475 QUINTESSENCE INTERNATIONAL VOLUME 45 • NUMBER 6 • JUNE 2014 Enamel matrix derivative in combination with bone grafts: A review of the literature Richard J. Miron, MSc, PhD 1 /Vincent Guillemette 2 /Yufeng Zhang, Prof, DMD, Dr Med Dent, MSc, PhD 3 / Fatiha Chandad, Prof, MSc, PhD 4 /Anton Sculean, Prof, DMD, Dr Med Dent, MS, PhD, Dr hc 5 Objective: Over 15 years have passed since an enamel matrix derivative (EMD) was introduced as a biologic agent capable of periodontal regeneration. Histologic and controlled clinical studies have provided evidence for periodontal regeneration and substantial clinical improvements following its use. The purpose of this review article was to perform a systematic review comparing the effect of EMD when used alone or in combination with various types of bone grafting material. Data Sources: A literature search was conducted on several medical databases including Medline, EMBASE, LILACS, and CENTRAL. For study inclusion, all studies that used EMD in combination with a bone graft were included. In the initial search, a total of 820 articles were found, 71 of which were selected for this review article. Studies were divided into in vitro, in vivo, and clinical studies. The clinical studies were sub- divided into four subgroups to determine the effect of EMD in combination with autogenous bone, allografts, xenografts, and alloplasts. Results: The analysis from the present study demonstrates that while EMD in combination with certain bone grafts is able to improve the regeneration of periodontal intrabony and furcation defects, direct evidence supporting the combination approach is still missing. Conclusion: Further controlled clinical trials are required to explain the large variability that exists amongst the conducted studies. (Quintessence Int 2014;45:475–487; doi: 10.3290/j.qi.a31541) Key words: animals, bone grafts, Emdogain, enamel matrix derivative, intrabony periodontal defects, osteoinduction, preclinical studies, systematic review PERIODONTOLOGY Richard J. Miron Periodontitis, an infectious disease characterized by progressive attachment and bone degeneration, may ultimately result in tooth loss if left untreated. Results from a national survey conducted in the United States in 2009 and 2010 demonstrated that over 47% of the adult population aged 30 years and above had peri- odontitis, distributed as 8.7%, 30.0%, and 8.5% with mild, moderate, and severe periodontitis, respectively. 1 Such surveys clearly demonstrate the prevalence and importance of developing clear guidelines aimed at restoring a functional periodontal apparatus. Regenera- tive periodontal surgery aims to predictably restore the tooth’s supporting apparatus (ie, root cementum, peri- 1 Research Fellow, Faculté de Medecine Dentaire, Pavillon de Médecine Dentaire, Université Laval, Québec, Canada; and The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Bio- medicine Ministry of Education, School & Hospital of Stomatology, Wuhan Uni- versity, Wuhan 430079, People’s Republic of China. 2 Research Student, Faculté de Medecine Dentaire, Pavillon de Médecine Den- taire, Université Laval, Québec, Canada. 3 Associate Professor, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, People’s Republic of China. 4 Head of Research, Groupe de Recherche en Écologie Buccale, Faculté de Mede- cine Dentaire, Pavillon de Médecine Dentaire, Université Laval, Québec, Canada. 5 Head, Department of Periodontology, School of Dental Medicine, University of Bern, Switzerland. Correspondence: Dr Richard J. Miron, Faculté de Medecine Dentaire, Pavillon de Médecine Dentaire, 2420 Rue de la Terrasse, Université Laval, Québec, G1V 0A6, Canada. Email: [email protected]
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475
Q U I N T E S S E N C E I N T E R N AT I O N A L
VOLUME 45 • NUMBER 6 • JUNE 2014
Enamel matrix derivative in combination
with bone grafts: A review of the literature
Richard J. Miron, MSc, PhD1/Vincent Guillemette2/Yufeng Zhang, Prof, DMD, Dr Med Dent, MSc, PhD3/ Fatiha Chandad, Prof, MSc, PhD4/Anton Sculean, Prof, DMD, Dr Med Dent, MS, PhD, Dr hc5
Objective: Over 15 years have passed since an enamel matrix derivative (EMD) was introduced as a biologic agent capable of periodontal regeneration. Histologic and controlled clinical studies have provided evidence for periodontal regeneration and substantial clinical improvements following its use. The purpose of this review article was to perform a systematic review comparing the effect of EMD when used alone or in combination with various types of bone grafting material. Data Sources: A literature search was conducted on several medical databases including Medline, EMBASE, LILACS, and CENTRAL. For study inclusion, all studies that used EMD in combination with a bone graft were included. In the initial search, a total of 820 articles were found, 71 of which were
selected for this review article. Studies were divided into in vitro, in vivo, and clinical studies. The clinical studies were sub-divided into four subgroups to determine the effect of EMD in combination with autogenous bone, allografts, xenografts, and alloplasts. Results: The analysis from the present study demonstrates that while EMD in combination with certain bone grafts is able to improve the regeneration of periodontal intrabony and furcation defects, direct evidence supporting the combination approach is still missing. Conclusion: Further controlled clinical trials are required to explain the large variability that exists amongst the conducted studies. (Quintessence Int 2014;45:475–487; doi: 10.3290/j.qi.a31541)
1 Research Fellow, Faculté de Medecine Dentaire, Pavillon de Médecine Dentaire,
Université Laval, Québec, Canada; and The State Key Laboratory Breeding Base
of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Bio-
medicine Ministry of Education, School & Hospital of Stomatology, Wuhan Uni-
versity, Wuhan 430079, People’s Republic of China.
2 Research Student, Faculté de Medecine Dentaire, Pavillon de Médecine Den-
taire, Université Laval, Québec, Canada.
3 Associate Professor, The State Key Laboratory Breeding Base of Basic Science of
Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of
Education, School & Hospital of Stomatology, Wuhan University, Wuhan 430079,
People’s Republic of China.
4 Head of Research, Groupe de Recherche en Écologie Buccale, Faculté de Mede-
cine Dentaire, Pavillon de Médecine Dentaire, Université Laval, Québec, Canada.
5 Head, Department of Periodontology, School of Dental Medicine, University of
Bern, Switzerland.
Correspondence: Dr Richard J. Miron, Faculté de Medecine Dentaire, Pavillon de Médecine Dentaire, 2420 Rue de la Terrasse, Université Laval, Québec, G1V 0A6, Canada. Email: [email protected]
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VOLUME 45 • NUMBER 6 • JUNE 2014
odontal ligament, and bone) that has been lost follow-
ing periodontal disease or trauma.2-5 Results from lon-
gitudinal clinical studies have provided some evidence
that chronic periodontal disease can be successfully
treated.6 Patient education and training in personal
hygiene combined with meticulous plaque control fol-
lowed by nonsurgical and surgical periodontal treat-
ment aiming to disrupt the subgingival plaque biofilm
has been reported. All of these methods are aimed at
reducing periodontal pocket depth (PD).6,7
One well-established method to enhance periodon-
tal regeneration is the use of an enamel matrix deriva-
tive (EMD).8 The use of EMD has been shown to
enhance regeneration of root cementum, periodontal
ligament, and alveolar bone, and to result in substantial
clinical improvements evidenced by probing depth
reduction, gain in clinical attachment, and bone fill.9
This review article plans to give insight into the
advances made with respect to the combination of
EMD with a bone grafting material. A number of in
vitro, in vivo, and clinical studies are discussed eliciting
the use of this combination for bone and periodontal
regeneration.
BIOLOGIC RATIONALE OF THE USE OF EMD
Over 15 years ago, EMD was first introduced as an
adjunctive to periodontal surgery. It was originally
developed at BIORA, in Malmö, Sweden, but has since
been commercially available from Straumann, Basel,
Switzerland. The development of Emdogain for peri-
odontal regeneration mimics the normal development
of periodontal tissues.10 The histologic observation that
amelogenin, which until then was considered an
enamel-specific protein, is deposited onto the surface
of developing tooth roots prior to cementum forma-
tion, led to the hypothesis that amelogenin might be
responsible for the differentiation of periodontal tis-
sues.10 This hypothesis was the basis of a number of
biologic and clinical studies thereafter.10-16 Based on
these observations, the purified amelogenin fraction
was given the working name EMD, and this formulation
has been the basis for numerous publications support-
ing its use in periodontal regeneration.
The major components of EMD are amelogenins, a
family of hydrophobic proteins derived from different
splice variants and controlled post-secretory from the
expression of a single gene that accounts for more than
95% of the total protein content.17 These proteins self-
assemble into supramolecular aggregates that form an
insoluble extracellular matrix that functions to control
the ultrastructural organization of the developing
enamel crystallites.17 Other proteins found in the
enamel matrix include enamelin, ameloblastin (also
called amelin or sheathlin), amelotin, apin, and various
proteinases.18,19
Previous in vitro research has documented and
characterized the role of EMD in many cell types. Boss-
hardt20 has published a review article of the biologic
mediators associated with EMD at the cellular and
molecular levels. It was demonstrated that EMD has a
significant influence on the cell behavior of many cell
types by mediating cell attachment, spreading, prolif-
eration, and survival, as well as expression of transcrip-
matrix constituents, and other molecules involved in
the regulation of bone remodeling.20
Fig 1 Periodontal regeneration follow-ing treatment of a human intrabony defect with a combi-nation of Emdogain + natural bone mineral (eg, Bio-Oss spongio-sa). D, dentin; G, graft; NB, new bone; NC, new cementum.
D
NB
NB
GNC
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VOLUME 45 • NUMBER 6 • JUNE 2014
COMBINATION OF BONE GRAFT + EMD
Although histologic and controlled clinical studies have
provided evidence for periodontal regeneration and
substantial clinical improvements following the use of
EMD in intrabony defects (Fig 1), concerns have been
expressed regarding the viscous nature of EMD, which
may not be suffi cient to prevent fl ap collapse in peri-
odontal defects with a complicated anatomy. A fl ap
collapse may subsequently lead to a limitation of the
space available for regeneration, thus limiting the clin-
ical outcomes.21,22 In order to overcome this potential
limitation and improve the clinical results obtained
with EMD, various combinations of EMD with diff erent
types of grafting materials have been utilized.
CLASSIFICATION OF BONE GRAFTS
The primary goal of bone grafts is to facilitate recruit-
ment of bone-forming osteoblasts capable of prolifer-
ating and diff erentiating on an osteoconductive sur-
face promoting the formation of new bone.23 A variety
of biologic and synthetic materials are available for the
surgical treatment of alveolar bone loss (Fig 2).
Although autogenous bone (AB) graft is considered
the gold standard, many other materials, including
bone allografts, xenografts, and alloplasts, are exten-
sively being studied in order to avoid the drawbacks
and limitations of AB, which include donor site morbid-
ity and additional surgical costs.24-28 The ideal bone
grafting material should generate and sustain suffi -
cient alveolar bone for long-term function, have low
Figs 2a to 2h Scanning electron micros-copy (SEM) images of various bone grafts that are commonly used in dentistry at low and high magnifi cation: (a and b) Autog-enous bone (AB) harvested via a bone scraper; (c and d) demineralized freeze-dried bone allograft (DFDBA); (e and f) a natural bone graft from bovine origine (Bio-Oss xenograft); (g and h) a synthetic calcium phosphate.
a
d
g
b
e
h
c
f
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morbidity and complication rate, as well as a short
healing time.
The regenerative potential of bone grafts is gov-
erned by three fundamental mechanisms.23 The ideal
grafting material should provide:
• an osteoconductive matrix, which allows vascular
invasion and cellular infiltration
• osteoinductive factors, which recruit and induce
mesenchymal cells to differentiate into mature
bone-forming cells
• osteogenic cells contained inside the bone graft
capable of laying new bone matrix.
Autogenous bone
AB (often termed autologous bone) grafting involves
the harvesting of bone obtained from the same indi-
vidual receiving the graft.29 Common in oral and maxil-
lofacial surgery is the harvesting from the mandibular
symphysis (chin area) or anterior mandibular ramus
(the coronoid process). Commonly employed harvest-
ing techniques include grinding of bone blocks with a
bone mill, harvesting with piezosurgery, collection of
drilling particles (bone slurry) with a bone trap, or using
a bone scraper.29,30 The advantages of AB grafts are
their osteoinductive potential, their ability to be used
as blocks or particulate, and the incorporation of osteo-
genic cells located inside their bone matrix.30 Their
limitations are their morbidity from the donor site and
unpredictable resorption.31
Allografts
Allografts involve the harvesting of bone obtained from
another human individual receiving the graft. These are
commonly obtained from bone banks built from
donated cadavers.32 There are three types of bone
allografts available on the market:
• fresh or fresh-frozen bone
• freeze-dried bone allograft (FDBA)
• Demineralized freeze-dried bone allograft (DFDBA).
Currently, the use of allografts is permitted in the United
States; however, their use in most countries in Europe
and Asia is not permitted. The advantages of allografts
are their availability when compared to AB, their lack of
donor site morbidity, and their ability to contain osteo-
inductive growth factors and cytokines embedded in
the bone matrix.23 Disadvantages are their possible
transmission of disease and lack of osteogenic cells.
Xenografts
Xenografts are bone substitutes derived from a species
other than human, such as animals and plants. One
well-documented xenograft is natural bone mineral
(NBM), which is a highly purified anorganic bone matrix
mineral from bovine origin ranging in size from
0.25 mm to 1 mm under the trademark name Bio-Oss®
(Geistlich Biomaterials).33,34 A clinical case is presented
in Figs 3 to 7, demonstrating its combination with EMD.
The advantages of xenografts include their availability,
safety, surface characteristics that are comparable to
AB, and little to no long-term resorption. Their limita-
tions include limited mechanical stability, inability to
alter resorbability, lack of osteoinductive potential, and
patients’ fear of “animal origin”.33,34
Alloplasts
Alloplasts are synthetically fabricated of hydroxyapatite
(HA), beta-tricalcium phosphate (β-TCP), polymers, and
bioactive glasses.35-38 They are osteoconductive and
recent research suggests that some may also be osteo-
inductive.23,39 Recently, alloplasts have been fabricated
with the incorporation of growth factors and/or cyto-
kines.23 Their advantages are their availability, safety,
and modifiable resorbability. Their limitations include
surface characteristics, limited clinical cases, and lack of
osteoinduction.
RESOURCES SELECTION
In order to gather all available biologic data relevant to
the topic, a systematic approach was applied by search-
ing databases including MEDLINE, PubMed, Embase,
and Cochrane Databases up until 28 May 2013. The
initial search criteria for “enamel matrix proteins”,
“enamel matrix derivative”, and “emdogain” generated
820 initial articles (Fig 3). Of these, an individual hand
search was established and screened for all in vitro, in
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Q U I N T E S S E N C E I N T E R N AT I O N A L
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VOLUME 45 • NUMBER 6 • JUNE 2014
vivo, and clinical studies utilizing EMD with any type of
bone grafting material. A total of 6 in vitro, 15 in vivo,
and 19 clinical studies were selected after careful
review and are presented in the remainder of this arti-
cle. In addition, a secondary search of possible articles
relevant to the topic was undertaken in other data-
bases to identify possible additional studies that may
have been missed.
In vitro studies
To date, only six studies have tested the combination of
EMD with various bone grafting materials. In the first in
vitro study conducted by Reichert et al,40 the combina-
tion of EMD with seven various bone grafts was tested
for the proliferative ability of a commercially available
hip-bone derived osteoblastic cell line (HHOBc, Promo-
Cell). In this study, the proliferation of osteoblasts was
only significantly upregulated on Bio-Oss particles fol-
lowing 7 days of incubation. The authors report that no
clear correlation between bone grafts coated with EMD
could be observed and that further investigations were
necessary to understand the exact modus of interac-
tion between EMD and bone grafts.
Further research from our laboratory was con-
ducted to develop the regenerative potential of Bio-Oss
in combination with EMD.41,42 Recently, we demon-
strated that EMD significantly increased cell attach-
ment, proliferation, and differentiation of human pri-
mary osteoblasts and periodontal ligament (PDL) cells
on EMD-coated Bio-Oss particles when compared to
control particles in vitro.41 EMD also stimulated the
release of growth factors, cytokines, and differentiation
early stimulation in both MSC types after 24 hours. Both
osteopontin and periostin mRNA were upregulated in
BMSCs, and higher levels of bone sialoprotein were
observed in only PDLFs following treatment with EMD.
In contrast, they found that expression of BMP-4 was
consistently downregulated by both MSC types follow-
ing treatment with EMD. In conclusion, it was sug-
gested that early upregulation of several important
bone-related genes suggests that EMD may have a
significant stimulatory effect in the commitment of
mesenchymal cells to osteogenic differentiation. How-
ever, future research was suggested to determine the
effects of EMD on late differentiation and mineraliza-
tion of osteoblasts.
In vivo animal studies
A number of in vivo studies with various defect models
are now available demonstrating the effect of EMD in
combination with a bone graft (Table 1). Boyan et al46
were the first to test the effects of EMD in vivo by test-
ing the ability for EMD with/without DFDBA to form
ectopic bone formation in nude mice. While EMD was
not able to induce ectopic bone formation alone, it was
shown that it had an osteopromotive effect on bone
regeneration when it was combined with DFDBA.46
Since then, three additional studies have studied the
effects of EMD on ectopic bone formation. All studies
were unable to find any evidence that EMD promoted
ectopic bone formation in pectoralis muscles, thigh
muscles, and the dorsal surface in either a rat or mouse
model.45,47,48
The effect of EMD on bone formation has also been
tested in a number of animal pure bone defect models.
Two studies in rat calvaria demonstrated nonsignificant
improvements of bone formation when combining
EMD with either deproteinized bovine bone mineral
(DBBM) or bioglass (BG).49,50 In rabbit calvarial defects,
Murai et al51 showed little advantage for the use of EMD
in titanium caps containing either β-TCP or β-TCP +
EMD. The other rabbit calvaria study showed statisti-
cally significant improvements in bone formation when
EMD was combined with Bio-Oss.52 In the remaining
two studies, EMD had a significantly positive improve-
ment in a rat femur defect when combined with Bio-
Oss when compared to Bio-Oss alone,53 as well as
improved healing of bone defects following extraction
when combined with AB when compared to AB alone.54
To date, five studies have demonstrated the ability
for EMD to enhance periodontal regeneration in both
rat and dog intrabony defects. Fernandes et al55 created
Class III furcation defects in five mongrel dogs and
showed that the combination of EMD with BG was non-
significantly superior to either the use of EMD alone or
BG alone. Donos et al56 studied the effects of bone for-
mation under periosteal flaps of the mandibular ramus
and found no advantage of a combination of GBR +
DBBM + EMD when compared to either GBR + DBBM or
GBR + EMD alone. In a one-wall intrabony defect, Shi-
rakata et al57 showed that EMD in combination with a
CaP cement generated significantly new bone forma-
tion when compared to EMD alone. Yamamoto et al58
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demonstrated a significant advantage (P < .05) when
EMD was combined with bovine-derived xenograft
(BDX) when compared to BDX alone for the treatment
of intrabony defects in dogs. Most recently, Oortgiesen
et al59 demonstrated that EMD in combination with CaP
was able to significantly increase new bone formation
Table 1 Chronological list demonstrating the various animal models testing the efficacy of EMD in combina-tion with a bone graft when compared to either a bone graft alone or EMD alone
Study Models Study design Duration Treatment groups Outcome P value
Boyan et al46 32 miceEctopic bone formation in calf muscle
56 days
DFDBA Ectopic BF
< .05EMD No ectopic BF
DFBDA + EMD Greater ectopic BF
Donos et al49 40 ratsBilateral calvarial defects
120 days
EMD W = 2.96; L = 1.70
NSDBBM W = 1.78; L = 0.33
EMD + DBBM W = 1.76; L = 1.36
Donos et al56 20 ratsBone formation under periosteal flap of man-dibular rasmus
60, 120 days
GBR + DBBM Bone fill = 19%
NSGBR +EMD Bone fill = 15%
GBR + DBBM + EMD Bone fill = 9.5%
Fernandes et al55 5 dogsTreatment of Class III furcation defects
90 days
BG PR = 1.5%
NSEMD PR = 1.0%
EMD + BG PR = 6.3%
Murai et al51 14 rabbits Calvaria defects 30, 90 daysβ-TCP New BF 36.6%
NSΒ-TCP + EMD New BF 42.2%
Donos et al47 16 ratsEctopic bone formation in pectoralis muscles
60, 120 daysDBBM No ectopic BF
NSEMD + DBBM No ectopic BF
Prata et al54 10 ratsIntrabony defects fol-lowing extraction
7, 21, 42 daysAB BF = 62%
< .05AB + EMD BF = 72%
Shirakata et al57 4 dogsOne-wall intrabony defects
70 days
EMD BF = 2.33 mm
< .0001CaP cement BF = 3.50 mm
EMD + CaP cement BF = 3.07 mm
Yamamoto et al58 24 dogs Intrabony defects 56 daysBDX New BF 31.6%