Abstract
Objectives
Many recent adhesives on the market exhibit reasonable clinical performance. Future innovations in adhesive materials should therefore seek out novel properties rather than simply modifying existing technologies. It is proposed that adhesive materials that are “bio-active” could contribute to better prognosis of restorative treatments.
Methods
This review examines the recent approaches used to achieve therapeutic polymers for dental adhesives by incorporating bio-active components. A strategy to maintain adhesive restorations is the focus of this paper.
Results
Major trials on therapeutic dental adhesives have looked at adding antibacterial activities or remineralization effects. Applications of antibacterial resin monomers based on quaternary ammonium compounds have received much research attention, and the loading of nano-sized bioactive particles or multiple ion-releasing glass fillers have been perceived as advantageous since they are not expected to influence the mechanical properties of the carrier polymer.
Significance
The therapeutic polymer approaches described here have the potential to provide clinical benefits. However, not many technological applications in this category have been successfully commercialized. Clinical evidence as well as further advancement of these technologies can be a driving force to make these new types of materials clinically available.
1
Incorporation of QAC-based resin monomers
Quaternary ammonium compounds (QACs) are a group of cationic antimicrobials widely used for numerous industrial and pharmaceutical purposes . In 1994, to develop non-agent-releasing antibacterial dental resins, Imazato et al. combined alkylpyridinium, a type of QAC, with a methacrylate group, and successfully synthesized a novel dental resin monomer, 12-methacryloyloxydodecylpyridinium bromide (MDPB) ( Fig. 1 ). While the QAC group is responsible for the antibacterial activity of MDPB, the methacrylate group allows for copolymerization with other conventional monomers. Since antibacterial monomers are immobilized in the resin matrix and do not leach out after curing, incorporating these monomers imposes no negative influences on the mechanical properties of the carrier material . Without releasing these active agents, QAC-based resinous materials can exhibit stable and long-term antibacterial effects .
1.1
Antibacterial effects
Experimental antibacterial adhesive systems were first prepared by incorporating MDPB into the primer of commercial self-etching adhesive Liner Bond 2 . Since then, the antibacterial activity of this prototype has been investigated and confirmed by a number of in vitro studies. Based on the findings of this experimental material, Clearfil Protect Bond, employing a 5% MDPB-containing primer, was developed and commercialized (sold as Clearfil SE Protect in USA and Clearfil Mega Bond FA in Japan).
Before curing, the MDPB-containing primer can kill bacteria rapidly because of the bactericidal activity of unpolymerized MDPB. It can thereby act as a cavity disinfectant. When the primer containing MDPB was kept in direct contact with planktonic bacteria, all bacteria were killed within 30 s . It is noteworthy that the Clearfil Protect Bond primer was able to penetrate a 500-μm-thick dentin block and eradicate caries-related species inside the dentin . In vivo studies using beagle dogs found that the MDPB-containing primer could also inactivate Streptococcus mutans in the cavity . Since residual bacteria are one of the primary causes of secondary caries, the cavity-disinfecting effects of the MDPB-containing primer may improve the outcomes of restorative treatments of caries lesions.
After curing, MDPB-containing resins can inhibit the growth of bacteria that comes into contact with the material, thereby acting as a so-called “contact inhibitor” ( Fig. 2 ). When S. mutans was incubated in contact with the cured primer/adhesive surface containing MDPB, the number of viable bacteria was significantly reduced . However, materials containing MDPB only exhibited bacteriostatic, rather than bactericidal effects, against the contacting bacteria. Two possible reasons for the reduction in antibacterial activity after curing have been proposed; (i) the movement of the immobilized molecules is limited, and (ii) the density of the QAC group of MDPB exposed on the outer surface is not high enough to kill bacterial cells.
MDPB-containing adhesives have been suggested to be effective in root caries arrestment and dental pulp preservation. This is attributed to their lesion-disinfecting effects and bacteriostatic functionality on contact with bacteria after curing. In a S. mutans -induced artificial root caries model, a MDPB-containing adhesive completely prevents lesion progress . As for pulp preservation, it has been confirmed using beagle dog models that the antibacterial primer containing MDPB can kill bacteria in the cavity, thus maintaining pulp vitality and primary odontoblastic function in infected, non-exposed and exposed cavities .
Besides MDPB, several other QAC monomers have been developed that can be utilized in resinous dental materials. Methacryloxylethyl cetyl dimethyl ammonium chloride (DMAE-CB, Fig. 3 ), synthesized by Chen’s group, provided a commercial etch and rinse adhesive with stable antibacterial activities that does not damage the bonding capacity . In recent years, significant efforts have been devoted to developing QAC monomers with improved properties. For instance, QAC monomers with two methacrylate groups have been synthesized to enhance the polymerization capacity ( Fig. 4 ). Antibacterial monomers with radio-opacity have also been developed using iodine as a counter ion ( Fig. 5 ).
1.2
Inhibitory effects against matrix metalloproteinases
Although modern adhesives can achieve satisfying immediate bonding to dentin, they demonstrate a loss of bond strength over time. Enzymatic degradation of the collagen matrix by host-derived matrix metalloproteinases (MMPs) plays a significant role in the destruction of the bonded interface . One strategy to improve the durability of resin–dentin bonds is to use inhibitors that inactivate MMPs at the bonded interface . Chlorhexidine has been found to be a non-specific MMPs inhibitor , and applying this agent to adhesives has been reported to be beneficial for the preservation of the resin–dentin bonds in vitro . Similar to chlorhexidine, a QAC disinfectant of benzalkonium chloride effectively inhibited both soluble recombinant MMPs and matrix-bound dentin MMPs . Tezvergil-Mutluay et al. speculated that QAC monomers may inhibit MMP activity. Using both soluble rhMMP-9 and matrix-bound endogenous MMPs, they found that QAC monomers, including MDPB, exhibited MMP inhibition behavior that was comparable to that of chlorhexidine . Noticeably, MDPB at 5%, which is the concentration utilized for the primer of commercial adhesive Clearfil Protect Bond, achieved 89% inhibition of soluble rhMMP-9 and approximately 90% inhibition of matrix-bound MMPs. Compared with chlorhexidine or benzalkonium chloride, which may leach out from bonded interfaces over time, polymerizable MMP-inhibitors are advantageous as they can be retained in the hybrid layer for years by copolymerization. Several investigations into bond durability, including in vivo studies, revealed that the MDPB-containing adhesive produced a more durable interface than conventional adhesives . Such improved durability achieved by MDPB-containing adhesives may be partially explained by the inhibitory effects of MDPB on MMPs.
2
Incorporation of nanoparticles
2.1
Antibacterial effects of silver nanoparticles
The antibacterial, antifungal, and antiviral actions of silver ions have been extensively investigated. Silver ions have been considered for applications as an antibacterial component in resinous dental materials. However, polymers filled with silver ions typically release a burst of ions and lose their antibacterial activity within a short period . Compared with free silver ions, reduced silver nanoparticles incorporated into a polymeric matrix provide a large reservoir of silver ions that can be released in a more controlled manner at a steady rate, allowing for long-term antibacterial effects . The direct incorporation of silver nanoparticles into a polymer matrix is a common strategy for preparing antibacterial resinous materials . However, silver nanoparticles are difficult to disperse, as nano-sized particles tend to aggregate. In 2011, a new technique for preparing dental polymers with evenly dispersed silver nanoparticles was described using coupling photo-initiated free radical polymerization of dimethacrylates with in situ silver ion reduction . The experimental composites containing 0.08% of silver nanoparticles exhibited a 40% reduction in bacterial coverage .
As opposed to QAC monomer-containing resins whose bacteriostatic effects depend on the direct contact of bacteria with the material surface, resinous materials loaded with silver nanoparticles can inhibit bacteria on its surface as well as bacteria suspended in the culture medium away from the surface . Therefore, QAC monomers and silver nanoparticles could show complimentary behavior for inhibiting bacteria. Experimental adhesives containing both QAC monomers and silver nanoparticles exhibited significantly enhanced antibacterial potency before and after curing compared with adhesives that used either agent alone .
2.2
Remineralization by calcium phosphate nanoparticles
To develop resinous materials with remineralization capabilities, calcium and phosphate ion-releasing fillers can be incorporated. The release and precipitation of calcium and phosphate can enhance the formation of hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), which is the structural prototype for the major mineral component of teeth. In vitro studies revealed that methacrylate-based composites containing calcium phosphate fillers could release calcium and phosphate ions to supersaturated levels for apatite precipitation, and thus could effectively remineralize tooth lesions . However, calcium phosphates containing resinous materials have the drawback of low mechanical strength. To develop experimental composites with high Ca and PO 4 release rates and with acceptable mechanical properties, Xu et al. combined nano-sized dicalcium phosphate anhydrous (DCPA) with silica-fused whiskers as co-fillers . As the nanoparticles have a high surface area, high levels of Ca and PO 4 can be released with a relatively small amount of DCPA filler. This leaves room in the resin for a significant amount of silica-fused whiskers that can reinforce the mechanical properties. However, the silica-fused whisker-reinforced nanocomposite is relatively opaque with a whitish color owing to a refractive index mismatch between the whiskers and resin, and cannot be light-cured .
Amorphous calcium phosphate nanoparticles (NACP) were synthesized and combined with barium boroaluminosilicate glass particles, a typical dental glass filler similar to those in hybrid composites, to yield light-curable, weight-bearing, Ca and PO 4 -releasing composites . One advantage of the composites containing calcium phosphate fillers is that they are “smart” and could release relatively high amounts of Ca and PO 4 when the pH is reduced from neutral to cariogenic of pH 4.0 . Furthermore, these materials can rapidly neutralize the acidic medium, increasing the pH from 4.0 to 5.69 within 10 min . The “smart” release of Ca and PO 4 as well as the neutralizing effects are promising material attributes to combat acid attack-induced mineral loss. A recent in vitro study using a 30-day demineralization/remineralization cyclic regimen found that NACP nano-composites could effectively remineralize the demineralized human enamel. These remineralization effects were 4-fold that of a commercial fluoride-releasing composite .
Based on these successful composites, Xu et al. conducted an approach to combine amorphous calcium phosphate with antibacterial components (QAC monomer or silver nanoparticles) ( Fig. 6 ), and achieved a novel dental bonding agent with remineralization capacity and long-lasting antibacterial activity . Such new materials having both remineralization and antibacterial properties may be of great benefit to preserve durable bonding interfaces and fight against secondary caries.
2
Incorporation of nanoparticles
2.1
Antibacterial effects of silver nanoparticles
The antibacterial, antifungal, and antiviral actions of silver ions have been extensively investigated. Silver ions have been considered for applications as an antibacterial component in resinous dental materials. However, polymers filled with silver ions typically release a burst of ions and lose their antibacterial activity within a short period . Compared with free silver ions, reduced silver nanoparticles incorporated into a polymeric matrix provide a large reservoir of silver ions that can be released in a more controlled manner at a steady rate, allowing for long-term antibacterial effects . The direct incorporation of silver nanoparticles into a polymer matrix is a common strategy for preparing antibacterial resinous materials . However, silver nanoparticles are difficult to disperse, as nano-sized particles tend to aggregate. In 2011, a new technique for preparing dental polymers with evenly dispersed silver nanoparticles was described using coupling photo-initiated free radical polymerization of dimethacrylates with in situ silver ion reduction . The experimental composites containing 0.08% of silver nanoparticles exhibited a 40% reduction in bacterial coverage .
As opposed to QAC monomer-containing resins whose bacteriostatic effects depend on the direct contact of bacteria with the material surface, resinous materials loaded with silver nanoparticles can inhibit bacteria on its surface as well as bacteria suspended in the culture medium away from the surface . Therefore, QAC monomers and silver nanoparticles could show complimentary behavior for inhibiting bacteria. Experimental adhesives containing both QAC monomers and silver nanoparticles exhibited significantly enhanced antibacterial potency before and after curing compared with adhesives that used either agent alone .
2.2
Remineralization by calcium phosphate nanoparticles
To develop resinous materials with remineralization capabilities, calcium and phosphate ion-releasing fillers can be incorporated. The release and precipitation of calcium and phosphate can enhance the formation of hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), which is the structural prototype for the major mineral component of teeth. In vitro studies revealed that methacrylate-based composites containing calcium phosphate fillers could release calcium and phosphate ions to supersaturated levels for apatite precipitation, and thus could effectively remineralize tooth lesions . However, calcium phosphates containing resinous materials have the drawback of low mechanical strength. To develop experimental composites with high Ca and PO 4 release rates and with acceptable mechanical properties, Xu et al. combined nano-sized dicalcium phosphate anhydrous (DCPA) with silica-fused whiskers as co-fillers . As the nanoparticles have a high surface area, high levels of Ca and PO 4 can be released with a relatively small amount of DCPA filler. This leaves room in the resin for a significant amount of silica-fused whiskers that can reinforce the mechanical properties. However, the silica-fused whisker-reinforced nanocomposite is relatively opaque with a whitish color owing to a refractive index mismatch between the whiskers and resin, and cannot be light-cured .
Amorphous calcium phosphate nanoparticles (NACP) were synthesized and combined with barium boroaluminosilicate glass particles, a typical dental glass filler similar to those in hybrid composites, to yield light-curable, weight-bearing, Ca and PO 4 -releasing composites . One advantage of the composites containing calcium phosphate fillers is that they are “smart” and could release relatively high amounts of Ca and PO 4 when the pH is reduced from neutral to cariogenic of pH 4.0 . Furthermore, these materials can rapidly neutralize the acidic medium, increasing the pH from 4.0 to 5.69 within 10 min . The “smart” release of Ca and PO 4 as well as the neutralizing effects are promising material attributes to combat acid attack-induced mineral loss. A recent in vitro study using a 30-day demineralization/remineralization cyclic regimen found that NACP nano-composites could effectively remineralize the demineralized human enamel. These remineralization effects were 4-fold that of a commercial fluoride-releasing composite .
Based on these successful composites, Xu et al. conducted an approach to combine amorphous calcium phosphate with antibacterial components (QAC monomer or silver nanoparticles) ( Fig. 6 ), and achieved a novel dental bonding agent with remineralization capacity and long-lasting antibacterial activity . Such new materials having both remineralization and antibacterial properties may be of great benefit to preserve durable bonding interfaces and fight against secondary caries.
