Journal of Adhesion Science and Technology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tast20

Current modifications of dental adhesive systems

for composite resin restorations: a review in
literature

Dimitrios Dionysopoulos, Olga Gerasimidou & Constantinos Papadopoulos

To cite this article: Dimitrios Dionysopoulos, Olga Gerasimidou & Constantinos Papadopoulos
(2021): Current modifications of dental adhesive systems for composite resin restorations: a review
in literature, Journal of Adhesion Science and Technology, DOI: 10.1080/01694243.2021.1924499

To link to this article: https://doi.org/10.1080/01694243.2021.1924499

Published online: 12 May 2021.

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JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY
https://doi.org/10.1080/01694243.2021.1924499

Current modifications of dental adhesive systems for

composite resin restorations: a review in literature
Dimitrios Dionysopoulos , Olga Gerasimidou and
Constantinos Papadopoulos
Department of Operative Dentistry, Faculty of Dentistry, School of Health Sciences, Aristotle
University of Thessaloniki, Thessaloniki, Greece

ABSTRACT ARTICLE HISTORY

Currently, dental caries is prevalent all around the world and Received 2 March 2021
composite resins are widely used as restorative materials for its Revised 23 April 2021
treatment. Adhesion of composite resins to tooth tissues is Accepted 27 April 2021
achieved using a variety of dental adhesive systems and is crucial
KEYWORDS
for the survival of composite resin restorations. Adhesive dentistry Dental adhesive systems;
began in 1955 by Buonocore and up to date developing technol- composite resin
ogy led to evolution of adhesive strategies from no-etch to total restorations; antibacterial
etch (4th and 5th generation) and to self-etch (6th, 7th and 8th activity; remineralizing
generation) adhesive systems. Although adhesive agents allow a agents; anti-
more conservative restorative approach, achieving durable bond enzymatic activity
strength remains a matter of concern mainly due to degradation
of the resin-dentin interface in the challenging oral environment.
Endogenous collagenolytic enzymes, matrix metalloproteinases
and cystein cathepsins are responsible for the time-dependent
degradation of hybrid layer collagen. Additionally, bacterial
enzymes, metabolites and oral fluids can penetrate into the resin-
dentin interface and may be involved in the degradation of the
hybrid layer. Various modifications have been suggested to
develop adhesive systems with particular functions to tackle these
problems such as incorporation of matrix metalloproteinase inhib-
itors, antibacterial and remineralizing agents into adhesive sys-
tems, as well as improvement of their mechanical and chemical
properties. This literature review focuses on the principles, current
status and future of the different techniques and materials
designed to prevent the degradation of hybrid layer and bond
strength of composite resin restorations.

Introduction
The development of adhesive dentistry has significantly changed the design and techni-
ques of tooth cavity preparation and restoration. Cavity preparations no longer require
retaining grooves or clear internal dihedral angles for mechanical retention of restora-
tions, thus saving significant healthy tooth tissues during preparation following the

CONTACT Dimitrios Dionysopoulos ddionys@dent.auth.gr Department of Operative Dentistry, Aristotle

University of Thessaloniki, Thessaloniki 54124, Greece
ß 2021 Informa UK Limited, trading as Taylor & Francis Group
2 D. DIONYSOPOULOS ET AL.

principles of Biomimetic Dentistry. One of the most important advantages of using

dental adhesive systems is the reduction of microleakage of restorations, which may
lead to the formation of secondary caries. Despite the use of dental adhesives and new
composite restorative materials, the longevity of tooth restorations is not enough satis-
factory. In a recent study it has been demonstrated that failure rate of tooth restora-
tions reaches to 15–20% after 12 years and the most common reasons of failure include
secondary caries, marginal fractures and defects, wear and post-operative sensitiv-
ity [1,2].
It is well known that the bond of composite resins to dentin is weaker than to
enamel due to the heterogeneous structure and composition of dentin. Indeed, while
enamel presents a hard crystalline structure with high surface energy and is composed
mainly of hydroxyapatite (HAp) crystals that form enamel prisms, dentin is composed
of collagen and hydroxyapatite, is less mineralized and has lower surface energy.
Additionally, dentin substrate after cavity preparation is covered with smear layer, has
collagen matrix and presence of dentinal tubules, which contain dentinal fluid [3].
Adhesion failure of the composite resins to dental tissues may result in microleak-
age, discoloration, secondary caries and post-operative sensitivity [4]. This condition
can accelerate the degradation of interface components and lead finally to failure of
the tooth restoration. As a matter of fact, contemporary research is focused on the
development of novel dental adhesive systems by applying various modifications on
their composition [5,6]. There are many studies that have tried to address the origin of
resin-dentin bond failure in order to achieve a stronger and more stable bond.
Therefore, the purpose of this literature review was to describe the problems regarding
the use of dental adhesives and to present the modifications that have been proposed
to improve the longevity of composite resin restorations.

Factors associated with failure of composite resin restorations

Failure of resin-dentin bond and consequently of the composite resin restorations is
mainly attributed to degradation of the collagen matrix by proteolytic enzymes, such as
matrix metalloproteinases (MMPs) and hydrolytic enzymes, such as cysteine cathe-
psins. Other factors associated with failure of composite restorations are enzymatic
hydrolysis of the resins, microleakage and pulpal reaction to the chemicals derived by
the adhesive systems [2,3].

Degradation of the resin-dentin interface by enzymes

Hybrid layer formation between the dental adhesive and the dentin is crucial for the
survival of composite resin restorations [7]. Hybrid layer is formed in two steps: 1) the
first step includes etching of the dentinal surface usually with phosphoric acid
(35–37%) for 15 sec (etch-and-rinse adhesive systems), which removes calcium phos-
phates leading to formation of micropores on dentin substrate and exposure of the col-
lagen scaffold, and 2) the second step involves penetration of the adhesive monomers
into the exposed network of collagen fibrils providing micromechanical retention.
These monomers, which contain both hydrophilic and hydrophobic groups, penetrate
 JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY 3

into the forming micropores of dentin and are stabilized by photopolymerization

induced by a dental light-curing unit [8]. Durability of the forming bond demands add-
itional chemical bonds between the functional groups of the adhesive monomers and
the remnant hydroxyapatite of dentin [9]. However, the formation of chemical bonds
is difficult to take place since there is only a weak affinity between the functional
groups of the monomers and the hydroxyapatite of depleted collagen [10].
As it was mentioned before, hybrid zone is formed at the resin-dentin interface and
contributes significantly to bond strength [7,11]. Degradation of the collagen matrix by
MMPs and cysteine cathepsins is considered to be one of the most important factors of
failure of composite resin restorations [12–15]. MMPs are a group of 23 mammalian
enzymes capable of degrading all extracellular matrix components. Human dentin
matrix contains at least MMP-2 and MMP-9 (gelatinolytic activity), MMP-8 (collage-
nolytic activity), and enamelysin MMP-20 [16–18]. The incomplete infiltration of colla-
gen fibers by the adhesive agent result to exposure of the fibers and to collagenolytic
activity of MMPs, which may be activated by low pH values during the etching of den-
tin [19]. As a consequence, the hybrid layer degenerates and bond strength gradually
weakens [20]. MMPs are synthesized by dentinoblasts, encapsulated in dentin matrix
and can attack type I collagen, which is the main structural component of dentin [12].
These enzymes can be activated by proteinases, chemical agents, low pH, heating,
cariogenic bacteria, as well as by mechanical stimuli [15,21,22].
The cysteine cathepsins are members of the family of papain-like cysteine proteases.
They have unique reactive-site properties and an uneven tissue-specific expression pat-
tern. Their activity includes targeting, zymogen activation, inhibition by protein inhibi-
tors and degradation [23]. There are 11 human cysteine cathepsins (B, C, F, H, K, L, O,
S, V, X and W), existing at the sequence level according to bioinformatic analysis of
the draft sequence of the human genome [24]. Lysosomal cathepsins require a slightly
acidic environment in order to be optimally active. Thus, cysteine cathepsins were ini-
tially considered as intracellular enzymes, responsible for non-specific, bulk proteolysis
in the acidic environment of the endosomal/lysosomal compartment, where they
degrade intracellular and extracellular proteins [25].
The enzymes may also cause decomposition of the resinous parts of the adhesives. It
has been found that hydrolysis of hydrophilic monomers can reduce the resin-dentin
bond strength [13,26–28]. The flow of fluids through the dentin tubules at the restor-
ation interface may induce hydrolysis of the resin tugs and thus, may reduce the sealing
capacity of the adhesives [27]. Furthermore, the methacrylates of the adhesives, which
contain ester bonds, may also undergo chemical or enzymatic hydrolysis [29].
Considering that saliva contains a variety of cholesterol esterases and pseudocholines-
terases that can promote degradation of dimethacrylates, the integrity of the resin-
dentin bond in this aggressive environment is doubtful [28,30].

Microleakage and pulp irritation

When the composite resin is detached from cavity walls due to polymerization shrink-
age and creation of high shrinkage stresses, marginal gaps are formed at the interface
resulting in microleakage, secondary caries and eventually pulp irritation [31–34].
4 D. DIONYSOPOULOS ET AL.

Moreover, masticatory forces induce mechanical stress on the interface resulting in the
distortion of the collagen of hybrid zone and adhesive agent which leads to increased
microleakage [12,35]. As a result, bacteria, oral fluids, microbial enzymes and metabo-
lites can easier penetrate the margins of the restorations causing degradation of the
hybrid zone [32,34]. It has been found that microbial collagenases are able to increase
nanoleakage into the hybrid zone, reducing the resin-dentin bond strength [30].
Application of cavity disinfectants before restorations cannot completely eliminate
microorganisms in the prepared cavity and they do not offer long-term antimicrobial
activity, so the remaining bacteria may lead to caries formation and pulp irritation
[32,36–38]. Pulp irritation is a major reason of failure of composite restorations.
Factors affecting pulp reaction may include trauma of dentin during preparation of
cavity, as well as toxicity of the released components of the composite material [34].
According to previous studies regarding biocompatibility of adhesive systems, their
resin components such as monomers and comonomers may potentially cause pulp tox-
icity [34,38,39]. Resin monomers such as bis-phenol glycidyl methacrylate (Bis-GMA),
triethylene glycol dimethacrylate (TEGDMA), and hydroxyethyl methacrylate (HEMA)
are the most toxic components of the adhesives [39,40]. Their toxic effect depends on
the amount of their release, the permeability of dentin and the duration of their contact
with the pulp tissue [34,39]. These monomers can also damage the regenerative and
restorative properties of the dentino-pulpal complex [41].

Development and evolution of dental adhesive systems

The first attempt to develop adhesive systems for resin-dentin bonding was in the early
1950s and since now eight generations of adhesive systems have been introduced in
dentistry (Table 1) [42,43]. Nowadays, the first three generations are no longer in use.

Table 1. The generations of the dental adhesive systems [42–45].

Date of
Generation introduction Composition Adhesive strategy Steps Smear layer
1st 1950s HCl þ GPDM No more in use 2 (etching/bonding) Remains
2nd Early 1980s Bis-GMA, HEMA No more in use 1 (bonding) Remains
3rd Late 1980s Acid or chelating No more in use 2 (etching/bonding) Partially removed
agent þ PMDM,
NPG-GMA
4th Early 1990s H3PO4 þ primer þ Etch-and-rinse 3 (etching/priming/bonding) Removed
Bis-GMA, HEMA (total-etch)
5th Late 1990s H3PO4 þ primer þ Etch-and-rinse 2 (etching/priming þ bonding) Removed
Bis-GMA, HEMA (total-etch)
6th Early 2000s 4-MET, 10-MDP þ Self-etch 1 or 2 (etching þ priming/bonding) Remains
Bis-GMA, HEMA
7th 2000s 4-MET, 10-MDP þ Self-etch 1 (etching þ priming Remains
Bis-GMA, HEMA (all-in-one) þbonding)
8th Early 2010s 4-MET, 10-MDP þ Self-etch 1 (etching þ priming Remains
Bis-GMA, (all-in-one) þbonding)
HEMA þ Nano-fillers
Universal Early 2010s Hydrophilic, hydrophobic 1. Etch-and-rinse 1. Etching/priming þ bonding Removed
and neutral monomers 2. Selective-etch 2. Enamel etching/dentin or
3. Self-etch etching þ priming þ bonding Remains
3. Etching þ priming þ bonding
Bis-GMA: bis-phenol glycidyl methacrylate, GPDM: glycerophosphoric dimethacrylate.
HEMA: hydroxyethyl methacrylate, 10-MDP: 10-methacryloyloxydecyl dihydrogenphosphate.
4-MET: 4-methacryloyloxyethyl trimellitic acid, NPG-GMA: N-phenylglycine glycidyl methacrylate, PMDM: pyromellitic
diethylmethacrylate.
 JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY 5

Modern adhesives tend to simplify the bonding steps in order to make them friendlier
for the dental clinician [44].
First-generation adhesives were introduced in a publication by Buonocore in 1956,
which indicated that a resin containing glycerophosphoric dimethacrylate (GPDM)
could bond to etched dentin by hydrochloric acid [46]. Although the bond strength to
dentin was very low (2–3 MPa), this study laid the foundations of adhesive restorations
and adhesive dentistry [43].
The 2nd generation of dental adhesives was developed in the early 1980s and consisted
mainly of phosphomethacrylate esters without reinforcing fillers, such as Bis-GMA and
HEMA. They exhibited improved wettability on the surface of dentin and were able to
form ionic bonds with calcium (Ca) of the smear layer. Nevertheless, the low stability
and mechanical strength of smear layer resulted in many cohesive bond failures [43].
The 3rd generation appeared in the late 1980s and was characterized by the effort to
remove or modify the smear layer of the dentin surface using acidic conditioners or
chelating agents. The bonding agent was usually a solution of pyromellitic diethylme-
thacrylate (PMDM) and N-phenylglycine glycidyl methacrylate (NPG-GMA). This gen-
eration improved the resin-dentin bond strength compared to the adhesives of the
previous generation [43].
The 4th generation of dental adhesives introduced the idea of total-etch technique,
which significantly improved the adhesion of composite restorations to enamel and
dentin [43,45]. This technique includes three steps; etching, priming and bonding. In
the first step, an etching agent (usually 37% phosphoric acid) is applied to dentin for
15 sec and removes smear layer, as well as demineralizes the peritubular and intratubu-
lar dentin for better penetration of the bonding agent. However, this demineralization
leads to collapsing of collagen fibrils. For this reason, application of a primer follows
containing one or more hydrophilic monomers, which afford two active groups; a
hydrophilic and a hydrophobic. The hydrophilic groups are oriented to dentin, rehy-
drate collagen fibrils and increase surface energy and wettability of dentin surface,
while the hydrophobic groups are oriented to resin monomers of the bonding agent.
Subsequently, the resin bonding agent penetrates the network of the collagen fibers of
the dentin and creates a micromechanical bond (20 MPa). As a result, a hybrid zone
is formed, which is the main mechanism of adhesion between resin and dentin [43,45].
In 5th generation adhesive systems the total-etch technique was simplified in two
steps for time saving and convenience of the dentist, by combining primer and bond-
ing agent in one application [4,32,36]. Although described as single-step adhesive sys-
tems, they require separate step for etching of the enamel and dentin and some of
them require multiple applications of the adhesive agent. Despite the fact that this gen-
eration of adhesives achieves similar values of bond strength compared to 4th gener-
ation, they exhibit decreased bond longevity [43].
Sixth generation adhesive systems were introduced in the early 2000s and are known
as self-etch adhesives. The primer and conditioner consisting of acid-modified mono-
mers are in one bottle, while the bonding resin is separately in another. This type of
acid-modified monomers includes 4-methacryloyloxyethyl trimellitic acid (4-MET) and
10-methacryloyloxydecyl dihydrogenphosphate (10-MDP). Clinical application is
implemented in one or two-step techniques; in one-step, the primer-conditioner is
6 D. DIONYSOPOULOS ET AL.

Table 2. Classification of the modern adhesive systems according to their adhesive strat-
egy [42,54].
Adhesive strategy Number of steps Clinical procedure
Etch-and-rinse 3 Etching / priming / bonding
2 Etching / priming þ bonding
Self-etch 2 Etching þ priming / bonding
1 Etching þ priming þ bonding
Universal 2 (etch-and-rinse) Etching / priming þ bonding
1 (self-etch) Etching þ priming þ bonding
2 (selective-etch) Enamel etching / dentin etching þ priming þ bonding
Glass ionomer 2 Conditioning þ bonding

initially applied followed by the bonding resin in separate stages, while in two-step
technique the components of the two bottles are mixed before application in one step.
The main difference of self-etch adhesives in comparison with 4th and 5th generation
is that the smear layer is not removed because there is no rinsing, but the resin mono-
mers infiltrate smear layer and integrate it in the hybrid zone [44].
Similarly, 7th generation adhesive systems which were introduced in 2000s, are sin-
gle bottle self-etch adhesive systems with all the components required for etching, pri-
ming and bonding in a single bottle (all-in-one) [30,44]. In spite of the easier handling
and time saving that the dental practitioner gains, this type of adhesives have presented
lower bond strength than that of 4th and 5th generations’ [30].
In 2010, Voco Company introduced 8th generation adhesive systems which contain
nano-fillers and belongs to self-etch adhesive systems [42]. The addition of nano-fillers
with average size of 12 nm increases the penetration of the monomers and the range of
the hybrid zone and improves their mechanical properties [47,48]. It also increases
bond strength with enamel and dentin, absorption of stresses and longevity of the
resin-dentin bond [49].
One of the most recent innovations (2011) in adhesive dentistry is the introduction
of the Universal adhesive systems. They are known as multi-purpose adhesive systems,
because they can be used for etch-and-rinse, self-etch and selective-etch adhesive strat-
egies [50,51]. Selective-etch technique regards separate etching of the enamel of the
cavity before the application of the Universal adhesive all over the prepared cavity.
These adhesives contain monomers which are hydrophilic, hydrophobic and neutral in
a single bottle. It has been demonstrated that this combination forms a sufficient bond
between the hydrophilic surface of the tooth tissues and the hydrophobic surface of
composite resins [52,53].
Nowadays, in order to simplify the classification of dental adhesive systems it has
been proposed to categorize them according to the adhesive strategies that are applied
in clinical practice (Table 2). In particular, the dental adhesive systems are classified in
three main categories: a) etch-and-rinse, b) self-etch and c) glass ionomer [54].

Modifications of dental adhesive systems

To address the failure of composite resin restorations due to microleakage, secondary
caries, degradation of dentinal collagen and hydrolysis of the resin, various modifica-
tions of the dental adhesives systems have been proposed (Table 3). These modifica-
tions aimed to: a) eliminate cariogenic bacteria by incorporating antimicrobial agents,
 JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY 7

Table 3. Modifications of contemporary dental adhesive systems.

Modifications
of adhesives Substances incorporated into adhesive systems
Antimicrobial Chlorhexidine Bioactive Quaternary Hesperidin Doxycyclin Fluorine Zinc
agents glasses ammonium salts compounds
Anti- Chlorhexidine Bioactive Proanthrocyanidine Hesperidin Doxycyclin Copper Zinc
enzymatic glasses
agents
Remineralization Fluorine Bioactive Nano-hydroxyapatite Tricalcium Copper
agents compounds glasses phosphate

b) inhibit collagenolytic activity of enzymes and hydrolysis of resins with addition of

anti-enzymatic agents, and c) reduce demineralization of tooth tissues by incorporating
remineralization agents.

Adhesive systems with antimicrobial agents

Aiming to exhibit antimicrobial activity the addition of various antimicrobial agents in
the composition of the adhesive systems has been suggested. Most of the used anti-
microbial agents are supposed to eliminate the remaining bacteria in the prepared
tooth cavity and to prevent the formation of microbial plaque at the margins of the res-
toration [55]. Such antimicrobial agents that have been added in the composition of
various adhesive systems are i) quaternary ammonium salts, ii) chlorhexidine, iii) hes-
peridin and iv) doxycyclin.

Quaternary ammonium salts (QAS)

Quaternary ammonium salts are used in the food industry due to their low toxicity
and antimicrobial activity [56]. The mechanism of their antimicrobial action is as fol-
lows: QAS molecule is positively charged and when approaches the negatively charged
cell wall of the bacteria causes changes in the electrostatic balance and permeability of
their cell membrane, resulting in cytolysis due to derangement in osmotic pressure
[38,55,57,58]. It has also been claimed that QAS influence the adhesion and growth of
microbes on the tooth tissues, as well as the formation of biofilms [59,60].
Quaternary ammonium compounds with methacrylate monomers (QAMs) also
exhibit antimicrobial activity and can adhere to the negatively charged cysteine chains
of the metalloproteinases, inhibiting their adverse activity. These compounds have also
been found to inhibit the activity of the proteolytic enzymes cathepsins [9,61]. In previ-
ous studies it has been reported long-term antimicrobial activity of adhesives that con-
tained QAMs [38,56,57,62]. Modification of adhesives with 12-methacryloyloxydodecyl
1-pyridiniumbromide (MDPB) did not alter their adhesive properties or change their
handling characteristics [62,63]. These results led to introduction in 2004 of the first
adhesive with antimicrobial properties (Clearfil Protect Bond, Kuraray) [60,62,64].
Another QAM that has been used in adhesive systems is the methacryloxylethylcetyl
ammonium chloride (DMAE-CB), which was incorporated into Single Bond 2 (3 M
ESPE) at a content of 3 wt%. This adhesive system exhibited long-term antimicrobial
properties without losing its adhesive capability [65]. The mechanism of antimicrobial
activity of DMAE-CB has been attributed to its selective action on the function of GTF
8 D. DIONYSOPOULOS ET AL.

gene of the Streptococcus mutans, inhibiting glutan synthesis [59,60]. DMAE-CB has
low toxicity, similar to Bis-GMA and like other QAMs inhibits the action of MMPs
when there is at a content of 0.5–5 wt% [66].
A more recent modification of adhesives with QAM was with dimethylaminodo-
decyl methacrylate (DMADDM), which has very effective antimicrobial properties
[41,57]. Its addition to Clearfil SE Bond (Kuraray) at a content of 5 wt% did not
adversely affect its adhesive properties [67,68]. Moreover, its addition to Scotchbond
MP at the same concentration resulted in a significant reduction in microbial plaque,
microbial metabolic activity and lactic acid production [69]. Previous investigations
regarding cytotoxicity of DMADDM in human gingival fibroblasts reported much less
cytotoxicity than Bis-GMA [61,70].
Quaternary ammonium dimethacrylate (QADM) is another monomer that exhibits
strong antimicrobial properties because its molecule provides active groups at both
ends [71]. It presents low viscosity, so it can be mixed easily with other methacrylates
and has high potential for incorporation of reinforcing fillers without impairing the
handling of the material [71]. Incorporation of 10% QADM into the Scotchbond MP
(3 M ESPE) did not reduce its adhesive properties [38,72]. Furthermore, it has been
demonstrated that the addition of QADM to both primer and bonding resin results in
enhanced antimicrobial activity against the bacteria remained in the dental tubules or
those penetrating the margins of the restorations due to microleakage [72].

Chlorhexidine
Chlorhexidine is widely used in dentistry for its strong and prolonged antimicrobial
activity [73]. It is a cationic bisbiguanide and is able to inhibit the MMPs’ collageno-
lytic activity, improving the longevity of the bond between adhesives and dentin
[22,28]. It has been found that the minimum concentrations that are adequate for this
inhibition are 0.001% for MMP-2, 0.02% for MMP-8, and 0.002% for MMP-9 [74]. It
can also inhibit the activity of cysteine cathepsins and other proteolytic enzymes
[12,73]. When chlorhexidine approaches a MMP molecule, it modifies its structure and
then inhibits its interaction with collagen. Another possible mechanism is the binding
of chlorhexidine to Ca and zinc (Zn) ions of MMPs, resulting in loss of the catalytic
activity of MMPs. In addition, chlorhexidine can be bonded to decalcified dentin,
which is likely to be associated with prolonged inhibitory activity against MMP at
resin-dentin interface [28]. The effect of chlorhexidine on two etch-and-rinse (0.2%)
adhesive systems (XP Bond and Ambar) and one primer (0.1%) of a two-step self-etch
adhesive system (Clearfil SE Bond) have been investigated [13,75]. The results of the
studies indicated that bond strength to dentin was not negatively affected and that
chlorhexidine was gradually released, thereby prolonging its beneficial activ-
ities [76,77].
Chlorhexidine has also been added to etching agents of adhesive systems. In a previ-
ous study, dentin specimens were etched with 37% phosphoric acid gel containing 2%
chlorhexidine prior to bonding with composite resin and after two years of artificial
aging in water, bond strength and microleakage were tested. The results showed that
the addition of chlorhexidine to the etching agent resulted in deceleration of degrad-
ation of the bond with dentin [78].
 JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY 9

Hesperidin
Hesperidin is a flavonoid glycoside obtained from citrus extract with antimicrobial and
remineralizing properties. In particular, Ghorab and Ibraheim [79], who focused on
the antibacterial activity of experimental adhesives containing hesperidin in three dif-
ferent concentrations (0.1, 0.5 and 1%) reported that the adhesive material with 0.5%
hesperidin could achieve a promising antibacterial effect against Streptococcus mutans
without deleterious effects in adhesive properties. Hesperidin has been used experimen-
tally for first time to a modification of Clearfil SE (Kuraray) primer [13]. In a previous
report bovine dentin was submitted to artificial caries challenge using pH-cycling and
the induced demineralization was assessed by micro-radiography. The outcomes of the
study indicated that hesperidin is capable to remineralize superficial and subsurface
lesions [80]. It has also been claimed that the ability of hesperidin to induce remineral-
ization of dentin might be attributed to its interaction with collagen proteins [80]. As a
matter of fact, a stable organic matrix seems to be essential for the remineralization
process, as it supports the deposition of calcium and phosphorus ions and prevent their
further release from tooth tissues [76].

Doxycycline
Doxycycline is a broad-spectrum tetracycline-class antibiotic used in the treatment of
infections caused by bacteria and certain parasites. It can also inhibit the activity of
various cariogenic bacteria such as Streptococcus mutans, Lactobacillus acidophilus
and Actinomyces viscosus [21]. Moreover, it is capable of inhibiting the activity of met-
alloproteinases by binding zinc and calcium ions by chelation [21,80]. In an experi-
mental study, nanotubes containing doxycycline were fabricated and incorporated into
the Scotchbond MP adhesive agent. This adhesive has been shown to demonstrate a
sustained release of doxycycline leading to inhibition of the activity of metalloprotei-
nases and caries formation [81].

Adhesive systems with anti-enzymatic activity

Addition of MMP inhibitors to adhesive systems may provide improved longevity of
composite resin restorations [13,82]. The MMP inhibitors reduce the degradation of
collagen fibers within the hybrid zone by eliminating the endogenous enzymatic activ-
ity. As it was mentioned before, chlorhexidine may present such properties by electro-
statically binding to the negatively charged sides of the MMP molecule, inhibiting the
function of its active side. Furthermore, binding of chlorhexidine to Zn or Ca ions
found in MMP molecule can result in loss of the collagenolytic activity of
MMPs [21,81].
It has been shown that the ability of MMPs to degrade collagen depends on the con-
centration of calcium (Caþ2) and zinc (Znþ2) as well as the Zn/Ca ratio [83]. Zinc is
also known for its antimicrobial properties. Hence, it has been suggested to incorporate
relatively high concentrations of Zn into dental adhesives to decrease collagen degrad-
ation by MMPs [83]. In a previous investigation experimental Zn-doped adhesives pre-
pared by mixing the primer or the bonding agent with 20% ZnO or 2% ZnCl2,
promoted an improved sealing of the resin-dentin interface, a decrease of the hybrid
10 D. DIONYSOPOULOS ET AL.

layer porosity, and an increment of dentin mineralization, without altering physical,

chemical or mechanical properties of the material [84].
Another way of inhibiting the activity of MMPs is to induce conformational changes
in the 3-D structure of the enzyme by specific proteins, thereby inhibiting the molecu-
lar mobility that is important for their enzymatic activity [28,39]. At the same time,
these substances can stabilize the collagen matrix and improve the mechanical proper-
ties of the hybrid zone, thus strengthening the resin-dentin bond [13]. One of these
proteins is proanthrocyanidin, which is derived by grape seed extract and is a natural
collagen crosslinker and inhibits the production and activity of MMP [13,80,85].
Another crosslinker is the aforementioned hesperidin, which is extracted from citrus
[13]. An in vitro study reported that hesperidin, which was added in Clearfil SE primer
(Kuraray), showed improved resin-dentin bond strength, hardness and elasticity of the
interface. On the other hand, addition of grape seed extract had a negative effect on the
bond strength [13]. This is in coincidence with other studies for adhesives containing
grape seed extract, which presented contradictory results [13,85,86].

Adhesive systems containing remineralizing agents

Various fluorine compounds have been added to dental adhesives such as sodium
fluoride (NaF), strontium fluoride (SrF2), fluoro-alumino-silicate glass, cetylamine
hydrofluoride, etc., to protect composite resin restorations from demineralization of
the hybrid zone and formation of secondary caries by releasing fluoride ions [87,88].
The anticariogenic mechanisms of action of fluoride ions include enhance of reminer-
alization, reduction of demineralization and antimicrobial activity [88]. In recent years,
it has been postulated that the rise of pH in hybrid zone may be significantly beneficial
for reduction of demineralization [89]. Thereby, novel adhesive systems have been
introduced, which are able to release alkaline ions, such as Ca and phosphates (PO43)
and neutralize acids [90,91]. These adhesives can enhance remineralization of hydroxy-
apatite crystals in the partially demineralized region of dentin and especially in hybrid
zone [92]. Such compounds that can be used as a source of Ca and PO43 are bioactive
glasses, calcium phosphate and nano-hydroxyapatite (n-HAp), contributing to remin-
eralization by forming and precipitating calcium phosphate salts on the exposed surfa-
ces of dentin [92].
Bioactive glasses are a group of surface reactive glass-ceramic biomaterials. The bio-
compatibility and bioactivity of these glasses has led them to be investigated extensively
for use as implant devices in the human body to repair and replace damaged calcified tis-
sues such as bones and teeth [93,94]. Bioactive glasses, in addition to remineralization
properties can provide antimicrobial activity, which probably attributed to the increased
pH that can be achieved due to continuous release of alkaline Naþ and Kþ ions and are
exchanged with Hþ or H3Oþ ions [95,96]. It is argued that the increase in pH has the
effect of inhibiting the action of MMPs, as they show the highest collagenolytic activity at
pH ¼ 7 [95]. The biological activity of bioactive glasses can be enhanced by synergistic
action with ions such as Zn, Ag, Si, Nb, F and Cu [89,96,97]. It has been found that add-
ition of Nb-containing bioactive glass in adhesives increases their radiopacity without
affecting the bioactive properties, microhardness, adhesive strength and degree of
 JOURNAL OF ADHESION SCIENCE AND TECHNOLOGY 11

conversion [98]. It has also been found that the release of copper (Cu2þ) from an adhesive
which contained nano-bioactive glass can cause inactivation of MMPs and remineraliza-
tion of the resin-dentin interface [99]. Another study reported that addition of amorphous
calcium phosphate nanoparticles to adhesives resulted in a significant increase in release
of Caþ2 and PO43 ions at a low pH environment [58,90,100].
Tricalcium phosphate (TCP) has been used in dental adhesives offering remineraliz-
ing properties. It is a calcium salt of phosphoric acid with the chemical formula
Ca3(PO4)2 and exists as three crystalline polymorphs a, a’, and b. There are differences
in chemical and biological properties between the beta and alpha forms, the alpha form
is more soluble and biodegradeable. Both forms are available commercially and are
present in formulations used in medical and dental applications [101]; a-polymorph is
used in nanoparticles as an additive to adhesives and has been shown to increase bond
strength to dentin [102,103]. Most commercial forms of tricalcium phosphate are in
fact hydroxyapatite. It has been argued that hydroxyapatite nanoparticles when added
to adhesives can cause remineralization in the collagen network [104]. In a previous
in vitro study, it was found that the addition of 7% nano-hydroxyapatite in Scotbond
MP (3 M) increased bond strength to dentin [92]. It is important to note that the adhe-
sives containing remineralizing agents have the property to create new crystalline struc-
tures. These structures entrap MMPs and cathepsins in the demineralized dentin
inhibiting their activity and protecting collagen from degradation [28].

Conclusions
Modern dental adhesive systems used in composite resin restorations tend to simplify
their application to make them more user-friendly to the dental clinician. However,
microleakage, resin-dentin interface degradation and pulpal irritation are still main
concerns of composite resin restoration survival. To address these issues many experi-
mental studies have been implemented, where an attempt was made to modify the
adhesives by incorporating agents which present antimicrobial properties, inhibit the
activity of metalloproteinases and have the capacity of remineralization. Recent
research indicated that the modified adhesives may exhibit improved properties result-
ing in a more stable resin-dentin interface and bond strength. Despite this evidence
more clinical research is needed to confirm the effectiveness of the new modified dental
adhesives and to determine the developmental direction of this technology.

Disclosure statement
No potential conflict of interest was reported by the author(s).

ORCID
Dimitrios Dionysopoulos http://orcid.org/0000-0001-5388-2201
Olga Gerasimidou http://orcid.org/0000-0001-8890-2831
12 D. DIONYSOPOULOS ET AL.

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