U Translated from English to Spanish - www.onlinedoctranslator.

com

From Buonocore's pioneering acid etching technique to self-adhesive

restorers. A state-of-the-art perspective on rapidly advancing dental
adhesive technology
art an Meerbeek / Kumiko oshihara / Kirsten an Landuyt / Yasuhiro oshida / arleen eumans

Abstract: This literature-based OPINION PAPER reflects in an introductory historical perspective on the rapid advancement of dental adhesive
technology. Past and current techniques for bonding to dental tissue, in particular defining tin as the most challenging bonding substrate, are
critically evaluated. Including the historical perspective in (1), this article focuses on fourteen elements that are considered to be of primary
importance with respect to the current state of dental adhesive technology. In (2) the primary mechanisms involved in adhesion to enamel and
especially to dentin are treated with (3) also revisiting the previously introduced adhesion-decalcification concept (AD concept) as the basis of
biomaterial-hard tissue interaction; the worldwide accepted classification of current adhesives into etch-and-rinse (E&R) and self-etch (SE)
adhesives is presented in (4), together with the presentation of their respective PLUS-MINUS balances in (5) and (6); the nomination of GOLD-
STANDARD E&R (7) and SE (8) adhesives is based on evidence of successful long-term clinical and laboratory performance, resulting in a
complete 3-step E&R bonding route recommended in (9) and the combined 3-step selective enamel E&R with 2-SE bonding route in (10);
11) Description of the main bond degradation pathways and eight strategies to preserve bond stability; (12) Covers the age of the PROS and
CONS of the latest 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 state of the art of recent research and developments towards self-adhesive
restorative materials that no longer require any kind of pretreatment.

eywords: review, bonding, dentin, adhesion, self-adhesive.

J Adhes Dent 2020; 22: 7-34. Submitted for publication: 26.01.20; accepted for publication: 27.01.20
doi: 10.3290/j.jad.a43994

(1) HISTORICAL PERSPECTIVE OF MILESTONES IN DENTAL 1951. 3,110,111 Used the functional monomer glycerophosphate dimethacrylate (GPDM),
ADHESIVE TECHNOLOGY which is still found today as the primary functional monomer in some popular dental
Dental adhesive technology continues to evolve at a rapid pace (Fig. 1). We adhesive products, such as the Optibond FL/XTR/niversal family of products
have already learned to adhere effectively and durably to enamel 65 years (Kerr). Landmark research identified Kramer and McLean, who demonstrated in 1952 that

ago with Buonocore's invention of the “ACID-ETCHING TECHNIQUE”. 2 GPDM improved adhesion to dentin by “penetrating the surface and forming an

Before Buonocore, the first attempts to bond acrylic resin to tooth structure intermediate layer.”0 Much later, this research

must be attributed to the Swiss chemist Hagger in

Full Professor, KU Leuven (University of Leuven), Department of Oral Health Sciences, BIOMAT - Biomaterials Senior Lecturer, Hokkaido University, Graduate School of Medicine, Dentistry and
Research Group, and UZ Leuven (University Hospitals of Leuven), Dentistry, Leuven, Belgium. Idea and concept of Pharmaceutical Sciences, Department of Biomaterials, Sapporo, Japan. ritually correct
paper, wrote the document. the manuscript.
Senior Research Fellow, National Institute of Advanced Industrial Science and Associate Professor, KU Leuven (University of Leuven), Department of Oral Health Sciences, BIOMAT -
Technology (AIST), Health Research Institute, Takamatsu and Visiting Research Fellow, Biomaterials Research Group and UZ Leuven (University Hospitals of Leuven), Dentistry, Leuven,
Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Belgium. Critically review the manuscript.
Sciences, Department of Pathology and Experimental Medicine, Okayama, Japan.
Critically reviewed the manuscript and provided TEM and FIB/SEM photomicrographs.
correspondence: rof. Dr. B. Van Meerbeek, KU Leuven (University of Leuven), Department of Oral Health
Associate Professor, KU Leuven (University of Leuven), Department of Oral Health Sciences, BIOMAT - Sciences, BIOMAT, Kapucijnenvoer 7, block a - inset
Biomaterials Research Group and UZ Leuven (University Hospitals of Leuven), Dentistry, Leuven, Belgium. Critically
001, BE-3000 Leuven, Belgium; Tel. + 32-16-337587;
review the manuscript.
email: [email protected]

Vol 22, No 1, 2020

Figure 1 Diagram illustrating the historical evolution of dental adhesive technology.
 Van Meerbeek et al.

The middle layer was labeled the "hybrid layer."126 However, history also the underlying pulp, even with a dentin mulcher in between. 13,164 Instead,
learned that copying Buonocore's aciditch technique to dentin, while dissolution/removal of the smear layer was obtained, for example, with a
generating a bond strength of 15-20 MPa to enamel, was a logical but calcium chelator such as EDTA (17%), which was applied and rinsed off
overly simple research and development (R&D) attempt.21 before bonding using the well-known Gluma adhesive (Bayer Dental).
First generation adhesives contained GPDM as an active ingredient. GPDM Alternatively, aqueous solutions of acidic monomer were used, such as
has ionic binding potential with hydroxyapatite (HAp) through its phosphate Scotchprep 'gold' bottle (3M Dental), containing 2.5% maleic acid.
functional group (Fig. 1). However, according to recent research, this chemical blended with 55% 2-hydroxyethyl methacrylate (HEMA) as part of the
interaction of GPDM with HAp-based substrates should be qualified in the sense popular Scotchbond 2 two-step bonding agent. (3M Dental). As a settling
that, although GPDM adsorbs onto HAp, it is unable to form a stable chemical adhesive, Scotchbond 2 (3M
bond.44 Surfactant comonomers such as Bowen's N-(2-hydroxy-3-methacryloxy propyl)-N-phenylglycine Dental) was one of the first bonding agents to receive the American
(NPG-GMA) were added to the early GPDM-based adhesive formulations. One of the Dental Association (ADA) label of “provisional acceptance” and later “full
first commercially available dentin bonding agents was marketed as Cervident (SS acceptance,” which was based on short-term success of 1 and 3-year
White) in the 1960s.16 However, these early adhesives exhibited a very low, clinical results, respectively, recorded in independent clinical trials. 48,223
unstable bond strength of 2-3 MPa to dentin.
In the late 1970s and 1980s, research in dental adhesive technology To avoid collateral pulp damage, milder phosphoric acid alternatives, e.g.
focused on the synthesis of a wide range of functional monomers, all maleic, nitric and citric acids, or lower concentrations of phosphoric acid stripping
designed to chemically interact with either inorganic (HAp) or organic agents were initially used, gradually evolving towards fourth-generation adhesives.
(collagen) dentin components.5,7,49,167 These second-generation They make use of the “TOTAL-ETCH” technique, which was introduced from
adhesives were classified into calcium- and collagen-bonding types. Japanese research originally conducted by the Fusayama research group, which
Products such as Clearfil Bond System F (Kura ray), which was already was far ahead of its time. 7,83 The term "total etching" refers to the simultaneous
commercially available in 1978, Bondlite (Kerr/Sybron), J&J VLC Dentin etching of enamel and dentin using phosphoric acid. 4,58 Along with the research
Bonding Agent Johnson & Johnson Dental) and goal to interact with dentin more intensively, these total-etch adhesives evolved into
Scotchbond (3M Dental) contained phosphorus esters of methacrylate multi-step systems that included the separate use of CONDITIONER and PRIMER

derivatives. Some additional bond strength was gained, but rarely prior to application of the actual ADHESIVE RESIN in a typical three-step
application procedure.215 The term bonding agent no longer encompasses the multi-
exceeded 5-6 MPa, while these bonding agents were also subsequently
step application procedure and was therefore replaced by “ADHESIVE SYSTEM.”
associated with suboptimal clinical outcomes.1,197, 223,231 These second-
While research understood that dentin, unlike enamel, required specific
generation, mostly single-solution ADs insufficiently treated the rather thick and
pretreatment strategies, these multi-step adhesives presented more complicated
compact STAIN LAYER resulting from the bur preparation. At that time, the surface
and obviously longer clinical application procedures. The use of the term
smear was not considered sufficient to interfere with the potential (chemical)
ONDITIONER originated in the early 1990s, sounding more aggressive than
interaction of the functional monomer with the pure dentin substrate. These
recorded in the traditional fear of adverse pulp reactions. In addition to complete
adhesives actually adhered to the smear layer, which in turn was too weakly
adhered to the underlying dentin. Typical of that era, “DENTIN ADHESIVE removal of the smear layer, 30–40% phosphoric acid conditioning agents

AGENTS” were marketed, emphasizing their explicit design and development to demineralize dentin to several micrometers depth and, after thorough rinsing with

adhere to the challenging dentin substrate, while enamel bonding after acid etching water, expose a microporous network of HAp-poor collagen fibrils (Figure 1c). The

was already considered satisfactory. FIRST applied later

A milestone in the rapidly evolving dental adhesive technology was serves as an adhesion promoter. Contains hydrophilic monomers, such as the

the introduction by Nakabayashi in 1982 of the term “HYBRID LAYER” monofunctional HEMA monomer in particular. Due to its low molecular weight and

(Fig. 1), which referred to the structure formed on the dentin surface by therefore small size, together with its high hydrophilicity through its short carbon
chain ending in a hydroxyl group, HEMA is an effective surface wetting agent and
prior demineralization (partial/total) followed by infiltration. of monomers
interdiffusion agent that permeates into moist, demineralized collagen-rich dentin.
and their subsequent polymerization.126 Abandoning the concept of
Your face. Adequate infiltration should be achieved clinically in a short application
chemical interaction with dental tissue, as was pursued with second-
time of 10 to 20
generation adhesives, the research community became increasingly
s. Today, HEMA is still added to many commercial adhesives, also because it can
convinced of the need for micromechanical interlocking with tooth
act as a cosolvent for other monomers to prevent water/monomer phase separation.
surfaces as the main adhesion mechanism. The basis for third-
205,210 However, the main disadvantages of EMA are (1) its low polymerization
generation adhesives was laid when the earlier Japanese concept of
capacity, (2) its low contribution to mechanical strength, (3) its high water
etching dentin to remove the smear layer, already introduced by
absorption, and (4) its unfavorable biocompatibility, particularly in terms of its
Usayama et al in 1979, 7 gained worldwide acceptance and led to the
documented allergic potential.208,209 In current adhesives, manufacturers try to
commercialization of the Japanese bonding agent Clearfil New Bond
(Kuraray) in 1984. Phosphoric acid etching was followed by the substantially reduce the HEMA content or even replace HEMA with alternative

application of a two-component chemical curing bonding agent already monomers such as methacrylamide monomer variants.

containing the unctional monomer 10- Total-etch primers contain monomers dissolved in different solvent
methacryloyloxydecyl dihydrogen phosphate (10-MDP). Today, 10-MDP combinations of ethanol, acetone and/or water, with the solvent acting as
is still considered one of the most effective functional monomers, but in a vehicle to facilitate mono-infiltration and resin wrapping of individual
years past it was not used with the intention of chemically interacting collagen filaments. After application, the primer is gently air dried to
with HAp. After phosphoric acid etching, no HAp remains up to a few prevent solvent evaporation. If the solvent remained, it would impair the
micrometers deep into the dentin surface to interact. Particularly in hybridization and subsequent polymerization of the resin within the 4 to 6
Europe and the USA, the application of phosphoric acid etching agents μm thick hybrid layer. Therefore, these total-etch primers are primarily
to dentin was still discouraged because of their presumed arm effect on intended to render the wet collagen ibril network more receptive to

Vol 22, No 1, 2020 9

Van Meerbeek et al.

subsequent infiltration of mineral hydrophobic monomers as contained in component adhesives to three-step adhesives, having obtained favorable long-term
the actual bonding agent or ADHESIVE RESIN applied in the final third clinical efficacy, 22,223
adhesive step. Infiltration of the latter into the open dentinal tubules & D focused on a next phase in SIMPLIFICATION, firstly by reducing the number of
results in the formation of abundant resin labels, application steps (Fig 2), while commonly also claiming to reduce the technical
Over the course of a long period of time with the evolution of dental adhesive sensitivity of multi-step adhesives as an important marketing tool of the next
technology in the late 1980s and early 1990s, a better understanding of the generation(s) of simplified adhesives.
mechanisms involved in adhesion to dentin was achieved and new research Simplified adhesives combine at least two of the three main functions of etching,
techniques were introduced that allowed a deeper characterization of adhesive- reaming and bonding. However, they no longer allow application inaccuracies to be
dentin interfaces with higher magnification/resolution. Particularly noteworthy was compensated for by the ext application step, so they are arguably less forgiving of
the argon ion bombardment technique developed by Inokoshi et al in the early application errors.5th generation adhesives re
1990s, which served as a surface topography enhancement technique to visualize - STEP ETCH & RINSE ADHESIVES (2-E & Ras) that combine
hybrid layer and resin label formation at adhesive-dentin interfaces using scanning
electron microscopy (SEM) (Figure 1a).0,
179,220,221 Furthermore, Nakabayashi and Watanabe in 1983127 and 198528
must have been among the first to report, initially in the Japanese
literature, on the use of electron microscopy of
(TEM) to ultramorphologically characterize ultrathin 60- to 90-nm cross
sections of adhesive-dentin interfaces.129,130 TEM revealed substantially
more ultrastructural detail, essentially allowing an "in-depth" look at
hybrid layers with minimized artifactual involvement due to shrinkage-
contraction effects (Figs. 1b, 1d to 1g). 84,185,186,188,

196,213,216,217,226,227,230 While it is much easier and

Therefore, SEM interfacial character is most frequently used.
The ization requires cross-sectioning/polishing/fracturing techniques, by which the
true interfacial ultrastructure can never be observed free of artifacts; any infiltration
of defective resin will be obscured by the staining effects of the sample preparation.

The real breakthrough of fourth generation adhesives came when global

dentin etching with 30-40% phosphoric acid etchants was no longer considered
detrimental to the ULP. Even today, three-step adhesives are considered the first
class of adhesives to achieve a favorable clinical outcome.39,42,148,152,222,223 A clear
distinction must be made between total-etch adhesives that provide water/etaol-based
primers and those that provide acetone-based primers. The vast scientific
documentation on the collapse of collagen fibrils due to post-etch drying convinced
most dentists to only dry dentin in batches, keeping the dentin visibly moist with so-
called water.
61,62,84,85,185,186,188 Especially the bonding performance of adhesive systems
featuring acetone-based primers benefited from wet bonding. The ketone helps
displace residual water, while the water simultaneously keeps the demineralized
collagen-fibril network active for resin infiltration. However, the major disadvantage
of the wet bonding technique is its high sensitivity to the properly required degree of
dentin surface moisture, with both too wet and too dry dentin severely reducing
adhesion performance.147,184,186 Advantageously, adhesives providing
water/ethanol-based primers appeared less sensitive to various degrees of dentin
surface moisture. 26 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 gently air-dried
dentin and therefore NO wetonding technique was applied.150

Most recent classifications use the term 'ETCH & RINSE' (E&R) rather than
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 rinse phase and in particular the critical post-
rinse drying phase, in light of the wet/dry bonding techniques mentioned above. 215
Fourth generation ration adhesives are today referred to as three-step etch and rinse
adhesives (3E and Ras), as they involve the successive application of a conditioner,
primer and bonding resin in three application steps (Fig. 2). 15

Although dental adhesive technology has evolved from single-step/multi-

10 The Journal of Adhesive Dentistry

 Van Meerbeek et al.
Figure 2 Overview of direct adhesive protocols using conventional etch-and-

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

the primer and bonding etch adhesives) remains

agent in “one bottle” that dentin can be
adhesives (Figs. 1 and 2). over-etched by
15 While popular in routine phosphoric acid, the
clinical practice, a deeper the resin will be
significant price is paid for able to infiltrate into the
EASE OF USE, as
exposed collagen-fibril
- E&Ras generally network in the short
exhibit lower clinical and time of clinical
laboratory application. The
performance.39,148,152 phenomenon of
Their bonding performance 'NANOLEAKAGE',
was typically improved introduced by Ano et al
when one-bottle adhesives in 1995,171,172 refers to
were applied in multiple the diffusion of small
successive, 6 potentially ions or molecules in
photopolymerizable layers incompletely saturated
separately, or were hybrid layers of resin in
followed by the application the absence of
of an additional bonding marginal spaces (which
layer, essentially would cause
transforming the simplified microleaks). This
adhesives back into multi- nanofiltration, also
step adhesives. 07 Other documented in
major deficiencies of 2- 3D Coutinho et al.6 ,
E&Ras, compared to 3- when associated with
E&Ras, are (1) its lower water absorption and
resin content along with hydrolysis, should be
higher solvent content,09 considered as the main
(2) thinner adhesive film BOND-DEG
thickness with lower stress RADATION
absorption MECHANISM in dentin.
0,42,137
effects,46,118,142,225 (3)
Sixth Generation
lower mechanical
Adhesives Today they are
strength,77,78 (4) higher called 2-STEP SELF-
hydrophilicity, permeability, ETCHING ADHESIVES (2-
and water SEas) which provide a
absorption,8,103,163,183,193,1 self-etching acid primer,
95 and (5) generally basically combining the

reported lower acid etchant with a primer,

followed by the application
concentration of
of a classic adhesive resin
lower laboratory 9 as
(Figs. 1 and 2). 15 As
well as (6) inferior regards simplification of
clinical performance, application,
the latter particularly
- Seas no longer
with regard to class V
require a rinsing phase,
restorations and their
which is why they are
annual failure
sometimes also called
rates.148,152,215,222
"etch and dry" adhesives
A significant risk to bond
stability associated with both (Lorenzo
- and 2-step E&Ras Breschi, personal
(formerly known as total- communication). SE

Vol 22, No 1, 2020 11

 Van Meerbeek et al.
adhesives can be contains methacrylic
subdivided according to esters of phosphoric
their acidity and self-etch acid as functional
aggressiveness, as monomers dissolved in
described below along with water. Monomers such
their simplified one-step as diHEMA phosphate
versions.215 are not very stable in
Seventh generation water; the adhesive
adhesives are the true 1- even contained pure
STEP SELF-ETCHING phosphoric acid, which
ADHESIVES or “all-in-one”
explains its low
adhesives that combine
viscosity and strong
the three functions of
(self) etching ability.
etching, priming and
Similar to that
bonding in a single
produced by E&R
application step without a
adhesives, a 3- to 4-μm
water rinsing phase (Figs.
thick hybrid layer was
1 and 2). 15
produced with full
Considering 1-step
exposure to the
and 2-step SE
collagen in the dentin
adhesives together, elf-
with the difference that
etch adhesives can be
the dissolved calcium
subdivided into
phosphates were not
'STRONG' (pH < 1),
removed (rinsed away)
'INTERMEDIATE
but were embedded
STRONG' (pH = 1-2),
within the hybrid layer.
'MILD' (pH 2) and
Strong SE adhesives
'ULTRA-MILD' (pH >
failed in dentin
2.5) self-etch (SE)
because (1) the
adhesives (Fig. 1). One
collagen within 3-4 μm
of the first 1-step
was no longer
adhesives marketed
supported by the
was Adper rompt-L
mineral, (2) there was
Pop (3M ESPE), which
no chemical bonding
quickly gained
involved, (3) the
popularity among
infiltrated resin did not
dentists thanks to its
polymerize adequately
easy and fast
and remained highly
application in
hydrophilic,
combination with a
unique single-dose
packaging/dispensing
system. However,
unknown at the time of
its introduction, the
strong self-etch
approach of Adper
Prompt L-Pop (3M
ESPE) as well as other
strong SE adhesives
led to on-table bonding
to dentin, while
relatively acceptable
bonding performance
to enamel was
achieved thanks to its
strong etch
aggressiveness.86,232
This 1-step adhesive

12 The Journal of Adhesive Dentistry

 Van Meerbeek et al.
Fig. 3. Overview of direct adhesive protocols
using universal adhesives (UA).

and (4) calcium soft and especially

phosphates embedded in ultra-soft SE
the relatively exposed adhesives to enamel.
collagen-fibril network 228 This is most likely
were not hydrolytically due to a combination
stable, which destabilized of factors, i.e. (1) the
the adhesive interface over lower
time. The accelerated micromechanical
bond degradation interlocking potential
documented in dentin was achieved by the lower
subsequently confirmed etching effect of the
clinically in terms of higher acidic functional
short-term restoration loss monomers contained
rates and higher annual in (ultra-)soft self-etch
failure rates compared to
adhesives; (2) the
reference
lower chemical
adhesives.18,148,202
reactivity of the
The most functional monomers
favorable bonding (also with 10-MDP
performance to dentin nanosheets; see
was obtained with the below) with enamel
“SOFT” SE adhesives HAp crystals; (3) their
that combine being larger with (4) a
micrometric cannula higher crystallinity
interlocking with than dentin HAp
chemical bonding, crystals, making the
whose primary target Ca harder to
bonding mechanism reach; and finally (5)
is detailed below, as also the parallel
this class of (ultra)soft crystal or anization in
adhesives can still be enamel rods
considered the most compared to the
reliable approach for cross-linked
a durable bond to orientation of HAp in
dentin (Figs. 1e and dentin, making Ca
1f). 28,229 However, a easier to reach and
major drawback interact in dentin.
remains the inferior However, this
bonding efficiency of

Vol 22, No 1, 2020 13

 Van Meerbeek et al.
drawback can be adhesives are the so-
logically called LEVEL
compensated by ADHESIVES (UA)
selectively pre- which can be applied
etching the enamel according to the
with phosphoric acid dentist's personal
and then applying SE choice in either full
adhesive over the E&R or SE bonding
pre-etched enamel modes, or the
and unetched dentin. combined mode which
These common includes the selective
ones are the E&R name with a 1-SE
"intermediate strong" bonding mode (Figures
SE adhesives that 1g and 3). These next-
were developed as a generation adhesives
compromise to more are described in more
effectively bond to depth in this document.
enamel through Today, bonding to
stronger etching, dentin is even more
without losing the challenging and has long
potential for chemical hampered our adhesive

bonding to dentin. Two efforts. However, adhesive

of the most successful restoration of teeth in a

adhesives in this class RELIABLE,

are 1-SEa G-Bond GC) PREDICTABLE and

which combines the LONG-LASTING manner

functional monomers can now be considered a

fact.
10-DMP and
A further simplification
- Methacryloyloxyeth
involves the development
yl trimellitic acid
(4-
of SELF-ADHESIVE
MET), 3,122,155,201
RESTORATIVE
nd the GPDM-based 2-
MATERIALS that no longer
SEa Optibond XTR
(Kerr), for which good require a separate prior

laboratory and clinical application of an

data have been adhesive.218 They are the
published.44,52,75,151,2 logical advancement of
00 self-adhesive luting
Mild 1-SEas evolved
composites, obviously for
from the combination of
restorative procedures
self-etch primer with
requiring a higher level of
bonding resin, which, as
self-adhesion. Although
for 2-step E&R adhesives,
the first self-adhesive
should generally be
restorative composites
considered "TRADE-OFF"
were launched several
adhesives that are easy to
years ago, their well-
use, at the expense of
documented inferior
bond
performance in both
durability.39,101,148,222
laboratory and clinical
However, the latest
research did not lead to a
generation of -step
real breakthrough.
adhesives have definitely
However, it seems that a
improved both in
new wave of self-adhesive
laboratory and clinical
restoration materials is just
performance, approaching
around the corner.
the superior performance
of multi-step
adhesives.228
The newest
eighth generation

14 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

orner, as different companies are developing and marketing new self-adhesive

dental restoratives.

(2) PRIMARY MECHANISMS of adhesion

The primary adhesive mechanisms of any dental material that tends to adhere to
dental tissue, in particular adhesives, cements and lately also self-adhesive
restoratives, involve (1)
URFICIAL MOISTURE, (2) MICRORETENTION (or micromechanical interlocking)
and (3) CHEMICAL INTERACTION (Fig 4). To achieve a durable bond, clinically one
should always strive to make optimal use of these three basic bonding mechanisms.
Adequate surface wetting is a primary requirement for achieving good interfacial
contact between the adhesive material and the adherend or substrate. For a liquid to
spread uniformly across a solid surface, the surface tension of the liquid must be
Figure 4 Basic bonding opportunities for adhering to dental tissue.
less than the surface free energy of the substrate. Surface wetting behavior is
commonly determined by contact angle measurements that ideally approach zero.
Obviously, non-liquid materials, such as self-adhesive and restorative luting
compounds, have a certain viscosity that makes it difficult to spread their surface
uniformly within a certain period of time. Several factors play co-determining roles,
It is obtained mainly in two ways, with MECHANICALLY (MICRO) ROUGHING and
such as (1) surface roughness, (2)
CHEMICALLY (SELF) ETCHING. Cavity preparation using burs roughens the
substrates with high surface energy (e.g. E.g. etched enamel) versus low (e.g. E.g.,
surface, thereby eliminating surface contamination. Furthermore, surfaces that are
dentin covered with a smear layer), (3) bond-promoting effects such as capillary
poorly receptive to bonding, such as aprismatic and fluorotic noun, and vitreous
forces (e.g. e.g., bonding to etched enamel), (4) surface
scleral dentin, need to be at least hardened and optionally even partially/completely
hydrophilicity/hydrophobicity, and (5) interfacial pores (air, moisture) that weaken
removed.
bond integrity. In complicated dental bonding to dentin as an intrinsically moist tissue
7,50,139,194,212,256 Evidently, surface debris spreads across the cavity walls, which, as
(fluid-filled tubules), bonding materials should be initially hydrophilic (low water
contact angle) to adequately wet moist dentin, while ideally they should transform mentioned

after polymerization to a hydrophobic state (high water contact angle). water contact previously, may interfere with binding. Unquestionably, enamel requires etching with
angle) to limit water absorption and prevent degradation of hydrolytic bonds. 2 hydrogen peroxide and sufficient microretention to achieve a durable bond. 37,215
Therefore, adhesives must achieve a balance between hydrophilicity before curing Etching of enamel eliminates any interference from the smear layer; simultaneously it creates deep
and hydrophobicity after polymerization. Hermetic sealing of adhesive dentin etched pits, in which relatively simple resins flow by capillary action and interlock
surfaces is primarily impossible, considering the extremely high permeability of micromechanically. Nowadays, phosphoric acid etching dentin has become less
dentin, not only with its numerous dentinal tubules that form the direct connection to preferred, as it completely demineralizes the 3 to 6 μm surface layer, exposing a
the pulp, but also with the highly microporous intertubular dentin structure. Bur microporous collagen-fibril network that is hardly fully hybridized through resin
residue directly interferes with surface wetting as it smears and compacts through interdiffusion. In the complete resin envelope of exposed collagen, the thick, mineral-
enamel and dentin.13,115,181,182,214 This surface smear should be treated free, collagen-rich E&R hybrid layer is less tight and less resistant to hydrolytic
appropriately as bonding attempts degradation and enzymatic biodegradation. An intense and long-lasting chemical
Previously, they clearly failed when they adhered to the smear layer, which in turn interaction of the resin with collagen should not be expected with an E&R approach,
was not sufficiently adhered to the underlying unaffected tooth tissue. This smear as at best only secondary chemical formation occurs, but generally does not
layer should also be considered the main obstacle that self-adhesive cements and contribute to the durability of the bond. The alternative approach of soft SE makes
restoratives applied without retreatment must overcome and therefore must use of acidic functional monomers that provide microretention to the dentin by mild
sufficiently deal with this surface smear by virtue of their own chemistry. 14,119,156,180 (self-)etching and thus partial demineralization of the 1 μm surface layer.
Furthermore, they rely on the primary chemical (ionic) interaction of the functional
Cavity finishing with softer burs that leave thinner and less compact smear monomer with HAp that remains abundantly available within the submicron hybrid
layers,28,51 In addition to the use of alternative cavity preparation tools such as sono- layer (Figures 1e to 1g).
abrasion, sandblasting, and femtosecond laser ablation are means to reduce smear In fact, chemical interaction is the most intimate contact possible between atoms
layer interference with the junction.121,215 and molecules and is believed to contribute especially to the durability of bonds. It
Microretention or micromechanical interlocking is most likely the primary does not translate into higher bond strength, but will prevent bond strength reduction
mechanism of attachment to mineralized materials such as enamel and dentin. upon aging.1 The chemical interaction should primarily target the inorganic HAp
Microretention can be component of tin to interact ionically with, as part of the above elements.

Vol 22, No 1, 2020 15

 Van Meerbeek et al.

Figure 5 Diagram detailing the concept of

adhesion-ecalcification (AD) with
the ADHESION pathway in (a, the MODIFIED
ADHESION pathway in (a, and the
DECALCIFICATION pathway in (b).

SE soft (ultra) moderate binding mode. Such primary chemical bonding (3) Revised concept of ADHESION-DECALCIFICATION
Almost 20 years ago,
Yoshida et al introduced the concept of DA
with organic tissue components such as dentin collagen is very
challenging and typically only involves weak secondary van der Waals in 2001.239 and Yoshioka et al. 55 This model is still valid today and
defines how molecules interact with hard tissues such as tooth enamel and dentin.
forces and hydrogen bonding that provide little resistance to degradation.

16 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

as bone (Fig 5). It involves an adhesion (Figs. 5a, a) and a decalcification route (Fig the long term. Since the Ca salt of phosphoric
i3 acid is not very stable, this acid is an
5b). The key point is the formation of a stable ionic bond to calcium (Ca) within HAp 10-MDP CH, HHHHHHHHHH
effective tooth etchant for an E&R bonding mode. Like ise, maleic acid has been
or, in other words, the ability of the molecule to produce stable monomer-Ca. CH,=CCOCCCCCCCCCCC-
used in the past as a milderIIetchantHHHHHHHHHH
replacing phosphoric acid. As mentioned above,
Determination of the stability of monomer-Ca salts has been used to screen new
candidate functional monomers for their chemical bonding potential. 11,237, 252,254 EITHER
one of the first 1-step adhesives, marketed as Adper Prompt L-Pop (3M ESPE), was 0
characterized
Molecules such as oxalic acid, polyalkenoic acid, specific acid-functional
UVAUOR characteristics of 10-IDP
as a “strong” E adhesive, since the Ca salts of the contained diHEMA-phosphate
monomers and the more recently developed biodegradable phosphorylated pullulan
1. Methacrylate
functional functional
onomer weregroup
notforstable.
POLYMERIZATION for IONIC BONDING
and it dissociates easilywith
in Ca of HAp (adhesion
phosphoric acid;route)
(PPL) follow the ADHESION ROUTE, by which the molecules adhere to the HAp- 3. Spacer with adequate length: a. efficient SEPARATION of both functional end groups
therefore, Adper Prompt
based tissue with only a limited decalcification effect.
- Popb.(3M
provides HYDROPHOBICITY
ESPE) etched enamel strongly, giving a relatively stable adhesion to 3
ect (figure 5a1 . Anion adhesion forces phosphate and hydroxyl anions to
enamel, but etched dentin too strongly, destabilizing
for ETCHING: its bond to dentin. FJ
leave HAp to maintain the interface electron. neutral. Minor surface Enables MICRO-MECHANICAL INTERLOCKING and NANO-LAYERING d

demineralization is beneficial in light of providing microretention (micromechanical

(4) CLASSIFICATION of current adhesives
interlocking). Oxalic acid, and oxalates in particular, have been used as dentin/root
Entin adhesion now involves the use of one of two approaches, namely
desensitizers,7,189 since their short and simple molecular structure with two
Figure
the 6 Key features of the
ETCH-AND-RINSE most effective
(E&R) or (ultra)functional monomer currently
gentle SELFETCH (SE) bonding
interconnected carboxyl groups stably binds ionically to the dentin. available, 10-methacryloyloxydocyl dihydrogen phosphate (10-MDP).
mode. 15 Both bonding modes have their PROS and CONS in terms of
HAp Ca; form high stable Ca that helps occlude open tubules as part of an effective
bonding effectiveness and long-term bond durability, obviously with
treatment of dentin/root sensitivity. Polyalkenoic acids are polymers with abundant
scientifically documented product dependency and thoroughly
carboxyl groups that are able to "grab" (ionically bind to) Ca at so many different and
documented better bonding performance of multi-step adhesives
adjacent HAp sites that they self-adhere to the mineralized tissue. 56,238,239
compared to that of simplified TRADE-OFF E&R and SE Adhesives.
Polyalkenoic acids are the functional polymers that make conventional and resin-
modified glass ionomers adhere to tooth enamel and dentin, while
Proper surface preconditioning with an aqueous polyalkenoic acid conditioner
remains necessary to reduce potential interference of strawberry smear with GI. self-
adhesion. 7,43,82 As the main functional ingredients, (ultra) mild SEas contain acidic
functional monomers, of which the functional monomer 10-MDP (Fig. 6) has been
most extensively investigated for its chemical binding potential. These functional
monomers interact ionically through their phosphate group with the Ca of HAp,237,

248,249,252 adding chemical bonding potential to the surface microretention realized

by the limited surface decalcification and etching effect induced by the acid
functional monomer. Finally, PPL has the potential to bond under moist conditions,
opening prospects for its use as a “bioadhesive” or for bone regeneration and pulp
capping, and for serving as a functional ingredient of root canal sealers. 9,140
The unique chemical interaction of 10-MDP with HA necessitates the design of a
MODIFIED ADHESION PATHWAY (Fig. 5a. Among the various acidic functional
monomers, 10-MDP chemically (ionically) binds to Ca from HAp but also attacks and
releases substantial Ca from the HAp-based substrate (Fig 6). 242 Such Ca release
causes 10-MDP to self-assemble into nanosheets of approximately 4 nm, a process
driven by the stable salt formation of 10-MDP-Ca, a structure that was first
chemically confirmed by Fukegawa et al in 2006. 5 and later also visually tested
using high-resolution TEM by Yoshihara et al in 2010.252,254 Using scanning
transmission electron microscopy (STEM), energy dispersive
spectroscopy (EDS)
STEM, X-ray diffraction (XRD) and nuclear molecular magnetic
resonance (NMR), recent research characterized ultra-morphologically
and chemically the interaction mechanisms of
10-MDP with bulk dentin in a manner similar to that which occurs
clinically.248 Hydrolytically stable 10-MDP-Ca salts were found to consist of CaRPO,
meaning that the two hydroxyl (OH) groups of the phosphate group of 10-
MDP reacted ionically with Ca. This stable structure is expected to
contribute to the formation of durable nanolayers of 10-MDP-Ca salts in
the hybrid and adhesive layer and thus improve the clinical longevity of
the adhesively bonded restoration.
When the ionic bond formed to the Ca of HAp is not stable, a
DECALCIFICATION PATHWAY is followed (Fig. 5b), as is done with cetic and citric
acid, the latter being used as a root canal irrigant in endodontics. 15,234 Since calcium
lactate is not very old, the continuous production of lactic acid by bacteria will result
in a progressive decalcification of the tooth structure, which together with the
enzymatic degradation of the dentin matrix by MMP, will lead to caries (cavities) in

Vol 22, No 1, 2020 17

Van Meerbeek et al.

SELF-ETCH adhesive with IONIC BINDING and

STABLE NANO-LAYERING
METHACRYLATE SPACE FUNCTIONAL HYDROPHOBIC
group HYDROPHYLIC
R TO ____J
group for forIONIC BINDING • 3 LJ L-. XXX X. XX IX X
polymerization andNANO-LAYERING COP-OH
2 II AK KX i

10-MDP

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

The main E&R bonding mechanism (surface) demineralization, while narrow but
can be described as diffusion-based deeply etched pits are created, into which
micromechanical interlocking. The E&R resin is drawn by capillary action to form
technique involves phosphoric acid etching to MICRO-resin ags. After polymerization, the
produce deeply etched pits in HAp-rich resin is micromechanically interlocked,
enamel and to demineralize dentin to a depth producing the most durable bond to the
of 4 to 6 μm, exposing a HAp-free collagen dental tissue, so enamel should always be
network with an abrupt transition to the preserved as much as possible when
unaffected underlying dentin. dentin (Fig. 1c). preparing teeth.
Any superficial stains are completely Bonding to dentin has always been more challenging.

removed. By rinsing off the phosphoric acid Following an E&R approach, phosphoric acid should be

etchant, the enamel can be allowed to air dry, considered quite aggressive on dentin, resulting in a time-

turning a matte white as a clinically visible dependent depth of demineralization. Etching should definitely be

sign that the enamel has been adequately imitated at a maximum of 15 s in order not to over-etch the dentin:

etched. It is a disadvantage that this enamel the deeper the dentin is etched, the more difficult it is for the

etching effect cannot be evaluated using a dentin to infiltrate to the demineralization depth. After thorough

water-based wet bonding technique, where rinsing with water, a technique-sensitive water-based wet bonding

the etched surface is only wiped dry and kept technique must be applied for E&R adhesives providing acetone-

visibly moist. In enamel, phosphoric acid based primers (3-E&Ras) or combination primers/adhesive resins

creates wide etched pits between the enamel & R (2-E&Ras).

prisms which, after resin infiltration, result in An elegant dry bonding technique is much less technique

MACRO-resin labels. In the enamel-prism sensitive for adhesives providing water/ethanol based primers (3-

cores, individual HAp crystals are thinned by E and Ras) or combination primer/adhesive resins (2-E and Ras).

sixteen The Journal of Adhesive Dentistry

Van Meerbeek et al.

Clinically, the etched enamel appears matt white until it dries and

the dentin becomes opaque, which is easy to standardize.

However, dentin should never be air-dried for too long (dried out),

as the collagen coagulates into clots that can hardly be infiltrated

by the resin. After air drying, application of a water/ethanol-based

primer will re-wet the partially collapsed collagen network,

facilitating interdiffusion of the resin. Primer (or E&R primer/bond

resin combo) needs to be applied for at least 15 seconds and

really can't be applied for long enough. Actively rubbing the

application of a water/ethanol based primer will re-wet the partially

collapsed collagen network, facilitating resin interdiffusion. Primer

(or E&R primer/bond resin combo) needs to be applied for at least

15 seconds and really can't be applied for long enough. Actively

rubbing the application of a water/ethanol based primer will re-wet

the partially collapsed collagen network, facilitating resin

interdiffusion. Primer (or E&R primer/bond resin combo) needs to

be applied for at least 15 seconds and really can't be applied for

long enough. Actively rubbing

sixteen The Journal of Adhesive Dentistry

 Van Meerbeek et al.

Brushing the dentin surface with a microbrush applying light finger pressure will However, 10-MDP is not the perfect functional monomer, as it is still
locally intensify the interaction of the functional monomer with the dentin, basically sensitive to hydrolytic degradation into its two esters linking both
“massaging” the resin into the glue network. Regular application of a fresh primer functional groups to the central spacer group (Fig. 6). In fact, 10-MDP
solution outside the distribution pit will further promote resin infiltration. The need to appeared hydrolytically unstable in water, as it can be degraded to
gently air dry the primed surface to help the primer solvent evaporate is often dihydro hydroxydocyl phosphate and methacrylate., 124 Since SEas
underestimated; on gentle air drying, the gloss film no longer moves as a clinical contain water, such monomer hydrolysis is expected to compromise their
sign that the primer solvent has been adequately removed. The primer should be clinical performance. 23 Linking the favorable binding potential of 10-MDP
repeated/extended when opaque stains remain visible on the dentin surface. It is to its molecular structure taught the research community how functional
advantageous to have a primer that contains a photoinitiator, in order to carry the monomers with effective binding potential to dentin should be designed,
photoinitiator deep into the exposed collagen network. The final step involves the opening opportunities to synthesize 10-MDP analogues with similar onset
uniform application of the adhesive resin in a visibly thick layer which should always
effectiveness but higher dentin yield.
be light-cured separately and immediately to stabilize the adhesive interface and
hydrolytic resistance. In this search for more hydrolytically stable
block immediate water absorption through osmosis of the underlying dentin. After
functional monomers, phosphonate- and acrylamide-based monomers
polymerization, the resin is micromechanically cross-linked forming resin tags in the
have been synthesized, but have so far failed to approach the binding
dentin tubules as well as through inter- and intratubular hybridization without any
efficiency and chemical interaction potential of 10-MDP.24,252 However,
primary chemical interaction involved.
the new
Fluorocarbon functional onomer 6-methacryloxy-2,2,3,3,4,4,5,5-
Alternatively, SE (ultra) soft bonding simplifies adhesion to dentin by avoiding
octafluorohexyl hydrogen phosphate seemed very promising, which is
the E&R process through the incorporation of specific monomers with acidic
called MF8P and synthesized by Kuraray Noritake. 50
functional groups, which behave simultaneously as conditioning and priming agents.
RD and TEM revealed formation of MF8P-Ca salt and nanosheet ring on
Self-etching enamel does not superficially dissolve or dilute HAp as phosphoric acid
dentin, as previously documented for 10-DP.249,252 The MF8P-Ca salt
does; it does not produce deep microretentive etching pits, so the self-etching effect
was as stable as that of 10-MDP, and MF8P was as hydrophobic as 10-
is insufficient to achieve a durable bond to enamel.
Therefore, SE adhesives are usually preceded by selective enamel etching with
MDP, while a significantly higher bonding strength to dentin was
phosphoric acid following the clinical procedure described above.
recorded for MF8P than for 10-MDP.250 This investigation concluded that
despite its shorter molecular size, MF8P possesses similar
The dentin surface is only partially demineralized by
characteristics to 10-MDP, most likely associated with the strong
(ultra) gentle self-etching, whereby microretention is only
chemical bond between fluoride and carbon. Since a favorable bonding
created within the first surface micrometer and the collagen
strength to dentin was recorded, MF8P can be considered a good
queens are surrounded and PROTECTED by HAp. Because
candidate functional monomer for bonding. As a continuation of the
superficial smearing may interfere with binding, mild SEs are
MF8P study, the longer chain analogue of 12 carbons 8-methacryloyloxy
preferable to ultramild SEs. Extending self-etching will
2,2,3,3,4,4,5,5,6,6,7,7-dodecafluorooctyl dihydrogen phosphate, designated as
reduce interference from the stain layer. Upon resin
MF12P, was found to be readily chemically adsorbed onto HAp and resulted in a
infiltration, a typical submicron HAp-rich hybrid layer is
more stable formation. that 10-MDP and
produced, which produces a micromechanical interlock with
MF8P, confirming that MF12P is a good candidate for a functional monomer for a
chemical bonding potential, since calcium remains durable bond.243 According to current knowledge, there are currently no commercial
abundantly available as an acceptor to react with the adhesives containing MF8P.
functional monomer that was infiltrated into this submicron MF8/12P as a functional monomer, which should most likely be attributed to the
hybrid layer. Of the many functional monomers investigated, higher cost of monomer synthesis and therefore the price of the product.
10-MDP is the most effective today (Fig. 6). The main
features of 10-MDP are:

(Figure 62) according to the adhesion route of the AD concept detailed

above (Fig. 5a). Among different functional monomers investigated, 10-MDP
rates are the best for chemical bonding potential; 54,211,237,242,244,253 (3) The long
carbon spacer group effectively prevents steric hindrance between methacrylate and
phosphoric acid ester group, but also provides hydrophobicity to reduce water
uptake (Fig 6, as well as allowing parallel self-alignment of adjacent 10-MDP
molecules during nanocoating; (4) Making 10-MDP unique among functional
monomers is its substantial etching effect, which produces microretention and thus
enables micron-sized interlocking, but also substantially releases dentin from
Ca rom as the driving force of 10-MDP nanosheet Figs 6 and 7). While primary ionic
binding should be considered as the main benefit of 10-MDP, more data are
currently being collected, demonstrating that the nanosheets result in stable D-
structures that additionally contribute to bond durability and therefore merit further
studies. For example, a recent ultramorphological and chemical structural analysis at
the atomic level revealed that both hydroxyl groups of 10-MDP react ionically
with Ca to produce a stable CaRPO4 structure, which is resistant to water
and acids.248

Vol 22, No 1, 2020 17

Van Meerbeek et al.

Figure 8 The PLUS-MINUS balance of

conventional E&R

ETCH&RINSE AND adhesives.

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 Yo
Annual Failure Rate of (22.0)% for 3-E&Ra,» (*4.9)% for 2-E&Ra (Peumans et al., 2014);
Possibility to apply a separate solvent-free/poor hydrophobic adhesive resin in a sufficiently thick film
thickness, providing stress-absorbing potential.
Phosphoric acid is (too) aggressive for DENTIN = demineralizes dentin deeply (4-5 pm);
- 2: Dentinal HAp as the natural protection of collagen is removed;
- 3: Collagen is deeply exposed;
- 4: Thick hybrid layers should be produced (resin infiltration should diffuse deeply);
- s: E&R hybrid layers are vulnerable to leakage and enzymatic (bio-)degradation;
- 6: Only weak secondary chemical interaction (van der Waals forces, hydrogen binding,...).
balance

(5) PLUS/MINUS BALANCE of ETCH & sufficient film thickness, which current generation AUs
RINSE adhesives (Fig 8) generally lack (see below).
Most likely the main PLUS point of E&Ras is the : MINUS is that phosphoric acid is (too) aggressive
effective diffusion-based bonding mechanism involving for dentin, whereby the dentin is demineralized deeply for 4-5
deep micro-mechanical interlocking in both enamel and μm.
dentin. 15 : Dentina HAp since the natural protection of
: Due to its aggressive etching, phosphoric collagen is completely removed/dissolved.
acid completely dissolves surface stains which are : The collagen is deeply exposed (Fig. 1c).
effectively removed with a thorough spray of water, Thick hybrid layers must be produced in
so the stain layer will not interfere with the bond. short clinical application times; the resin must be
: E&R is the best approach for enamel. It is infiltrated to several meters depth.
proven that this bond to the enamel is long lasting. : Thick hybrid E&R layers are vulnerable to
E & Ras has a long history, especially micro/nanoeakage and enzymatic biodegradation.
some 3-E & Ras that have been on the market for Only weak secondary chemical interaction is
more than 20 years, such as the gold standard 3-E involved (van der aals forces, hydrogen bonds), which will
& Ra Optibond FL (Kerr) (see below). not contribute substantially to the bond durability.
There is independent evidence of the
effectiveness of long-term clinical linkage of E&Ras (6) PLUS/MINUS BALANCE of soft SELF-ETCHING

in at least one randomized controlled clinical trial adhesives (Fig. 9)

(RCT) beyond 10 years of clinical service in the : PLUS is the surface hybridization of about 1 μm

scientific literature, although a clear product obtained with soft SEas, which is relatively easy to fuse for

dependence must be considered.150 resin in the short time of clinical application. It is not the

: According to a meta-analysis of clinical thickness of the hybrid layer, but the quality of the hybrid
layer, which is important with regard to the durability of the
effectiveness in non-carious class V lesions without
bond.
macroretention, the average annual failure rate
: Dentin is only partially demineralized, enough to
(AFR) of 3-E&Ras was 3.1 (±2.0)%, which is
provide micromechanical interlocking.
significantly higher than that recorded for the most
popular 2-E&Ras on the market which presented an : Due to only partial demineralization, the
average AFR of 5.8 (±4.9)%.148 The latest recorded color exposure is limited, so it is better protected
AFR for E&Ras also has a large standard deviation against enzymatic biodegradation.40,41
4: The HAp-rich submicron hybrid layer offers
(r), pointing to a relatively wide variation in recorded
opportunities for primary chemical (ionic) interaction,
clinical efficacy among commercial 2-E&Ras.
: In particular, 3-E & Ras involving the application of although this is highly dependent on the functional

a poor hydrophobic adhesive resin/no separate resin at an monomer.237,244,246,253 Today, 10-MDP is considered to
insufficiently thick film thickness, can provide shock/stress be the most effective functional monomer that combines
absorption potential in high stress cavity configurations moderate etching,42 providing surface microretention, with
(polymerization shrinkage). This emphasizes the need for long-lasting chemical interaction that additionally results in

18 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

a stable 10-MDP-Ca Eng salt nanolayer. :Soft SE adhesives are also present with a long
41,248,249,251 track record, especially for some 2-SEas that have been in
the

Vol 22, No 1, 2020 19

Van Meerbeek et al.
Figure 9 The PLUS-MINUS balance of

'MILD'SELF-ETCH E
conventional soft SE
adhesives.

Shallow hybridization (<1um) = 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 Yo
LOWEST AFR of (21.5)% for 2-Sea, > 3.6 (±4.9)% for 1-SEa (Peumans et al., 2014);
Possibility to apply a separate solvent-free/poor hydrophobic adhesive resin in a sufficiently thick
film thickness, providing stress-absorbing potential.

- 1: ENAMEL: selective etching with phosphoric acid recommended;

- 2: Potential smear-layer interference (ultra-mild/mild S Ea);
- jt Functional monomers sensitive for hydrolytic degradation.

The / 11 k L1! balance

market for over 20 years, such as Clearfil SE Bond effective functional monomer (Fig. 6) and therefore can be
(Kuraray Noritake) with the gold standard SE being found in most SEas and even in UAs (see below), 10-MDP is
Clearfil not perfect with respect to its hydrolytic stability.124,170

SE Bond 2 (Kuraray Noritake) and its improved

polymerization efficiency the latest commercially
available version.
There is independent evidence in the literature of the
effectiveness of long-term clinical linkage of EE in at least one
randomized clinical trial (RCT) beyond 10 years of clinical
service, although a clear dependence on the product must be
considered. 49
According to a meta-analysis of clinical
effectiveness in non-carious class V lesions without
macroretention, the average annual failure rate (AFR)
of 2-SEas was 2.5 (± 1.5)%, with that for the easier-to-
use 1-SEas (AFR = 3.6 ± 4.9%) being only slightly
lower than the previously mentioned AFR for 3-E &
Ras (AFR = 3.1 ± 2.0%).148
As for 2-E&Ras (compared to their 3-E&Ra counterparts), the
AFR standard deviation of 1-SEas is substantially higher, again
pointing to wide product variation.
: As advantageous to 3-E&Ras (compared to their 2-
E&Ra counterparts), 2-SEas involving the application of a
separate resin-free/poor hydrophobic adhesive resin in a
sufficiently thick film thickness, can provide impact/stress-ab.
absorption potential in high voltage cavity configurations.

1: MINUS is the unsatisfactory (self) etching effect on the

enamel which provides insufficient microretention for
macro/micro- formation of resin labels. Since enamel requires
phosphoric acid and therefore an E&R approach, selective
etching of enamel with phosphoric acid, while reasonably
avoiding etching of adjacent dentin, is recommended and is
now a routinely applied technique.
: Possible interference from the smear layer cannot be
completely excluded, as it interferes more with ultra-soft SE
adhesives (pH>2.5) than with mild pH adhesives.
: Although 10-MDP is currently considered the most

20 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

(7) GOLD STANDARD E&R ADHESIVE (Fig 10) self-rewetting effects to avoid collagen collapse that would
When sufficient and consistent evidence of long-term prevent adequate resin infiltration, as has long been suggested.
favorable bonding performance appears from both .87,226 As is definitely required for E & Ras that provide
laboratory and clinical research, commercial adhesives acetone-based primers (in the case of 3-E

can be considered GOLD STANDARD (GS). & Ras) or combined primer/adhesive resins (2-E & Ras), the

GS1: With over 25 years on the market, highly technique-sensitive water-based wet bonding technique

Optibond FL (Kerr) 3-step E&R adhesive had the seemed redundant or Optibond FL (Kerr). Most likely also other

highest immediate and 1-year predicted bond E&Ras that provide water based primers
(3-E & Ras) or combination primer/adhesive resins (2-E & Ras)
strength to dentin in a meta-analysis that included
do not require wet bonding. In other words, not all E&Ras need
over two thousand strength tests. evidence
by definition be applied following the highly technique-sensitive
reported in nearly 300 articles. 9
GS2: As mentioned above, a high retention rate of 94% as wetting technique, as many research reports and much trade

recorded for Optibond FL (Kerr) in an independent thirteen-year literature seem to suggest, sometimes even leading to E&Ras

RCT for non-retentive Class V restorations.150 being mistakenly called "wet-bonding" adhesives.

Of note, the 13-year clinical data were obtained when Optbond

GS3: A very low AFR of 1.8 (± 0.8)%, based on
FL (Kerr) was applied following a gentle drying approach. This
6 CT, was recorded for Optibond FL (Kerr) in a
significant finding emphasizes that since Optibond FL (Kerr)
meta-analysis of clinical effectiveness of adhesives
provides an ethanol/water-based primer, it may make use of
in non-retentives

Vol 22, No 1, 2020 21

Van Meerbeek et al.

Figure 10 Evidence justifying the nomination of

OptiBond FL (Kerr) as the gold standard E&R
adhesive, based on meta-analytical laboratory testing9
and clinical data,148 as well as its superior clinical
performance in a thirteen-year randomized clinical
trial.150

Figure 11 Evidence justifying the nomination of Clearfil

SE Bond (Kuraray Noritake) as the legacy standard
SE adhesive, based on meta-analytical laboratory39
and clinical data,148 as well as its superior clinical
performance in a thirteen-year randomized clinical
trial,150 although it is clinically recommended to be
used in a 3-step combined enamel E&R selective
bonding mode with 2-SE.

Class V (Kuraray Noritake; now

restorations,148 the succeeded by Clearfil
clinical model SE Bond 2 with
considered most claimed higher
appropriate (most polymerization
objective) to evaluate efficacy) presented
the clinical efficacy of with the second
adhesives.222 highest immediate and
Based on two predicted 1-year bond
meta-analytic trials of strength to dentin in a
clinical and laboratory meta-analysis that
effectiveness along included over 2000
with an independent bond strength tests in
RCT, Opti bond FL nearly 300 papers. 9
(Kerr) deserves to be GS2: Currently, the
recognized as the gold 13-year retention rate
standard E&R of 96% recorded for
adhesive (Fig 10). Clearfil SE Bond
(Kuraray Noritake) is
(8) SE GOLD- the highest. Retention
STANDARD rate reported in long-term
ADHESIVE (Fig independent RCTs of
11) retained Class V
GS1: With more restorations.149

than 20 years in GS3: A very low AFR

the market, the of 2.2 (± 1.7)% was
- SE step adhesive recorded, based on
Clearfil SE Bond 12 RCTs, for Clearfil

22 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

SE Bond (Kuraray providing water-based

Noritake) in an ETA primers are more

analysis of the technique-tolerant and

clinical efficacy of allow the dentin to air dry

adhesives in smoothly without

unattended class V compromising resin

interdiffusion.
restorations.148
As the most
Based on two meta- important bonding
analytic trials of clinical step, actively rub the
and laboratory efficacy primer onto the
along with an enamel and in
independent RCT, particular the dentin
Clearfil SE Bond for at least 15 s.
(Kuraray Noritake) Priming cannot be
deserves recognition done for long enough
as the gold standard – the longer, the
SE adhesive (Fig. 11). better. Continuously
Having consistently apply "fresh" primer
produced favorable to the dentin
laboratory bonding substrate. It is
effectiveness data that advisable to use a
has been confirmed by primer that also
long-term clinical bonding contains a
effectiveness data, it is photoinitiator to carry
expected that both the the polymerization
gold standard E&Ra initiator deep into the
Optibond FL (Kerr) and exposed collagen-
the older SEa standard fibril network
Clearfil SE Bond 2 (although it will not
(Kuraray Noritake) will be
cure at this step due
routinely used as
to inhibition of
controls/references in
polymerization by
laboratory research.
oxygen). The priming
(9) RECOMMENDED step should be
3-Step Complete E&R completed by gently
Bonding Route The air drying to prevent
recommended three- solvent evaporation
step complete E&R as much as possible.
bonding route of Separately apply a
application is (Fig 12): solvent-free/solvent-
Etch enamel and
free adhesive resin in
dentin with 30–40%
a visibly thick layer
phosphoric acid, bond into
with stress
enamel and finish into
absorption potential.
dentin to limit etching of
After gently blowing
dentin to a maximum of 15
with air to evenly
s to avoid over-etch of
spread the adhesive
dentin. Rinse with water
resin (not to thin the
briefly for 5 to 10 s and
adhesive film
then air dry until the
thickness),7.98
etched enamel appears
Immediate/separate
frosty white as a clinical
adhesive
sign of sufficient enamel
polymerization will
etching and the dentin
prevent rapid water
appears opaque. Dentin
absorption through
can only be air dried
briefly, only to visibly
osmosis from the
remove water. E&Ras underlying dentin.

Vol 22, No 1, 2020 23

Van Meerbeek et al.

190,208 It is
recommended to apply
flowable composite
over adhesives that
result in a thin film
thickness to stabilize
the interface and allow
for the stress
absorption potential
mentioned above.

(10) PREFERRED 3-
Step Combined
Selective E&R and 2- Figure 12 recommended the
complete 3-step E&R
SE Enamel Bonding bonding route.
Route
The preferred bonding
protocol combines
selective enamel E&R
with 2-step SE in three
application steps (Fig
13):

1. Selectively etch
enamel with 30-40%
phosphoric acid, avoiding
etching adjacent dentin
(although this should not
be considered too
unfavorable, considering
the reasonably good 3- Figure 13 Preferred 3-step
E&R bonding mode combined selective
mentioned above). If enamel E&R with - SE
dentin is not touched, bonding route.
enamel etching may be
prolonged even beyond
15 s. Rinse thoroughly
and air dry as described
above for the full
recommended 3-E&R
route. voltage absorption
2. As the most important potential. After gently
bonding step, actively rub blowing with air to
the 10-MDP-based gentle evenly spread the
self-etch primer for at least adhesive resin, the
15 s. Self-etch primer cannot adhesive resin
be run for long enough; It should ALWAYS
continuously supply “fresh” be light-cured
primer onto the dentin separately and
substrate. The immediately on the
Primer finishes with a dentin.
gentle air drying to
promote solvent Considering that it is
evaporation. the most intimate
. As for the full E&R route, contact that can be
apply in the final step achieved between
a solvent-free/poor atoms and molecules,
adhesive resin in a chemical bonding must
visibly thick layer with always be strived for in

24 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

order to achieve a although the actual

lasting bond to dentin. degree of involvement
Therefore, the final 3- of the latter
step combined degradation pathway
selective enamel E&R
is still unclear (see
followed by the 2-step
below). Eight
SE bonding route
strategies have been
should be considered
as the proposed in recent

today's PREFERRED literature to potentially

joining protocol. improve bonding.
of & R and/or SE (Fig.
(11) MAIN PATHWAYS 14).
OF BOND
DEGRADATION and 1. Improvement of
eight CLINICAL E&R and SE
STRATEGIES proposed bonding by
to PRESERVE BOND treatment with
STABILITY NON-THERMAL
While modern dental ATMOSPHERIC
adhesive technology has PLASMA (for E &
allowed for a ductile bond Ras and SEas)
to enamel and dentin An interesting
when proper bond lines improvement in bonding
are precisely followed, has been suggested after
other NON-MATERIAL treatment of dentin with
circumstances related to non-thermal atmospheric
the patient, tooth, and/or plasma (NTAP). 4 Plasma
operator may cause is defined as partially
bonds to clinically ionized loops containing
deteriorate more rapidly. 5 electronically excited
Furthermore, laboratory atoms and molecules, as
research still reveals bond well as ionic species and
degradation under free radicals. These highly
accelerated aging reactive particles can
regimes. Also, simplified rapidly cross-link to form
link various chemical
functional groups on the
surface of substrates.
Application protocols do
Overall, NTAP was
not (yet) achieve the
suggested to affect
bonding performance that
different properties of
can be predictably
relevance to dental
obtained using the above
bonding, such as
mentioned older standard
increased wettability of the
adhesives and their
dentin surface,4 enhanced
recommended/preferred
resin polymerization, and
bonding routes. Therefore,
deeper resin penetration.
several strategies have
4,94,258 Another possible
been developed to further
optimize the binding and reason for the bond-

counteract the main bond promoting effect could be

degradation pathways, as that NTAP activates the

there are (1) water dentin surface by

sorption with hydrolytic depositing free radicals or
bond degradation peroxides, thus

mechanisms and (2) intensifying the interaction

between adhesive
enzymatic
monomers and dentin
biodegradation,
collagen. 2 However,

Vol 22, No 1, 2020 25

Van Meerbeek et al.

several laboratory lengthy) protocol to

experiments, using remineralize the
microtensile bond strength demineralized dentin
and fracture toughness surface, defies logic,
tests, did not provide especially when one
consistent support in favor considers that there is an
of dentin plasma effective alternative SE
treatment to improve E&R approach, whereby the
and SE bonding.8,9,10 dentin is only partially
Therefore, this strategy demineralized and most of
should not be considered the dentinal collagen
sufficiently effective (Fig. remains
14). surrounded/protected by

ineral. However, this

2. BIOMIMETIC
dental remineralization
REPAIR of E&R
technology may be of
hybrid layers by interest to develop
REMINERALIZATION minimally invasive
(for E & Ras) restoration techniques
Tay and Pashley
using materials with
introduced a guided tissue
remineralization potential,
remineralization technique
or for example, so that it is
in 2008. 92 With this
no longer necessary to
technology, proof of
remove all carious tissue
concept was achieved for
in deep caries lesions with
biomimetically repairing
a high risk of pulp
E&R hybrid layers.95,191
exposure. Finally, the fact
This research aimed to
that E&R hybrid layers can
develop a means to
be remineralized confirms
prevent the degradation of
how sensitive E&R hybrid
denuded collagen within
layers are to degradation,
incompletely resin-
since fully resin-saturated
infiltrated dentin-adhesive
E&R hybrid layers should
interfaces produced by
not be remineralizable.
E&R adhesives. A
biomimetic 3. ETHANOL WET
remineralization scheme
BOND to improve resin
was shown to result in
infiltration/interdiffusion
intra- and interfibrillar
(for Ey Ras)
remineralization after
Their strategy focuses on
several months.7,87,191
the E&R binding mode
While E&R hybrid layers
with the intention of
could be remineralized in
completely replacing water
the laboratory, the direct
within the exposed
clinical applicability of this
olanzapine-fibril network. 5
biomimetic strategy to
This strategy is based on
extend the longevity of
a gradual exchange of
adhesive-dentin junctions
surface water for ethanol,
is unclear. Furthermore,
the latter solvent
the rationale behind the
functioning as a better
approach of first
medium to facilitate the
demineralizing the dentin
interdiffusion of more
aggressively using
hydrophobic joint resin
phosphoric acid as part of
into the deeply exposed
an E&R bonding mode, in
collagen-fibril network of
order to use in a
phosphoric acid. 137,138
subsequent phase a
This approach originated
sophisticated (and
in sample processing for

26 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

electron microscopy, enzyme exposure and

when, after fixation, activation by different
samples are gradually types of adhesives are not
ehydrated in ascending always consistent, and the
concentrations of ethanol delaying/stopping effects
before being critical point of bond degradation by
dried or mixed with HMDS the use of MMP inhibitors
(hexamethyldisilazane) for vary between studies. It is
SEM, or before being very evident that MMPs
exchanged for epoxy resin are exposed/activated by
and embedded in epoxy phosphoric acid etching
resin for TEM. 143,224 This following the E&R bonding
method is probably the mode, while this is not
most effective strategy to always confirmed with SE
improve E&R adhesives.0,41 When, for
loading,168,169 but it is example, dentin powder
clinically impractical. was exposed to the gold
due to the clinical time standard E&Ra Optibond
required for successive FL (Kerr) and the gold
applications of ethanol, as standard SEa Clearfil SE
it requires at least several Bond (Kuraray Nori take-
minutes (Fig. 14). up) under clinical
application conditions,
gelatin zymography
4. INHIBITION of revealed the release of
ENZYMATIC MMP-2 (not MMP-9) by
BIODEGRADATION the E&R adhesive, while
(for E & Ras in no enzyme release could
particular) be detected for the soft
Atrial SE adhesive, most likely
metalloproteinases due to the limited dentin
(MMPs) are a group of demineralization effect.41
enzymes that are The latter contrasting data
responsible for the for E&R vs SE bonding
degradation of were confirmed in a
extracellular matrix subsequent study.
proteins during normal
organogenesis, growth,
and tissue renewal. 78
Although the expression
and activity of MMPs in
adult tissues has been
reported to be normally
quite low, MPs, together
with cysteine cathepsins,
have been linked to the
biodegradation of
adhesive-dentin
interfaces. 5.109 However,
the proportional
contribution of such
enzymatic activity to bond
degradation remains
unclear. Hydrolytic effects
due to water uptake
probably represent the
most important/relevant
bond degradation
pathway. Data regarding

Vol 22, No 1, 2020 27

 Van Meerbeek et al.

STRATEGIES to improve E&R and SE bonding:

Figure 14 Critical evaluation of eight
suggested strategies to improve the E&R
and SE link.
INSUFFICIENTLY EFFECTIVE:
1. Bonding following NON-THERMAL ATMOSPHERIC PLASMA TREATMENT (for E&LRa's and SEa's)

EFFECTIVE but PRINTED . -

2. Biomimetic repair of E&R hybrid layers by RE-MINERALIZATION (for E&.Ra's) 2
3. ETHANOL WET-BONDING to improve resin infiltration/interdiffusion (for E&.Ra's) 1§
Bond-dlegradation RETARDING:
4. INHIBITION of enzymatic bio-degradation (for E&Ra'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)

Recent study on 2-E&Ra Scotchbond 1 XT (3M Oral Scotchbond Multi-Purpose (3M Oral Care) and 2-E&Ra
Care), revealing the presence of MMP-2 (again
Single Bond 2 (3M Oral Care) after - months of
without MMP-9), unlike the data recorded for 2-SEa
artificial aging, a significant reduction in bond strength was
Clearfil Protect Bond (Kuraray Noritake) and 1-SEa G-
recorded after 18 months of aging despite post-etch HX
Bond (GC), for which no enzymatic activity was
treatment. However, when the two adhesives were applied
detected.40 Clearly, depending on the acidity of the
using an ethanol wet bonding technique in the same study,
adhesive and the etching/demineralization
their bond strength
aggressiveness, MMP activation was obtained by
remained stable after aging for 9 and 8 months. 168 In full
treating dentin powder with the strong SEa Adper
agreement with this study, the adhesion to dentin of
Prompt L-Pop. 0 Although conflicting data have been
Gold standard 3-E&Ra Optibond FL (Kerr) with CHX added to
reported in the literature,108 a significant direct correlation between
its primer did not significantly decrease with aging.
gelatinolytic activity and the pH of the SE adhesive was also found.134 3 and 6 months by storing the sample in water, while storage
Overall, it can be logically concluded that enzymes in water for 12 months resulted in a significant drop in bond
play a significantly more important role in the strength to the level when Optibond FL (Kerr) was applied
degradation of E&R bonding than SE adhesive without CHX. 1 Another study by Zheng et al.259 revealed that
interfaces, as also recently confirmed by Li et al in four MMP inhibitors (2% CHX, 0.05% green tea extract, 1 mM
2019 (unpublished observations at KU Leuven ferrous sulfate, 0.2 mM galardin)
BIOMAT). prevented a decrease in bond strength of the gold standard 3E
To counteract enzymatic biodegradation, a long list of and Ra Optibond FL (Kerr) after 9 months of aging, but not of
potential MMP inhibitors has been tested in laboratory the gold standard SE adhesive Clearfil SE Bond (Kuraray
investigations for their binding stability-promoting effect, as Noritake), for which bond strength did not decrease
summarized in a systematic review and meta-analysis by with/without MMP inhibition. Looking for clinical evidence of
Montagner et al. 17 The most documented MMP inhibitor is bond degradation in
chlorhexidine digluconate (CHX), a nonspecific MMP inhibitor, Inhibition, a meta-analysis by Göstemeyer and Chwendicke,0
which is either (1) incorporated into the acid etching agent, although it included only 10 RCTs and 7 studies testing CHX,
which is rinsed away from the surface, (2) incorporated into concluded that dentists can perform caries pretreatments to
the adhesive, or (3) applied as a solution directly onto the inhibit hybrid layer degradation (not damaging the bond), while
dentin after etching and thus remains in contact with the a beneficial effect is (so far) not supported by sufficient clinical
surface (most commonly used MMP inhibition strategy). A data. evidence.
positive effect on maintaining bond stability was documented
In situ zymography allowed to precisely localize
for relatively short-term sample aging (up to 6 months),
proteolytic activity directly to the adhesive cross-link in
providing evidence that MMP inhibition can REMOVE bond
cross section.107 When, for example, 1-ethyl-3-(3-
degradation. However, this effect was no longer detected for
dimethylaminopropyl) carbodiimide (EDC) was used
longer-term aging (1 year and more), so it can be stated that
as an MMP inhibitor, the authors found that in situ
MMP inhibition DOES NOT STOP the degradation (as the
zymography showed hybrid layers produced by the
degradation of hydrolytic bonds continues). In a representative
gold standard 3-E&Ra Optibond FL (Kerr) and the
study by Sadek et al,168 2% CHX was applied separately after
market representative 2-E&Ra Scotchbond 1XT (3M
phosphoric acid etching. Although a non-significant decrease
ral Care) exhibited “intense” collagenolytic activity,
in bond strength or 3-E & Ra was obtained

28 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

while “almost no” fluorescence signal was detected fibers possessing improved biochemical and biomechanical
when the adhesive was cross-linked. properties and greater resistance against enzymatic
dentin was pretreated with EDC.107 Close evaluation of biodegradation. .105,106,136,175 The term "cross-linking" in the
the pro biological sciences refers to the chemical bonding between

However, in situ video zymographic amino acid side chains within collagen molecules. 9 Intrinsic

photomicrographs revealed a qualitatively cross-links stabilize the molecular arrangement within collagen

significant difference in fluorescence, presumably fibrils, improving their tensile properties.165

indicating collagenolytic activity, at the interfaces Biomodification of dentin matrices by extrinsic collagen
ross linkages has been proposed to improve fibrillar resistance
produced by the two adhesives investigated.
to enzymatic degradation as well as to improve the tensile
Substantially more intense fluorescence was
properties of the dentin matrix by additional inter- and
detected in the E&R hybrid layer (and within the
intramolecular cross-linking reaction.11,53,70
underlying dentin tubules) produced by 2-E&Ra;.
Previous studies have shown that several collagen cross-
Some reduction in fluorescence, albeit not very
linkers, such as proanthocyanidin and lutaraldehyde in
convincing due to the different angle of the 3D
particular, effectively induce bond-promoting effects when
reconstructed interfacial structure, appeared when
employed over a wide range of application times (10 min - 40
dentin was pretreated with EDC prior to adhesive
h). , 12,30,73,99
application. 107 However, hardly any green
Some authors have reported satisfactory results at clinically
fluorescence, indicative of collagenolytic activity,
feasible time points.53,70,73,93,175 Compelling data have been
was observed at the 3-E&Ras interface; it even
reported in support of dentin biomodification strategies, such
seemed to be concentrated at the top of the hybrid
as the use of three cross-linking primers, containing
layer, where resin infiltration would be expected to
proanthocyanidin, riboflavin, and lutaraldehyde, when applied
have optimally occurred, thus potentially even
for a relatively clinically prolonged time of 60 s prior to
resulting in a false positive result for in situ MMP
adhesive application. , appeared effective in minimizing the
activity. The limited collagenolytic activity located reduction in bond strength of 2-E & Ra Single Bond Plus (3M
at an unexpected interfacial point, together with Oral Care) and 1-SEa etricN-Bond (Ivoclar
the complete absence of green fluorescence after Vivadent).70 The stable bond strength ensured with both
pretreatment with adhesives was attributed to a reduced n-situ collagenolytic
EDC, could have been more objectively interpreted activity of MMPs, particularly when roanthocyanidin was used.
as limited and totally absent collagenolytic activity, Since glutaraldehyde significantly reduced cell viability, its
respectively, at the adhesive interface clinical use was rightly advised against. However, less
produced by an adhesive such as the older convincing data were obtained in the study conducted by
standard 3-E&Ra Optibond FL (Kerr), which has Parise Gré et al.
been extensively documented to work well. That's 36 Although stable mini-interfacial fracture toughness was
why, recorded after 6 months of aging following biomodification of
Finally, recently unpublished research revealed that MP-2
dentin with 6.5% wt proanthoyanidin in a
and -9 rapidly lose their activity (up to 35% of their initial
Clinically relevant, the incorporation of 0.5% UVA-activated
activity within 24 hours and reaching almost 0% after one
riboflavin and 5% glutaraldehyde by weight into the dentin
week of incubation at 37°C). Considering the limited lifetime of
bonding protocol appeared. not having been effective. Overall,
MMPs, one should wonder how MMPs are involved in the
the benefit of using collagen crosslinkers appeared in that
bond degradation process, since they are only activated by a
one-time acidic adhesive treatment and, in principle, no further study to be largely dependent on the crosslink and the

acidic activity occurs in the adhesive crosslink. to product. 136

expose/activate "fresh" MMPs. In contrast, in caries, enzymes

are continuously produced in the acidic environment created 6. EFFICIENT POLYMERIZATION CONVERSION
by bacteria, and demineralization runs parallel to the of adhesives (for both E & Ras and SEas)
enzymatic degradation of the dentin's organic component, The importance of properly polymerizing adhesives
eventually leading to tooth decay (cavities). should not be underestimated. A well-cured adhesive
is a basic prerequisite for achieving a long-term stable
5. BIOMODIFICATION OF DENTIN BY COLLAGEN
adhesive interface. As a general guideline, the
CROSS-LINKING (for E & Ras in particular)
adhesive should always be light-cured separately and
The operating principle of this cross-linking promotion strategy
applied immediately to the dentin (and enamel). By
involves, in addition to the inactivation of matrix-bound
enzymes (MMP), the enhancement of intra and intra-matrix doing so, water absorption of the adhesive interface
cross-links. from the underlying dentin via osmosis is
intermolecular collagen cross-linkers, which essentially makes reduced/blocked.04,206, 208,210 Often, contrary to
the collagen more resistant to biodegradation.26 Both synthetic and manufacturer instructions, the adhesive must also be light-
naturally occurring collagen cross-linkers have been applied to modify cured prior to adhesively bonding semidirect/indirect
dentin, most specifically to make demineralized collagen-rich restorations with E&R/SEa-assisted omposite cements. While
E&R hybrid layers more durable, with the dentin collagen following a direct restorative procedure, it is best to apply the

Vol 22, No 1, 2020 29

Van Meerbeek et al.

adhesive in a visibly thick layer to achieve the stress blow air over your application until the resin film no longer
absorption potential, when adhesively cementing moves. The only exceptions are some HEMA-free and mostly
semi-direct/indirect ceramic/composite restorations, the acetone-based 1-step adhesives which instead must be
adhesive should be thoroughly diluted with air until the thoroughly air-dried.205 Within such adhesives, the adhesive
adhesive no longer moves and does not pool prior to light monomers are separated from the water, a process triggered
curing. In this way, the perfect fit of the restoration is not by the rapid evaporation of the solvent once dispensed.
compromised. Considering also that the adhesive cementation Following polymerization, the droplets formed will be trapped
procedure takes a clinically significant period of time, water within the adhesive, potentially compromising the durability of
droplets will be incorporated into the adhesive interface if the the bond. This can be avoided by vigorous air drying of the
adhesive is not directly light-cured.97,98 External transmission adhesive, thereby removing interfacial water and thus
Evidently, such interfacial droplets/porosities weaken the
improving the long-term bonding effectiveness.
adhesive interface and reduce the clinical lifetime of the
restoration. In fact, laboratory research showed that complete 7. Additional HYDROPHOBIC RESIN SEALING
self-curing of adhesive-bonded ceramic restorations on dentin, (for E & Ras and SEas)
regardless of the ambient temperature directly affecting The placement of an additional bonding layer, which
chemical curing (room or body temperature), resulted in a results in (1) increased hydrophobicity, (2) improved
lower immediate bond strength to dentin than when the
polymerization efficiency, and (3) thicker film
adhesive (on the dentin side) was light-cured only and
thickness, helps to further stabilize and protect the
separately or when both the adhesive and the composite
adhesive interface against water ingress from the
cement were light-cured separately.7,98 Pre-curing of the
underlying dentin tissue (via osmosis) as well as water
adhesive prior to adhesive cementation can be safely
absorption from the external oral environment. This
performed without risk of restoration fit complications, if the
nicely practical technique has been repeatedly
adhesive is sufficiently diluted with air or if modern AUs are
advocated to improve the performance of 2-E&Ras
employed which rarely achieve a film thickness higher than 10
and 1-SEas in particular simplified ones which
μm (depending also on air blowing time/pressure). For well-
combine the primer with the adhesive resin in a
fitting restorations, cement spaces are typically larger than 50
solvent-richer, resin-poorer single-solution adhesive,
μm, so only a small portion of the available space is consumed
as well as and more recently also for AUs which
by the separately diluted, light-curing adhesive. Of course,
typically come in thin film thickness. Both extensive
when employing an “Immediate Dentin Seal” (IDS) method
laboratory,4,52,145,162,176 and clinical research96,141 have
prior to an adhesive cementation procedure, the adhesive
demonstrated the bond-promoting effect of
should not be thinned with air and is best applied in a thick
extrahydrophobic resin sealing, allowing to conclude
visible layer (e.g. E.g. for direct restorations) followed by an
that the application of extra hydrophobic layer will
additional layer. stabilization by applying a flowable compound
retard the bond degradation of E&R and SE bonding
over the adhesive layer.57 There is then obviously no risk that
the restoration may not sit perfectly, as the conventional/digital
modes, basically by converting 2-E&Ras to 3-E&Ras,
impression will be taken after the IDS procedure.
1-SEas to 2-SEas and
- SE / 2-E and R_UA in 2-SE / 3-E and R_UA. This strategy
and degradation is directly related to water absorption.
is certainly clinically feasible and practical (Fig. 14).
5.160 Therefore, the final adhesive interface should be as
hydrophobic as possible to limit water absorption. First, Alternatively, a similar beneficial effect can be obtained by

adhesives must polymerize optimally,19,25,69,132 considering in applying a flowable composite over a low film thickness

particular (1) their often hydrophilic nature, (2) the possible adhesive. This may be particularly beneficial in deep proximal

inclusion of residual solvent, and also (3) the thin film boxes of posterior restorations, which will additionally lead to
thickness of simplified single-solution adhesives and especially greater marginal adaptation at the critical cervical and axial
UAs (mostly below 10 μm) compared to inhibition of margins of the ox;166 the thicker flowable composite material
polymerization by oxygen. To achieve durable bonds, applied may even serve as an internal shock/stress absorber.
adhesives must be optimized to contain an effective 42, 25,230 As mentioned above, the addition of flowable
photoinitiator system together with a monomer formulation that composite applied over the adhesive as part of an IDS
is well balanced for mono/bifunctional monomers as opposed procedure will also stabilize the adhesive interfaces of
to cross-linking monomers.7.112 In addition to measuring bond adhesively cemented direct/indirect partial
effectiveness immediately and after long-term aging, restorations.100,157,199
adhesives must be evaluated for water solubility and water
absorption as a function of time, which must remain low at all 8. Primary IONIC BONDING of functional
times. Furthermore, their intrinsic mechanical properties (e.g., monomer with HAp together with stable
ultimate tensile strength, fracture toughness) must be monomer-Ca salt NANOLAYERING (for SEAS)
determined in light of the effects of plasticization on water Soft self-etch and newer AUs contain (bi)functional
absorption.77,78,158 acidic monomers.146,228 Many different mono functionals have
In light of the efficient polymerization of the adhesive, been synthesized and used in dental adhesives. 24,209
sufficient solvent removal is indispensable for primers or In general, such a functional monomer occurs with a
combination primer/adhesive resin formulations in a single triple molecular structure, consisting of an acid
solution, such as AUs. It is clinically recommended to gently

30 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

functional group separated from a (meth)acrylate while more hydrolysable 10-MDP analogues have
group by a spacer group. already been synthesised.243,250 but they did not
(Figures 6 and 7). The polymerizable (meth)acrylate lead to commercially available adhesives, most likely due
group will copolymerize with other monomers to build to higher production costs and consequently higher
into the resin matrix of the adhesive and the adjacent market price.
resin-based composite. The spacer group, when
sufficiently long, effectively separates the (12) PROS and CONS of UNIVERSAL
polymerizable (meth)acrylate group from the acid ADHESIVES (UA)
functional group and provides droplet hobicity to the Ongoing research into dental adhesive technology aims to

functional monomer. Potential acidic unctional groups improve the clinical techniques dentists employ to add resin-

are phosphate, phosphonate or carboxyl based materials to tooth structure in light of a minimally
invasive dental restoration concept. 1 The latest generation of
groups,124,209,228,242,244 which will demineralize HAp or
UNIVERSAL ADHESIVES (UA) combine primer with adhesive
chemically bind to HAp, as defined by the adhesion-
resin, allowing for simplified and rapid clinical bonding
decalcification (AD) concept (Fig. 5).
39,255 procedures with relatively low technical
sensitivity.38,65,125,144,174 The term “UNIVERSAL” refers to
According to this AD concept, acidic molecules their application options, allowing them to be used either
first adhere to HAp by electrostatic interaction and following an E&R or SE bonding mode (Fig 3), while offering
remain bound through stable Ca monomer-salt application versatility with bonding potential to both (reclaimed)
formation following the ADHESION PATHWAY (Fig. in glass (via silane) and glass. Deficient zirconia ceramics
abundant demineralization following the (through 10-MDP) for indirect dental restoration
DECALCIFICATION ROUTE (Fig. 5b). Previous indications.102,177,235,236,247
studies have shown that the AD pathway followed by The E&R universal bonding mode involves a
the functional monomer depends on its molecular phosphoric acid etch step followed by a thorough
structure with the acidic functional group inducing water rinse prior to application of a primer/bonding
different etching capabilities.28,242 Following the resin combination (Fig. 3). Monomers diffuse into the
decalcification pathway by Trong SE adhesives (and micro-
E&R adhesives), a several micrometer deep hybrid Etch pits into enamel to form micro and macrotags and into the
layer is formed, in which substantial collagen is exposed collagen-fibril network in dentin to form a 3-5 µm
deprived of its surrounding HAp. The calcium hybrid layer, as achieved with conventional E&Ras. Therefore,
phosphates produced are embedded within the this bonding mode mainly uses diffusion-based
network of exposed collagen fibrils, essentially micromechanical interlocking. While E&R bonding is
destabilizing the adhesive surface which becomes undoubtedly the best enamel bonding strategy, the resulting
highly sensitive to hydrolytic degradation. This strong thick, HAp-free hybrid layer formed on the den tin is very
SE approach is no longer followed. Otherwise, the sensitive to degradation over time (as detailed above for
adhesion route will typically result in a submicron conventional E&Rs).
HAp-rich hybrid layer without much collagen The universal SE bonding mode involves the use
exposure. of onomers with an acidic functional group
In addition to the actual acidic functional group, (phosphate, carboxyl group) that, in principle,
the chemical structure of the spacer group and its simultaneously attacks (desmine) and infiltrates dentin
length co-determine the potential for chemical to a depth of approximately 1 μm. In general, the SE
interaction with HAp and dentin. 210,253 Among many bonding mode has inferior performance to the E&R
functional monomers, 10-MDP is currently considered bonding mode in enamel, so the enamel remains to
one of the most effective monomers for strongly be electively etched with phosphoric acid (E&R) (Fig.
ionically binding to HAp, thus forming stable 10-MDP- 3). However, SE bonding has chemical bonding
Ca salts (Figures 5a, 6, and 7). 237,249 Furthermore, potential as an added benefit to achieve a long-lasting
10-MDP was shown chemically and ultrastructurally to bond. Its chemical binding capacity depends on the
self-assemble into nanosheets. 248,249,252,254 The chemically functional onomer contained. As mentioned above,
stable bond between 10-MDP and HAp was shown to contribute to 10-MDP is the most effective monomer at present; it is
the bond durability, as demonstrated by both exclusively bifunctional with a chemical bond and a
laboratories. 1 and clinical research,148 favourable long-term polymerization group at both ends of the monomer
clinical data having been recorded in particular for the 10- separated by a long hydrophobic spacer (Fig. 6). As
MDP-based 2-SEa Clearfil SE Bond (Kuraray detailed above, 10-MDP (1) etches, releasing Ca from
Noritake).149 Regularly structured monomer nanolayers are also dentin, (2) ionically binds Ca from HAp, and (3) elf
thought to contribute to bond stability, the first direct assembles into stable Ca nanosheets that are
evidence having recently been provided, as detailed arranged in three dimensions at the adhesive
above.248 Many current adhesives, and AUs in interface (Fig. 7). The favorable bonding properties of
particular, contain the functional monomer 10-MDP, 0-MDP inspired most dental manufacturers to
manufacture UA based on 10-MDP.

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Van Meerbeek et al.

In terms of immediate performance (restoration retention, monomer 10-MDP. With a micromechanical binding
marginal seal), many currently commercially available mechanism based primarily on diffusion, the function
adhesives are clinically effective, although there is some of 10-MDP is not entirely clear when UAs are used in
product dependency. However, the long-term bonding an E&R mode. There have been some reports on the
performance of this new generation of UAs, particularly for tin, chemical interaction of 10-MDP with collagen,74 but
is still insufficiently proven, and UAs have also been this definitely requires further in-depth research to
associated with several shortcomings.41 FIRST, their low film confirm the relevance of these findings with respect to
thickness, often below 10 μm, allows oxygen to inhibit the durability of the adhesive interface.
polymerization of the adhesive layer over a significant Although most AUs contain 10-MDP, there may still be
proportion of its depth. Suboptimal polymerization insufficiently differences in performance between 10-MDP-based AUs, as
stabilizes the adhesive interface and may promote water the concentration and quality (purity) of 10-MDP have been
absorption from the underlying dentin by osmosis. The thin shown to significantly affect binding efficiency. 28,246,254
adhesive layer is also thought to reduce the ability of the Currently, manufacturers do not usually publish data on
adhesive layer to absorb the stress (polymerization shrinkage) monomer concentration and quality and therefore remain
imposed on the adhesive interface. SECOND, many AUs unknown.
contain the monofunctional monomer HEMA. As mentioned
above, being a small and low molecular weight molecule, EMA (13)FUTURE DENTAL ADHESIVE
is a good diffusion agent and also acts as a cosolvent for other TECHNOLOGY
less water-soluble monomers, especially since water is an It is not known whether adhesives have reached a level of

essential component of UA (up to 40%). ent to enable SE link clinical performance that can still be improved, particularly

potential. HEMA also helps prevent phase separation between given the documented superior performance of gold standard

hydrophilic and hydrophilic adhesive components. However, adhesives. 19 We do not know if we have achieved a success

the inherently high hydrophilicity of HEMA also promotes water rate well above the

absorption across the osis from the underlying dentin into the 90% of what can be achieved with dental bonding. To
clinically distinguish adhesives in terms of bond performance,
adhesive interface. Furthermore, HEMA does not
much longer follow-up is now needed to observe differences in
polymerize efficiently and is therefore only weakly
clinical performance between generations of adhesives.
integrated into the polymer network. Since HEMA newer adhesives, even when compared to the gold standard
makes the adhesive interface prone to hydrolytic traditional multi-step adhesives.155 Furthermore, many current
degradation, alternative monomers for HEMA are speakers and articles emphasize that patient- and operator-

definitely needed and are being incorporated into new related factors may have a greater impact on restoration
longevity than the adhesive materials employed. 5 However,
UA formulations. A THIRD reason for the potentially
further R&D is still needed to make adhesives less technique-
compromised bonding performance of UAs is related
sensitive under suboptimal field control conditions, to bond
to the incorporated silane that many UAs contain to better/longer to receptive dental substrates for bonding, and
chemically bond to glass-rich ceramics, thus avoiding eventually to develop “true” self-adhesive amalgam
the need for a separate ceramic (silane) alternatives that are inexpensive, easy and quick to place (see
primer.35,236,247 These UAs cannot be highly acidic (pH below).
Current research is promoting the development of
> 2.5), to ensure silane stability in the acidic aqueous
adhesive materials that do more than simply adhere to dental
solution; however, higher pH decreases the etching of
tissue. We all desire materials that have additional therapeutic
the UAs and therefore the bonding effectiveness.
potential, to be able to make our cavity preparations even less
FOURTH and finally, although the functional monomer invasive than is now possible with the current adhesive
10-MDP effectively ionically binds to HAp, resulting in generation and to prevent early restoration replacement due to
a stable monomer-salt nanosheet of bond degradation and caries recurrence. This therapeutic
effect is generally referred to as “BIOACTIVITY,” although the
Ca,240,248,249,251,252 The esters of 10-MDP, which link
definition is a matter of strong debate.98 Bioactivity may
the hydrophobic spacer to the methacrylate and
potentially involve antibacterial, anti-enzymatic, nd/or
phosphate unctional groups on
remineralization effects, all highly desirable material
both ends of the monomers are sensitive to hydrolytic properties. However, while it may not be that difficult to design
degradation. This deficiency encourages the search and develop bioactive adhesive materials, combining activity
for 10-MDP analogues that combine excellent with mechanical stability may represent the greatest R&D
chemical interaction with high hydrolytic resistance, challenge.
since some 10-MDP analogues with improved For example, studies investigating materials containing ioactive
hydrolytic stability have already been glass fillers have focused primarily on their bioactive efficacy. The
synthesized.43,250 results of laboratory research did not demonstrate that surface-
UAs can optionally be applied in a full 2-E&R, a reacted pre-filled glass ionomer (sPRG) resin-based omposites
full 1-SE or a combined 2-step selective enamel E&R exhibited desirable antibacterial properties, as the concentration of
phase followed by a 1-SE bonding mode (Fig 3). ions released by the restorative material did not appear sufficient to
Many AUs contain the most effective functional inhibit bacterial growth.245

32 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

This study also showed that the sPRG-filled composite on the

other hand promoted bacterial adhesion due to structural
changes in the surface area and increased surface roughness
promoting attachment and iofilm formation. Although bioactive
glass may exhibit antibacterial effects, this effect can be
counteracted by an unstable surface integrity, which, with the
release of ions and, in particular, with dissolution, results in
rougher and more irregular restorative surfaces that promote
bacterial adhesion.
When seeking to develop bioactive materials that are clinically
effective, it is essential not only to focus on their bioactive
(antibacterial) characteristics but 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 unaesthetic 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 have been
developed.33,35,257 For example, the antimicrobial monomer
12-methacryloyloxydodecyl pyridinium bromide (MDPB) was
added to the commercial adhesive Clearfil SE Protect (Kuraray
Noritake).79,233 Numerous in vitro studies have confirmed the
contact antibacterial effect of MDPB, whereas the clinical
suppression of secondary caries and Clearfil SE Protect
(Kuraray Noritake) has not been proven so far (Clearfil SE
Protect brochure, Kuraray Nori take). In addition to quaternary
ammonium methacrylate compounds immobilized in dental
adhesives and composites without release potential, other
antibacterial releasing agents such as chlorhexidine and
nanosilver particles have been investigated for their anticaries
properties, but seemed less effective due to uncontrolled
short-circuiting. live burst launch.3

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Van Meerbeek et al.

Figure 15 Transmission electron microscopy (TEM) of the interface produced by the self-adhesive, bulk-fill hybrid restorative Surefil One (Dentsply Sirona) with bur-cut
dentin. The self-adhesive restorative material interacted closely with the dentin, with no signs of surface wear.
mineralization or hybridization could be observed.

Cetylpyridinium chloride (CPC) is also a highly self-adhesive restorative materials that no longer
effective broad-spectrum antibacterial agent. 59 CPC require a separate prior application of an adhesive.
disrupts the microbial cell membrane by altering its They are the logical complement to self-adhesive
electrical balance, a mechanism that is unlikely to be cementation composites,2,153, 154,173 obviously for
affected by microorganism mutations and is pathogen- restoration procedures that require a higher level of self-
independent. 31,159 A more detailed description of the antibacterial adhesion. While the first self-adhesive restorer
potential of CPC in the oral environment can be found in the literature. Omposites have been on the market for several years, but
4,76,92 The FDA approved CPC as an over-the-counter their documented inferior performance in both laboratory and
drug and for use in oral hygiene aids such as clinical research114,156 did not lead to a real breakthrough. Self-
mouthwashes and toothpastes.159 When CPC was adhesive fluid composites were developed for the first time.
incorporated into the bonding resin in an earlier According to the manufacturer's instructions, the first
study,131 the antibacterial effect appeared to be commercially available self-adhesive flowable composite,

confined to the area in direct contact with the resin. Vertise Flow (Kerr), did not require any etching or acid bonding

To induce CPC release, CPC was incorporated into protocol prior to application. Vertise Flow (Kerr) combines

poly(2-hydroxyethyl methacrylate)/trimethylolpropane phosphoric acid ester ethacrylate with GPDM as

trimethacrylate hydrogels.8 Such hydrogels could be functional monomers. Rahimian-Imam et al.61 reported that

recharged with CPC, but the CPC release remained this self-adhesive fluid flap exhibited less microleakage than
conventional fissure flaps. However, when used as a sealant
relatively short; furthermore, increased water uptake
in a split-mouth linical test, the retention rates of the self-
was reported as another drawback. To overcome this
adhesive flowable composite were significantly lower
deficiency, another promising strategy is to load CPC
compared to those of three conventional flowable composites
into an inorganic compound to release CPC in a
bonded with an adhesive.1 After 24 months, the retention rate
controlled manner, as studied before when CPC was
of the self-adhesive composite was only 62.9%. 1 Another self-
incorporated into montmorillonite (Mont) clay,4 termed
adhesive restorative material remained in the experimental
“CPC_Mont”. In addition to the launch of CPC, this
phase and not marketed. 6 However, the self-adhesive
CPC_Mont technology is considered to have
essence of this
rechargeability of
Experimental restorative material for enamel and dentin
CPC. A recent study demonstrated that CPC can be
was hypothetically attributed to a form of nano-interaction,
effectively inserted into Mont and can also be
related to its relatively high pH (>2.0) and viscosity (compared
reloaded with CPC.104 The addition of 1 or 3% by
to conventional adhesive solutions).
weight of CPC_Mont in a 1-step SEa conferred
antibacterial properties to the adhesive without Different companies are developing and marketing
reducing its binding potential or increasing its new self-adhesive dental restoratives, such as the so-
cytotoxicity.104 called hybrid adhesive restorative elf (mass filling)
Surefil One (Dentsply Sirona) (Fig. 15).
(14) Continuous evolution towards SELF-
When producing self-adhesive restoratives, some
ADHESIVE RESTAURANTS
companies (first) target developing countries and position their
A further simplification involves the development of
new product on the dental market as an amalgam replacement

34 The Journal of Adhesive Dentistry

 Van Meerbeek et al.

material, partly also in response to the global initiative of the

United Nations Environment Programme (UNEP) to reduce
mercury consumption. Although UNEP has questioned the
environmental safety of amalgam, amalgam in fact remains
the posterior restorative material of choice in any developing
country, where access to modern and more expensive
aesthetic dental composites is difficult.

Vol 22, No 1, 2020 35

Van Meerbeek et al.

Specially developed for these markets, these self- bioactive interaction with the surrounding dental
adhesive lining materials can nevertheless be a tissue is highly questionable, as the material will
cost-effective substitute for amalgam with a much no longer come into direct contact with the dental
better aesthetic result. They are usually indicated tissue. Fortunately, the company adapted the
to be placed in bulk, like amalgam, without any material's instructions for use, now instructing not
additional bond-promoting media in retention only to engrave, but also to apply an adhesive of
"amalgam" cavities, while a separate pre-etch or your choice.
adhesive application step is
9.
recommended to restore teeth that do not
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