From Buonocore's pioneering acid etching technique...

to self-adhesive restorations. An overview of the current

state of rapidly advancing dental adhesive technology
Bart Van Meerbeek / Kumiko Yoshiharab / Kirsten Van Landuyt / Yasuhiro Yoshidad / Marleen Peumans

Summary: This OPINION DOCUMENT based on the literature, reflects in a historical perspective

introductory the rapid advancement of dental adhesive technology. Past and current techniques of bonding to dental tissue,
particularly to dentin as the most challenging bonding substrate, are critically evaluated. Including the historical perspective in (1), this
paper focuses on fourteen points that are considered to be of primary importance with respect to the current situation of dental
adhesive technology. In (2) the primary mechanisms involved in adhesion to enamel and especially to dentin are discussed, having
also (3) reviewed the previously introduced adhesion-decalcification concept (AD concept) as the basis of biomaterial-hard tissue
interaction; in (4) the globally accepted classification of current adhesives into etch-and-rinse (E&R) and self-etch (SE) adhesives is
presented, together with the presentation of their respective PLUS-MINUS balances in (5) and (6); The designation of GOLD
STANDARD (7) and SE (8) E&R adhesives is based on long-term satisfactory laboratory and clinical performance testing, resulting in a
recommended 3-step complete E&R bonding route in (9) and the preferred 3-step combined selective enamel E&R bonding route
with the 2-SE bonding route in (10); (11) Description of the main adhesion degradation pathways and eight strategies to preserve
adhesion stability; (12) Coverage age of the PROS and CONS of the most recent generation of UNIVERSAL adhesives. Looking ahead,
some expected future developments in dental adhesive technology have been suggested in (13), together with (14) a first
determination of the status of the latest research and developments towards self-adhesive restorative materials that no longer
require any pretreatment.
Keywords: review, bonding, dentin, adhesion, self-adhesive.
J Adhes Dent 2020; 22:7–34. Submitted for publication: 01/26/20; accepted for publication: 01/27/20
doi: 10.3290/j.jad.a43994

Translated by: Jaime Paul Ramos Vargas, DDS email: [email protected] 04/26/2020

(1)HISTORICAL PERSPECTIVE OF MILESTONES IN DENTAL 1951 63,110,111.

ADHESIVE TECHNOLOGY He used the functional monomer glycerophosphate dimethacrylate
Dental adhesive technology continues to evolve at a rapid pace (Fig. 1). (GPDM), which is still considered today as the main functional monomer in
We have already learned to adhere effectively and durably to enamel 65 some popular adhesive products, such as the Optibond FL/XTR/Universal
(Kerr) family of products. Landmark research identified Kramer and
years ago with the invention of Buonocore with the "ACID ETCHING
McLean, who demonstrated in 1952 that GPDM improved adhesion to
TECHNIQUE"22. Before Buonocore, the first attempts to adhere acrylic
dentin by "penetrating the surface and forming an intermediate layer" 90.
resin to dental structure must be attributed to the Swiss chemist Hagger in
Much later, this middle layer was---

Full Professor, KU Leuven (University of Leuven), Department of Oral Health the manuscript. d Full Professor, Hokkaido University, Graduate School of
Sci ences, BIOMAT – Biomaterials Research group & UZ Leuven (University Medicine, Dentistry and Pharmaceutical Sciences, Department of
Hospitals Leuven), Dentistry, Leuven, Belgium. Idea and paper concept, wrote the Biomaterials, Sapporo, Japan. Critically proofread the manuscript.
paper.
Associate Professor, KU Leuven (University of Leuven), Department of Oral
b
Senior Researcher, National Institute of Advanced Industrial Science and Health Sciences, BIOMAT – Biomaterials Research group & UZ Leuven
Technology (AIST), Health Research Institute, Takamatsu & Visiting Re (University Hospitals Leuven), Dentistry, Leuven, Belgium. Critically proofread
searcher, Okayama University, Graduate School of Medicine, Dentistry and the manuscript.
Pharmaceutical Sciences, Department of Pathology & Experimental Medicine,
Okayama, Japan. Critically proofread the manuscript and provided TEM and
Correspondence: Prof. Dr. B. Van Meerbeek, KU Leuven (University of Leuven),
FIB/SEM photomicrographs.
Department of Oral Health Sciences, BIOMAT, Kapucijnenvoer 7, block a –
Associate Professor, KU Leuven (University of Leuven), Department of Oral box 7001, BE-3000 Leuven, Belgium; Tel. +32-16-337587;
Health Sciences, BIOMAT – Biomaterials Research group & UZ Leuven email: [email protected]
(University Hospi tals Leuven), Dentistry, Leuven, Belgium. Critically proofread

Vol 22, No 1, 2020 7

Van Meerbeek et al

20

8 The Journal of Adhesive Dentistry

 Van Meerbeek et al

labeled as the "hybrid layer"126. However, history also learned that copying which was applied and rinsed off before bonding with the well-known
Buonocore's acid-etching technique to dentin, while generating a bond Gluma adhesive (Bayer Dental). Alternatively, aqueous solutions of acidic
strength of 15-20 MPa to enamel, was a logical but overly simple attempt monomers were used, such as the "gold" bottle of Scotchprep (3M Dental),
at research and development (R&D).21 which contained 2.5% maleic acid mixed with 55% 2-hydroxyethyl
methacrylate (HEMA) as part of the popular two-step bonding agent
First generation adhesives contained GPDM as an active ingredient.
Scotchbond 2 (3M Dental). As a third-generation adhesive, Scotchbond 2
GPDM has an ionic binding potential to hydroxyapatite (HAp) through its
(3M Dental) was one of the first bonding agents to receive the American
phosphate functional group (Fig 1). According to recent research, this
Dental Association (ADA) label of “provisional acceptance” and later “full
chemical interaction of GPDM with HAp-based substrates should, however, acceptance,” which was based on successful short-term clinical results of 1
be qualified in the sense that, although GPDM adsorbs to HAp, it is unable
and 3 years, respectively, reported in independent clinical trials.48,223
to form a stable chemical bond244. The early GPDM-based adhesive
To avoid collateral damage to the pulp, milder alternatives to
formulations were supplemented with surface-active co-monomers such
phosphoric acid, e.g. malic, nitric and citric acids, or lower
as N-(2-hydroxy-3-methacryloxypropyl)-N-phenylglycine (NPG-GMA) from
concentrations of phosphoric acid etchants were initially employed, in
Bowen116. One of the first commercially available dentin bonding agents
a gradual evolution towards fourth generation adhesives. They use the
was marketed as Cervident (SS White) in the 1960s.16 These early
"TOTAL ENGRAVING" technique, which was introduced on the basis of
adhesives, however, had a very low, unstable bond strength to dentin, of
Japanese research originally carried out by the Fusayama research
2-3 MPa.
group, which was far ahead of its time57 ,83. The term "total etching"
In the late 1970s and 1980s, research into dental adhesive refers to the simultaneous etching of enamel and dentin using
technology focused on the synthesis of a wide range of functional phosphoric acid14,58. Along with the research goals of interacting with
monomers, all designed to chemically interact with inorganic (HAp) or dentin more intensively, these total-etch adhesives evolved into multi-
organic (collagen) dental components5, 7,49,167. These second generation step systems that included the separate use of a CONDITIONER and
adhesives were classified into calcium and collagen adhesives6. PRIMER prior to application of the actual ADHESIVE RESIN in a typical
Products such as Clearfil Bond System F (Kuraray), which was already three-step application procedure215. The term adhesive agent no
commercially available in 1978, Bondlite (Kerr/Sybron), J&J VLC Dentin longer covered the multi-stage application process and was therefore
Bonding Agent (Johnson & Johnson Dental), and Scotchbond (3M replaced by "ADHESIVE SYSTEM". Although research understood that
Dental) contained phosphorus esters of methacrylate derivatives. dentin, in contrast to enamel, required specific pretreatment
Some additional adhesion strength was obtained, but it rarely strategies, these multi-step adhesives presented more complicated
exceeded 5-6 MPa, while these adhesive agents were subsequently and, obviously, slower clinical application procedures. The use of the
associated as well with clinical results term CONDITIONER originated in the early 1990s, sounding less
suboptimal71,197,223,231. These second-generation adhesives, mostly aggressive than the traditional etching on the fear of adverse pulpal
single-solution, did not sufficiently address the rather thick and reactions. In addition to the complete removal of the smear layer,
compact SMEAR LAYER layer resulting from milling preparation. The phosphoric acid conditioning agents demineralize dentin to several
superficial smear layer was then considered insufficiently capable of micrometers deep and, after thorough washing with water, expose a
interfering with the possible (chemical) interaction of the functional microporous network of HAp-poor collagen fibers (Fig. 1c). The
monomer(s) with the pure dentin substrate. These adhesives actually PRIMER applied subsequently serves as an adhesion promoter.
bonded to the smear layer, which in turn was too weakly attached to This contains hydrophilic monomers, such as the monofunctional
the underlying dentin. Typical of that time, "DENTIN BONDING monomer HEMA in particular. Due to its low molecular weight and
AGENTS" were marketed, highlighting their explicit design and therefore small size, together with its high hydrophilicity through its short
development to adhere to the challenging dentin substrate, while carbon chain ending in a hydroxyl group, HEMA is an effective surface
adhesion to enamel after acid etching was already considered wetting agent as well as interdiffusion agent to infiltrate the surface of
satisfactory. A milestone in the rapidly evolving dental adhesive moist and demineralized collagen-rich dentin. Adequate infiltration should
technology was the introduction by Nakabayashi in 1982 of the term be achieved clinically within a short application time of 10 to 20 s. Today,
"HYBRID LAYER" (Fig. 1), which referred to the structure formed on HEMA is still added to many commercial adhesives, also because it can act
the surface of dentin by prior demineralization (partial/total) followed as a cosolvent for other monomers in preventing water/monomer phase
separation205,210
by infiltration of monomers and their subsequent polymerization126. . However, the main disadvantages of HEMA are: 1) its low
Abandoning the concept of chemical interaction with dental tissue, as polymerization capacity, 2) its low contribution to mechanical strength, 3)
its high water absorption and 4) its unfavorable biocompatibility,
was pursued with second-generation adhesives, the research
particularly with regard to its documented allergic potential208,209. In
community gradually became convinced of the need for
current adhesives, manufacturers are trying to substantially reduce the
micromechanical interlocking with dental surfaces as the main
HEMA content or even replace it with alternative monomers such as
adhesion mechanism. The foundation for third-generation adhesives methacrylamide monomer variants.
was laid when the earlier Japanese concept of etching dentin to Typical total-etch primers contain monomers dissolved in different
remove the smear layer, as already introduced by Fusayama et al. in combinations of ethanol, acetone and/or water solvent, with the solvent
197957, gained worldwide acceptance and led to the commercialization of acting as a carrier to facilitate monomer infiltration and resin incorporation
the Japanese bonding agent Clearfil New Bond (Kuraray) in 1984. into individual collagen fibers. After application, the primer is gently air
Phosphoric acid etching was followed by the application of a chemically dried to promote solvent evaporation. If the solvent were to remain, it
curing two-component bonding agent already containing the functional would impair the hybridization and subsequent polymerization of the resin
monomer 10-methacryloxydecyl dihydrogen phosphate (10-MDP). Today, within the 4- to 6-μm-thick hybrid layer. Therefore, these total-etch
10-MDP is still considered one of the most effective functional monomers, primers are primarily aimed at making the wet collagen fiber network
but in years past it was not used with the intention of chemically more receptive to subsequent infiltration. of monomers further
interacting with HAp. After phosphoric acid etching, no HAp remains up to hydrophobic, such as containinghe adhesive agent wave
a few micrometers deep on the dentin surface with which to interact. ADHESIVE RESIN that It is applied inhe third and last passed
Particularly in Europe and the United States, the application of phosphoric adhesive. The infiltration of the latter in dentinal tubules
acid etchants to dentin was then still discouraged because of their Openings lead to the formation of abundant resin "tags", which together
presumed detrimental effect on the underlying pulp, even with an with intertubular hybridization constitute the mainly micromechanical
intervening dentin barrier13,164. Instead, dissolution/removal of smear layer layers interlocking bonding mechanism of total-etch adhesives (Figs. 1a to 1d).
was achieved, for example, with a calcium chelator such as EDTA (17%), Along with the evolution of dental bonding technology in the late

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Van Meerbeek et al

1980s and early 1990s, a better understanding of the mechanisms involved

in dentin adhesion was achieved through the introduction of new research
techniques that allowed for a more in-depth characterization of the
dentin-adhesive interfaces at higher magnification/resolution. Of particular
note is the argon ion bombardment technique developed by Inokoshi et al.
in the early 1990s, which served as a surface topography enhancement
technique to visualize hybrid layer and resin formation at adhesive-dentin
interfaces using scanning electron microscopy (SEM) (Fig. 1a) 80,179,220,221.
Furthermore, Nakabayashi and Watanabe in 1983127 and 1985128 must
have been among the first to report, initially in the Japanese literature, on
the use of transmission electron microscopy (TEM) to ultramorphologically
characterize ultrathin 60 to 90 nm cross sections of the adhesive-dentin
interfaces129,130. TEM revealed substantially more ultrastructural detail,
allowing essentially a "side-on" look at the hybrid layers with minimized
artifactual involvement due to section shrinkage effects (Figs. 1b, 1d to 1g)184,185,186,188,
196,213,216,217,226,227,230.
Although much easier and therefore more frequently used, SEM interface
characterization requires cross-sectioning/polishing/fracturing techniques,
whereby the actual interfacial ultrastructure can never be observed free of
artifacts; any defective resin infiltration will be obscured by the smearing
effects of the sample preparation.
The real breakthrough of fourth generation adhesives came when
worldwide dentin etching with 30-40% phosphoric acid was no longer
considered harmful to the pulp. Even today, three-step adhesives are
considered the first class of adhesives to achieve a favorable clinical
outcome39,42,148,152,222,223. A clear distinction needs to be made between
total-etch adhesives that provide water/ethanol-based primers and those
that provide acetone-based primers. Extensive scientific documentation on
collagen fibrillation collapse due to post-etch drying convinced most
dentists to dry dentin only, keeping the dentin visibly moist by the so-
called WET (water) BONDING TECHNIQUE61, 62,84,85,185,186,188. Especially the
adhesion performance of adhesive systems providing acetone-based
primers benefited from wet adhesion. Acetone helps displace residual
water, while the water simultaneously keeps the demineralized network of
collagen fibers accessible for resin infiltration. However, the major
disadvantage of the wet bonding technique is its high sensitivity to the
degree of dentin surface moisture required correctly, since both wet and
dry dentin severely reduce the adhesive behavior147,184,186. Advantageously,
adhesives providing water/ethanol-based primers appeared less sensitive
to varying degrees of dentin surface moisture226. A thirteen-year follow-
up of class V restorations bonded with Optibond FL (Kerr), a total-etch
adhesive providing a water/ethanol-based primer, revealed a 94%
retention rate when the adhesive was applied to a gently air-dried dentin
and therefore no moist bonding technique was applied.150
More recent classifications use the term "ETCH&RINSE" (E&R) instead
of total etch, since today all adhesives are applied simultaneously to
enamel and dentin. The classification of these adhesives as E&R adhesives
clearly highlights the great clinical importance of the rinsing stage and, in
particular, the critical post-rinse drying stage, in light of the
aforementioned dry/wet bonding techniques215. Fourth generation
adhesives are now referred to as three-phase etch-and-rinse adhesives
(3E&Ras) as they involve the successive application of a conditioner, a
primer and a bonding resin in three application phases (Fig. 2).215
While dental adhesive technology evolved from one-step/one-
component adhesives to three-step adhesives, having achieved favorable
long-term clinical efficacy222,223, research and development focused on a
next phase of SIMPLIFICATION, first by reducing the number of application
steps (Fig. 2), while also commonly claiming to reduce sensitivity to multi-
step adhesives technique as an important marketing tool for the next
generation(s) of simplified adhesives. Simplified adhesives combine at least
two of the three main functions of etching, priming and adhesion.
However, they no longer allow application inaccuracies to be compensated
for by the next application step, so one could say that they are less
forgiving of application errors. Fifth generation adhesives are 2-STEP
ETCH&RINSE ADHESIVES (2-E&Rinses) that combine

10 The Journal of Adhesive Dentistry

 Van Meerbeek et al

Fig 2 Overview of the accession protocols direct

with adhesives
conventional etch and rinse (E&R) and self-etch (SE).

primer and bonding over-etched by

agent in "one bottle" phosphoric acid,
adhesives (Figs. 1 and deeper than the
2)215. Although popular resin will be able to
in routine clinical
infiltrate the exposed
practice, there is a
collagen fiber
significant price to pay
for their ease of use, as
network in the short
2-E&Ras typically time of clinical
exhibit lower clinical application. The
and laboratory phenomenon of
performance39,148,152. "NANOFILTRATION",
Their adhesion introduced by Sano
performance was et al in 1995171,172,
typically improved refers to the
when one-bottle diffusion of small
adhesives were applied ions or molecules in
in several successive incompletely
layers96, potentially
saturated hybrid
photocured separately,
layers of resin in the
or followed by the
application of an
absence of marginal
additional adhesion "gaps" (which would
layer, essentially cause
transforming the microfiltration). This
simplified adhesives nanofiltration, also
back into multi-step documented in 3D
adhesives207. Other (Coutinho et al.36),
major shortcomings of when associated
2-E&Ras, compared to with water
3-E&Ras, are: 1) its absorption and
lower resin content hydrolysis, should be
coupled with a higher
considered as the
solvent content,209 2)
BOND-
a thinner adhesive film
thickness with lower DEGRADATION
stress absorption MECHANISM
effects,46,118,142,225
3) lower principle on
mechanical strength,77,78 4) dentin.20,42,137
higher hydrophilicity, Sixth generation
permeability, and water adhesives are
absorption,68,103, 163,183,193,195
5) nowadays called 2-STEP
and a lower laboratory SELF-ETCHING
bond strength,39 as ADHESIVES (2-SEas)
well as (6) an inferior which provide an acid
clinical performance, self-etching primer,
the latter particularly basically combining the
with regard to class V acid etchant with a
restorations and their primer, followed by the
annual failure application of a classic
148,152,215,222
rates.
adhesive resin (Figs. 1
A major risk and 2)215. As regards
regarding bond the simplification of
stability associated application, 2-SEas no
with 3- and 2-step longer require a
E&Ras (previously rinsing phase, which
known as total-etch is why they are
adhesives) remains sometimes also
that dentin may be called "etch&dry" 11
 Van Meerbeek et al

adhesives (Lorenzo strong self-etch

Breschi, personal approach of Adper
communication). Prompt L-Pop (3M
ESPE), as well as
SE other strong SE
adhesives can adhesives, led to
be further stable adhesion to
subdivided according dentin, while
to their acidity and relatively acceptable
self-etching adhesion
aggressiveness, as performance to
enamel was achieved
described below,
thanks to its strong
along with their etch
simplified single-step aggressiveness86,23
versions.215 2. This one-step
Seventh adhesive contains
generation methacrylic esters of
adhesives are true phosphoric acid as
self-etching one-step functional
adhesives or "all-in- monomers dissolved
one" adhesives that in water. Monomers
combine the three such as diHEMA
functions of etching, phosphate are not
priming and bonding very stable in water;
in a single the adhesive even
application step contained pure
without a water phosphoric acid,
rinsing phase (Figs. 1 which explains its
and 2)215. low acidity and
Considering one-step strong (self-)etching
and two-step SE performance. Similar
adhesives together, to that produced by
self-etch adhesives E&R adhesives, a 3-
can be subdivided to 4-μm thick hybrid
into "STRONG" layer with full
(pH<1), collagen exposure
"INTERMEDIATE was produced in
STRONG" (pH=1-2), dentin, with the
"SOFT" (pH≈2) and difference that the
"ULTRA SOFT" dissolved calcium
(pH>2.5) self-etch phosphates were not
adhesives (SE) (Fig removed (rinsed
1). One of the first 1- away) but embedded
step adhesives in the hybrid layer.
marketed was Adper Strong SE adhesives
Prompt-L Pop (3M failed in dentin
ESPE), which quickly because (1) the
gained popularity collagen within the -
among dentists due 34 μm was no longer
to its easy and fast supported by
application in mineral, (2) there
combination with a was no chemical
unique bonding involved, (3)
application/single- the infiltrated resin
dose system. did not polymerize
However, unknown adequately and
at the time of its remained highly-
introduction, the

12
 Van Meerbeek et al

Fig 3 Summary of direct bonding protocols

using universal adhesives (UA).

hydrophilic and (4) reactivity of the

the calcium functional monomers
phosphates (also lower
embedded in the nanolayering of 10-
relatively exposed MDP; see below) with
collagen fiber network enamel HAp crystals;
were not (3) their being larger
hydrolytically stable, with (4) higher
destabilizing the crystallinity than
adhesive interface dentin HAp crystals,
over time. The making the target Ca
accelerated bond harder to reach; and
degradation finally (5) also the
documented in dentin parallel crystal
was subsequently organization in
confirmed clinically in enamel rods
terms of higher short- compared to the
term restoration loss cross-orientation of
rates and higher HAp in dentin, making
annual failure rates Ca easier to reach and
compared to interact in dentin.
reference However, this
18,148,202
adhesives. drawback can be
The most clinically compensated
favourable bond by selective pre-
performance to dentin etching of the enamel
was obtained with the with phosphoric acid,
"MILD" SE adhesives then applying the SE
combining adhesive to the pre-
micromechanical etched enamel and
interlocking with the unetched dentin.
chemical adhesion, of Together with the
which their primary increasing use of soft
bonding mechanism is SEas and - as enamel
detailed below, as this clearly requires
class of (ultra)soft phosphoric acid
adhesives can still be etching and therefore
considered today the an E&R procedure -
most reliable also called SELECTIVE
approach for long- ENAMEL ETCHING, a
lasting bonding to clinically popular
dentin (Figs. 1e and combined E&R/SE
1f)228,229. However, a bonding routine has
major drawback resulted (Fig. 2).
remains the lower Less common are
adhesion "intermediate strong"
effectiveness of soft
and especially ultra- SE adhesives that
soft SE adhesives to were developed as a
enamel228. This compromise to bond
should most likely be more effectively to
attributed to a
combination of enamel through
factors, namely: stronger etching,
without losing the
(1) the lowest potential for chemical
potential of bonding to dentin.
Micromechanical
entanglement Two of the most
achieved by the lower successful adhesives
etching effect of the in this class are 1-SEa
acidic functional G-Bond (GC)
monomers contained combining the
in the (ultra)soft self-
etch adhesives; (2) the functional monomers
lower chemical 10-DMP and 4-

Vol 22, No 1, 2020 13

Van Meerbeek et al

methacryloxyethyltri RESTORATIVE
mellitic acid (4- MATERIALS that no
MET)23,122,155,201, and 2- longer require a
SEa Optibond XTR separate pre-
application of an
(Kerr) based on adhesive218. They are
GPDM, for which good the logical
laboratory and clinical advancement of self-
data have been adhesive luting
,52,75,151,200.
obtained44
composites, obviously
“Soft” 1-SEs have for restorative
evolved from the procedures requiring
combination of self- a higher level of self-
etch primer and adhesion. Although
adhesive resin, which, the first self-adhesive
as with 2-step E&R restorative
adhesives, should composites were
generally be launched several
considered as easy-to- years ago, their well-
use “TRADE-OFF” documented inferior
adhesives at the performance in both
expense of adhesion the laboratory and
durability39,101,148,222. clinical research did
However, the latest not lead to a real
generation of 1-step breakthrough.
adhesives has However, it seems
definitely improved in that a new era of self-
performance both in adhesive restorative
the laboratory and in materials is just
the clinic, approaching around the corner, as
the superior new self-adhesive
performance of multi- dental restorative
step adhesives228. materials are being
The most recent developed and
eighth generation marketed by different
adhesives are the so- companies.
called UNIVERSAL
ADHESIVES (UAs)
which can be applied (2) PRIMARY
according to the MECHANISMS of
dentist's personal adhesion
choice in either the The primary adhesive
full E&R or SE bonding mechanisms of any
modes, or the dental material tend
combined mode to adhere to dental
involving enamel- tissue, particularly
selective E&R with a adhesives, cements
1-SE bonding mode and lately also self-
(Figs. 1g and 3). These adhesive restorations,
state-of-the-art involve (1) SURFACE
adhesives are WETTING, (2)
extensively discussed MICRORETENTION (or
in this paper. micromechanical
Today, bonding to interlocking) and (3)
dentin is even more CHEMICAL
difficult and has held INTERACTION (Fig 4).
back our bonding For a lasting bond,
efforts for a long time. one must always
However, adhesive clinically strive to
restoration of teeth in make optimal use of
a RELIABLE, these three basic
PREDICTABLE and adhesion
DURABLE manner can mechanisms.
Adequate surface
now be considered a
wetting is a primary
fact. A further requirement to achieve
simplification involves good interfacial contact
the development of between the adhesive
SELF-ADHESIVE material and the

14 The Journal of Adhesive Dentistry

 Van Meerbeek et al

adherend or substrate. This superficial smear

For a liquid to spread layer must be
uniformly across a solid appropriately treated, as
surface, the surface previous bonding
tension of the liquid attempts clearly failed to
must be less than the adhere to the smear
surface free energy of layer, which in turn was
the substrate. Surface insufficiently attached to
wetting behavior is the underlying
commonly determined unaffected tooth tissue.
by contact angle This smear layer should
measurements that also be considered the
ideally approach zero. main obstacle to be
Obviously, non-liquid overcome by self-
materials, such as self- adhesive cements and
adhesive cementation restoratives that are
and restoration applied without
compounds, have a pretreatment and must
certain viscosity that therefore sufficiently
makes it difficult to treat this superficial
spread evenly over their smear layer by virtue of
surface in a certain their own
period of time. Several chemistry114,119,156,180.
factors play co- Cavity finishing with
determinant roles, softer burs that leave
including 1) surface thinner and less
roughness, 2) substrates compacted smear layer28,51, as
with high (e.g., etched well as the use of
enamel) versus low (e.g., alternative cavity
smear layer-covered preparation instruments
dentin) surface energy, such as sonoabrasion,
3) adhesion-promoting sandblasting, and
effects such as capillary femtosecond laser
forces (e.g., adhesion to ablation, are means to
etched enamel), 4) reduce smear layer
surface interference with
hydrophilicity/hydropho adhesion.121,215
bicity, and 5) interfacial Microretention or
pores (air, moisture) that
weaken adhesion micromechanical
integrity. In the interlocking is most
complicated adhesion to likely the main
dentin as an intrinsically mechanism of
moist tissue (fluid-filled
tubules), bonding
attachment to
materials should be mineralized tissues
initially hydrophilic (low such as enamel and
water contact angle) to dentin.
adequately wet moist
dentin, while ideally they
should transform after
polymerization to a
hydrophobic state (high
water contact angle) to
limit water absorption
and prevent degradation
of the hydrolytic bond42.
Hermetic sealing of
adhesive-dentin
interfaces is mainly
impossible, considering
the extremely high
permeability of dentin
with its numerous
dentinal tubules forming Fig 4 Basic opportunities
the direct connection to for adhesion to dental
the pulp and also the tissue.
highly microporous
intertubular dentin
structure. Bur residue
directly interferes with
surface wetting by
smearing and
compacting through Microretention can be
enamel and achieved mainly in
dentin113 ,115,181,182,214
. two ways, by
Vol 22, No 1, 2020 15
Van Meerbeek et al

MECHANICAL MICRO chemical bonding

ROUGHING and by occurs, but will
CHEMICAL (SELF) generally not
ETCHING. Cavity contribute to bond
preparation by means durability. The
of a milling cutter alternative approach
roughens the surface, of soft SE uses acidic
thereby eliminating functional monomers
surface that provide
contamination. microretention to the
Furthermore, poorly dentin by means of
bond-receptive gentle (self-)etching
surfaces such as and thus partial
aprismatic and demineralization of
fluoridated enamel the 1-μm surface
and vitreous scleral layer. Furthermore,
dentin need to be at they rely on the
least roughened and primary chemical
optionally even (ionic) interaction of
partially or completely the functional
removed 47,50,139,194,212,256
monomer with HAp,
Obviously, surface which remains
debris smears across abundantly available
the cavity walls, within the submicron
which, as mentioned hybrid layer (Figs. 1e
above, can interfere to 1g).
with bonding. Enamel In fact, chemical
undoubtedly requires interaction is the most
phosphoric acid intimate contact
etching and sufficient possible between
microretention to
achieve long-lasting atoms and molecules
adhesion137,215. and is believed to
Enamel etching contribute especially
eliminates any to the durability of
interference from the adhesion. It does not
smear layer; translate into
simultaneously it increased bond
creates deep etched strength, but will
pits, into which
relatively simple prevent bond strength
resins flow by capillary reduction with
action and become aging81. The chemical
micromechanically interaction should be
intertwined. directed primarily to
Phosphoric acid- the inorganic HAp
etched dentin has component of dentin
become less popular with which to interact
nowadays, as it
completely ionically, as part of the
demineralizes the 3-
to 6-μm surface layer,
exposing a
microporous network
of collagen fibers that
is hardly fully
hybridized through
resin interdiffusion.
The incomplete resin
envelope of the
exposed collagen
makes the thick,
mineral-free, collagen-
rich E&R hybrid layer
less watertight and
less resistant to
hydrolytic degradation
and enzymatic
biodegradation. An
intense and long-
lasting chemical
interaction of the
resin with collagen
should not be
expected with an E&R
approach, as at best
only secondary
16 The Journal of Adhesive Dentistry
 Van Meerbeek et al

Fig 5 Schematic detailing the adhesion-

decalcification (AD) concept with the
ADHESION pathway in (a1), the MODIFIED
ADHESION pathway in (a2), and the
DECALCIFICATION pathway in (b).

mentioned SE (ultra)soft adhesion mode. This type (3) Review of the concept of ADHESION-DECALCIFICATION
Primary chemical secondary van der
bonding with organic Waals forces and
tissue components hydrogen bonding
such as dentin that provides little
collagen is very resistance to
difficult and typically degradation.
involves only weak Almost 20 years ago,

Vol 22, No 1, 2020 17

Van Meerbeek et al

the so-called AD
concept was
introduced by Yoshida
et al in 2001239 and
Yoshioka et al 255.
This model is still valid
today and defines
how molecules
interact with hard
tissues such as tooth
enamel and dentin, as
well as with bone (Fig
5).

18 The Journal of Adhesive Dentistry

 Van Meerbeek et al

It involves an at so many different

adhesion route (Figs and adjacent sites on
5a1,a2) and HAp that they self-
decalcification (Fig adhere to mineralized
tissues56,238,239
.
5b). The key point is Polyalkenoic acids are
the formation of a the functional
stable ionic bond with polymers that make
calcium (Ca) within conventional and
HAp or, in other resin-modified glass
words, the ability of ionomers adhere to
the molecule to tooth enamel and
produce stable Ca dentin, while
monomer salts. adequate surface
preconditioning with
Determination of the an aqueous
stability of monomer- polyalkenoic acid
Ca salts has been used conditioner remains
to screen new necessary to reduce
candidate functional potential interference
monomers for their of the smear layer
chemical bonding with glass ionomer self-
adhesion37,43,82
potential.211,237, 252,254 . As main
functional ingredients,
Molecules such as (ultra)soft SEas
oxalic acid, contain acidic
polyalkenoic acid, functional monomers,
specific acid functional of which the
monomers and the functional monomer
more recently 10-MDP (Fig 6) has
developed been most extensively
biodegradable investigated for its
phosphorylated chemical adhesion
pullulan (PP L) follow potential. These
the adhesion functional monomers
pathway, by which interact ionically
molecules adhere to through their
HAp-based tissue with phosphoric group with
limited decalcification the Ca237,248,249,252 of
effect (Fig 5a1). Anion HAp, adding a
adhesion forces chemical bonding
phosphate and potential to the
hydroxyl anions out of surface
HAp to maintain the microretention
electron-neutral performed by the
interface. Less surface limited decalcification
demineralization is and surface etching
beneficial as it effect induced by the
provides acidic functional
microretention monomer. Finally, PPL
(micromechanical has the potential to
interlocking). Oxalic adhere under moist
acid, and oxalates in conditions, thus
particular, have been opening prospects for
used as dentin/root its use as a
desensitizers27,189
, as their "bioadhesive" for
chann simple, short bone regeneration
molecular structure and pulp capping, and
el with two to serve as a
interconnected functional ingredient
carboxyl groups stably in root canal
binds ionically to the sealers.29,140
Ca of HAp; they form The extraordinary
stable Ca salts that
based on HAp (Fig 6)242. This release of Ca causes (4) CLASSIFICATION of current adhesives
help occlude open chemical interaction
tubules as part of an of 10-MDP with HAp
effective treatment of made it necessary to
dentin/root design a MODIFIED
sensitivity. ADHESION ROUTE (Fig
Polyalkenoic acids are 5a2). Among various
polymers with acidic functional
abundant carboxyl monomers, 10-MDP
groups that are chemically (ionically)
capable of "grabbing" binds Ca from HAp but
(ionically binding) Ca also etches and thus

Vol 22, No 1, 2020 19

Van Meerbeek et al

releases a substantial with the volume of

amount of Ca from dentin similar to that
the substrate. 10-MDP produced
self-assembles into 4 clinically248. The
nm nanosheets, a
process driven by the hydrolytically stable
formation of stable salts of 10-MDP-Ca
10-MDP-Ca salts, a were found to consist
structure first of CaRPO4, meaning
confirmed chemically that the two hydroxyl
by Fukegawa et al. in (OH) groups of the
200655 and phosphate group of
subsequently also 10-MDP reacted
visually verified by
high-resolution TEM ionically with Ca. This
by Yoshihara et al. in stable structure is
2010252,254. Using expected to
scanning transmission contribute to the
electron microscopy durable
(STEM), energy nanostratification of
dispersive 10-MDP-Ca salts in
spectroscopy (EDS), X- the hybrid and
ray diffraction (XRD)
and molecular nuclear adhesive layer and
magnetic resonance thus improve the
(NMR), recent clinical longevity of
investigations the bonded
characterized restoration.
ultramorphologically When the ionic
and chemically the bond formed with the
interaction Ca of HAp is not
mechanisms of 10-
MDP stable, a
DECALCIFICATION
10-MDP CH, ROUTE is followed (Fig
i 3 HHHHHHHHHH 5b), as is done with
2=
CH CCOC acetic and citric acid,
CCCCCCCCC - the latter being used
II as an irrigant of the
HHHHHHHHHH root canal in
11 endodontics15,234.
either Since ca-lactic acid is
not very stable, the
either continuous
effecti
production of
MAJORR lactic acid by
ve acid
characier8yes8cs bacteria From
will
the in
of 10-MDP lead to a
the
functional group progressive
for POLYMERIZATION
decalcification of the
for IONIC
tooth structure, which
BONDING
with Ca of
HAp
together with the
MMP
(adhesion enzymatic
degradation of the
route)

(3) Spacer with adequate dentin matrix, will

length: cause long-term caries
a. efficient SEPARATION of
both functional end groups (cavities). Since the Ca
b. provides salt of phosphoric acid
HYDROPHOBICITY
is not very stable, this
for acid is a dental
ETCHING:
Enables MICRO-MECHANICAL
etchant for an E&R
INTERLOCKING and NANO- bonding mode.
LAYERING
Similarly, maleic acid
has been used in the
Fig 6 Main characteristics past as a milder
of the most effective etchant replacing
functional monomer phosphoric acid. As
currently available: 10- mentioned above, one
methacryloxydecyl of the first 1-step
dihydrogen phosphate adhesives, marketed
(10-MDP). as Adper Prompt L-
Pop (3M ESPE), was

20 The Journal of Adhesive Dentistry

 Van Meerbeek et al

characterized as a
“strong” SE adhesive,
since the Ca salts of
the functional
monomer contained
in diHEMA-phosphate
were not stable and
easily dissociated in
phosphoric acid;
therefore, Adper
Prompt L-Pop (3M
ESPE) strongly etched
enamel, making the
enamel bond
relatively stable, but
etched dentin too
strongly, destabilizing
its bond to dentin.

Bonding to dentin
now involves the use
of one of two
approaches, namely
the ETCH-AND-RINSE
(E&R) bonding mode
or the (ultra)soft SELF-
ETCH (SE) bonding
mode215
. Both adhesion
modes have their
PROS and CONS in
terms of adhesion
effectiveness and
long-term durability,
obviously with a
scientifically
documented product
dependency and
better adhesion
performance of multi-
step adhesives
compared to that of
simplified TRADE-OFF
E&R and SE adhesives.

Vol 22, No 1, 2020 21

Van Meerbeek et al

Fig. 7 Bonding mechanism of a soft SE adhesive based on 10-MDP, explaining the primary ionic binding of the (bifunctional) 10-MDP monomer with the
Ca of hydroxyapatite that remained within the HAp-rich submicron hybrid layer, together with the stable 10-MDP-Ca nanostratification, as illustrated by
transmission electron microscopy (TEM) photomicrographs of a representative adhesive-dentin interface at different magnifications in ad, and by
pseudo-3D scanning electron microscopy/focused ion beam (FIB/SEM) reconstruction of a similar adhesive-dentin interface.

The main E&R been adequately

adhesion mechanism etched. It is a
can be described as a disadvantage that this
diffusion-based enamel etching effect
micromechanical cannot be evaluated
interlocking. The E&R using a water-wet
technique involves adhesion technique,
phosphoric acid where the etched
etching to produce surface is only flash
deeply etched pits in dried and remains
the HAp-rich enamel visibly wet. In enamel,
and to demineralize phosphoric acid
the dentin to a depth creates wide etched
of 4 to 6 μm, exposing pits between the
a HAp-free collagen enamel prisms which,
network with an when infiltrated by
abrupt transition to the resin, give rise to
the underlying MACRO-resin "tags".
unaffected dentin (Fig In the cores of enamel
1c). Any superficial prisms, individual HAp
smear layer is crystals are thinned by
completely removed. (surface)
By rinsing off the demineralization,
phosphoric acid while narrow but
etchant, the enamel is deeply etched pits are
allowed to air dry, created, into which
turning frosty white as resin is drawn by
a clinically visible sign capillary action to
that the enamel has form MICRO-resin

22 The Journal of Adhesive Dentistry

 Van Meerbeek et al

"tags". After collagen network,

polymerization, the facilitating
resin is interdiffusion of the
micromechanically resin. The primer (or
E&R primer/bond
cross-linked, resin combination)
producing the most must be applied for at
durable bond to least 15 s and in fact
dental tissue, so cannot be applied for
enamel should always such a long time.
be preserved as much Actively rubbing the
as possible when dentin surface with a
preparing teeth. microbrush using light
Bonding to dentin finger pressure will
has always been more locally intensify the
difficult. Following an interaction of the
E&R approach, functional monomer
phosphoric acid with the dentin,
should be considered essentially
rather aggressive "massaging" the resin
towards dentin, into the collagen
resulting in a time- network. Regular
dependent depth of application of fresh
demineralization. primer solution
Etching should outside the dispenser
definitely be limited well will further
to a maximum of 15 s promote resin
in order not to over- infiltration. The need
etch the dentin: the to gently air dry the
deeper the dentin is primed surface to help
etched, the more evaporate the primer
difficult it will be for solvent is often
the resin to infiltrate underestimated; by
to the demineralized gently air drying, the
depth. After thorough glossy film no longer
water washing, a wet moves as a clinical
bonding technique sign that the primer
amenable to the solvent has been
technique for E&R adequately removed.
adhesives providing
acetone-based The
primers (3-E&Ras) or
combined primer/E&R primer
adhesive resins (2-
E&Ras) should be has to
mandatory. A delicate
dry bonding technique repeated/extended
is much less when opaque spots
susceptible to the are observed on the
technique in the case dentin surface. It is
of adhesives that advantageous to have
provide a primer that contains
water/ethanol-based a photoinitiator, in
primers (3-E&Ras) or order to carry the
combination photoinitiator deep
primer/adhesive into the exposed
resins (2-E&Ras). collagen network. The
Clinically, drying until final step involves the
the etched enamel uniform application of
appears frosty white the adhesive resin in a
and the dentin visibly thick layer that
becomes opaque is should always be
easy to standardize. separately
However, dentin and
should never be air-
dried for too long immediately
(desiccation), as the light-cured to stabilize
collagen collapses into the adhesive interface
clumps that can and block immediate
hardly be infiltrated absorption of water
by the resin. Upon by osmosis from the
gentle air drying, underlying dentin.
application of a After polymerization,
water/ethanol-based the resin is
primer will re-wet the micromechanically
partially collapsed cross-linked forming
Vol 22, No 1, 2020 23
Van Meerbeek et al

resin tags in the the functional

dentinal tubules, as monomer that
well as through inter- infiltrated into this
and intratubular submicron hybrid
hybridization without layer. Of the many
any primary chemical functional monomers
interaction. investigated, 10-MDP
Alternatively, the is the most effective
use of (ultra) soft SEs today (Fig. 6). The
simplifies bonding to main features of 10-
dentin by avoiding the MDP are: (1) its
E&R process through methacrylate
the incorporation of functional group at
specific monomers one end of the
with acidic functional monomer that allows
groups, which the monomer to be
simultaneously incorporated into the
behave as 3D polymer network
conditioning and of the adhesive by
priming agents. Self- copolymerization (Fig.
etching of enamel 61); (2) At the other
does not superficially extreme, 10-MDP
dissolve and dilute possesses a
HAp as phosphoric hydrophilic
acid does; it does not phosphoric acid ester
produce deep functional group that
microretentive can ionically bind Ca
etching pits, so the of HAp (Fig. 62)
self-etching effect is according to the
insufficient to achieve adhesion route of the
long-lasting adhesion AD concept detailed
to enamel. Therefore, above (Fig. 5a).
SE adhesives are Among the different
commonly preceded functional monomers
by selective enamel investigated, 10-MDP
etching with rates better for
phosphoric acid chemical bonding
following the clinical potential;
54,211,237,242,244,253
procedure described (3) The
above. long carbon spacer
The dentin surface group effectively
is only partially prevents steric
demineralized by hindrance between
(ultra)soft self- methacrylate group
etching, whereby and phosphoric acid
microretention is only ester, but also
created within the provides
first surface hydrophobicity to
micrometer and the reduce water sorption
collagen remains (Fig. 63), in addition to
surrounded and allowing parallel self-
PROTECTED by the alignment of adjacent
HAp. Because the 10-MDP molecules
surface smear layer during nanolayering;
can interfere with (4) making 10-MDP
adhesion, soft SEas unique among
are preferable to functional monomers
ultra-soft SEas. is its substantial
Prolonging self-etch etching effect, which
will reduce produces
interference from the microretention and
smear layer. Upon thus enables
resin infiltration, a micromechanical
typical submicron interlocking, but also
HAp-rich hybrid layer substantially releases
is produced, which Ca from dentin as the
produces a driving force for 10-
micromechanical MDP nanolayering
interlock with (Figs. 64 and 7) While
chemical bonding primary ionic binding
potential, since the should be considered
abundantly available as the main benefit of
calcium remains as an 10-MDP, more data
acceptor to react with are currently being

24 The Journal of Adhesive Dentistry

 Van Meerbeek et al

collected, binding effectiveness

demonstrating that and chemical
nanolayering results in interaction potential
stable 3D structures of 10-MDP124,252.
that additionally However, the new
contribute to bond
durability and fluorocarbon
therefore deserve functional monomer
further studies. For 6-methacryloxy-
example, a recent 2,2,3,3,4,4,5,5-
chemical and octafluorohexyl
ultramorphological dihydrogen phosphate
structural analysis at seemed very
the atomic level promising, referred to
revealed that both as MF8P and
hydroxyl groups of 10- synthesized by
MDP react ionically
with Ca to produce a Kuraray Noritake250.
stable CaRPO4 XRD and TEM
structure, which is revealed the
resistant to water and formation of MF8P-Ca
acids.248 salts and nanolayering
However, 10-MDP in dentin, as
is not the perfect previously
functional monomer, documented for 10-
as it is still sensitive to MDP249,252. The
hydrolytic degradation MF8P-Ca salt was as
into its two esters stable as 10-MDP, and
linking both functional MF8P was as
groups to the central hydrophobic as 10-
spacer group (Fig. 6). MDP, while a
In fact, 10-MDP significantly higher
appeared to be bond strength to
hydrolytically unstable dentin was recorded
in water, as it can be for MF8P than for 10-
degraded to MDP250. This
hydroxydecyl research concluded
dihydrogen phosphate that despite its
and methacrylate2,124. shorter molecular
Since SEAs contain size, MF8P possesses
water, such monomer characteristics similar
hydrolysis is expected to those of 10-MDP,
to compromise their most likely associated
clinical with the strong
performance123. chemical bond
Linking the favorable between fluorine and
binding potential of carbon. Since a
10-MDP to its favorable bond
molecular structure strength to dentin was
taught the research recorded, MF8P can
community how be considered a good
functional monomers functional monomer
with effective binding candidate for bonding.
potential to dentin In the continuation of
should be designed, the MF8P study, the
opening opportunities longer chain 12-
to synthesize 10-MDP carbon 8-
analogues with similar methacryloyloxy
binding effectiveness analogue
but higher hydrolytic 2,2,3,3,4,4,5,5,6,6,7,7-
resistance. In this dodecafluorooctyl
search for more dihydrogen
hydrolytically stable phosphate, referred
functional monomers, to as MF12P, was
phosphonate- and found to be readily
acrylamide-based chemically adsorbed
monomers have been by HAp and resulted
synthesized, but have in more stable binding
so far failed to than 10-MDP and
approximate the MF8P, confirming that

Vol 22, No 1, 2020 25

Van Meerbeek et al

MF12P is a good
candidate for the
functional monomer
for durable
binding243. According
to current knowledge,
no commercial
adhesive containing
MF8/12P as functional
monomer(s) currently
exists, which should
probably be attributed
to the higher cost of
monomer synthesis
and therefore the
price of the product.

26 The Journal of Adhesive Dentistry

 Van Meerbeek et al

Fig 8 The PLUS-MINUS balance of

conventional E&R adhesives.

ETCH&RINSE
Diffusion-based bonding through 'micro-mechanical' interlocking;
Complete smear-layer removal;
Best approach for ENAMEL: it is proven; the bond is long-lasting!
Long track record, especially for 3-step E&R adhesives (>20 years);
Proven long-term clinical bonding effectiveness (>10 years), but
Annual Failure Rate of (22.0)% for 3-E&Ra, » (24.9)% for 2-E&Ra (Peumans et al.. 2014);
Possibility to apply a separate resin-free/poor hydrophobic adhesive resin in a sufficiently thick film
thickness, providing stress-absorbing potential.

The / |l|y balance

(5) BALANCE PLUS/MINUS of ETCH hydrophobic adhesive resin, in a sufficiently

adhesives thick film thickness, could provide
& RINSE (Fig. 8) shock/stress absorption potential in high
1: The main PLUS point of E&Ras is stress cavity configurations (polymerization
probably the effective diffusion-based shrinkage). This highlights the need for
bonding mechanism involving deep sufficient film thickness, which is generally
micromechanical interlocking in both lacking in current generation UAs (see
enamel and dentin.215 below).
2: Due to its aggressive etching, acid 1: MINUS is that phosphoric acid is (too)
Phosphoric acid completely dissolves the aggressive for dentin, for what the
surface smear layer which is effectively dentine HE
removed by water spray, so the surface deeply demineralizes to 4-5 μm.
smear layer will not interfere with adhesion. 2: The HAp dentin as
3: E&R is the best approach for protection natural of the
enamel. It is proven; This bond to the collagen is completely removed/dissolved.
enamel is long lasting. 3: Collagen is exposed in depth (Fig 1c).
4: E&Ras have a long track record, 4: Thick hybrid layers must be generated in
especially for some 3-E&Ras that have been short clinical application times; the resin must be
on the market for more than 20 years, such
infiltrated to several micrometers depth.
as the gold standard 3-E&Ra Optibond FL 5: Thick hybrid E&R layers are vulnerable to
(Kerr) (see below). micro/nano leakage and enzymatic
5: There is evidence in the scientific biodegradation.
literature 6: There is only a weak secondary chemical
independent of the long-term clinical interaction (van der Waals forces, hydrogen
adherence efficacy of E&Ras in at least one bonding), which will not contribute substantially
randomized controlled clinical trial (RCT) to the durability of the bond.
beyond 10 years of clinical service, although
a clear product dependence should be
considered.150 (6) PLUS/MINUS BALANCE of soft SELF-ETCH
6: According to a meta-analysis of adhesives (Fig 9)
clinical efficacy in non-carious Class V lesions 1: PLUS is the shallow hybridization depth of
without macroretention, the mean annual about 1 μm achieved with soft SEas, which is
failure rate (AFR) of 3-E&Ras was 3.1 relatively easy for the resin to diffuse in the short
(±2.0)%, which is significantly higher than time of clinical application. It is not the thickness
that reported for the most popular 2-E&Ras of the hybrid layer, but the quality of the hybrid
on the market that had a mean AFR of 5. 8 layer that matters in terms of adhesion
(±4,9)%148. This latest AFR recorded for durability.
2E&Ras also has a large (r) standard 2: The dentin is only partially
deviation, indicating a relatively wide demineralized, which is sufficient to provide
variation in the reported clinical efficacy micromechanical interlocking.
3: Due to only partial demineralization,
among commercial 2-E&Ras.
7: In particular, 3-E&Ras involving the
the
application of a resin-free/poorly Collagen exposure is limited, so it is better

Vol 22, No 1, 2020 27

 Van Meerbeek et al

protected against enzymatic biodegradation40,41.

4: The HAp-rich submicron hybrid layer
offers opportunities for primary (ionic) chemical
interaction, although this is highly dependent on
the functional monomer237,244,246,253. Today, 10-
MDP is considered to be the most effective
functional monomer that combines moderate
etching242, providing surface microretention,
with long-lasting chemical interaction that
additionally results in a stable 10-MDP-Ca salt
nanolayer.241,248,249,251
5: Soft SE adhesives also come with a long
track record, especially for some 2-SEas that
have been on the market for over 20 years,

28 The Journal of Adhesive Dentistry

 Van Meerbeek et al

Fig 9 The PLUS-MINUS balance of

conventional soft SE adhesives.
biomak.
MILD' SELF-ETCH
Shallow hybridization (< 1 pm) = easy for resin to diffuse;
Partial demineralization = sufficient 'micro-mechanical' interlocking;
Limited collagen exposure = less vulnerable for enzymatic biodegradation;
Primary chemical (IONIC) interaction, but this depends on the functional monomer!
Long track record, especially for 2-step SE adhesives (>20 years);
Proven long-term clinical bonding effectiveness (>10 years), but
LOWEST AFR of (±1.5)% for 2-Sea, > 3.6 (±4.9)% for 1-SEa (Peumans et al., 2014);
Possibility to apply a separate resin-free/poor hydrophobic adhesive resin in a sufficiently thick
film thickness, providing stress-absorbing potential.

The / Ik balance

such as the gold standard Clearfil SE (Kuraray considered the most effective functional
Noritake), with Clearfil SE Bond 2 (Kuraray monomer (Fig 6) and can therefore be found in
most SEas and even UAs (see below), 10-MDP is
Noritake) and its improved polymerization not perfect when it comes to its hydrolytic
efficiency being the latest version available on stability.124,170 Vol 22, No 1, 2020
the market. (7) THE GOLD-STANDARD E&R ADHESIVE
6: There is independent evidence in the (Fig 10) When sufficient and consistent
literature of the long-term clinical adherence evidence of favorable long-term adhesion
efficacy of ESas in at least one randomized performance appears, both in the laboratory
clinical trial (RCT) beyond 10 years of clinical and in clinical research, commercial adhesives
service, although a clear product dependence can be considered as GOLD STANDARD (GS).
must be considered149. GS1: On the market for over 25 years, E&R
7: According to a meta-analysis of clinical Optibond FL (Kerr) 3-step adhesive was shown
efficacy in non-carious Class V lesions without to have the highest immediate and predicted 1-
macro-retention, the mean annual failure rate year bond strengths to dentin in a meta-analysis
that included over two thousand bond strength
(AFR) of 2-SEas was 2.5 (±1.5)%, while that of
tests reported in nearly 300 papers.39
the easier-to-use 1-SEas was 3.6 (±4. 9%), being GS2: As mentioned above, a high retention
only slightly lower than the AFR already rate of 94% was recorded for Optibond FL (Kerr)
mentioned for the 3-E&Ras (AFR = in an independent thirteen-year RCT for non-
3,1±2,0%)148. In retentive Class V restorations150. This
As for the 2-E&Ras (compared to its 3-E&Ra important conclusion highlights that, as
counterparts), the standard deviation of the Optibond FL (Kerr) provides an ethanol/water-
AFR of the 1-SEas is substantially higher, which based primer, it can make use of self-
also indicates a wide product variation. reintegration effects to avoid collagen collapse
8: As is advantageous for 3-E&Ras that would prevent adequate resin infiltration,
(compared to their 2-E&Ra counterparts), 2- as has long been suggested187 ,226. As it is
SEas which involves the application of a definitely required for E&Ras providing
separate resin-free/poorly hydrophobic acetone-based primers (in the case of 3-E&Ras)
adhesive resin in a sufficiently thick film or combined primer/adhesive resins (2-E&Ras),
thickness, can provide shock/stress absorption the highly technique-sensitive water-based wet
potential in high stress cavity configurations. bonding technique seemed redundant for
Optibond FL (Kerr). Most likely, other E&Ras
1: MINUS is the unsatisfactory (self)etching
that provide water-based primers (3-E&Ras) or
effect on the enamel which provides insufficient combination primer/adhesive resins (2-E&Ras)
microretention for the formation of will also not require wet adhesion. In other
macro/micro-resin "tags". Since enamel words, not all E&Ras need by definition be
requires phosphoric acid and therefore an E&R applied using the highly technique-sensitive
approach, selective etching of enamel with wet-adhesion technique, as many research
phosphoric acid, while reasonably avoiding reports and much of the trade literature seem
etching of adjacent dentin, is recommended to suggest, even leading at times to E&Ras
and is now a routinely applied technique. being mistakenly called "wet-adhesion"
2: The possible interference of the smear adhesives.
layer cannot be totally excluded, as it is more GS3: In a meta-analysis of the clinical
interfering for ultra-soft adhesives (pH>2.5) efficacy of adhesives in non-retentive class V148
than for soft SE adhesives (pH≈2). restorations, a very low AFR of 1.8 was
3: Although 10-MDP is nowadays recorded.
29
 Van Meerbeek et al

(±0,8)%,
based on 6 RCTs, for Optibond FL (Kerr), the
clinical model considered most appropriate
(most objective) to evaluate the clinical efficacy
of adhesives222.

30
 Van Meerbeek et al

Fig 10 Evidence supporting the designation of

OptiBond FL (Kerr) as the gold standard E&R
adhesive, based on meta-analytical
laboratory39 and clinical148 data, as well as its
superior clinical performance in a thirteen-year
randomized clinical trial150.

Fig 11 Evidence to justify the

designation of Clearfil SE Bond adhesive
(Kuraray Noritake) as the gold standard SE
adhesive, based on meta-analytical clinical and
laboratory data39, as well as its superior
clinical performance in a thirteen-year
randomized clinical trial150, although it is
clinically recommended for use in a three-step
combined selective enamel E&R with 2-SE
bonding mode.

Based on two dentin in a meta-

meta-analytic trials of analysis that included
laboratory and clinical over 2000 bond
efficacy, along with an strength tests in
independent RCT, nearly 300 papers.39
Opti bond FL (Kerr) GS2: Currently, the
deserves recognition 13-year retention rate
as the gold standard of 96% reported for
E&R adhesive (Fig. Clearfil SE Bond
10). (Kuraray Noritake) is
the highest retention
(8) THE GOLD- rate reported in long-
STANDARD term independent
ADHESIVE SE(Fig 11) RCTs of non-retentive
GS1: On the market Class V restorations.149
for over 20 years, the GS3: A very low AFR
two-step SE adhesive of 2.2 (±1.7) %, based
Clearfil SE Bond on 12 RCTs, was
(Kuraray Noritake; recorded for Clearfil
recently replaced by SE Bond (Kuraray
Clearfil SE Bond 2 with Noritake) in a meta-
improved analysis of the clinical
polymerization effectiveness of
efficiency) was adhesives in non-
reported to have the retentive class V
second highest mean restorations.148
immediate and
predicted one-year Based on two
bond strength to meta-analytical trials

Vol 22, No 1, 2020 31

Van Meerbeek et al

of clinical and air dry without

laboratory efficacy compromising resin
along with an interdiffusion.
As the most
independent RCT, important bonding
Clearfil SE Bond step, actively rub the
(Kuraray Noritake) primer on the enamel
deserves to be and in particular the
dentin for at least 15
recognized as the gold s. Priming cannot be
standard SE adhesive done for a long
(Fig 11). enough time: the
Having longer, the better.
Continuously apply
consistently produced "fresh" primer to the
favourable adhesion dentin substrate. It is
efficacy data in the recommended to use
laboratory that have a primer that also
contains a
been confirmed by photoinitiator to carry
long-term adhesion the polymerization
efficacy clinical data, initiator deep into the
it is expected that exposed collagen fiber
network (although it
both the gold will not cure at this
standard E&Ra step due to inhibition
Optibond FL (Kerr) of polymerization by
and the gold standard oxygen). The priming
step should be
SEa Clearfil SE Bond 2 completed with a
(Kuraray Noritake) will gentle air drying to
be routinely used as promote solvent
controls/references in evaporation as much
as possible.
laboratory research. Apply separately a
solvent-free adhesive
(9) Recommended resin in a visibly thick
3-step E&R adhesion layer with potential to
path. absorb stress. After
The recommended gentle air-blowing to
evenly spread the
three-step E&R full adhesive resin (not to
adhesion route is (Fig thin the adhesive film
12): thickness), the
Etch enamel and adhesive resin should
dentin with 30-40% ALWAYS be separately
phosphoric acid, and immediately light-
cured to dentin, also
starting at the enamel as part of indirect
and ending at the adhesive cementation
dentin to limit etching procedures using
of the dentin to a E&Ra-assisted
maximum of 15 s to composite cements,
avoid over-etch of the but after prior air-
dentin. Rinse briefly thinning to avoid
with water for 5 to 10 mismatches in the
restoration.97,98 An
s and then air dry immediate/separate
until the etched adhesive
enamel appears polymerization will
frosted white as a prevent rapid osmotic
clinical sign of water absorption
sufficient enamel from the underlying
etching and the dentin. 190,208
It is
dentin appears advisable to apply a
flowable composite
opaque. Dentin can over adhesives
only be air dried resulting in a thin film
briefly, just to visibly thickness to better
remove water. E&Ras stabilize the interface
that provide water- and allow for the
based primers are aforementioned
more forgiving of the stress absorption
technique and allow potential.
the dentin to gently

32 The Journal of Adhesive Dentistry

 Van Meerbeek et al

(10) Preferred route

for selective enamel
etching combined
with 3-step E&R and
2-SE adhesives The
preferred bonding
protocol combines E&R
selective enamel etching
with 2-SE in three
application steps (Fig
13):
1 Selectively etch
enamel with 30-40%
phosphoric acid,
avoiding etching Fig 12 The
adjacent dentin recommended three-
(although this step route to E&R
should not be adhesion.
considered too
unfavorable,
considering the
reasonably good
bonding mode of 3-
E&R mentioned
above). If dentin is
not touched,
enamel etch may
even be removed
beyond 15 s. Rinse
thoroughly with
water and air dry as
described above for
the recommended
full 3-E&R route.
2 As the most Fig 13 Preferred route
important bonding for selective enamel
step, actively rub etching combined with
the 10-MDP-based 3-step E&R and 2-SE
mild self-etch adhesives.
primer for at least
15 s. The self-etch
primer does not
have enough time;
continuously supply
"fresh" primer to
the dentin
substrate. The visibly thick with
primer is finished potential to
with a gentle air absorb stress.
drying to promote After gently
evaporation of the blowing with air
solution. to evenly spread
3 As for the the adhesive
complete E&R resin, it must
route, apply a ALWAYS be
separately and
solvent-free
immediately light-
adhesive resin in cured on the
one coat in the dentin.
final step.
Considering that it is
the most intimate
contact that can be
achieved between
atoms and molecules,
an attempt must be
made to achieve a
lasting chemical bond

Vol 22, No 1, 2020 33

Van Meerbeek et al

with dentin. recent literature to

Therefore, the potentially improve
ultimate 3-step E&R E&R and/or SE
combination selective adhesion (Fig. 14).
glaze followed by a 2-
step SE bonding route 1. Improving E&R
and SE adhesion by
should be considered NON-THERMAL
as today's PREFERRED ATMOSPHERIC
bonding protocol. PLASMA treatment
(for both E&Ras and
(11) The main SEas)
TO
pathways of bond An interesting
degradation and the improvement in
eight clinical adhesion has been
strategies proposed suggested after
treatment of dentin
to preserve with non-thermal
adhesion stability. atmospheric plasma
While modern dental (NTAP).94 Plasma is
adhesive technology defined as partially
ionized gases
has allowed for long- containing
lasting bonding to electronically excited
enamel and dentin atoms and molecules,
when proper bonding as well as ionic and
free radical species.
routines are followed These highly reactive
clinically precisely, particles can rapidly
other circumstances cross-link to form
UNRELATED TO THE various chemical
functional groups on
MATERIAL, PATIENT, the surface of
TOOTH, AND/OR substrates. In general,
OPERATOR may cause NTAP was suggested
bonds to clinically to affect different
properties of
deteriorate more importance for dental
rapidly45. adhesion, such as
increasing the
wettability of the
Furthermore, the dentin surface64,
simplified adhesion improving resin
protocols do not (yet) polymerization and
achieve the adhesion deeper resin
performance that can penetration64,94,258.
be predictably Another possible
obtained using the reason for the
above-mentioned adhesion-promoting
gold standard effect could be that
adhesives and their NTAP activates the
recommended/prefer dentin surface by
red adhesion routes. depositing free
Therefore, several radicals or peroxides,
strategies have been thus intensifying the
proposed to further interaction between
optimize adhesion adhesive monomers
and counteract the and dentin
main adhesion collagen32. However,
degradation several laboratory
pathways, as there experiments, using
are: 1) water uptake both microtensile
with hydrolytic bond strength testing
adhesion degradation and fracture
mechanisms and 2) toughness testing, did
enzymatic not provide consistent
biodegradation, support in favor of
although the actual dentin plasma
degree of treatment to improve
involvement of this E&R and SE
last degradation adhesion.8,9,10
pathway remains Therefore, this
unclear (see below). strategy should not be
Eight strategies have considered sufficiently
been proposed in effective (Fig 14).

34 The Journal of Adhesive Dentistry

 Van Meerbeek et al

2. BIOMIMETIC potential, for

REPAIR of E&R hybrid example, so that it is
no longer necessary
layers by to remove all carious
REMINERALIZATION tissue in deep caries
(for E&Ras) lesions with a high risk
In 2008, Tay and of pulp exposure.
Finally, the fact that
Pashley introduced a hybrid E&R layers can
guided tissue be remineralized
remineralization confirms how
technique192. With sensitive to
this technology, a degradation hybrid
proof of concept was E&R layers really are,
achieved to since fully resin-
biomimetically repair saturated hybrid E&R
layers should not be
the hybrid layers of remineralizable.
E&R95,191. A biomimetic
remineralization
scheme was shown to 3. ETHANOL WET
result in intra- and BONDING to improve
interfibrillar resin
remineralization after filtration/interdiffusio
several months17,87,191. n (for E&Ras)
Although E&R hybrid This strategy focuses
layers could on the E&R mode of
effectively be bonding with the
remineralized in the intention of
laboratory, the direct completely replacing
water within the
clinical applicability of exposed collagen fiber
this biomimetic network.95 This
strategy to prolong strategy relies on a
the longevity of gradual exchange of
dentin-adhesive surface water for
bonds is unclear. ethanol, the latter
Furthermore, the solvent serving as a
justification for the better medium to
facilitate the
approach of first interdiffusion of, in
aggressively particular, the more
demineralizing dentin hydrophobic resin
using phosphoric acid into the deeply
as part of an E&R exposed collagen fiber
bonding mode, in network by
order to subsequently biphosphoric acid.137,138
use a sophisticated This approach
originated in the
(and lengthy) protocol processing of
to remineralize the specimens for
demineralized dentin electron microscopy,
surface, defies logic, when after fixation
especially considering specimens are
that there is an gradually dehydrated
effective alternative in ascending
approach, SE, concentrations of
ethanol before being
whereby dentin is critical point dried or
only partially HMDS
demineralized and (hexamethyldisilazane
most of the dentin ) dried for SEM, or
collagen remains before being
surrounded/protected exchanged for epoxy
by mineral. resin and embedded
in epoxy resin for
SEM.143,224 This
However, this dental method is most likely
remineralization the most effective
technology may be of strategy to improve
interest for E&R adhesion,168,169 but
developing minimally it is clinically
invasive restoration impractical due to the
techniques using clinical time needed.
materials with for successive
remineralization applications of

Vol 22, No 1, 2020 35

Van Meerbeek et al

ethanol, since it conditions, gelatin

requires at least zymography revealed
several minutes (Fig. release of MMP-2
14). (not MMP-9) by the
E&R adhesive,
4. INHIBITION OF whereas no enzyme
BIODEGRADATION
release could be
ENZYMATIC (for E&Ras detected for the mild
in particular)
SE adhesive, most
Matrix likely due to the
metalloproteinases limited demineralizing
(MMPs) are a group effect of dentin. 41
of enzymes
responsible for the
degradation of
extracellular matrix
proteins during
organogenesis,
growth and normal
tissue renewal178.
Although MMP
expression and
activity in adult
tissues have been
reported to be
generally quite low,
MMPs, together with
cysteine cathepsins,
have been linked to
the biodegradation of
adhesive-dentin
interfaces95,109.
Hydrolytic effects due
to water sorption
probably represent
the most
important/relevant
bond degradation
pathway. Data
regarding enzyme
exposure and
activation by different
types of adhesives are
not always consistent,
and the effects of
adhesion degradation
and adhesion arrest
using MMP inhibitors
vary across studies. It
is very evident that
MMPs are
exposed/activated by
phosphoric acid
etching following an
E&R bonding mode,
whereas this is not
always confirmed for
SE adhesives 40,41

When, for example,

dentin powder was
exposed to the gold
standard E&Ra
Optibond FL (Kerr)
and the gold standard
SEa Clearfil SE Bond
(Kuraray Nori take)
under clinical
application

36 The Journal of Adhesive Dentistry

 Van Meerbeek et al
Fig 14 Critical appraisal of eight
suggested strategies to improve E&R
and SE coupling. STRATEGIES to improve E&R and SE bonding:
INSUFFICIENTLY EFFECTIVE:
1. Bonding following NON-THERMAL ATMOSPHERIC PLASMA TREATMENT (for E&LRa'sand SEa's)

EFFECTIVE but IMPRAGTICAL; *

2. Biomimetic repair of E&R hybrid layers by RE-MINERALIZATION (for E&Ra's) 121
3. ETHANOL WET-BONDING to improve resin i nf ¡I tration/in te rd iff usion (for E&Ra's) 181

Bond-degradation RETARDING:
4.
5U I
INHIBITION of enzymatic bio-degradation (for E&LRa's in particular)
5. BIOMODIFICATION of dentin by collagen cross-linking (for e&Ra's in particular)

Bond-degradation RETARDING and PRACTICAL:

6. Effective POLYMERIZATION CONVERSION of adhesives (for E&Ra's and SEa's)
7. Extra HYDROPHOBIC resin sealing (including flowable composite applied onto adhesive) (for E&Ra's and SEa's)
8. Primary IONIC BINDING of the functional monomer with hydroxyapatite along with stable monomer-Ca salt NANO-
LAYERING (for SEa's)

The latest contrast data for the E&R link vs. SE E&Ra Single Bond 2 (3M Oral Care) at 9 months
were confirmed in a subsequent study on 2-E&Ra of artificial aging, a significant reduction in bond
Scotchbond 1 XT (3M Oral Care), which revealed strength was recorded after 18 months of aging
the presence of MMP-2 (again without MMP-9), despite post-etch CHX treatment. However,
in contrast to the data recorded for 2-SEa Clearfil when in the same study the two adhesives were
Protect Bond (Kuraray Noritake) and 1-SEa G- applied using a wet bonding technique with
Bond (GC), for which no enzymatic activity was ethanol, their bond strength remained stable
detected40. Obviously, depending on the acidity after aging for 9 and 18 months.168 In full
of the adhesive and the aggressiveness of the agreement with this study, the bond strength to
etching/demineralization, MMP activation was dentin of the gold standard 3-E&Ra Optibond FL
obtained by treating the dentin powder with the (Kerr) with added CHX to his
strong SEa Adper Prompt L-Pop40. Although primer No decreased
contradictory data have been reported in the significantly with 3 and 6 months aging by
literature108, a significant direct correlation was storage of the sample in water, whereas storage
also found between gelatinolytic activity and the in water for 12 months resulted in a significant
pH of the SE adhesive. Overall, it can be logically drop in adhesion strength to the level that
concluded that enzymes play a significantly occurred when Optibond FL (Kerr) was applied
greater role in the degradation of E&R bonding without CHX.41 Another study by Zheng et al.259
than SE adhesive interfaces, as also recently revealed that four MMP inhibitors (2% CHX,
confirmed by Li et al. in 2019 (unpublished 0.05% green tea extract, 1 mM ferrous sulphate,
0.2 mM galardin) prevented the adhesion
observations at KU Leuven BIOMAT). strength of the gold standard adhesive 3E&Ra
To counteract enzymatic biodegradation, a Optibond FL (Kerr) from decreasing after 9
long list of potential MMP inhibitors has been months of aging, but not that of the gold
tested in the laboratory for their stability- standard adhesive SE Clearfil SE Bond (Kuraray
promoting effect on bonds, as summarized in a Noritake), for which the adhesion strength did
systematic review and meta-analysis by not decrease with/without MMP inhibition. In
Montagner et al.117. The most widely the search for clinical evidence of inhibition of
documented MMP inhibitor is chlorhexidine bond degradation, a meta-analysis by
digluconate (CHX), a nonspecific MMP inhibitor, Göstemeyer and Schwendicke60, although
which was either (1) incorporated into the acid- including only 10 RCTs and 7 studies testing CHX,
etching agent, which was rinsed off the surface, concluded that dentists can perform cavity
(2) incorporated into the adhesive, or (3) applied pretreatments for inhibition of hybrid layer
as a solution directly onto the dentin after degradation (not damaging the bond), while a
etching and thus remained in contact with the beneficial effect is not (so far) supported by
surface (the most frequently used MMP sufficient clinical evidence.
inhibition strategy). A positive effect on In situ zymography allowed to precisely
maintaining bond stability was documented for localize proteolytic activity directly in the cross
relatively short specimen aging (up to 6 months), section of the interface adhesive. 107 When, for
providing evidence that MMP inhibition can example, 1-ethyl-3-(3-dimethylaminopropyl)
DELAY bond degradation. However, this effect carbodiimide (EDC) was used as an MMP
was no longer detected for long-term aging (1
year and more), so it can be stated that MMP inhibitor, the authors found that in situ
inhibition DOES NOT STOP bond degradation zymography showed hybrid layers produced by
(since hydrolytic bond degradation continues). In the gold standard 3-E&Ra Optibond FL (Kerr) and
a representative study by Sadek et al,168 2% CHX the market representative 2-E&Ra Scotchbond
was applied separately after phosphoric acid 1XT (3M Oral Care) showed "strong"
etching. Although a non-significant decrease in
bond strength was obtained for 3-E&Ra collagenolytic activity, while "almost zero"
Scotchbond Multi-Purpose (3M Oral Care) and 2- fluorescence signal was detected when dentin

Vol 22, No 1, 2020 37

Van Meerbeek et al

was pretreated with EDC.107 cross-links stabilize the molecular arrangement

However, a close evaluation of the in situ within collagen fibers, improving their tensile
zymographic photomicrographs provided properties.165
revealed a qualitatively significant difference in Biomodification of dentin matrices by
fluorescence, presumably indicating extrinsic collagen crosslinking has been proposed
collagenolytic activity, at the interfaces produced to improve the resistance of fibers to enzymatic
by the two adhesives investigated. A substantially degradation as well as to improve the tensile
more intense fluorescence was detected in the properties of the dentin matrix by creating
E&R hybrid layer (and within the underlying additional inter- and intramolecular crosslinks
dentinal tubules) produced by 2-E&Ra; some 11,53,70 Previous
studies have shown that various
reduction in fluorescence, although not very collagen crosslinkers, such as proanthocyanidin
convincing due to the different angle of the 3D and glutaraldehyde in particular, effectively
reconstructed interfacial structure, appeared induce adhesion-promoting effects when
when dentin was pretreated with EDC prior to employed over a wide range of application times
adhesive application. 107 However, hardly any (10 min–40 h). 3,12,30,73,99 Some authors reported
green fluorescence, indicative of collagenolytic satisfactory results in moments
activity, was observed at the 3-E&Ras interface; it Clinically
even seemed to be concentrated at the top of Convincing data have been reported in support
the hybrid layer, where resin infiltration would of dentin biomodification strategies, such as the
be expected to have optimally occurred, thus use of three cross-linking primers, containing
potentially even leading to a false positive result proanthocyanidin, riboflavin and glutaraldehyde,
for in situ MMP activity. The limited when applied over a clinically still relatively long
collagenolytic activity located at an unexpected period of 60 s prior to adhesive application, appear
interfacial point, together with the complete to be effective in minimizing the bond strength
absence of green fluorescence after EDC reduction of 2-E&Ra Single Bond Plus (3M Oral
pretreatment, could have been more objectively Care) and 1-SEa TetricN-Bond (Ivoclar Vivadent).
interpreted as representing a limited and totally 70
The stable adhesion strength ensured with
absent collagenolytic activity, respectively, at the both adhesives was attributed to the reduction of
adhesive interface produced by an adhesive such the in situ collagenolytic activity of MMPs,
as the gold standard 3-E&Ra Optibond FL (Kerr), particularly when proanthocyanidin was used.
whose good performance has been abundantly Because glutaraldehyde significantly reduced cell
documented. Therefore, the sensitivity of the viability, its clinical use was rightly discouraged.
adhesive interface to enzymatic biodegradation However, less convincing data were obtained in a
appears to be adhesive/product dependent, and study by Parise Gré et al.136. Although stable
is clearly lower for adhesives that have shown fracture resistance of the miniinterface was
laboratory and clinical evidence of favorable recorded after 6 months of aging when
adhesive efficacy. biomodifying dentin with 6.5% proanthocyanidin
Finally, recently unpublished research in a clinically relevant setting, incorporation of
revealed that MMP-2 and -9 rapidly lose their 0.5% UVA-activated riboflavin and 5%
activity (up to 35% of their initial activity within glutaraldehyde into the dentin bonding protocol
24 hours and reaching almost 0% after one week did not appear to be effective. Overall, the
of incubation at 37°C). Considering the limited benefit of using collagen crosslinkers appeared in
lifetime of MMPs, it is worth asking how MMPs that study to be largely crosslinking and product
are involved in the bond degradation process, dependent.136
since they are only activated by a one-time acidic
adhesive treatment and, in principle, no further
acidic activity occurs at the adhesive interface to 6. The effective POLYMERIZATION CONVERSION
expose/activate “fresh” MMPs. In contrast, in of adhesives (for both E&Ras and SEas)
caries, enzymes are continuously produced in the The importance of properly polymerizing
acidic environment created by bacteria, and adhesives should not be underestimated. A well-
demineralization occurs in parallel with the polymerized adhesive layer is a basic
enzymatic degradation of the dentin's organic requirement for achieving a long-term stable
component, ultimately leading to tooth decay
(cavities). adhesive interface. As a general guideline, the
5. BIOMODIFICATION OF DENTIN BY COLLAGEN
adhesive should always be light-cured separately
and immediately after application to dentin (and
CROSS-LINKING (for E&Ras in particular) enamel). In this way, water absorption from the
The operating principle of this cross-linking underlying moist dentin adhesive interface
enhancement strategy involves, in addition to through osmosis is reduced/blocked.204,206,208,210
the inactivation of matrix binding enzymes Often going against the manufacturer's
(MMP), the enhancement of intra- and instructions, the adhesive should also be light-
intermolecular cross-links of collagen, basically cured prior to the creation of semi-direct/indirect
making collagen more resistant to adhesive restorations with E&R/SEa-assisted
biodegradation26. Synthetic and natural collagen composite cements. While following a direct
cross-linkers have been applied to biomodify restorative procedure, the adhesive should best
dentin, more specifically to make collagen-rich be applied in a visibly thick layer to achieve stress
demineralized hybrid E&R layers more durable, absorbing potential, when HE
with collagen dentinal fibers possessing cement
improved biochemical and biomechanical restorations ceramics/composi
properties and greater resistance to enzymatic semi-direct/indirect, he adhesive must
biodegradation 105,106,136,175 The term “cross- diluted
linking” in the biological sciences refers to the completely air-filled until the adhesive no longer
chemical bonding between amino acid side moves and does not build up before being light-
chains within collagen molecules.59 Intrinsic

38 The Journal of Adhesive Dentistry

 Van Meerbeek et al

cured. In this way, the perfect fit of the blow gently when applying them until the resin
restoration is not compromised. Considering also film no longer moves. The only exceptions are
that the adhesive cementation procedure some HEMA-free and mostly acetone-based one-
requires a clinically significant period of time, step adhesives which should instead be
water droplets will be incorporated into the thoroughly air-dried. 205 Within such adhesives,
adhesive interface if the adhesive is not directly the adhesive monomers are separated from the
light-cured.97,98 water, a process that is triggered by the rapid
Obviously, such interfacial droplets/porosities evaporation of the solvent once it has been
weaken the adhesive interface and reduce the dispensed. After polymerization, the formed
clinical lifetime of the restoration. Laboratory droplets will be trapped within the adhesive,
investigations effectively demonstrated that compromising the durability of the adhesion. This
complete self-healing of ceramic restorations can be avoided by vigorous air drying of the
bonded to dentin, irrespective of the ambient adhesive, thereby removing water from the
temperature that directly affects chemical curing interface and thus improving long-term adhesion
(room temperature versus body temperature), effectiveness.
resulted in a lower immediate bond strength to
dentin than when the adhesive (on the dentin 7. Extra sealing of hydrophobic resin (both for
side) was light-cured alone and separately or E&Ras as for SEas)
when both the adhesive and the composite The placement of an additional adhesive layer,
cement were light-cured separately. 97,98 Pre- resulting in (1) increased hydrophobicity, (2)
curing of the adhesive prior to adhesive improved polymerization efficiency, and (3)
thicker film thickness, helps to further stabilize
cementation can be safely performed without and protect the adhesive interface against water
the risk of restorative complications, if the ingress from the underlying dentin tissue (via
adhesive is diluted with sufficient air or modern osmosis) as well as water absorption from the
UAs are used which rarely reach a film thickness external oral environment. This clinically practical
higher than 10 μm (depending also on the air technique has been repeatedly advocated to
blowing time/pressure). In well-fitting improve the performance of, in particular,
restorations, cement spaces are typically larger simplified 2-E&Ras and 1-SEas that combine
than 50 μm, so only a small portion of the primer with adhesive resin into a solvent-richer,
available space is added to the separately diluted resin-poorer single-solution adhesive, as well as,
and light-cured adhesive. Of course, when more recently, for UAs that typically come in thin
employing an “Immediate Dentin Seal” (IDS) film thickness. Both extensive
approach prior to an adhesive cementation laboratory1,4,52,145,162,176 and clinical research96,141
procedure, the adhesive should not be thinned have demonstrated the adhesion promoting
with air and is best applied in a visible thick layer effect of extra hydrophobic resin sealing, leading
(e.g. for direct restorations) followed by further to the conclusion that application of an extra
stabilization by application of a flowable hydrophobic layer will retard the adhesion
degradation of both E&R and SE adhesion modes,
composite over the adhesive layer157. So, there essentially converting 2-E&Ras to 3-E&Ras, 1-
is obviously no risk that the restoration may not SEas to 2-SEas, and 1-SE/2-E&R_UAs to 2-SE/3-
sit perfectly, as the conventional/digital E&R_UAs. This strategy is certainly clinically
impression will be taken after the IDS procedure. feasible and practical (Fig. 14). Alternatively, a
The degradation of the bonds is directly similar beneficial effect can be obtained by
related to the sorption of water95 ,160. Adhesives applying a flowable compound over a low film
should in first place thickness adhesive. This may be particularly
polymerize beneficial in the deep proximal boxes of posterior
optimally19,25,69,132 considering in particular: 1) restorations, which will further lead to better
their often hydrophilic nature, 2) the possible marginal adaptation at the critical margins of the
inclusion of residual solvent, and also 3) the thin cervical and axial boxes;166 the thicker applied
film thickness of simplified single-solution flowable composite may even serve as an
adhesives and especially UAs (mostly less than 10 internal stress buffer.142, 225,230 As mentioned
μm), as opposed to the inhibition of above, the addition of flowable composite
polymerization by oxygen. To achieve durable applied over the adhesive as part of an IDS
bonds, adhesives should be optimized to contain procedure will also stabilize the adhesive
interfaces of partial restorations.
an effective photoinitiator system together with semi-direct/indirect
a well-balanced monomer formulation for performed
mono/bi-functional monomers as opposed to adhesively.100,157,199
cross-linking monomers.67,112 In addition to
measuring bond effectiveness immediately and
after long-term aging, adhesives should be 8. Primary ionic bonding of the functional
evaluated for water solubility and water monomer to HAp along with
absorption over time, which should be kept low NANOSTRATIFICATION of the stable Ca salt
at all times. Furthermore, their intrinsic monomer (for SEas)
mechanical properties (e.g., ultimate tensile Soft self-etch and new UAs contain (bi)functional
strength, fracture toughness) must be acidic monomers 146,228 Many different functional
determined in light of the effects of plasticization
on water absorption.77,78,158 monomers have been synthesized and used in
In view of the efficient polymerization of the dental adhesives 124,209 In general, such a
adhesive, sufficient removal of solvents from functional monomer exhibits a triple molecular
primers or from combined single-solution structure, consisting of an acidic functional group
primer/adhesive resin formulations such as UAs separated from a (meth)acrylate group by a
is indispensable. It is clinically recommended to

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Van Meerbeek et al

spacer group (Figs. 6 and 7). The polymerizable higher market price.
(meth)acrylate group will copolymerize with
other monomers that will build into the resin (12) PROS and CONS of UNIVERSAL
matrix of the adhesive and the adjacent resin- ADHESIVES (UAs)
based composite. The spacer group, when Ongoing research in dental adhesive technology
sufficiently long, effectively separates the aims to improve the clinical techniques dentists
polymerizable (methyl) acrylate group from the use to bond resin-based materials to tooth
acidic functional group and provides structure, as this is a minimally invasive dental
hydrophobicity to the functional monomer. restoration concept31. The term "UNIVERSAL"
Potential acidic functional groups are phosphate, refers to its application options, which allow
phosphonate or carboxyl groups,124,209,228,242,244 them to be used following an E&R or SE adhesion
which will demineralize HAp or chemically bind model (Fig. 3), while offering application
to HAp, as defined in the adhesion-decalcification versatility with a (claimed) adhesion potential to
(AD) concept (Fig ).239,255
5
glass-rich ceramics (via silane) and glass-poor
zirconia (via 10-MDP) for indirect tooth restoration
According to this AD concept, acidic molecules 102,177,235,236,247
indications.
first attach to HAp by electrostatic interaction
and either remain bound through the formation The E&R universal adhesion mode involves a
of stable Ca-monomer salts following the phosphoric acid etching step followed by a water
ADHESION PATHWAY (Fig 5a) or are easily rinsing phase before applying a primer and
uncoupled when no stable Ca-monomer salt is adhesive resin mixture (Fig. 3). Monomers diffuse
produced, leading to abundant demineralization into the micropits created by etching in enamel
following the DECALCIFICATION PATHWAY (Fig to form micro- and macrotags and into the
5b). Previous studies have shown that the AD network of exposed collagen fibers in dentin to
route followed by the functional monomer form a 3-5 μm hybrid layer, as achieved with
depends on its molecular structure and that the conventional E&R. Thus, this adhesion mode
acidic functional group induces different etching mainly uses diffusion-based micromechanical
capabilities.228,242 Following the decalcification interlocking. While the E&R mode of bonding is
route by strong SE adhesives (and E&R undoubtedly the best bonding strategy to
adhesives), a deep hybrid layer of several enamel, the resulting thick, HAp-free hybrid layer
micrometers is formed, in which substantial that forms on dentin is very sensitive to
collagen is deprived of its surrounding HAp. The degradation over time (as detailed above for
calcium phosphates produced become conventional E&Ras).
embedded in the network of exposed collagen The SE bonding mode with UAs involves the
fibers, essentially destabilizing the adhesive on use of monomers with an acidic functional group
the ground which becomes highly sensitive to (phosphate, carboxyl) that in principle etch
hydrolytic degradation. This strong SE approach (demineralize) and infiltrate dentin
is no longer followed. Otherwise, the adhesion simultaneously to a depth of approximately 1-
route will typically result in a HAp-rich submicron μm. In general, the SE adhesion mode is inferior
hybrid layer without much exposure to collagen. to the E&R adhesion mode on enamel, for which
In addition to the actual acidic functional group, enamel must still be selectively etched with
the chemical structure of the spacer group and phosphoric acid (E&R) (Fig. 3). However, SE
its length co-determine the potential for adhesion has chemical adhesion potential as an
chemical interaction with HAp and added benefit to achieve long lasting adhesion.
dentin.210,253Among the many functional This chemical binding capacity depends on the
monomers, 10-MDP is today considered one of functional monomer contained. As mentioned
the most effective monomers for strongly binding
above, 10-MDP is the most effective monomer
to HAp ionically, thus forming stable 10-MDP-Ca
today; it is uniquely bifunctional with a chemical
salts (Figs. 5a2, 6 and 7)237,249 . The chemically
linking and polymerization group at both ends of
stable bond between 10-MDP and HAp has been
shown to contribute to adhesion durability, as the monomer separated by a long hydrophobic
demonstrated in both laboratory81 and clinical spacer (Fig 6). As detailed above, 10-MDP (1)
investigations148 , with favorable long-term etches, thereby releasing Ca from dentin, (2)
clinical data in particular being recorded for 10- ionically binds Ca from HAp, and (3) self-
MDP based on the gold standard 2-SEa Clearfil SE assembles nanostratified into stable Ca salts that
Bond (Kuraray Noritake).149 Nanolayering is also extend three-dimensionally across the adhesive
thought to contribute to adhesion durability. interface (Fig 7). The favorable adhesion
structured properties of 10-MDP inspired most dental
regularly product manufacturers to manufacture UAs
They contribute to adhesion stability, with the based on 10-MDP.
first direct evidence having recently been In terms of immediate performance
provided, as detailed above.248 Many current (restoration retention, marginal sealing), many
adhesives, and in particular UAs, contain the adhesives currently available on the market are
functional monomer 10-MDP, while more clinically effective, although there is some
hydrolysis-resistant analogues of 10-MDP have product dependency. However, the long-term
already been synthesized243,250 but have not led adhesion performance of this new generation of
to commercially available adhesives, most likely UAs, particularly to dentin, is still not sufficiently
due to higher production costs and consequently demonstrated, and UAs have already been

40 The Journal of Adhesive Dentistry

 Van Meerbeek et al

associated with several deficiencies141. FIRST manufacturers and therefore remain unknown.
Suboptimal polymerization does not sufficiently
stabilize the adhesive interface and may promote (13) FUTURE DENTAL ADHESIVE
water absorption from the underlying dentin by TECHNOLOGY
osmosis. The thin adhesive layer is also thought It is not known whether adhesives have reached
to reduce the ability of the adhesive layer to a level of clinical performance that can still be
absorb stress (polymerization shrinkage) imposed improved, particularly considering the
on the adhesive interface. SECOND, many UAs documented superior performance of gold
contain the monofunctional monomer HEMA. As standard adhesives219. We do not know if we
mentioned above, being a small molecule with have achieved a success rate much higher than
low molecular weight, HEMA is a good diffusing the 90% that can be achieved with dental
agent and also acts as a cosolvent for other less bonding. To clinically distinguish adhesives in
terms of adhesion performance, much longer
water-soluble monomers, especially since water follow-up is now needed to observe clinical
is an essential component (up to 40%) of UA to performance differences between new
enable the adhesion potential of SE. HEMA also generations of adhesives, even when compared
helps prevent phase separation between the to traditional gold
standard multi-step
hydrophilic and hydrophobic adhesive adhesives155. Furthermore, many current
components. However, the inherent high speakers and papers highlight that patient- and
hydrophilicity of HEMA also promotes water operator-related factors may have a greater
absorption through osmosis from the underlying impact on restoration longevity than the
dentin to the adhesive interface. adhesive materials actually used45. However,
further research is still needed to make adhesives
Furthermore, HEMA does not polymerize less technique-sensitive under suboptimal field
efficiently and is therefore only weakly control conditions, to bond better/longer to
incorporated into the polymer network. Since poorly adhering dental substrates, and eventually
HEMA makes the adhesive interface prone to to develop "true" self-adhesive amalgam
hydrolytic degradation, alternative monomers for alternatives that are economical, easy and quick
HEMA are definitely needed and are being to place (see below).
incorporated into new UA formulations. A THIRD
reason for the potential compromise in adhesion In current research, the goal is to develop
performance of UAs is related to the adhesive materials that do more than just adhere
incorporated silane that many UAs contain to to dental tissue. We all desire materials that have
chemically bond to glass-rich ceramics, thus additional therapeutic potential, to be able to
avoiding the need for a separate ceramic primer make our cavity preparations even less invasive
(silane).235,236,247 These UAs cannot be highly acidic than is now possible with the current generation
(pH>2.5), to ensure silane stability in the acidic of adhesives and to prevent early restoration
aqueous solution; higher pH, however, decreases replacement due to bond degradation and caries
UA etching and therefore adhesion effectiveness. recurrence. Such a therapeutic effect is generally
FOURTH and finally, although the functional referred to as "BIOACTIVITY", although the
monomer 10-MDP binds ionically to HAp definition is subject to strong debate.198
effectively, leading to stable nanolayering of the Bioactivity may potentially imply antibacterial,
monomer-Ca salt,240,248,249,251,252 the esters of 10- antienzymatic and/or remineralization effects, all
MDP, which link the hydrophobic spacer to the of which are highly desirable material properties.
However, while it may not be that difficult to
methacrylate and phosphate functional groups at design and develop bioactive adhesive materials,
both ends of the monomers, are sensitive to combining bioactivity with mechanical stability
hydrolytic degradation. This deficiency may pose the greatest research and development
encourages the search for 10-MDP analogues challenge.
that combine excellent chemical interaction with
high hydrolytic resistance, since some 10-MDP For example, research studies on materials
analogues with improved hydrolytic stability have containing bioactive glass fillers have focused
already been synthesized.243,250 mainly on their bioactive efficacy. The results of
UAs can optionally be applied in a full 2-E&R
phase, a full 1-SE phase or a combined 2-step laboratory investigations did not demonstrate
E&R selective enamel etch phase followed by a 1- that surface prereacted glass ionomer resin
SE adhesion mode (Fig 3). Many UAs contain (sPRG)-based composites exhibited desirable
today's most effective functional monomer, 10- antibacterial properties, as the concentration of
MDP. With a micromechanical binding ions released by the restorative material did not
mechanism based primarily on diffusion, the appear sufficient to inhibit bacterial growth245.
function of 10-MDP is not entirely clear when This study also demonstrated that the sPRG-filled
UAs are used in an E&R mode. There have been composite, on the contrary, promoted bacterial
some reports on the chemical interaction of 10- adhesion due to structural changes of the surface
MDP with collagen74, but this definitely requires and increased surface roughness, which
further investigation to confirm the relevance of promoted adhesion and biofilm formation.
these findings with respect to the durability of Although bioactive glass may have antibacterial
the adhesive interface. effects, this effect can be counteracted by
Although most UAs contain 10-MDP, there unstable surface integrity, which, upon release of
may still be performance differences between
10-MDP-based UAs, as the concentration and ions and in particular upon dissolution, results in
quality (purity) of 10-MDP have been shown to rougher and more irregular restorative surfaces
significantly affect adhesion efficiency228,246,254. that promote bacterial adhesion. When it comes
Currently, data on the concentration and quality to developing bioactive materials that are
of monomers are usually not published by clinically effective, it is essential not only to focus

Vol 22, No 1, 2020 41

Van Meerbeek et al

on their bioactive (antibacterial) characteristics

but also to ensure that the basic primary
mechanical properties are maintained.
Furthermore, the clinical life of adhesive
restorations remains limited, as they remain
more sensitive to (secondary) caries than non-
esthetic amalgam restorations.89,120,135 Together
with the absence of antibacterial properties, the
lack of acid buffering may explain the increased
susceptibility of composites to secondary
caries.133 To prevent secondary caries around
composite restorations, adhesives and
composites containing antibacterial agents were
developed.33,35,257 For example, the antimicrobial
monomer 12-methacryloxydodecyl pyridinium
bromide (MDPB) was added to the commercial
adhesive Clearfil SE Protect (Kuraray
Noritake).79,233 Many in vitro studies have
confirmed the contact antibacterial effect of
MDPB, whereas the clinical suppression of
secondary caries by Clearfil SE Protect (Kuraray
Noritake) has not been proven so far (Clearfil SE
Protect brochure). In addition to quaternary
ammonium methacrylate, immobilized in
adhesives and dental composites without release
potential, other antibacterial releasing agents
such as chlorhexidine and nanosilver particles
have been investigated for their anti-caries
properties, but they seemed less effective due to
an uncontrolled and short-lived burst release.33

42 The Journal of Adhesive Dentistry

 Van Meerbeek et al

Fig 15 Transmission electron microscopy (TEM) of the interface produced by the self-adhesive hybrid Bulk-fill Surefil One (Dentsply Sirona) with bur-
cut dentin. The self-adhesive restorative material interacted closely with dentin, while no signs of demineralization or hybridization were observed on
the surface.

Cetylpyridinium chloride (CPC) is also a very the Composites of

effective broad-spectrum antibacterial agent159. cementation
CPC disrupts the microbial cell membrane by self-adhesive72,153,154,173, obviously
altering its electrical balance, a mechanism that for
restoration procedures that require a higher level
is probably not affected by mutations in of self-adhesiveness.
microorganisms and is independent of
pathogens131,159. A more detailed description of Although the first self-adhesive restorative
the antibacterial potential of CPC in the oral composites were marketed several years ago,
their documented inferior performance, both in
environment can be found in the literature24,76,92 CPC the laboratory and in clinical research114 ,156, did
is FDA approved as an over-the-counter drug and not lead to a real breakthrough. Self-adhesive
for use in oral hygiene aids such as mouthwashes fluid composites were the first to be developed.
and toothpastes159. When CPC was According to the manufacturer's instructions, the
incorporated into the bonding resin in a previous first self-adhesive flowable compound marketed,
study131, the antibacterial effect appeared to be Vertise Flow (Kerr), did not require any acid
confined to the area of direct contact with the etching or bonding protocol prior to application.
resin. To release CPC, polyethylene methacrylate Vertise Flow (Kerr) combines phosphoric acid
ester methacrylate with GPDM as functional
and trimethylolpropane trimethacrylate monomers. Rahimian-Imam et al161 reported that
hydroxides were incorporated into water this self-adhesive flowable composite exhibited
repellents88. These hydrogels could be less microleakage than conventional fissure
recharged with CPC, but the release of CPC was sealants. However, when used as a sealant in a
still relatively short; furthermore, increased split-mouth clinical trial, the retention rates of
water absorption was reported to be another the self-adhesive flowable composite were
drawback. To overcome this deficiency, another significantly lower compared to three
promising strategy is to load CPC into an conventional flowable composites bonded with
an adhesive91. After 24 months, the retention
inorganic compound to release CPC in a rate of the self-adhesive composite was only
controlled manner, as previously studied when 62.9%91. Another self-adhesive restorative
CPC was incorporated into montmorillonite material remained in an experimental phase and
(Mont) clay34, termed “CPC_Mont”. In addition to was not marketed66. However, the self-adhesion
CPC release, this CPC_Mont technology is capacity of this experimental restorative material
considered to have CPC recharging capabilities. A to enamel and dentin was hypothetically
recent study demonstrated that CPC can be attributed to a form of nanointeraction, related
effectively inserted into Mont and can also be to its relatively high pH (>2.0) and viscosity
(compared to conventional adhesive solutions).
reloaded with CPC104. The addition of 1 or 3 wt% Several companies are developing and
CPC_Mont in a 1-step SEa conferred anti- marketing new self-adhesive dental restorative
bacterial properties to the adhesive without products, such as the so-called self-adhesive
reducing its adhesion potential or increasing its (bulk-fill) hybrid restorative Surefil One (Dentsply
cytotoxicity104,104 Sirona) (Fig. 15).
When producing self-adhesive restorations,
(14) Ongoing evolution towards SELF- some companies (first of all) target developing
countries and position their new product on the
ADHESIVE RESTORATIONS dental market as an amalgam replacement
Another simplification is the development of self- material, partly also in response to the global
adhesive restorative materials that no longer initiative of the United Nations Environment
require a separate pre-application of an Programme (UNEP) to reduce mercury
adhesive. They are the logical advance of consumption. Although UNEP has questioned the

Vol 22, No 1, 2020 43

Van Meerbeek et al

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