies comparing regenerative
outcomes and complication rates in smokers with
non-smokers continue to confirm that smokers have
less reduction in probing depth (PD),
11,12
smaller
gains in CAL,
11,12,14,38,39
increases in recession
(REC),
40
significantly less bone fill/bone gain,
10,41
and a higher incidence of membrane exposure
10
and
are less likely to achieve ‡65% defect resolution
42
compared with non-smokers (SORT level A).
Biofilm control. Elements of plaque biofilm have
the capacity to trigger an exuberant proinflammatory
response that counteracts the wound-healing processes
necessary for periodontal regeneration. Clinical studies
demonstrate that poor plaque control and residual
periodontal infection are associated with compro-
mised outcomes after regenerative surgery.
14,43-49
A
Figure 1.
Procedural flowchart of the screening process. CS =case series; C =case report.
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
S79
Table 1.
Search Strategies
Topic of Interest (on intrabony
periodontal regeneration) Search Words (English)
Search Time
Frame (month/
year)
Total
Results
Citations
Used
Quality of
Evidence Used*
(n citations)
Diabetes Periodontal regeneration +diabetes
mellitus +human
10/02 to 3/14 28 3 Level 3 (3)
Tooth mobility Periodontal regeneration +tooth
mobility +human
Up to 3/14 63 3 Level 1 (2)
Level 2 (1)
Splinting Periodontal regeneration +splinting
+human
Up to 3/14 10 3 Level 1 (2)
Level 2 (1)
Non-surgical therapy Periodontal regeneration +non-
surgical therapy +human
10/02 to 3/14 40 2 Level 1 (1)
Level 2 (1)
Smoking Periodontal regeneration +smoking
+human
10/02 to 3/14 103 8 Level 1 (1)
Level 2 (6)
Level 3 (1)
Defect morphology: number of
walls, width, and depth
Periodontal regeneration +defect
morphology +human (152)
10/02 to 3/14 431 6 Level 1 (4)
Periodontal regeneration +bony
walls +human (7)
Level 2 (1)
Periodontal regeneration defect
width +human (43)
Level 3 (1)
Periodontal regeneration defect
depth +human (229)
Access flap surgery Periodontal flap surgery +
periodontal regeneration +
human patients
10/02 to 3/14 429 16 Level 1 (9)
Level 2 (5)
Level 3 (2)
Conservative and minimally
invasive surgery
Periodontal regeneration +
minimally invasive surgery +
human
10/02 to 3/14 38 17 Level 1 (6)
Level 2 (5)
Level 3 (6)
EMDs/enamel matrix proteins Enamel matrix derivatives/enamel
matrix proteins +periodontal
regeneration +human patients
Up to 3/14 110 43 Level 1 (40)
Level 2 (3)
PDGF Platelet-derived growth factor +
periodontal regeneration +
human patients
Up to 3/14 35 8 Level 1 (3)
Level 2 (5)
Laser periodontal therapy Laser periodontal therapy +
periodontal regeneration +
human patients
Up to 3/14 37 2 Level 2 (2)
Orthodontic treatment Orthodontic treatment +
periodontal regeneration +
intrabony/infrabony/intraosseous
defects +human patients
Up to 3/14 69 10 Level 1 (1)
Level 2 (9)
Endodontic treatment Endodontic treatment +
periodontal regeneration +
intrabony/infrabony/intraosseous
defects +human patients
Up 3/14 21 3 Level 2 (3)
*Level 1 =good-quality patient-oriented evidence (meta-analysis and randomized clinical trials); Level 2 =limited-quality patient-oriented evidence (lower-quality
clinical trial with inconsistent findings, cohort study, and case-control study); and Level 3 =other evidence (consensus guidelines, extrapolations from bench research,
usual practice, and case series).
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
S80
full-mouth plaque score and/or full-mouth bleeding
score of £15%,
50-52
£20%,
53,54
and £25%
55-58
have
been reported as measures of acceptable preoperative
oral hygiene (SORT level C).
Tooth-Related Considerations: Mobility
The effect of tooth mobility on regenerative therapy
remains controversial. In a retrospective study com-
paring results between degrees of mobility, Trejo
and Weltman
59
concluded that favorable periodontal
regenerative outcomes were achieved on teeth with
presurgical Miller Class 1 or 2 mobility.
60
After 1
year, no difference in PD and CAL was found between
non-mobile teeth (Class 0) and mobile teeth (Class 1
or 2). Participants maintained low plaque and gin-
gival index scores and were enrolled in a 2- to 3-
month maintenance program to limit inflammation.
59
The therapeutic potential of splinting was revisited by
Schulz et al.
61
Presplinting of mobile teeth treated
using a bone replacement graft resulted in signifi-
cantly reduced PD compared with non-splinted,
grafted teeth at 1 year. The authors conclude that the
observed differences may be attributable to loss of
bone grafting material caused by tooth mobility and
that tooth stability is beneficial to the wound-healing
process when using a bone replacement graft.
61
Cortellini et al.
57
performed GTR therapy on severely
mobile (Class 3), ‘‘hopeless’’ teeth. Twenty-two of
the 25 teeth were splinted preoperatively, and pa-
tients had a high degree of compliance with home
and professional care. After 5 years, 92% (23 of 25)
of teeth were in function with an average gain in
CAL of 7.7 mm at 1 year, which was maintained over
5 years. Siciliano et al.
62
reported on regenerative
outcomes on teeth with primarily 1-wall defects and
Class 1 or 2 mobility. Mobile teeth were splinted
before surgery, and, although no comparison be-
tween splinted and non-splinted teeth was made,
statistically significant improvements were reported
compared with baseline measurements
62
(SORT
level B).
Therapeutic Approaches and Surgical
Considerations
Surgical regenerative strategies diverge primarily
with respect to flap design and use of barrier mem-
branes and materials. Conventional flap access de-
signs primarily focus on buccal and lingual/oral flap
reflection beyond the limits of the intrabony defect,
whereas minimally invasive surgical approaches
primarily focus on conservative flap reflection to the
bony limits of the defect or to single-flap designs.
Both flap approaches have been reported incorporating
the use of membranes, bone replacement grafts, and/
or biomimetic agents (EMD and rhPDGF-BB).
Access flap surgery/GTR. Systematic reviews
provide evidence that clinical outcome measures for
GTR are superior to open flap debridement (OFD).
16,63-65
Studies also reported superior outcomes (PD,
CAL, and REC) for GTR compared with OFD
66-70
(Table 2).
38,51,71-85
Furthermore, a long-term study (>10
years) and two systematic reviews concluded that
regenerative outcomes were comparable between
resorbable and non-resorbable membranes.
16,39,64
Regarding membrane exposure, a meta-analysis
performed by Machtei
68
found statistically signifi-
cant differences in mean gain in vertical CAL be-
tween exposed and non-exposed membrane groups;
however, a mean difference of 0.47 mm in defect fill
was found between groups (SORT level A).
Conservative and minimally invasive flap access.
Several conservative and minimally invasive flap ap-
proaches, including minimally invasive surgery (MIS),
86
a modification called MIS technique (MIST),
53
modi-
fied MIST (M-MIST),
54
and the single-flap approach
(SFA),
87
have been described (Table 3).
88-98
These
techniques minimize the degree of wounding and flap
reflection and emphasize wound stability, primary
closure, and space maintenance.
99
The use of mi-
crosurgical instrumentation and magnification has
been advocated when performing these procedures.
99
Currently, studies comparing minimally invasive ap-
proaches to OFD are lacking. Harrel and Rees
86
described the MIS technique, which introduced
conservative surgical approaches to periodontal re-
generation. One- and 6-year results demonstrate
favorable clinical outcomes in combination with
EMD.
89,91
The MIST and M-MIST
54
techniques capi-
talize on papilla preservation incision designs. Studies
report significant reductions in PD, gains in CAL, and
minimal REC at 1 year compared with baseline
(Table 3).
52-56,58,88,94-96,99,100
The SFA introduced
by Trombelli et al.
75
involves limited reflection of
a buccal or lingual envelope flap and placement of
a barrier membrane. Improvements in PD and CAL were
reported at 6 and 12 months compared with baseline
(Table 3).
75,87,92
In a systematic review and meta-
analysis, Graziani et al.
101
concluded that, although
clinical performance may vary according to the type of
surgical flap used, a high rate of tooth retention and
improvements in periodontal clinical parameters is
possible when conservative surgery is used in the
treatment of intrabony defects (SORT level A).
Non-surgical therapy. Ribeiro et al.
94
compared
minimally invasive non-surgical technique (MINST)
with MIST in the treatment of intrabony defects. Using
mini-curets and very thin ultrasonic tips, they re-
ported that the MINST was comparable with MIST in
terms of PD reduction, CAL gain, and REC. In
a separate study, clinical and radiographic findings
were collected retrospectively from patients after non-
surgical therapy of intrabony defects.
98
Significant re-
ductions were found in radiographic defect depth and
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
S81
widening of the radiographic intrabony defect angle, with
complete fill in some cases (SORT level C).
Defect morphology: number of walls, width, and
depth. Regenerative techniques and the understanding
of the factors influencing success or failure have
evolved over time. Defects with a depth >3mmand
a radiographic defect angle £25 degrees were reported
to be most amenable to regenerative procedures using
conventional GTR-based approaches.
41,48,49,102-104
Using logistic regression analysis, Cosyn et al.
88
identified non-supportive anatomy—defined as pre-
dominantly a 1-wall defect—as a risk factor for failure
(odds ratio [OR] ‡10.4). In the same study, non-
supportive defect anatomy (1-wall versus 2-wall,
OR =58.8) and a thin-scalloped gingival biotype
(OR =76.9) were identified as risk factors for increased
REC at the midfacial aspect.
88
Conversely, other stud-
ies
37,38,48,72
and systematic reviews
16,63,99,105
have
concluded that periodontal regenerative approaches are
effective in the treatment of intrabony defects with a wide
range of depths, widths, and bony walls (SORT level B).
Space availability/maintenance and wound/clot
stability are key factors in determining success of
regenerative therapy.
99
The wound-stabilizing and
space-making properties of membranes are gener-
ally considered key factors underlying the effec-
tiveness of GTR.
106,107
Tonetti et al.
49
reported that
the amount of space available under the membrane,
rather than total depth of the intrabony defect, was
the most significant predictor of regenerative out-
come. Consistent with the latter findings, Trombelli
et al.
37
found no correlation between defect mor-
phology and gain in probing bone level.
PERIODONTAL REGENERATIVE MATERIALS
AND APPROACH
Bone Replacement Grafts and GTR in
Regeneration
Previous reviews summarized the many clinical
studies that demonstrated bone replacement grafts
and GTR are successful treatment modalities for
periodontal regeneration.
15,16
Since these reviews,
no RCTs and systematic reviews on bone replacement
grafts were identified. Two systematic reviews on GTR
have been published to update the field.
17,108
Clinical
studies have focused on new membranes and the use of
the GTR approach in combination with various bone
replacement and EMD.
40,66,71,78,80,109-132
With the
exception of studies that examined the use of GTR in
conjunction with EMD, the number of studies was
limited, and the overall conclusions were consistent
with earlier evidence-based reviews.
15,16
The discus-
sion of combination therapy using GTR and EMD is
discussed below.
Laser. The role of lasers in the treatment of
periodontitis remains controversial. At the center of
this polemic debate is the LAR protocol. Using the
Nd:YAG laser with this procedure, periodontal re-
generation is achievable on a previously diseased
root surface. Two recent publications, based on
human histology, suggest that this protocol may
have merit in periodontal therapy.
30,133
In the initial
histologic report on the protocol, Yukna et al.
133
reported that the six teeth treated with LAR**
demonstrated evidence of new attachment, with new
cementum and inserting PDL, after 3 months. Re-
cently, Nevins et al.
30
reportedthat,ofthe10
specimens evaluated after LAR treatment, five teeth
had evidence of periodontal regeneration, one tooth
had new attachment with new cementum and in-
serting collagen fibers, and the other four teeth
healed with a long junctional epithelium. Unlike the
previous study by Yukna et al.,
133
healing was ob-
served after 9 months, which is more consistent with
the normally observed 6 to 24 months for optimal
regeneration.
16,31,102,105,134-136
This report provides
proof of principle that LAR therapy can induce peri-
odontal regeneration (SORT level C).
Despite the evidence for new attachment and peri-
odontal regeneration, information about clinical pre-
dictability of this procedure has yet to be demonstrated.
There are no well-documented clinical reports or
randomized controlled studies that define the fre-
quency and extent of regeneration that can be ach-
ieved. However, this technique is intriguing in that it
is another approach to minimally invasive surgical
therapies as reviewed by Cortellini.
99
A minimally
invasive surgical approach may offer advantages in
regeneration of defects in the esthetic zone in which
minimal soft tissue change is required. Additionally,
because of the minimally invasive nature and ex-
pendable surgical materials required, this approach
may be appropriate for multiple defects as a first line
of management.
EMD. EMD has been available as a biologic peri-
odontal regenerative material for 15 years.
28,137
The
biologic properties of EMD have been summarized
recently.
138,139
Several studies have provided human
histologic evidences of intrabony regeneration asso-
ciated with EMD therapy.
3,4,28,29,32
EMD is present on
root surfaces for ‡4 weeks after application, and early
signs of periodontal wound regeneration can be ob-
served after 2 to 6 weeks.
140,141
Signs of clinical
improvement are present as early as 6 months after
treatment.
111,112,114,116,120,130
EMD versus OFD. The first RCT to compare the
effectiveness of EMD versus OFD was published
by Heijl et al.
137
Clinical reductions in PD, increases
in CAL, and increases in linear bone growth with EMD
were statistically superior to improvements observed
** LANAP, Millenium Dental Technologies.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
S82
Table 2.
Controlled Clinical Studies Using Access Flap and GTR Approaches
Study Study Design
Time
(months)
Treatment
(n defects)
Mean PD
Change
(mm) P
Mean CAL
Change
(mm) P
Mean
Linear Bone
Fill P
Mean REC
Change (mm)*P
Aimetti et al.,
2005
72
Paired 12 GTR-R (18) 3.44 <0.001 2.89 <0.001 2.13 mm <0.001 0.56 0.002
OFD (18) 2.39 <0.001 1.50 <0.001 1.05 mm <0.001 0.89 <0.001
GTR-R vs OFD 1.05 <0.001 1.39 <0.001 1.08 mm NS -0.330 NS
Cortellini and
Tonetti,
2005
51
Parallel 12 GTR-NR (12) 6.6 <0.001 1.68 <0.001 94.7% ND 0.2 NS
GTR-R (7) 5.9 <0.001 2.59 <0.001 88.9% ND 0.1 NS
GTR-R +BG (11) 6.3 <0.001 3.54 <0.001 88.2% ND -0.3 NS
EMD (10) 5.8 <0.001 4.59 <0.001 95.4% ND 0.2 NS
Tonetti et al.,
2004
74
Parallel 12 GTR +BG (61) 3.7 0.004 3.3 0.02 ND ND 0.3 0.04
PPF (59) 3.2 2.5 ND ND 0.7
Bianchi and
Bassetti,
2009
73
Case series 12 GTR +BG (14) 5.14 NS 4.57 <0.001 ND ND 0.57 0.46
Eickholz et al.,
2004
38
Case series 6 GTR (50) 4.22 <0.001 3.35 <0.001 0.70 mm NS ND ND
24 4.38 <0.001 3.38 <0.001 1.21 mm 0.005
Stavropoulos
et al., 2004
11
Case series 12 GTR-nonS (17) 5.5 <0.01 4.3 0.03 ND ND 1.2 NS
GTR-S (15) 4.5 3.2 ND ND 1.3
Stravropoulos
and Karring,
2005
76
Case series 12 GTR +BG (15) 5.0 <0.01 3.8 <0.01 4.7 mm <0.01 1.2 <0.01
60 4.6 <0.01 4.1 <0.01 4.9 mm 0.01 0.5 NS
Stravropoulos
and Karring,
2004
77
Case series 12 GTR (25) 4.9 <0.01 3.8 <0.01 ND ND 1.1 <0.01
60 to 72 4.0 <0.001 3.6 <0.01 ND ND 0.4 NS
Klein et al.,
2001
41
Case series 6 GTR (39) 4.2 <0.001 3.15 <0.001 1.30 mm <0.01 ND ND
24 4.3 <0.001 3.31 <0.001 1.54 mm <0.005 ND ND
Cortellini et al.,
2011
57
Parallel 12 GTR (25) 8.8 <0.001 7.7 <0.001 8.5 mm <0.001 1.1 0.006
12 Ext/implant/FPD ND ND ND ND ND ND ND ND
60 GTR (25) 8.9 NS 7.7 NS 8.6 mm NS 1.2 NS
60 Ext/implant/FPD ND ND ND ND ND ND ND ND
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
S83
Table 2. (continued)
Controlled Clinical Studies Using Access Flap and GTR Approaches
Study Study Design
Time
(months)
Treatment
(n defects)
Mean PD
Change
(mm) P
Mean CAL
Change
(mm) P
Mean
Linear Bone
Fill P
Mean REC
Change (mm)*P
Siciliano et al.,
2011
62
Parallel 12 GTR (20) 5.5 <0.001 4.1 <0.001 ND ND 0.5 NS
EMD (20) 2.9 <0.001 2.4 <0.001 ND ND 0.7 NS
Do¨ ri et al.,
2005
78
Parallel 12 EMD +BG +PRP (12) 5.5 <0.001 4.5 <0.001 ND ND 1.0 <0.01
12 EMD +BG (12) 5.5 <0.001 4.5 <0.001 ND ND 1.0 <0.01
60 EMD +BG +PRP (12) 4.9 <0.001 4.3 <0.001 ND ND 0.6 <0.01
60 EMD +BG (12) 5.0 <0.001 4.3 <0.001 ND ND 0.7 <0.01
Kim et al.,
2002
79
Case series,
paired
6 GTR-NR (12) 4.2 ND 2.6 0.012 ND ND ND ND
6 GTR-R (12) 4.1 ND 3.0 0.012 ND ND ND ND
60 GTR-NR (12) 2.6 ND 1.6 0.03 1.5 mm NS ND ND
60 GTR-R (12) 3.6 ND 3.0 0.01 2.1 mm 0.02 ND ND
Sculean et al.,
2004
80
Parallel 12 EMD (11) 4.6 <0.001 3.4 <0.001 ND ND 1.3 <0.001
GTR (11) 4.4 <0.001 3.2 <0.001 ND ND 1.2 <0.001
EMD +GTR (10) 4.4 <0.001 3.0 <0.001 ND ND 1.5 <0.001
OFD (10) 3.3 <0.001 1.6 <0.001 ND ND 1.7 <0.001
60 EMD (11) 4.3 <0.001 2.9 <0.001 ND ND 1.3 <0.001
GTR (11) 3.9 <0.001 2.7 <0.001 ND ND 1.2 <0.001
EMD +GTR (10) 4.0 <0.001 2.6 <0.001 ND ND 1.5 <0.001
OFD (10) 2.7 <0.001 1.3 <0.001 ND ND 1.7 <0.001
Slotte et al.,
2007
81
Case series 12 GTR +BG (24) 5.2 ND 4.2 ND 6.0 mm ND 1.0 ND
36 5.6 ND 4.1 ND 4.8 mm ND 1.6 ND
60 5.3 ND 4.3 ND 4.8 mm ND 1.3 ND
Sculean et al.,
2008
67
Parallel 12 EMD (10) 4.1 <0.001 3.4 <0.001 ND ND 0.7 <0.001
GTR (10) 4.2 <0.001 3.2 <0.001 ND ND 1.0 <0.001
EMD +GTR (9) 4.3 <0.001 3.3 <0.001 ND ND 1.0 <0.001
OFD (9) 3.7 <0.001 2.0 <0.001 ND ND 1.7 <0.001
120 EMD (10) 4.6 NS 2.9 <0.001 ND ND 0.7 NS
GTR (10) 3.4 NS 2.8 <0.001 ND ND 0.6 NS
EMD +GTR (9) 3.6 NS 2.9 <0.001 ND ND 0.6 NS
OFD (9) 3.5 NS 1.8 <0.001 ND ND 1.7 NS
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Table 2. (continued)
Controlled Clinical Studies Using Access Flap and GTR Approaches
Study Study Design
Time
(months)
Treatment
(n defects)
Mean PD
Change
(mm) P
Mean CAL
Change
(mm) P
Mean
Linear Bone
Fill P
Mean REC
Change (mm)*P
Pretzl et al.,
2008
82
Paired 12 GTR-R (15) 4.4 ND 3.3 0.001 ND ND ND ND
12 GTR-NR (15) 4.7 ND 3.4 <0.001 ND ND ND ND
120 GTR-R (8) 4.2 ND 3.5 0.005 2.7 mm 0.02 ND ND
120 GTR-NR (8) 2.4 ND 1.5 0.02 0.8 mm 0.04 ND ND
Pretzl et al.,
2009
83
Paired 12 GTR-R1 (15) 4.3 <0.001 3.89 <0.001 1.73 mm 0.01 ND ND
12 GTR-R2 (15) 5.16 <0.001 4.06 <0.001 2.11 mm 0.006 ND ND
120 GTR-R1 (11) 3.16 0.004 2.44 0.004 3.72 mm NS ND ND
120 GTR-R2 (11) 3.16 <0.001 2.44 0.002 3.49 mm 0.02 ND ND
Nygaard-Østby
et al., 2010
84
Paired 9 BG (20) 2.9 <0.05 2.5 <0.05 1.9 mm NS 0.4 NS
9BG+GTR (20) 3.2 <0.05 2.5 <0.05 2.5 mm <0.05 0.6 NS
120 BG (13) 2.7 <0.05 2.2 <0.05 1.3 mm NS 0.6 NS
120 BG +GTR (13) 4.2 <0.05 3.8 <0.05 3.9 mm <0.05 0.7 NS
Nickles et al.,
2009
85
Parallel 12 OFD (17) 3.71 ND 3.47 ND ND ND ND ND
12 GTR (18) 4.14 ND 3.67 ND ND ND ND ND
120 OFD (17) 4.41 ND 3.41 ND 2.03 mm 0.002 ND ND
120 GTR (18) 4.25 ND 2.89 ND 1.69 mm 0.02 ND ND
Paired 12 OFD (10) 3.60 ND 3.60 ND ND ND ND ND
12 GTR (10) 3.95 ND 3.50 ND ND ND ND ND
120 OFD (10) 4.40 ND 3.65 ND 2.15 mm 0.01 ND ND
120 GTR (10) 4.15 ND 2.85 ND 1.30 mm NS ND ND
R=resorbable; NR =non-resorbable; BG =bone graft; PPF =papilla preservation flap; nonS =non-smoker; S =smoker; Ext =extraction; FPD =fixed partial denture; ND =not defined; NS =not significant.
* Negative values indicate gain.
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
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Table 3.
Controlled Clinical Studies Using Conservative and Minimally Invasive Surgical Approaches
Study
Study
Design
Time
(months) Treatment (n defects)
Mean PD Change
(mm) P
Mean CAL Change
(mm) P
Mean Linear
Bone Fill P
Mean REC
Change
(mm) P
Cortellini and Tonetti,
2007
53
Case series 12 MIST +EMD (40) 5.2 <0.001 4.9 <0.001 77.6% ND 0.4 0.02
Cortellini and Tonetti,
2007
58
Case series 12 MIST +EMD (13) 4.8 <0.001 4.8 <0.001 88.7% ND 0.1 NS
Cortellini et al., 2008
55
Case series 12 MIST +EMD (40) 4.6 <0.001 4.4 <0.001 83% ND 0.2 0.04
Cortellini et al., 2009
56
Case series 12 MIST +EMD (40) 5.2 <0.001 4.9 <0.001 77.6% ND 0.4 0.02
Cortellini and Tonetti,
2011
52
Parallel 12 M-MIST (15) 3.1 <0.001 4.1 <0.001 77% NS 0.3 NS
M-MIST +EMD (15) 3.4 <0.001 4.1 <0.001 71% NS 0.2 NS
M-MIST +EMD +BG
(15)
3.3 <0.001 3.7 <0.001 78% NS 0.2 NS
Cortellini and Tonetti,
2009
54
Case series 12 M-MIST +EMD (15) 4.6 <0.001 4.5 <0.001 75.5% ND 0.07 NS
MIST +EMD (5) 5.0 <0.001 4.8 <0.001 ND ND 0.2
NS
Cosyn et al., 2012
88
Case series 12 MIST/M-MIST +BG
(84)
3.5 ND 3.1 ND 53% ND 0.5 ND
Harrel et al., 2005
89
Case series 11 MIS +EMD (160) 3.56 0.002 3.57 0.01 ND ND 0.01 ND
Harrel et al., 1999
90
Case series 21.7 MIS +BG (194) 4.58 <0.001 4.87 <0.001 ND ND ND ND
Harrel et al., 2010
91
Case series 72 MIS +EMD (142) 3.78 0.03 3.7 NS ND ND 0.0 ND
Trombelli et al., 2012
92
Parallel 6 SFA (14) 5.2 <0.001 4.5 <0.001 ND ND 0.7 0.006
DFA (14) 3.9 3.4 0.5 ND
Trombelli et al., 2010
75
Parallel 6 SFA +GTR (12) 5.3 <0.001 4.7 <0.001 ND ND 0.4 NS
SFA (12) 5.3 <0.001 4.4 <0.001 ND ND 0.8 0.005
Trombelli et al., 2009
87
Case
series
6–14 SFA/GTR (10) 5.2 <0.001 4.8 <0.001 ND ND 0.4 NS
Wachtel et al., 2003
93
Split-mouth 6 Microsurgery +EMD
(26)
3.3 <0.05 2.8 <0.05 ND ND 0.5 <0.05
6 Microsurgery (26) 2.2 <0.05 2.0 <0.05 ND ND 0.2 NS
12 Microsurgery +EMD
(26)
3.9 <0.05 3.6 <0.05 ND ND 0.3 NS
12 Microsurgery (26) 2.11 <0.05 1.7 <0.05 ND ND 0.4 NS
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Table 3. (continued)
Controlled Clinical Studies Using Conservative and Minimally Invasive Surgical Approaches
Study
Study
Design
Time
(months) Treatment (n defects)
Mean PD Change
(mm) P
Mean CAL Change
(mm) P
Mean Linear
Bone Fill P
Mean REC
Change
(mm) P
Ribeiro et al., 2011
94
Parallel 6 MIST (14) 3.51 <0.05 2.85 <0.05 ND ND 0.48 NS
MINST (13) 3.13 <0.05 2.56 <0.05 ND ND 0.45 NS
Ribeiro et al., 2011
95
Parallel 6 MIST (15) 3.55 <0.05 8.21 <0.05 0.95 <0.05 0.54 NS
MIST +EMD (15) 3.56 <0.05 9.21 <0.05 1.52 <0.05 0.46 NS
Mishra et al., 2013
96
Parallel MIST (12) 3.82 NS 2.64 NS 1.85 mm NS 0.55 NS
MIST-rhPDGF-BB
(12)
4.18 3.0 1.89 mm 0.82
Fickl et al., 2009
97
Split-mouth 6 Microsurger y (35) 2.1 <0.001 1.6 <0.002 0.7 0.04 0.5 0.02
6 Microsurgery +EMD
(35)
3.5 <0.001 2.7 <0.002 1.4 0.39 0.6 0.003
12 Microsurgery (35) 2.4 <0.001 1.7 <0.001 1.1 <0.001 0.7 0.002
12 Microsurgery +EMD
(35)
4.2 <0.001 3.7 <0.001 2.5 <0.001 0.5 0.008
Zucchelli et al., 2002
40
Parallel 12 EMD +SPP (30) 5.1 <0.05 4.2 <0.05 ND ND 1.0 <0.05
GTR +SPP (30) 6.5 <0.05 4.9 <0.05 ND ND 1.6 <0.05
SPP/access flap (30) 4.5 <0.05 2.6 <0.05 ND ND 1.9 <0.05
Nibali et al., 2011
98
Case series 12–18 Non-surgical therapy
(126)
Buccal: 2.24 <0.001 1.42 <0.001 ND ND MB or DB:
0.8
<0.001
Lingual: 2.29 <0.001 1.5 <0.001 ND ND ML or DL:
0.8
<0.001
BG =bone graft; DFA =double-flap approach; MINST =minimally invasive non-surgical technique; SFA =single-flap approach; SPP =simplified papilla preservation; ND =not defined; NS =not significant;
MB =mesio-buccal; DB =disto-buccal; ML =mesio-lingual; DL =disto-lingual.
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Table 4.
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With OFD With or Without EMD
Study Time (months) Study Design Treatments (n defects) PD Change (mm) PCAL Change (mm) PLinear Bone/Bone Fill P
Heijl et al., 1997
137
8 Split-mouth EMD (34) 3.3 <0.01 2.1 <0.01 0.9 mm <0.001
OFD (34) 2.6 1.5 -0.1 mm
16 EMD (34) 3.3 <0.01 2.3 <0.01 2.2 mm <0.001
OFD (34) 2.6 1.7 -0.2 mm
36 EMD (34) 3.1 <0.01 2.2 <0.01 2.6 mm <0.001
OFD (34) 2.3 1.7 0
Pontoriero et al., 1999
118
12 Split-mouth EMD (10) 4.4 <0.001 2.9 <0.001 ND
OFD (10) 3.5 1.8
Silvestri et al., 2000
127
12 Parallel EMD (10) 4.8 <0.01 4.5 <0.01 ND
OFD (10) 1.4 1.2
Okuda et al., 2000
146
12 Split-mouth EMD (18) 3.00 <0.05 1.72 <0.05 ND
OFD (18) 2.22 0.83
Froum et al., 2001
144
12 Split-mouth EMD (53) 4.94 <0.001 4.28 <0.001 3.83 mm <0.001
74.0%
OFD (31) 2.24 2.65 1.47 mm
22.7%
Sculean et al., 2001
126
12 Parallel EMD (14) 4.6 <0.05 3.4 <0.05 ND
OFD (14) 3.3 1.7
Sculean et al., 2004
80
60 EMD (14) 4.3 <0.001 2.9 <0.05 ND
OFD (14) 2.7 1.3
Tonetti et al., 2002
47
12 Parallel EMD (83) 3.9 <0.02 3.1 <0.01 ND
OFD (83) 3.3 2.5
Zucchelli et al., 2002
40
12 Parallel EMD (30) 5.1 <0.01 4.2 <0.01 ND
OFD (30) 4.5 2.6
Parodi et al., 2004
147
12 Case series EMD (16) 4.18 <0.01 3.12 <0.01 ND
36 EMD (16) 4.94 4.20
Francetti et al., 2004
143
12 Parallel EMD (12) 4.71 <0.05 4.14 <0.05 2.96 mm <0.05
OFD (12) 2.57 2.29 1.44 mm
24 EMD (12) 4.86 <0.05 4.29 <0.05 3.44 mm <0.05
OFD (12) 3.00 2.71 1.84 mm
Ro¨ sing et al., 2005
148
12 Split mouth EMD (14) 4.17 NS 2.01 NS 0.94 mm NS
OFD (14) 4.39 2.16 0.91 mm
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
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with OFD. Subsequently, 13 additional studies evalu-
ated the efficacy of EMD versus OFD, with the
majority confirming that OFD followed by EMD ap-
plicationresultedinsubstantialimprovements
in clinical measurements and bone fill with EMD
in the management of intrabony defects (Table
4)
40,47,80,118,126,127,137,142-148
(SORT level A).
Neither postoperative antibiotics
149
nor EDTA root
conditioning improved the clinical outcome of EMD
therapy.
150,151
EMD versus GTR. Of the 11 studies comparing the
clinical management of intrabony defects with EMD
versus GTR, all but one failed to show any significant
difference (Table 5)
40,62,66,80,110,117,118,125-129,142-148
(SORT level A). The noted exception was an RCT
that compared the two therapeutic modalities in
deep, non-contained intrabony defects.
62
In these
defects, GTR with titanium reinforcement was su-
perior. The latter results suggest that, in situations
in which defect configuration is broad or lacking in
wall containment, a supported barrier membrane
ma y be critical in the success of EMD-associated
regeneration. Additionally, no added clinical advan-
tage was observed when EMD was combined with
GTR.
80,117,126
EMD alone versus EMD used in combined therapy.
There are several studies in which EMD has been
used in combined therapy (Table 6).
71,78,109,111-
116,119-124,130-132,152-155
Histologic evidence of
periodontal regeneration has been demonstrated
when EMD is used in combination with autogenous
bone, a bovine-derived natural bone mineral (NBM),
††
bioactive glass,
‡‡
NBM +PRP, nanocrystalline hy-
droxyapatite (NHA), or biphasic calcium phos-
phate.
7,136,156-158
The majority of the studies
indicate no added benefits in either clinical and ra-
diographic gains when EMD is used with the addi-
tion of graft materials.
71,78,109,111,113,114,119-124,152-155
These updated studies confirmed the conclusions of
meta-analyses of RCTs that there are few addi-
tional benefits of EMD when used in conjunction
with other regenerative materials/approaches
159
(SORT level A). The exceptions are limited reports
that indicate that improved PD, CAL, and/or bone
fill is achievable when EMD augments the effect of
bone grafts
112,131
or bone graft enhances the effects of
EMD.
115,116,132
In summary, EMD is a semipurified protein
preparation from developing porcine teeth that
contains a mixture of low-molecular-weight pro-
teins. Although there were initial concerns about
the poorly characterized nature of this preparation,
recent reports suggest that the mixture may work
Table 4. (continued)
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With OFD With or Without EMD
Study Time (months) Study Design Treatments (n defects) PD Change (mm) PCAL Change (mm) PLinear Bone/Bone Fill P
Grusovin and Esposito, 2009
145
12 Parallel EMD (15) 4.2 NS 3.4 NS 2.5 NS
OFD (15) 3.9 3.3 2.5
Chambrone et al., 2010
142
12 Parallel EMD 4.00 NS 3.46 NS ND
OFD 3.49 3.65
24 EMD 4.21 <0.05 5.69 NS ND
OFD 3.28 5.24
NS =not significant.
†† Bio-Oss, Geistlich Pharma North America, Princeton, NJ.
‡‡ PerioGlas, NovaBone, Jacksonville, FL.
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Table 5.
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With EMD Versus GTR
Study Time (months) Study Design Treatments (n defects) PD Change (mm) PCAL Change (mm) PLinear Bone/Bone Fill P
Pontoriero et al., 1999
118
12 Split-mouth EMD (10) 4.4 NS 2.9 NS ND
GTR (30) 4.5 3.1
Silvestri et al., 2000
127
12 Parallel EMD (10) 4.8 NS 4.5 NS ND
GTR (10) 5.9 4.8
Sculean et al., 2001
126
12 Parallel EMD (14) 4.1 NS 3.4 NS ND
GTR (14) 4.2 3.1
EMD +GTR (14) 4.3 3.4
Sculean et al., 2004
80
60 Parallel EMD (14) 4.3 NS 2.9 NS ND
GTR (14) 3.9 2.7
EMD +GTR (14) 4.0 2.6
Zucchelli et al., 2002
40
12 Parallel EMD (30) 5.1 <0.01 4.2 <0.01 ND
GTR (30) 6.5 4.9
Minabe et al., 2002
117
12 Parallel EMD (22) 5.4 NS 3.0 NS 40% NS
GTR (23) 4.6 3.0 35%
EMD +GTR (24) 5.0 3.2 49%
Silvestri et al., 2003
128
12 Parallel EMD (49) 5.3 NS 4.1 NS ND
GTR (49) 5.6 4.3
Sanz et al., 2004
66
12 Parallel EMD (35) 3.8 NS 3.1 NS ND
GTR (32) 3.3 2.5
Sipos et al., 2005
129
12 Split-mouth EMD (12) 2.86 NS 1.28 NS 1.63 mm NS
GTR (12) 3.02 1.65 1.58 mm
Sculean et al., 2006
125
12 Split-mouth EMD (10) 4.1 NS 3.2 NS ND
GTR (10) 4.6 3.0
96 Split-mouth EMD (10) 3.4 NS 2.8 NS ND
GTR (10) 3.7 2.9
Crea et al., 2008
110
12 Parallel EMD (19) 3.5 NS 2.9 <0.05 50.5% NS
GTR (20) 3.5 2.5 57.0%
36 Parallel EMD (19) 3.1 NS 2.4 <0.05 58.8% NS
GTR (20) 3.2 2.0 53.7%
Siciliano et al., 2011
62
12 Parallel EMD (20) 2.9 <0.001 2.4 <0.001 ND
GTR (20) 5.5 4.1
NS =not significant.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
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Table 6.
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With EMD Versus Combined Therapy
Study
Time
(months)
Study
Design
Treatments
(n defects)
PD Change
(mm) P
CAL Change
(mm) P
Linear Bone/Bone
Fill P
Guida et al., 2007
111
12 Parallel EMD (14) 5.6 NS 4.6 NS ND
EMD +AB (14) 5.1 4.9
Yilmaz et al., 2010
131
12 Parallel EMD (20) 4.6 <0.01 3.4 <0.01 2.8 mm <0.001
EMD +AB (20) 5.6 4.2 3.9 mm
Gurinsky et al., 2004
112
6 Parallel EMD (34) 4.0 NS 3.2 NS 2.6 mm/55.3% <0.001
EMD +DFDBA (33) 3.6 3.0 3.7 mm/74.9%
Hoidal et al., 2008
113
6 Parallel DFDBA (20) 2.45 NS 1.63 NS 2.33/47.3% NS
EMD +DFDBA (17) 2.56 1.47 1.91 mm/46.3%
Rosen and Reynolds, 2002
119
6 Case series EMD +DFDBA (10) 8.4 NS 9.2 NS ND
EMD–FDBA (12) 8.9 NS 9.1 NS ND
Al Machot et al., 2014
152
12 Parallel EMD (19) 3.2 2.0 ND 1.6 mm NS
NHA (19) 2.6 1.5 ND 1.6 mm
Lekovic et al., 2000
116
6 Split-
mouth
EMD (21) 1.91 <0.001 1.72 <0.001 1.33 mm/28.9%) <0.001
EMD +NBM (21) 3.43 3.13 3.82 mm/81.3%
Scheyer et al., 2002
120
6 Split-
mouth
NBM (17) 3.9 NS 3.7 NS 3.0 mm/67.0% NS
EMD–NBM (17) 4.2 3.8 3.2 mm/63.3%
Sculean et al., 2002
123
12 Parallel NBM (16) 6.5 NS 4.9 NS ND
EMD-NBM (16) 5.7 4.7
Velasquez-Plata et al.,
2002
130
6 Split-mouth EMD (16) 3.8 NS 2.9 NS 3.1 mm/64.9% NS for bone fill
EMD +NBM (16) 4.0 3.4 4.0 mm/76.9% <0.05 for bone fill
Zucchelli et al., 2003
132
12 Parallel EMD (30) 5.8 NS 4.9 <0.01 4.3 mm <0.01
EMD +NBM (30) 6.2 5.8 5.3 mm
Sculean et al., 2005
122
12 Parallel EMD (15) 4.5 NS 3.9 NS ND
EMD +NBM (15) 4.2 3.2
Sculean et al., 2002
121
12 Parallel EMD (14) 4.22 NS 3.07 NS ND
EMD +BG (14) 4.15 3.22
Sculean et al., 2005
124
12 Parallel EMD (12) 4.5 NS 3.9 NS ND
EMD +BG (13) 4.2 3.2
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Table 6. (continued)
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With EMD Versus Combined Therapy
Study
Time
(months)
Study
Design
Treatments
(n defects)
PD Change
(mm) P
CAL Change
(mm) P
Linear Bone/Bone
Fill P
Sculean et al., 2007
71
48 Parallel EMD (12) 4.2 NS 3.4 NS ND
EMD +BG (13) 4.1 3.4
Kuru et al., 2006
115
8 Split-mouth EMD (26) 5.03 <0.05 4.06 <0.05 2.15 mm <0.05
EMD +BG (26) 5.73 5.17 2.76 mm
Jepsen et al., 2008
114
6 Parallel EMD (35) 2.55 NS 1.83 NS 2.07 mm NS
EMD +BCP (38) 1.93 1.31 2.01 mm
Do¨ ri et al., 2005
78
12 Parallel EMD +NBM (12) 4.5 NS 3.1 NS ND
EMD +b-TCP (12) 4.8 NS 3.7 NS ND
Do¨ ri et al., 2013
153
120 Parallel EMD +NBM (11) 3.9 3.1 NS
EMD +b-TCP (12) 4.0 3.0
Do¨ ri et al., 2008
154
12 Parallel EMD +NBM +PRP (13) 6.0 NS 5.0 NS ND
EMD +NBM +PRP (13) 5.7 NS 4.8 NS ND
EMD +NBM (12) 5.0 NS 4.3 NS ND
Do¨ ri et al., 2013
155
60 Parallel EMD +NBM +PRP (12) 4.9 NS 4.3 NS ND
EMD (19) 3.9 3.7 ND
Bokan et al., 2006
109
12 Parallel EMD +b-TCP (19) 4.1 NS 4.0 NS ND
OFD (19) 3.8 2.1 ND
AB =autogenous bone; NHA =nanocrystalline hydroxyapatite; NBM =natural bone mineral; BG =bioglass; BCP =biphasic calcium phosphate; b-TCP =beta tricalcium phosphate; NS =not significant.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
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synergistically on multiple levels to enhance peri-
odontal regeneration.
138
Whenappliedtoroot
surfaces, the proteins are absorbed into the hy-
droxyapatite and collagen fibers of the root surface,
in which they induce cementum formation followed
by periodontal regeneration. Clinical use of EMD
can generally be characterized as safe with excel-
lent clinical healing and limited complications. EMD
alone or in combination with graft materials provide
clinical outcome and long-term clinical stability com-
parable with GTR.
67,71,80,137,160,161
Although charac-
terization of the EMD preparation remains incomplete,
the challenge, as with allografts, is to provide a con-
sistent batch of EMD, so the regenerative response is
predictable.
rhPDGF-BB
rhPDGF-BB has been shown to enhance periodontal
regeneration.
162
Clinical application of the re-
combinant form of this growth factor indicates that it
can promote regeneration of bone, ligament, and
cementum.
27,31
Two RCTs using rhPDGF-BB have
been reported (Table 7).
163,164
The first study was
a prospective, masked, RCT to evaluate the safety
and efficacy of rhPDGF-BB used in conjunction with
synthetic b-tricalcium phosphate (b-TCP).
164
This
study demonstrated that the use of rhPDGF-BB was
safe and effective in the treatment of intrabony
periodontal defects. Although improvements in PD
and CAL were not significantly superior to grafted
(control) intrabony defects, there was significant
improvement in bone formation and accelerated
wound healing as depicted by ‘‘the area under the
curve’’ when grafted with rhPDGF-BB +b-TCP.
Follow-up studies showed that the improved bone fill
and linear bone growth continued to improve over 36
months, reaching maximal statistical significant bone
fill after 24 months.
134,135
In a report of a subset of
this study population, after 5 years, the use of
rhPDGF-BB resulted in a stable, physiologic at-
tachment in the presence of good patient compli-
ance.
165
When deterioration of the regenerative result
was present, it was associated with patients’ smoking
habits and poor compliance with supportive periodontal
care.
165
The second multicenter RCT confirmed after
6 months not only improved bone fill but significant
improvement of PD and CAL as well.
163
In summary, rhPDGF-BB can be safely used
with therapeutic results comparable with other
regenerative approaches (SORT level A). The unique
advantages of this system are that no barrier mem-
brane is required and there is consistency in the
concentration of rhPDGF-BB delivered to a re-
generative site, which would suggest more consistent
clinical results.
THE RELATIONSHIP OF REGENERATIVE
TREATMENT TO ENDODONTIC AND
ORTHODONTIC THERAPY
Recent studies confirm that endodontically treated
teeth with no evidence of pulpal or periapical pathology
respond favorably to regenerative therapy.
62-64
The
regenerative outcomes of teeth with severe bone loss
approaching the root apex were reported recently in
a study that evaluated 22 of 25 teeth requiring
endodontic therapy 3 months before GTR surgery.
57
Statistically significant reductions in PD and gains in
CAL documented at 1 year were maintained for 5
years. However, no RCTs were identified on the
relationship between regenerative treatment and
endodontic treatment. Therefore, the best-practice
management approach is based on one retrospec-
tive study
63
and two case series
166,167
that reported
no adverse influence of root canal treatment on the
periodontal regenerative outcome (SORT level C).
In reviewing the relationship between regenerative
treatment and orthodontic treatment, there are sev-
eral case reports/series describing the treatment of
intrabony defects by means of orthodontic therapy,
alone or in combination with periodontal therapy.
168-176
Additionally, one RCT was identified that evaluated
the effect of periodontal regeneration combined with
orthodontic treatment on clinical parameters in in-
trabony defects as discussed below.
177
Case series/reports have documented improve-
ment of intrabony defects with orthodontic tooth
movement alone, including bodily movement into in-
trabony defects;
169,172,173
extrusive movement, such
as a mesially tilted tooth with 1- or 2-wall intrabony
defect;
168,170,171
and orthodontic intrusion.
174-176
Moreover, case reports suggest no adverse effects of
orthodontic movement of teeth that had previously
undergone regenerative therapy for intrabony de-
fects.
178-180
Recently, the first RCT evaluated the role of com-
bined periodontal regenerative orthodontic treatment of
2- or 3-wall intrabony defects.
177
In this clinical trial, 47
patients were randomized into orthodontic extrusive
force with pretreatment grafting of EMD +DFDBA plus
orthodontic extrusion (test group) or EMD +DFDBA
grafting alone (control group). After 1 year, both
groups had improved PD, CAL, and bone fill; however,
the test sites had significantly greater mean increase in
open probing CAL in 2-wall intrabony defects than
controls (SORT level C).
Patient Preferences and Clinical Outcomes
Patient options for regenerative approaches have
increased. Personal and religious preferences can be
respected as the clinician offers the appropriate re-
generative modalities. The advent of GTR, EMD,
rhPDGF, and LAR permits patients to select non–tissue
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
S93
Table 7.
Controlled Clinical Studies Comparing Treatment of Intrabony Defects With rhPDGF-BB 1b-TCP Versus b-TCP Alone
Study
Time
(months)
Study
Design Treatments (n defects)
PD Change
(mm) P
CAL Change
(mm) P
Linear Bone/Bone
Fill P
Nevins et al., 2005
164
6 Parallel rhPDGF–b-TCP (60) 4.43 NS 3.8 NS 2.6 mm/7% <0.001
b-TCP (59) 4.20 3.5 0.9 mm/18%
rhPDGF–b-TCP non-smoker (18) ND 60% <0.001
rhPDGF–b-TCP non-smoker (12) ND 16%
b-TCP smoker (12) ND 39% NS
b-TCP smoker (11) ND 25%
rhPDGF–b-TCP 1- to 2-wall defect
(40)
ND 53% <0.001
rhPDGF–b-TCP 3-wall/Cir defect
(42)
ND 4.8 NS 4.3
b-TCP 1- to 2-wall defect (12) ND 65% <0.001
b-TCP 3-wall/Cir defect (11) ND 21%
Nevins et al., 2013
135
12 rhPDGF–b-TCP (43) 4.46 NS 3.80 NS 2.88 mm/60% <0.001
b-TCP (45) 4.08 3.65 1.42 mm/33%
24 rhPDGF–b-TCP (29) 4.49 NS 4.09 NS 3.32 mm/68% <0.001
b-TCP (29) 3.80 3.31 1.81 mm/42%
36 rhPDGF–b-TCP (27) 4.57 NS 4.31 NS
b-TCP (28) 4.14 3.44
12 rhPDGF–b-TCP non-smoker ND 2.85 mm/62% <0.001
rhPDGF–b-TCP smoker ND 1.0 mm/27%
24 rhPDGF–b-TCP non-smoker ND 3.60 mm/72% <0.001
rhPDGF–b-TCP smoker ND 1.00 mm/25%
36 rhPDGF–b-TCP non-smoker ND 3.75 mm/82% <0.001
rhPDGF–b-TCP smoker ND 1.45 mm/30%
Jayakumar et al.,
2011
163
6 Parallel rhPDGF–b-TCP (27) 4.3 <0.005 3.7 <0.005 3.7 mm/65.6% <0.01
LBG
b-TCP (27) 3.2 2.8 2.8 mm/47.5% <0.004 %
BF
Cir =circumferential; NS =not significant; LBG =linear bone growth; BF =bone fill.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
S94
banked and non-porcine regenerative options. Histor-
ically, when DFDBA was the only regenerative ap-
proach, options, such as bioactive glass, b-TCP,
and ceramics were reasonable alternatives.
15
Al-
though these grafting procedures healed by the
formation of the long junctional epithelium, long-
term clinical stability was possible.
15
Now, these
materials are used primarily as scaffolding agents
to support regenerative approaches in wide/large
intrabony defects.
15,115,116,131,132
Clinical outcomes for both GTR and conservative/
minimally invasive procedures continue to demonstrate
therapeutic value for the periodontal patient (Tables 2
and 3). The majority of GTR studies report 12-month
clinical results,
11,51,57,62,72-74,76-78,80-83,85
although 5-
and 10-year results are now available (Table 2).
57,67,76-85
These reports document maintainable and signifi-
cantly reduced PD and gains in CAL compared with
pretreatment levels. Conversely, because of the more
recent introduction of minimally invasive/conserva-
tive flap procedures, very few long-term (>5years)
studies or comparisons with OFD are available.
91
The
great majority of articles present 6- to 12-month
results, demonstrating statistically significant re-
ductions in PD and gains in CAL (Table 2).
40,52-
56,58,75,87-90,92-98
However, Harrel et al.
91
concluded
that the therapeutic benefits of combining MIS and
EMD at 12 months remained stable at 6 years (Table 2).
Of note, REC values for conservative/minimally
invasive procedures tend to be
lower than those reported for
access flap surgery/GTR (Ta-
bles 2 and 3), suggesting that
minimally invasive techniques
are better suited for areas re-
quiring preservation of esthetics.
Nevertheless, it is important to
considerthatthepresenceofei-
ther a non-supportive defect
anatomy (OR =58.8) or thin-
scalloped gingival biotype
(OR =76.9) was identified as
ariskfactorforREConthe
midfacial aspect.
88
These find-
ings have significant implica-
tions in the esthetic zone, in
which minimizing REC is par-
amount.
Silvestri et al.
39
evaluated
tooth survival outcomes up to
16 years after GTR. A 90% tooth
survival rate was observed at
13 years, and post-surgical
CAL gains were maintained at
82% for 11 years. Prognosis
was negatively influenced by
smoking and lack of oral hygiene maintenance.
Indeed, results from a Kaplan-Meier analysis, cor-
relating survival rate and smoking status over time,
indicated that survival rates in smokers decreased at
a faster rate beginning 5 years after surgery; log-rank
testing showed that both smoking status and poor
compliance with oral hygiene programs were sig-
nificantly correlated with tooth loss.
39
Cortellini
and Tonetti
50
retrospectively evaluated tooth sur-
vival after GTR treatment up to 16 years and
concluded that tooth retention and clinical im-
provements can be maintained long term in most
patients. Of note, 96% of patients exhibited tooth
survival >10 years, with smokers contributing the
most lost teeth. Consistent with the latter finding, the
probability of losing ‡2 mm of regenerated CAL was
also shown to be significantly higher in smokers than
in non-smokers.
50
DISCUSSION
The goal of this systematic review is to update re-
search findings since the last consensus reviews on
the efficacy of bone replacement grafts and GTR.
15,16
Focus was on determinants for regenerative success,
new approaches for periodontal regeneration of in-
trabony defects, and the relationship of periodontal
regeneration to endodontic or orthodontic therapy.
These findings were presented above. To bring
clinical relevance to this body of information, clinical
Figure 2.
Decision treefor the management of intrabony defects. A/B/C/D/E are explained in paragraph ‘‘Summary
With Decision Tree to Guide Clinicians in Their Patient Management.’’
J Periodontol • February 2015 (Suppl.) Kao, Nares, Reynolds
S95
scenarios are addressed based on the information
and are reviewed below.
Clinical Scenario 1: What New Regenerative
Approaches Are There for Regeneration of
Intrabony Defects?
Inthisreview,theuseofbiologicsintheformofEMD
and rhPDGF-BB +b-TCPcanalsobeaddedtothelist
of available periodontal regenerative approaches. The
overall conclusion is that a beneficial result may
be seen as early as 6 months, but the maximal re-
generative results are not achieved until 1 or 2 years
later. Compared with OFD, EMD appears to support
greater improvements in both hard (defect fill) and soft
tissue parameters (CAL and PD), whereas rhPDGF-BB
+b-TCP may support greater improvements with de-
fect fill. The volume of bone fill for both of these bi-
ologics is comparable with those associated with
DFDBA and GTR approaches. Although there is proof
of principle for the use of laser as a regenerative ap-
proach,
30
there is an absence of data available to define
the predictability, frequency, and level of clinical
improvement that can be achieved with this ap-
proach. Minimally invasive approaches, with or
without the addition of biomaterials, represent via-
ble techniques in the treatment of intrabony defects.
These require microsurgical instruments and mag-
nification to perform accurately. Studies indicate
lower REC values compared with access flap/GTR
approaches.
Clinical Scenario 2: What Level of Evidence
Addresses the Decision When Selecting the Most
Appropriate Surgical Approach for Regeneration
of an Intrabony Defect?
The goal of evidence-based dentistry is to help prac-
titioners provide their patients with optimal care.
181
This concept is based on integrating sound research
evidence with personal clinical expertise and patient
values to determine the best course of treatment. Al-
though inclusion of studies evaluated included only
those materials that fulfill the criteria of histologic ev-
idence of periodontal regeneration, it should be ap-
preciated that this definition is problematic and
becoming more difficult to meet for ethical reasons.
Furthermore, although one of the inclusion criteria
was based on histologic evidence of periodontal re-
generation, the treatment decision is never based on
histology but rather on clinical determinants (as
outlined in Fig. 2) and long-term stability (‡3 years).
The latter is difficult to achieve because of the limited
number of study participants included in most of
these studies. Nevertheless, clinical evidence sub-
stantiates that periodontal regeneration of intrabony
defects is possible with the use of autogenous
bone, DFDBA, GTR, EMD, and rhPDGF-BB +b-TCP.
Furthermore, this review and previous consensus
reports substantiate that these approaches support
comparable improvements in clinical parameters
and bone fill.
15,16
Given the research evidence, the
selection of a regenerative approach is dependent
on the clinical expertise and experience of the
clinician and the patient’s desires. Although there are
justifiable reasons for strategic extraction,
182
current
evidence demonstrates that long-term stable results
are achievable with periodontal regeneration. The
ability to delay extraction by gaining more time through
periodontal regeneration should always be considered
as an option. This gained time may allow for advances
in implant dentistry, such as the following: 1) newer
technologies to enhance osseointegration; 2) more
predictable treatment strategies for peri-implantitis; and
3) improved methodology to address increasing esthetic
and functional demands of implant dentistry. Im-
plant dentistry is rapidly changing and improving;
as such, prolonging tooth survival through re-
generation appears to be a defensible and prudent
consideration.
Clinical Scenario 3: What Are the General
Principles of a Good Regenerative Approach?
Regenerative therapy represents a proven method
to improve clinical parameters, periodontal progno-
sis, and tooth retention. Achieving therapeutic goals
in periodontal regeneration necessitates the in-
corporation of sound clinical judgment and emphasis
on control of patient-centered variables both pre-
operatively and postoperatively. Surgical experience
and clinician skill should align with techniques that
maximize the biologic potential of the surgical site,
including space maintenance and wound stabilization.
Tooth stabilization appears to benefit periodontal
regenerative outcomes, whereas endodontically treated
teeth respond in a similar manner as vital teeth in
periodontal regenerative outcomes. Conservative/
minimally invasive techniques appear to result in less
REC postoperatively. These approaches may be better
suited for esthetically sensitive areas, although long-
term studies have yet to confirm the short-term
(1-year) outcomes.
Summary With Decision Tree to Guide Clinicians
in Their Patient Management
A decision tree is provided to show an overview of
clinical determinants that should be considered for
the best-practice management of intrabony defects
(Fig. 2). As with any therapeutic procedure, con-
sideration must be given to a patient’s desires and
expectations, as well as behavioral and systemic
issues. This along with the clinical determinants will
dictate whether therapy should be performed for
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
S96
posterior teeth (Fig. 2A). Exceptions to this decision
tree may be in the maxillary anterior esthetic zone in
which maintenance versus strategic extraction may
need to be considered. For posterior teeth, if the
intrabony defect is narrow and £3 mm in open PD,
conventional osseous surgery may be most appro-
priate and predictable for posterior teeth (Fig. 2B).
Debridement of the narrow defect is often adequate
to achieve clinical improvement, whereas ostectomy
can be performed on the broader crestal aspect
of the defect. Should the defect be broad and
>3 mm in open PD, one should consider periodontal
regeneration (Fig. 2C). Assessment of defect mor-
phology and the patient’s clinical and systemic-
behavioral determinants is critical for regenerative
success. Consideration of this in addition to the
patient’s desires will define the selection of the
regenerative approach (Fig. 2D). Although the cli-
nician and the patient together decide on the ap-
propriate material, the management of the defect
is based more on the osseous architecture. Narrow
3-wall defects are easily managed by a variety of
regenerative approaches, whereas broad, deep 2-
wall defects may require combination therapy that
provides scaffolding support to prevent tissue
collapse into the defect. Long-term stability is
possible, but the individual outcome is influenced
by smoking and compliance with periodontal
maintenance and monitoring. Should patient-
related or clinical determinants be unfavorable for
periodontal regeneration, then consideration, if
appropriate, might be given to strategic extraction
and placement of an implant-supported prosthe-
sis (Fig. 2E).
REVIEWERS’ CONCLUSIONS
The reviewers’ conclusions are the following: 1) The
use of biologics (EMD and rhPDGF-BB +b-TCP)
generally increase bone fill and improve CAL and
reduce PD compared with OFD procedures in the
treatment of intrabony defects. These improve-
ments are comparable with those found with
DFDBA and GTR regenerative approaches. 2)
Histologic evidence of regeneration has been
demonstrated with laser therapy, but there are no
data that define the clinical effectiveness and
predictability of this approach. 3) Clinical out-
comes will be most significantly influenced by
patient behaviors, surgical approach, and much
less by tooth and site characteristics. 4) Long-term
studies indicate that the clinical results achieved
with regenerative therapy are maintainable up to
10 years, even in severely compromised teeth.
Regenerative therapy is capable of improving tooth
prognosis.
ACKNOWLEDGMENTS
Dr. Nares has received lecture fees from DENTSPLY
(York, Pennsylvania). Dr. Reynolds has received
research funding from Millennium Dental Technol-
ogies (Cerritos, California) and Zimmer Dental
(Carlsbad, California), and is an unpaid consultant
for LifeNet Health (Virginia Beach, Virginia). Dr.
Kao reports no conflicts of interest related to this
review. The 2014 Regeneration Workshop was
hosted by the American Academy of Periodontology
(AAP) and supported in part by the AAP Foundation,
Geistlich Pharma North America, Colgate-Palmolive,
and the Osteology Foundation.
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Correspondence: Dr. Richard T. Kao, 10440 S. De Anza
Blvd., #D-1, Cupertino, CA 95014. E-mail: richkao@
sbcglobal.net.
Submitted November 18, 2013; accepted for publication
March 31, 2014.
Periodontal Regeneration: Intrabony Defects Volume 86 • Number 2 (Suppl.)
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