10-MDP Based Dental Adhesives: Adhesive Interface Characterization and Adhesive Stability—A Systematic Review

The incorporation of functional monomers in dental adhesive systems promotes chemical interaction with dental substrates, resulting in higher adhesion forces when compared to micromechanical adhesion only. The 10-MDP monomer, whose chemical structure allows for a polar behavior which is favorable to adhesion, also promotes the protection of collagen fibers through the formation of MDP-calcium salts. This systematic review aimed to characterize the interface created by 10-MDP containing adhesive systems through an evaluation of the following parameters: Formation of nano-layered structures, capacity to produce an acid-base resistant zone, and adhesion stability. The research was conducted using PubMed, Cochrane Library, Web of Science and Embase, limited to English, Spanish, and Portuguese articles. The research was done according to the PICO strategy. The 10-MDP monomer has the capacity to produce an acid-base resistant zone on the adhesive interface, which increases the response to acid-base challenges. The adhesion established by these systems is stable over time. To have the best of these adhesive solutions, a scrubbing technique must be used to apply the adhesive system on dental substrates, in order to improve monomers infiltration and to create a stable bond. Time must be given for the solution to infiltrate, hybridize and form the MDP-Ca, improving adhesive stability.


Introduction
The procedures for performing a resin composite restoration include enamel etching, dentin conditioning, dentin priming and application of a dentin bonding agent, prior to the resin composite filling. However, since the introduction of adhesive resin-based restoration procedures, dental adhesives have been remarkably improved, and most commercially available adhesive systems have

Materials and Methods
The protocol used for this systematic review followed the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [17].
The research strategy of the present work was formulated according to PICO (Problem, Intervention, Comparison, Outcome) as seen in Table 1. Capacity to create an acid-base resistant zone (ABRZ). Formation of nano-layered structures. Adhesive stability.

Search Strategy
A literature search was conducted in the Pubmed, Cochrane Library, Web of Science and Embase databases, using the search formulas described in Table 2. Only articles in English, Spanish or Portuguese, published until January 2019 were included. Table 2. Research strategy used.

Inclusion and Exclusion Criteria
The inclusion and exclusion criteria for selection and extraction of data are described in Table 3. According to the predetermined inclusion and exclusion criteria, all titles and abstracts were examined by one reviewer (M.C.) in order to find relevant studies; the full texts of the relevant studies were scrutinized by two reviewers (M.C. and E.C.) independently to select eligible studies on the outcomes described in the PICO strategy. Any disagreement was discussed, and the opinion of a third reviewer (A.S.C.) was sought if necessary.
Studies on commercially available adhesive systems were included in order to understand the 10-MDP performance compared to other functional monomers. Studies on specific formulations, where several groups were formed, varying on the concentrations of their components, were also included so that the mechanism of each one could be described or highlighted.
For each proposed outcome and included study, descriptive and quantitative information was extracted, including authors, year of publication, control and test groups, results (quantitative and qualitative) and relevant conclusions.
Due to the disparity of methodology, it was not possible to perform a quantitative analysis (meta-analysis).

Results
The initial search resulted in 1383 references: 274 from PubMed, 9 from Cochrane Library, 711 from Web of Science and 389 from Embase.
After evaluating titles and abstracts, 212 relevant studies were obtained. After full-text analysis, 72 references were included in this systematic review ( Figure 1).

Results
The initial search resulted in 1383 references: 274 from PubMed, 9 from Cochrane Library, 711 from Web of Science and 389 from Embase.
After evaluating titles and abstracts, 212 relevant studies were obtained. After full-text analysis, 72 references were included in this systematic review ( Figure 1). The key characteristics evaluated were: • Formation of nano-layered structures (MDP-Ca salts)-Formation/absence of nano-layered structures and morphology (Table 4); • Acid-base resistant zone (ABRZ)-Formation or absence of ABRZ, thickness, and differences between dentin ABRZ and enamel ABRZ (Table 5); • Adhesive stability-Measurement of adhesion forces (Table 6).

Author, Year Groups Results
Na Dentin ABRZ thickness: T1* > T2 > T3; Enamel ABRZ is very thin, compared to dentin ABRZ; Enamel ABRZ thickness < 0.5 µm in all groups but for T1* it appeared to be thicker. Dentin ABRZ formed under the hybrid layer, while enamel ABRZ was created along the interface between adhesive and enamel; ABRZ was confirmed at both enamel and dentin; it was influenced by the functional monomer contained in the adhesive system; Funnel-shaped erosion found at bonding interface between enamel and outer lesion in T3.  Long-term durability of the dentin-adhesive interface of two-step self-etching adhesives differed, depending on the particular adhesive; T1* showed no signs of degradation in bond strength and interfacial ultrastructure. 1%) compared to T1 (9.2%); T1*: blank outline of the enamel prisms; dentinal tubes were widened, with deposits on the intertubular dentin, without exposure of collagen fibrils; T2*: typical etching pattern on enamel; dentinal tubes were more widened and blocked by precipitates, with collagen fibrils exposed; conditioning of enamel and dentin allowed enhancement in the initial BS (p < 0.05); a reduction was observed in conditioned dentin after 20,000 thermocycles.
Superior BS of T2* correlated to the demineralized amount of tooth apatite by 10-MDP; Unreacted 10-MDP polymer within the adhesive layer did not ↓ the bond strength, despite application of 20,000 thermocycles. Dentin cohesive failure was found to be lower in the µSBt of T1 at 24 h; µSBt results in divergency of behavior between systems, not seen with SBt; Formation of monomer-Ca salts and initial BS were influenced by the length and hydrophilicity of the spacer chain of functional monomers. -37.2 mg/g: ↓ dentin BS during thermocycling; -57.9 mg/g: difference in dentin BS before and after thermocycling (p < 0.05); -57.9 mg/g: dentin exhibited more changes in the surface morphology than enamel and in the type of fracture mode during thermocycling; ↑ of MDP-Ca salts changed the morphology of the fractured enamel surface and ↑ the number of specimens that had less than half of the adhesive remaining at the enamel or dentin surface. Three 10-MDP molecules by different companies: T1*: 83% purity T2*: 90% purity T3*: ↑% than T1 and T2 T1*: µTBS did not ↓ after 100,000 thermocycles, contrarily to T1* and T2*; T3*: ↑Immediate µTBS than T1*, T2*; No pre-testing failure recorded for T3*, but several failures happened with the "aged specimens" of T1* and T2*.
Differences in the ultrastructure of the hybrid layer were observed between the different monomers used.  TF-XRD: T1* and T2* revealed production of 10-MDP-Ca salts; T2*: slightly shifted and ↓intensity; no detected peaks in T3 and T4; SEM: T1*, T2*: after ethanol rinsing most of the adhesive was retained; T4: smear debris remained; T3: all of the hybrid layer was removed; T1* and T2* µTBS stable before and after thermocycling (p > 0.05); Dentin µTBS: T2* and T3 ↑ than T1* and T4 at 24 h; T4 ↓ after thermocycling and T3 after aging; NL: T1 and T2-slight ↑ impregnation after thermocycling; T3 and T4: ↑ infiltration after thermocycling and in many cases the entire length of the hybrid layer was infiltrated.
Differences in T1* and T2* for TF-XRD analysis are related to the ratio of 10-MDP contained in each formulation; T2* and T3 gained ↑ bonding strength even after aging than the traditional T1* and T4, although T3 showed ↑ NL after thermocycling.

Discussion
Self-etch and universal adhesive systems were introduced in dentistry to reduce and facilitate the clinical application of these biomaterials, by overcoming some etch-and-rinse disadvantages such as a greater number of steps, longer application time, technique sensitivity and difficulty in controlling dentin wetness [40]. However, these adhesion strategies work less favorably with enamel, as acid etching is not necessary in order to demineralize collagen fibrils. In etch-and-rinse adhesives that step might lead to several micrometers depth of demineralized substrate, especially in dentin, which is not completely hybridized by the bond solution of those systems, promoting degradation, a process initiated by nanoleakage [41]. In mild and ultra-mild self-etch adhesive systems, the abundant presence of hydroxyapatite remaining around the collagen fibrils provides natural protection to the collagen and allows the functional monomers to potentially interact with the substrate. Typical resin tags will only be formed when using strong self-etching adhesives. The potential interaction of self-etch adhesives depends on the surface-preparation method [41][42][43].
Functional monomers are not the only components in adhesive systems formulations so the clinical protocol for self-etching adhesives application cannot be the same for all the commercial systems: different solvents may require changes in the protocols (time, application, . . . ) for better results. Active application of adhesives using a scrubbing technique promotes solvent evaporation, leading to the impregnation of a higher rate of monomers inside the smear layer, thus improving adhesive-interface quality. Solvent evaporation is also dependent on substrate characteristics (orientation of dentin surfaces) and on the uniformity of the adhesive layers. Long-term retention is achieved with high-quality chemical interaction between the adhesive and the substrate, through the formation of a hybrid layer, characterized as a three-dimensional collagen-resin biopolymer that provides a continuous and stable link between the adhesive and the dentin substrate; micromechanical retention may be additionally present when pre-etching the enamel or when using strong self-etching adhesive systems [27,34,43,44]. When talking about adhesive systems, interaction with collagen is probably the most important aspect, since the deterioration of collagen fibrils within the hybrid layer compromises the long-term stability of dentin bonding; the chemical properties of functional monomers are thought to account for the high bond strength with dentin [45].
Self-assembled nano-layered structures have been identified through adhesive interfaces of commercial self-etch and universal adhesive systems, both on enamel and dentin. These structures, which are typical of the 10-MDP monomer, are thought to produce a better water-stable interface which is favorable to adhesion, and may justify the higher adhesive stability of 10-MDP containing adhesive systems, along with the stable MDP-Ca salts [18][19][20]46]. Although nano-layered structures (which can be identified when 10-MDP based adhesives are used) are thought to play an important role in the adhesive stability bond strength, some doubts remain on the actual role of these structures. In fact, nano-layering cannot be responsible for durability of resin-dentin bond since it was not identified through all of the adhesive interfaces of the commercially available adhesive systems. These structures contribute to a higher resistance to biodegradation and to the longevity of the bond by enhancing the immediate performance of the adhesive systems [6,19,47,48].
Functional monomers give adhesive systems formulations the capacity to interact with dental substrates. However, functional monomers may decrease the degree of conversion of camphoroquinone/amine-curing adhesives; this decrease is monomer-dependent, meaning that a different degree of conversion was observed depending on the incorporated monomer and concentration used, but was reduced by simultaneous interaction of the functional monomer with hydroxyapatite [23,49,50]. Also, functional monomers are partially responsible for the hydrophobic/hydrophilic behavior of bonding resins [23,28,30]. Though more hydrophilic spacer carbon chain induces more water sorption and better dentin wettability, more hydrophobic functional monomers (MDP) are more suitable in order to avoid the effects of hydrolytic degradation [21,49,51].
Nanoleakage corresponds to defects at the resin-dentin interface from hydrolytic degradation, which may serve as pathways for degradation; double application self-etch adhesives may contribute to the durability of the bond by building a less permeable layer [33]. Also, applying the adhesive by employing a scrubbing technique enhances resin monomer infiltration of dentin, water chasing on the dentin surface and smear layer dissolution, improving the quality of the adhesive interface, especially on mild self-etching adhesive systems [34].
The 10-MDP monomer has a proven potential to interact with hydroxyapatite; the bond produced by 10-MDP containing adhesives appears to be very stable, as confirmed by the low dissolution rate of its calcium salts in water. Etching capacities are related to the substrate where it is applied, to the incorporated monomer and to the bonding potential of other commonly used functional monomers (4-META, phenyl-P). At different degrees the bonding potential is substantially low, or produces bonds which are not hydrolytically stable [52]. However, adhesion differentials between commercial adhesive systems are noticed depending both on the dental substrate and on other components included in the adhesives formulations. Some universal adhesives were found to produce poor adhesive interfaces by being less 10-MDP concentrated which suggests that an optimal concentration and purity of 10-MDP in self-etch and universal adhesives may exist so the maximum potential of this functional monomer is achieved [5,8,11,12,53].
The 10-MDP monomer has a long and hydrophobic spacer chain and creates a rich MDP-Ca salt adhesive interface, which improves adhesion strength, remaining stable after one year of water-storage [13,15,31,45,54]. Although all the advantages of this monomer, application protocols are crucial (substrate, time and technique) [34,55,56]. The application of an extra hydrophobic layer when using one-step self-etching or universal adhesive systems may improve the adhesive interface (in terms of durability and of resistance to degradation) and increase the long-term retention of restorative materials [57]. When using one bottle, self-etching or universal adhesive systems enamel etching may be recommended since these adhesive systems tend to have higher pH values, which lowers the ability to etch the enamel [58,59].
However, MDP-Ca salts were found to depend on the components that constitute commercial adhesives more strongly than on the concentrations of MDP and water in the adhesive [60]. Water concentration in adhesive systems was found to affect the efficacy of smear layer removal, and dentin bonding performance more strongly than the pH value of the adhesives [61,62] and ethanol was found to limit the dissociation of phosphate groups from the 10-MDP monomer [8]. 4-META was found to enhance both enamel and dentin bond-strengths more effectively than HEMA [63]. Although HEMA tends to improve bond strength, HEMA-free adhesives are preferred because of its hydrophilicity; on the other hand, HEMA brings solvents back into solution [1,54,64]; also, MDP-HEMA aggregates were found to compromise the MDP-collagen interaction leaving collagen fibrils unprotected by MDP and HEMA [21,[65][66][67]. Other components may compete for calcium against 10-MDP, such as zinc ions [68]. Calcium hydroxide was found to improve the degree of conversion without interfering with bond strength to dentin, or the extent of nanoleakage [69].
Adhesive systems containing 10-MDP have a proven interest. However, it is important not to forget, when using strong self-etching adhesive systems, that the adhesive solution may penetrate into dentinal tubules and reach the pulp, especially when restoring deep cavities. Current studies on cytotoxicity lack a complete understanding of the effect of these materials on the pulp, because it is difficult to mimic the clinical conditions of its application. Some studies have reported that minimally toxic concentrations of 10-MDP promoted an inflammatory response and suppressed odontoblastic differentiation of dental pulp cells [70,71]. Also, chemical properties of MDP-containing adhesives alter during storage because MDP hydrolysis leads to acidification of the adhesive solutions [72,73].

Conclusions
When selecting a functional monomer or adhesive system, 10-MDP monomer appears to be a safe choice because of its molecular structure which is favorable to adhesion, its hydrophobic behavior and characteristic adhesive interface which favors bond durability and strength.
10-MDP containing dental adhesives are biomaterials which can establish strong and durable adhesive interfaces. Although 10-MDP has a proven capacity to interact with hydroxyapatite, some clinical steps of application of these adhesives are crucial for the resultant bond interface.
To have the best of these adhesive solutions, selective enamel etching and a scrubbing technique must be used to apply the adhesive system on dental substrates, in order to improve monomers infiltration and to create a stable bond. Time must be given for the solution to infiltrate, hybridize and form the MDP-Ca, protecting collagen fibrils and improving adhesive stability.
Funding: This research received no external funding