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Review

Advances in Bioactive Dental Adhesives for Caries Prevention: A State-of-the-Art Review

by
Mohammed Zahedul Islam Nizami
1,
Apissada Jindarojanakul
1,2,3,
Qiang Ma
4,
Sang J. Lee
2 and
Jirun Sun
1,*
1
ADA Forsyth Institute, Somerville, MA 02143, USA
2
Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA 02115, USA
3
Department of Prosthodontics, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand
4
BISCO Inc., Schaumburg, IL 60193, USA
*
Author to whom correspondence should be addressed.
J. Funct. Biomater. 2025, 16(11), 418; https://doi.org/10.3390/jfb16110418 (registering DOI)
Submission received: 12 September 2025 / Revised: 3 October 2025 / Accepted: 5 November 2025 / Published: 7 November 2025
(This article belongs to the Special Issue Biomaterials for Management of Dental Caries and Periodontal Disease)
Browse Figure
Versions Notes

Abstract

The long-term success of composite restorations largely depends on the performance of dental adhesives at the adhesive–tooth interface. Despite ongoing improvements, secondary caries remains the leading cause of restoration failure, primarily due to the adhesive layer’s susceptibility to hydrolytic degradation, bacterial invasion, and limited biological functionality. This review provides a comprehensive overview of recent advances in bioactive dental adhesives for preventing recurrent caries, focusing on their mechanisms of action, material performance, therapeutic functions, and clinical potential. Bioactive adhesives combine durable bonding with biofunctional benefits, including remineralization, antimicrobial activity, enzymatic inhibition, and support for tissue regeneration. By integrating these properties, they enhance both the durability of the adhesive interface and oral health. Recent strategies include the incorporation of ion-releasing fillers such as calcium phosphate and bioactive glass, antimicrobial monomers such as MDPB and quaternary ammonium methacrylates, enzymatic inhibitors, and hydrolytically stable resin matrices. Together, these components strengthen the adhesive interface and provide biologically active effects to prevent recurrent caries. Although in vitro findings are promising, challenges remain, including limited long-term clinical data, the absence of standardized evaluation protocols, and barriers to clinical translation. Addressing these gaps is essential to ensure predictable clinical outcomes. Bioactive dental adhesives represent a paradigm shift in restorative dentistry, evolving from passive bonding agents to multifunctional therapeutic materials. By combining structural durability with biological protection, they hold significant potential to prevent recurrent caries and improve the long-term success of composite restorations.

1. Introduction

Composite restorations are widely used as direct filling materials for dental caries due to their superior esthetics, dentin-like flexural strength, and dependable bonding performance. The adhesive layer forms the primary interface with the dentin substrate, enabling both micromechanical interlocking and chemical bonding [1]. The structural integrity of this layer is crucial for maintaining bond strength, marginal sealing, resistance to hydrolytic degradation, and, ultimately, the long-term clinical success of the restoration [2].
Despite advances in restorative materials, secondary caries remains the leading cause of restoration failure [3,4,5]. Although many commercially available composites incorporate bioactive components such as fluoride release or antimicrobial agents, these strategies provide limited protection for the adhesive interface, the most vulnerable region of the restoration complex [2]. This interface is inherently prone to hydrolytic degradation, mechanical weakness, and lack of biological activity, rendering it susceptible to breakdown, bacterial infiltration, and recurrent caries.
To overcome these challenges, next-generation adhesives are being engineered with enhanced durability and hydrolytic stability through the replacement of degradation-prone monomers such as Bis-GMA and HEMA [6]. Beyond improved mechanical resilience, current strategies emphasize the integration of therapeutic functions into adhesive systems. Bioactive dental adhesives, defined as materials with biological activities beyond their restorative role [7], are now designed to promote remineralization, exert antibacterial effects, and stimulate tissue regeneration [8]. These multifunctional features not only reinforce the adhesive interface but also actively suppress secondary caries, thereby extending the clinical lifespan of restorations.
Recent efforts have centered on developing bioactive adhesive systems incorporating ion-releasing fillers, antimicrobial monomers, enzymatic inhibitors, and hydrolytically stable resin matrices [6,9,10,11]. These strategies aim to improve interface durability through mineral deposition, suppression of enzymatic degradation, and inhibition of bacterial growth. Nevertheless, despite encouraging in vitro outcomes, clinical translation remains constrained by the absence of long-term data, non-standardized testing protocols, and the persistent challenge of balancing bioactivity with mechanical performance [12,13].
Although no extensive reviews have been solely dedicated to this relatively new field, gaps remain in understanding the integration of therapeutic functions with durable adhesive performance. This review addresses these gaps by synthesizing current advances, highlighting material composition, mechanisms of action, clinical relevance, and emerging strategies. By presenting bioactive dental adhesives as multifunctional, smart biomaterials (i.e., adapting and responding to biological or environmental stimuli), this work underscores their potential to transform adhesive dentistry from passive bonding agents into dynamic contributors to oral health.

2. Materials and Methods

A comprehensive literature search was conducted to identify original studies, systematic reviews, and scientific reports relevant to bioactive dental adhesives for caries prevention. The search encompassed multiple databases, including PubMed, Scopus, and Web of Science, ensuring coverage of peer-reviewed and high-quality publications. Google Scholar was not used as a primary source to avoid non–peer-reviewed materials. Searches were limited to English-language publications and spanned the period from 1988 through June 2025. Although bioactive adhesives were not commercially available in the early years, this period was included to capture foundational research related to dental adhesives and bioactivity, using keywords such as dental adhesives, bonding agent, bioactive, bioactivity, caries prevention, antimicrobial effect, remineralization, and regeneration. Boolean operators (AND, OR) were applied to refine and expand the search as appropriate.
Studies were selected if they investigated the properties, mechanisms of action, therapeutic effects, or clinical potential of bioactive materials incorporated into, or relevant to, dental adhesives. Particular emphasis was placed on antibacterial activity, remineralization capacity, enzymatic inhibition, and mechanical durability. Exclusion criteria included non-peer-reviewed publications, conference abstracts, and studies not directly related to bioactive adhesives. The selected literature comprised in vitro and in vivo studies, clinical trials, and review articles. All sources were critically appraised for methodological quality and relevance. Key findings were synthesized thematically and organized according to the review’s main objectives: material composition, functional mechanisms, in vitro and in vivo performance, and translational challenges. This structured approach ensured a rigorous and transparent evaluation of the current landscape and emerging trends in bioactive dental adhesive systems for caries prevention.

3. Principle of Bioactive Dental Adhesives

3.1. Function of Bioactive Materials

The concept of bioactivity in dental adhesives marks a key advancement in restorative dentistry, extending beyond the primary function of bonding toward active therapeutic engagement with dental tissues. To begin, it is essential to understand the definition of “bioactive”. According to the 2018 consensus on “Bioactive Dental Materials,” restorative materials may be considered bioactive if, in addition to restoring or replacing tooth structure, they actively stimulate or direct specific cellular or tissue responses or regulate interactions with microbiological species [7]. Extending this definition further, Ferracane et al. (2023) identified three main therapeutic functions of bioactive materials: Remineralization, regeneration, and antibacterial activity [8]. Remineralization involves the chemical deposition of mineral ions onto the tooth surface [14]. Regeneration refers to stimulating the body’s natural ability to repair or regrow damaged tissues [15]. Antibacterial activity is defined as the ability to kill bacteria or inhibit their growth and disease-causing potential [15].
While the antibacterial effects of bioactive materials are well-defined and easily distinguishable, the differentiation between remineralization and regeneration is often more nuanced. The following explanation aims to clarify the distinction between these two therapeutic mechanisms. Remineralization is primarily a chemical process in which mineral ions, such as calcium and phosphate, are redeposited onto demineralized inorganic structures like enamel and dentin. This process halts further demineralization, restores mineral content, and creates a protective surface layer, especially on compromised tooth structures [16]. In contrast, regeneration is a biologically driven process that targets the organic components of the tooth, particularly the dental pulp and the dentin–pulp complex. It involves stimulating the body’s natural healing pathways, including the activation of odontoblasts or progenitor cells, to promote the formation of secondary or tertiary dentin [17].
As the term “bioactive” has gained significant attention in recent years, the FDI World Dental Federation released a policy statement in 2021 to further clarify what qualifies a restorative material as bioactive. This statement outlines five essential criteria that restorative materials must meet to be classified as bioactive [18]. These include: (1) a clearly defined mechanism of action, biological, chemical, or both; (2) scientific evidence of bioactivity demonstrated through in vitro or in situ studies; (3) a specified duration of the bioactive effect; (4) no significant adverse biological side effects; and (5) preservation of the material’s primary restorative function.

3.2. Mechanisms of Caries Prevention in Bioactive Dental Adhesives

Bioactive dental adhesives offer a multifaceted approach to caries prevention, combining robust mechanical adhesion with biologically active defense mechanisms. These materials interact actively with the oral environment, promoting remineralization, resisting microbial colonization, and stabilizing the adhesive–tooth interface. A key mechanism is the controlled release of therapeutic ions, primarily calcium, phosphate, and fluoride, which supports the remineralization of demineralized enamel and dentin and enhances the formation of fluorapatite, a more acid-resistant mineral than natural hydroxyapatite. Self-etching adhesives modify or remove the smear layer before sealing dentinal tubules, enhancing adhesive penetration, reducing bacterial contamination, and improving bonding efficacy. This sealing also reduces postoperative sensitivity and prevents bacterial ingress into the pulp [19,20,21].
In addition to mineral deposition, bioactive adhesives often incorporate antimicrobial components such as silver or zinc oxide nanoparticles and chlorhexidine [22,23,24]. These agents disrupt bacterial metabolism and biofilm formation at restoration margins, reducing secondary caries. Many formulations exhibit pH-responsive behavior, releasing ions in acidic conditions and buffering local pH to mitigate demineralization [25,26]. Enzymatic inhibitors prevent collagen breakdown by host-derived proteases, preserving the hybrid layer and enhancing long-term bond durability. Together, these mechanisms provide sustained caries protection, particularly for patients with high caries risk [27,28,29].
The caries prevention mechanisms include ion release, pH buffering, antimicrobial action, and stabilization of the hybrid layer at the adhesive–tooth interface, as discussed in Section 3.2.1, Section 3.2.2, Section 3.2.3 and Section 3.2.4. Collectively, these properties promote tooth repair and inhibit bacterial growth. Figure 1 illustrates the key functional components of bioactive adhesives preventing recurrent caries.

3.2.1. Bioactive Ion Release and Mineral Deposition at the Adhesive–Tooth Interface

One of the primary mechanisms by which bioactive dental adhesives prevent caries is the sustained release of therapeutic ions, namely calcium (Ca2+), phosphate (PO43−), and fluoride (F−), at the adhesive–tooth interface. These ions facilitate the nucleation and growth of hydroxyapatite or fluorapatite crystals, which are more acid-resistant than natural tooth minerals, promoting remineralization of demineralized enamel and dentin. Materials such as bioactive glass (e.g., 45S5 Bioglass) and nano-hydroxyapatite (nHAp) are commonly used to enable ion release, particularly under acidic, caries-prone conditions [30,31,32]. This mineral deposition reinforces the structural integrity of the adhesive–tooth interface, forms a stable, mineral-rich layer, and seals dentinal tubules, reducing postoperative sensitivity. It also fills micro-gaps, minimizing bacterial infiltration and microleakage.
The pH-responsive nature of many adhesives ensures that ion release occurs during cariogenic attacks, providing targeted remineralization precisely when needed [20,33]. Over time, this continuous ion exchange creates a dynamic, self-repairing environment that enhances the long-term durability of restorations. By stabilizing early carious lesions and reducing demineralization without invasive intervention, these adhesives align with the principles of preventive and minimally invasive dentistry. Overall, ion release and mineral deposition protect the restored tooth, promote healing and regeneration, and position bioactive dental adhesives as multifunctional agents in restorative care.

3.2.2. Dynamic pH-Responsive Buffering Function

A critical caries prevention mechanism of bioactive dental adhesives is their pH-responsive buffering capacity, which allows them to counteract the acidic conditions produced by cariogenic bacteria. When oral pH drops below the critical threshold (around pH 5.5), enamel and dentin become prone to demineralization. Advanced adhesives incorporate pH-sensitive components such as bioactive glass, calcium silicate, or phosphate-based fillers, which detect acidic shifts and release alkaline ions like calcium (Ca2+), phosphate (PO43−), fluoride (F−), or strontium (Sr2+) in response [25,34,35,36]. This controlled ion release neutralizes acidity at the adhesive–tooth interface, creating an environment less favorable for demineralization and bacterial growth. The buffering effect also helps restore a neutral or slightly basic environment, promoting remineralization.
Unlike conventional adhesives, these smart, self-regulated systems activate only during acid challenges, preserving their therapeutic content and extending functional life. By modulating pH in real time, pH-responsive adhesives maintain hybrid layer stability and reduce marginal degradation and secondary caries formation. This stimulus-responsive behavior exemplifies the transition from passive bonding agents to interactive materials that actively support tooth preservation [37].

3.2.3. Inhibition of Microbial Adhesion and Biofilm Formation

Another key mechanism by which bioactive dental adhesives prevent caries is the inhibition of bacterial adhesion and biofilm formation at the adhesive–tooth interface. Acidogenic bacteria, such as Streptococcus mutans, adhere to tooth surfaces and form biofilms that produce acids, leading to demineralization of enamel and dentin. To counteract this, bioactive adhesives incorporate antimicrobial agents as additive particles or functional monomers within the resin matrix, including silver nanoparticles (AgNPs), quaternary ammonium compounds (QACs), zinc oxide (ZnO), chlorhexidine, and chitosan. These agents disrupt bacterial membranes, inhibit metabolic activity, and prevent initial bacterial adhesion [22,38,39,40,41,42,43]. In addition to direct antimicrobial effects, many agents demonstrate contact-killing or ion-mediated actions [44]. For example, silver and zinc ions released over time inhibit bacterial growth without traditional antibiotics, providing sustained long-term antimicrobial protection, particularly at restoration margins where secondary caries often develops [27,45,46]. By reducing bacterial colonization and biofilm formation, bioactive adhesives preserve the adhesive interface and surrounding tooth structure, maintain cleaner restoration surfaces, lower caries risk at margins, and extend the longevity of restorations.

3.2.4. Stabilization of Hybrid Layer to Enhance Bonding Durability

The long-term efficacy of bioactive dental adhesives in caries prevention depends on the stability of the hybrid layer, which is crucial for durable bonding. The hybrid layer forms when adhesives infiltrate demineralized dentin, creating a micromechanical bond between tooth structure and restorative material. However, it is susceptible to enzymatic degradation by host-derived enzymes such as matrix metalloproteinases (MMPs) and cathepsins. Without adequate protection, this degradation can weaken the adhesive bond, create micro-gaps, and allow bacterial infiltration, potentially leading to secondary caries [29,47].
Bioactive adhesives stabilize the hybrid layer through multiple mechanisms. They often contain MMP inhibitors, such as chlorhexidine, benzalkonium chloride, or zinc ions, which inactivate collagen-degrading enzymes and preserve hybrid layer integrity. Functional monomers like 10-MDP chemically bond with calcium ions in dentin, forming a hydrolysis-resistant layer [48,49,50,51]. Additionally, the continuous release of calcium, phosphate, and fluoride ions from bioactive fillers (e.g., bioactive glass, nano-hydroxyapatite) promotes remineralization of the hybrid layer over time. This ongoing mineral deposition reinforces the bond, enhances resistance to hydrolytic degradation, and helps prevent carious lesion progression. Together, these mechanisms preserve the hybrid layer, minimize adhesive failure and bacterial infiltration, and significantly extend restoration longevity.

4. Overview of Bioactive Dental Adhesives

4.1. Chemical Composition of Dental Adhesives

Direct composite restorations are one of the most frequently performed dental treatments. In this procedure, a dentist first applies an adhesive resin to the prepared tooth surface to ensure intimate contact and facilitate bonding. Adhesive resins, also known as bonding agents, are formulated to promote strong adhesion between the natural tooth structure (enamel or dentin) and the composite material [52].
Dental adhesives generally consist of four primary components: Resin monomers, initiators, additives, and solvents. Resin monomers such as Bis-GMA, HEMA, UDMA, and TEGDMA form the polymer network and dictate the adhesive’s mechanical strength, viscosity, and crosslinking density [53]. Initiators, including light-activated camphorquinone (CQ) and chemically activated benzoyl peroxide (BPO) with a tertiary amine, trigger polymerization, either on demand by light or autonomously, with dual-curing options available [54,55,56]. Additives enhance adhesive performance and durability; functional monomers like 10-MDP chemically bond to both resin networks and tooth hydroxyapatite [51,57], while bioactive fillers, such as nanoparticles of amorphous calcium phosphate, bioactive glass, or hydroxyapatite, promote ion release, remineralization, and potential antibacterial effects. Other additives, such as stabilizers (e.g., monoethyl ether hydroquinone and butylated hydroxytoluene), are included to prevent premature polymerization and to extend the shelf life of the adhesives [53]. Finally, solvents like ethanol, acetone, and water ensure the proper penetration of adhesive components during application [53]. The bioactive components are loaded either in the resin network or as additives.

4.2. Current Challenges in Dental Adhesive Systems

While the adhesive layer is essential, it is also considered the most susceptible area within the layered structure of a bonded restoration [2]. The poor durability of the adhesive can lead to pathway formation for bacterial infiltration and the formation of secondary caries after the composite resin restoration is placed in the patient’s mouth. To address the durability challenges, researchers have been developing more durable and hydrolytically stable adhesives by replacing hydrolysis-prone traditional monomers such as Bis-GMA and HEMA. In 2020, Dr. Sun and his team introduced a novel dental adhesive formulation using TEG-DVBE/UDMA, which demonstrated comparable bonding performance to conventional systems while offering significantly improved durability [6]. Beyond enhancing mechanical stability, incorporating therapeutic functionality into the adhesive layer would offer additional clinical benefits. The integration of bioactive materials into dental adhesives could enable therapeutic effects such as remineralization or antimicrobial action. These advancements have the potential to redefine restorative dentistry by improving both the longevity and biological performance of resin-based restorations.

4.3. Bioactive Agents in Dental Adhesive Systems

Many manufacturers have developed bioactive resin restorative materials that provide fluoride-releasing or antimicrobial effects to prevent the secondary caries problem. However, the first intimate layer to the cavity is not the composite resin restoration layer, but rather the adhesive layer. Hence, the development of bioactive dental adhesives is crucial for advancing the future of restorative dentistry. The modification of dental adhesive to achieve bioactivity could be introduced by two components. The first and most common modification is the additives. Many studies have been adding bioactive particles to the dental adhesive to achieve remineralization, antibacterial, and/or regeneration. The details of each bioactive particle will be discussed in the following section. Second, the modification of the monomer. Some studies switched out the monomer to gain the bioactivity [58,59].
Traditional dental adhesives primarily offer mechanical retention, lacking therapeutic interaction. They neither release remineralizing ions nor prevent microbial infiltration, making restorations susceptible to recurrent decay, especially at the adhesive-tooth interface [60]. Thus, the bioactive approach represents a more holistic and long-term strategy for achieving restorative success. Over the years, dental adhesives have evolved beyond micro-mechanical retention to enhance chemical bonding and simplify protocols from three-step bonding to one-step universal adhesive systems. Future development aims to integrate therapeutic functions, such as remineralization, antimicrobial, and regenerative effects, often by integrating bioactive components. This section will explore prominent bioactive compounds currently used in dental adhesives. Table 1 summarizes the current bioactive components and their respective functions in bioactive dental adhesives.
Table 1. Bioactive Materials Used in Dental Adhesives.
Table 1. Bioactive Materials Used in Dental Adhesives.
TypesMaterialsBioactive
Function *		Mechanism of
Action		LimitationsAdhesive
Integration
Section 4.3.1
Calcium Phosphate Particles 		Amorphous Calcium Phosphate (ACP) [14] Remineralization Ion Exchange; Disruption of bacterial cell membrane Limited long-term stability Additives
Hydroxyapatite Nanoparticles
(n-HAp)		 Antimicrobial
Remineralization 		Ion Exchange; Disruption of bacterial cell membrane Prone to degradation upon moisture exposure Additives
Section 4.3.2
Bioactive Glass (BAG) 		Calcium Sodium Phosphosilicate [61] Remineralization
Antimicrobial
Regenerative 		Ion exchange elevates pH and activates reparative cellular responses. Potential to interfere with resin components Additives
Section 4.3.3
Antimicrobial Agents 		Nanoparticles of silver (NAg) [62] Antimicrobial Disrupt bacterial membranes and generate ROS May cause discoloration and cytotoxicity at high doses Additives
Quaternary ammonium dimethacrylate (QADM) [58] Antimicrobial Contact kills by disrupting bacterial membranes Limited sustained antimicrobial effect. Resin Monomer
Methacryloyloxydodecylpyridinium bromide (MDPB) [59] Antimicrobial Sustained contact-based membrane disruption Reduce the degree of conversion Resin Monomer
Nisin peptide [63] Antimicrobial Form pores in bacterial membranes Unstable; enzyme-prone degradation Additives
Glutaraldehyde [64] Antimicrobial Cross-links bacterial proteins, leading to cell death Tissue toxicity; polymerization interference Additives
Chlorhexidine [65] Antimicrobial Disrupts membranes; precipitates cytoplasm Short-term effectiveness; Leaching over time Additives
* Bioactive functions; Remineralization = Material can release ions that can deposit on the demineralized tooth structure. Antimicrobial = Material can kill cariogenic bacteria or inhibit their growth. Regenerative = Material can stimulate cells in the pulp.

4.3.1. Calcium Phosphate Particles

Calcium and phosphate ions are crucial for remineralization processes. A variety of calcium phosphate-based materials have been explored for incorporation into dental adhesive systems, including amorphous calcium phosphate (ACP), calcium silicate, dicalcium phosphate dihydrate (DCPD), β-tricalcium phosphate (β-TCP), and nanosized-hydroxyapatite (n-HAp) [66]. These materials act as reservoirs of calcium and phosphate ions, which are gradually released into the surrounding environment under acidic conditions or cariogenic settings. Once the ions are released, they can precipitate into hydroxyapatite-like crystals on the dental hard tissue surfaces, thereby promoting remineralization. Moreover, calcium phosphate particles, especially calcium phosphate nanoparticles, can also occlude the dentinal tubule [67]. With this property, calcium phosphate was also utilized as a desensitizing agent [68].
Among bioactive compounds, amorphous calcium phosphate (ACP) is one of the most widely used and thoroughly studied. As a non-crystalline, metastable form of calcium phosphate, ACP is highly soluble and capable of rapid ion release. When incorporated into dental adhesives, it serves as an immediate source of calcium and phosphate ions, promoting mineral nucleation and crystal growth within demineralized dentin. Its high solubility offers the advantage of fast and substantial ion release, making it effective for remineralization. However, this same property poses a challenge: ACP tends to spontaneously convert into more stable crystalline phases, such as octacalcium phosphate or apatite, upon exposure to moisture [69]. This transformation can reduce its long-term bioactivity and compromise its clinical durability [68].
To overcome ACP’s instability, various stabilization strategies have been developed to preserve its amorphous state until ion release is functionally required. One approach involves the use of casein phosphopeptides (CPP), which bind to ACP and form nanoclusters (CPP-ACP) that stabilize the amorphous phase while enabling controlled ion release [70,71]. Another method uses citrate ions (Cit-ACP) to inhibit crystallization by chelating calcium ions, preventing premature aggregation into crystalline forms [72]. Both CPP-ACP and Cit-ACP have shown enhanced enamel and dentin remineralization in laboratory and clinical studies, making them promising candidates for incorporation into next-generation dental adhesive systems [67]. ACP is also available in nano-sized form. Recent advancements have demonstrated that nano-sized ACP particles exhibit significantly higher efficiency in promoting enamel and dentin remineralization compared to their larger-sized counterparts [73]. This enhanced efficacy is primarily attributed to the increased surface area of nanoparticles, which allows for better adhesion to demineralized surfaces and more effective ion delivery. Several in vitro studies have confirmed that nano-ACP formulations facilitate deeper mineral penetration and faster restoration of enamel microhardness than conventional ACP [73]. Therefore, the incorporation of nano-sized ACP in dental materials offers promising improvements in non-invasive treatment strategies for early carious lesions.
Nano-hydroxyapatite (n-HAp), a synthetic form of calcium phosphate, has also been investigated in dental adhesive systems due to its close resemblance to the mineral composition of natural enamel and dentin (Ca10(PO4)6(OH)2; Ca:P ratio of 1.67). These nanoparticles serve as a bioavailable source of calcium and phosphate ions, promoting remineralization at the adhesive interface [74]. The process involves nucleation and growth of hydroxyapatite crystals, which fill demineralized areas, restoring mineral density, mechanical strength, and resistance to acid attack. Additionally, n-HAp reduces dentin permeability and occludes dentinal tubules, offering the added clinical benefit of alleviating dentin hypersensitivity [75]. In a study by Sadat-Shojai et al., hydroxyapatite was synthesized in nanorod form and added to dental adhesives at concentrations of 0.2–0.5 wt%, resulting in enhanced mechanical properties. However, the study did not assess the bioactivity of the modified dental adhesives. Additionally, the long-term stability of n-HAp within the adhesive matrix remains uncertain, as its gradual ion release may affect the mechanical integrity of the adhesive over time [76]. In addition to their remineralization properties, calcium phosphate particles have demonstrated antimicrobial potential. Nanoparticles such as ACP and HAp exhibit bacteriostatic, non-genotoxic activity by disrupting bacterial membranes. ACP, with its higher surface reactivity, causes significant external membrane damage, while HAp is more readily internalized and may inhibit bacterial resistance by interfering with efflux pumps. These mechanisms disrupt key membrane components in both Gram-positive and Gram-negative bacteria, offering added antibacterial benefits to their bioactive profile [77]. In summary, calcium and phosphate compounds, especially ACP and n-HAp, hold significant potential in advancing bioactive dental adhesives. Their capacity to promote remineralization, exert antimicrobial effects, and integrate with tooth structure represents a transformative step toward more biologically interactive and therapeutic dental adhesive systems.
Although experimental studies have shown promising results with calcium phosphate (CaP) containing dental adhesives, there are few, if any, such bonding agents are commercially available in the United States. CaP is more commonly incorporated into composites, liners, or cements rather than adhesives [78]. This limited translation may reflect challenges in achieving long-term stability, as the effects of aging and the durability of CaP-containing adhesives remain insufficiently studied [79].

4.3.2. Bioactive Glass

Bioactive glass (BAG) is a silica-based sodium calcium phosphosilicate known for its excellent bioactivity and compatibility with dental tissues. One of the most studied formulations, Bioglass® 45S5, comprises approximately 45 wt% SiO2, 24.5 wt% CaO, 24.5 wt% Na2O, and 6.0 wt% P2O5. Upon exposure to physiological fluids, BAG initiates surface reactions that release calcium and phosphate ions, leading to the formation of a hydroxycarbonate apatite (HCA) layer. This mineral closely mimics natural apatite in enamel and dentin, facilitating effective remineralization of demineralized tooth structures [80]. When bioactive silicate glasses encounter body fluids, they undergo a sequence of chemical reactions that culminate in the formation of a hydroxycarbonate apatite (HCA) layer. This layer is chemically and structurally like the natural apatite phase found in bone. The remineralization process, originally described by Hench, occurs in five distinct stages [81].
1.
Ion Exchange: The glass releases sodium and calcium ions into the surrounding fluid, while hydrogen ions (H+ or H3O+) enter the glass. This raises the local pH and begins breaking the silicon-oxygen (Si–O–Si) bonds.
2.
Silica Dissolution: The breaking of Si–O–Si bonds releases silicon into the fluid as silanol (Si(OH)4) molecules.
3.
Silica Gel Layer Formation: If the pH stays below 9.5, silanol molecules condense to form a porous silica gel layer on the glass surface, allowing further ion exchange.
4.
Calcium Phosphate Layer Formation: Calcium and phosphate ions from both the glass and fluid accumulate on the silica gel, creating a layer of amorphous calcium phosphate (ACP).
5.
HCA Crystallization: Carbonate ions incorporate into the ACP layer, which gradually crystallizes into hydroxycarbonate apatite (HCA), closely resembling the mineral phase of natural teeth and bone.
This process not only helps repair damaged tissue but also supports the integration of dental materials with natural tooth structure, making bioactive glass a powerful component in restorative dentistry. Beyond its remineralizing properties, BAG also plays an active role in regeneration by modulating cellular behavior. The ionic dissolution products from BAG can stimulate the expression of growth factor-related genes, enhance the differentiation of osteogenic cells, and support the deposition of bone matrix. In the context of dental tissue repair, these bioactive ions have been shown to induce the differentiation of odontoblast-like cells, thereby initiating reparative dentinogenesis, a critical process for healing and protecting pulp-dentin complexes following injury or decay [80,81].
In addition to its regenerative capabilities, BAG demonstrated antimicrobial activity, particularly against cariogenic pathogens such as Streptococcus mutans. According to a study by Xu et al., the release of ions from BAG resulted in a localized increase in pH, creating an environment that is inhospitable to acidogenic bacteria. This elevation in pH contributes to the suppression of bacterial biofilm formation and activity, thereby reducing the risk of secondary caries development around restorations [82]. Collectively, the multifunctional properties of BAG, encompassing remineralization, cellular stimulation, and antimicrobial action, make it an attractive and versatile component in advanced dental adhesive systems aimed at enhancing the longevity and therapeutic value of restorations.
With controlled use, BAG presents minimal biological risk. Studies have shown that BAG does not exhibit clinically significant cytotoxicity or genotoxicity [83]. A key limitation of incorporating BAG into adhesives is the potential interaction with other adhesive components, which must be assessed individually. Despite these challenges, BAG has been included in at least one commercially available adhesive, RE-GEN™ Universal Adhesive (Vista Apex, Racine, WI, USA).

4.3.3. Antimicrobial Agents

Incorporating antimicrobial agents into dental adhesives targets the persistent challenges of biofilm formation at restoration margins. Various compounds have been investigated for this purpose. Silver nanoparticles (NAg) disrupt bacterial membranes and generate reactive oxygen species (ROS) to exert their effect. Quaternary ammonium compounds, such as quaternary ammonium dimethacrylate (QADM), kill bacteria on contact by damaging their membranes [58,62,84]. Among commercially available adhesives, Clearfil SE Protect Bond Primer (Kuraray Noritake Dental Inc., Tokyo, Japan) is one of the few that incorporate MDPB as a monomer resin. Nisin peptide, a naturally occurring antimicrobial, forms pores in bacterial membranes, especially targeting Gram-positive bacteria [63]. Glutaraldehyde acts by cross-linking bacterial proteins, causing cell death, while chlorhexidine disrupts membrane integrity and precipitates cytoplasmic contents. Beyond its antimicrobial role, chlorhexidine pre-treatment has also been reported to enhance bond strength and reduce degradation at the adhesive interface [64,65]. The integration of these agents into dental adhesive systems offers a promising strategy to inhibit bacterial colonization and reduce secondary caries risk [85].

4.3.4. Multifunctionality

Some materials inherently offer multifunctionality, providing properties such as remineralization, antimicrobial effects, and tissue regeneration. Another strategy to achieve multifunctional dental adhesives involves combining single-function components, either materials with similar functions to boost efficacy or those with distinct therapeutic roles to broaden benefits. For example, Dr. Hockin H. K. Xu and colleagues studied the combination of quaternary ammonium dimethacrylate (QADM), an antimicrobial monomer, with silver nanoparticles (NAg), antimicrobial fillers [22]. This combination significantly enhanced antimicrobial efficacy without compromising adhesive mechanical properties. Building on this, they developed an experimental adhesive incorporating nanosized amorphous calcium phosphate (NACP) for remineralization alongside NAg for antimicrobial activity. This adhesive demonstrated extensive NACP infiltration into dentinal tubules and exhibited a substantially stronger inhibitory effect on cariogenic biofilms compared to the Scotchbond™ multi-purpose control. Notably, lactic acid production by biofilms in NAg-containing groups was reduced to one-quarter of that in the control, highlighting a potent suppression of cariogenic activity [86].

5. Trends in Bioactive Dental Adhesives Development

Recent innovations in dental adhesives have transformed them from simple bonding agents into bioactive materials capable of interacting with and protecting tooth structures. These advanced adhesives provide sustained protection by adapting to the dynamic conditions of the oral environment. However, traditional methacrylate-based resin networks, containing ester bonds in monomers such as Bis-GMA and HEMA, remain susceptible to hydrolytic and enzymatic degradation, leading to network breakdown and reduced longevity. As a result, hydrolysis-resistant formulations, including Bis-GMA-free and HEMA-free networks, have gained increasing attention for their superior durability. Such stable resin matrices are essential for the development of bioactive adhesives that combine long-term mechanical resilience with therapeutic functionality. These advanced resin systems in adhesives and resin composites were discussed in detail in previous reviews [87,88,89]. While most bioactive components described in this section were developed using methacrylate-based resins due to their commercial availability, these strategies can be adapted to alternative resin systems.
The advancements result from the integration of biomaterials science, bio-nanotechnology, and biomimetic engineering [90,91,92]. The incorporation of bioactive glass (e.g., 45S5), functionalized bioactive glass, and ion-releasing polymers enables the controlled release of calcium, phosphate, and fluoride ions, thereby enhancing enamel and dentin remineralization and helping to prevent secondary caries and their progression [93]. Nanotechnology has further improved these adhesives, with nano-hydroxyapatite improving mechanical strength, bonding performance, and exhibiting antimicrobial properties to inhibit biofilm formation [94,95,96,97,98,99]. Moreover, smart stimuli-responsive dental adhesives were also reported to demonstrate real-time protection by releasing ions in acidic/cariogenic environments, effectively countering tooth demineralization and promoting remineralization [28,100].
Over the past decade, significant development has been reported with the introduction of self-healing polymers, which have demonstrated the capability to repair microcracks, thereby extending the lifespan of adhesive bonds. The use of a widely recognized functional monomer has enhanced chemical bonding to hydroxyapatite, improving the strength and durability of the adhesive interface [57]. In addition, antimicrobial agents such as chlorhexidine and quaternary ammonium compounds were incorporated to inhibit enzymatic degradation, bacterial growth, and biofilm formation at the tooth and adhesive interface, thereby reducing the risk of bond failure [101,102]. At the same time, emerging eco-friendly strategies emphasized the use of natural antimicrobials, regenerative materials, and biocompatible formulations [103,104,105]. These developments aimed not only to restore tooth structure but also to maintain and promote long-term oral health.
Research on bioactive dental adhesives can be categorized into four general areas, including nanotechnology-based adhesives for improved strength and antimicrobial action; smart polymers and hydrogel-based adhesives that respond to oral conditions; enzymatic inhibitors to prevent collagen degradation and extend longevity of the bond; and clinical performance studies assessing their durability and biocompatibility in clinical settings. The first three categories reflect the evolving functional potential of these materials. Table 2 provides an integrated overview of key components, nanomaterials, smart polymers, hydrogels, and enzymatic inhibitors, highlighting their primary roles and benefits in improving adhesive performance and therapeutic value. Table 3 summarizes the key clinical performance attributes, offering a clear overview of current directions in clinical application.

5.1. Nanotech-Enhanced Dental Adhesive Systems

Nanotechnology has become a transformative strategy in advancing the properties of dental adhesives by enhancing their mechanical strength, biological performance, biocompatibility, and therapeutic functions. Nanoparticles, typically measuring between 1 and 100 nanometers, exhibit a high surface-area-to-volume ratio, allowing for more effective interactions with both the tooth surface, adhesive, and resin matrix interface [106,107,108]. These enhanced functionalities promote improved resin infiltration into collagen networks and influence the formation of a strong, durable, and more stable hybrid layer, particularly in demineralized dentin [47,109]. Common nanofillers such as nano-hydroxyapatite (n-HAp) [76,94,110,111,112], nano-silica [113,114,115,116], nano-zirconia [117,118,119], and nano titanium dioxide [117,120] showed a critical role in enhancing the performance of dental adhesives. They contributed to improving mechanical properties, including bond strength, elastic modulus, and greater fracture and wear resistance. Their nanoscale size allows for better dispersion within the adhesive matrix and tooth surface, leading to stronger and more durable adhesive interfaces. Especially, nano-hydroxyapatite demonstrated a key role in biomimetic remineralization by releasing calcium and phosphate ions, which promoted the restoration of mineral content in early carious lesions and improved dentin sealing, thereby enhancing the overall integrity and longevity of the adhesive interface [121,122].
Current research in dental adhesive technology has gradually more focused on incorporating antimicrobial nanoparticles, for example, silver [123,124], zinc oxide [23,46], copper oxide [125,126,127], and chitosan [128,129], which disrupt bacterial cell membranes and inhibit biofilm formation at the tooth-adhesive interface. These antimicrobial properties are decisive for preventing secondary caries progression and enhancing the longevity of the restorations. In addition, the development of pH-responsive nanomaterials is gaining momentum. These materials have been designed to release therapeutic ions in acidic/cariogenic environments, allowing adhesives to neutralize acidic conditions and prevent demineralization and thus, support real-time remineralization.
Advanced nanostructures, including dendrimers [130,131], nanogels [132,133,134], and nanotubes [135,136,137], were also under investigation for their potential in controlled drug delivery, self-healing mechanisms, and improved interaction with dental tissues. While both in vitro and in vivo studies have demonstrated promising results, several challenges remain, particularly in ensuring long-term biocompatibility, minimizing cytotoxic effects, and satisfying regulatory requirements for clinical use. Continued interdisciplinary collaboration is essential to overcome these barriers and successfully integrate these nanotechnologies into standard dental practice.

5.2. Smart Polymers and Hydrogels-Based Therapeutic Dental Adhesives

Smart polymers and hydrogels have emerged as next-generation materials in dental adhesive systems, owing to their ability to respond dynamically to environmental stimuli in the oral cavity. Unlike conventional adhesives, these advanced systems enable site-specific and time-dependent therapeutic functions, such as pH buffering, ion release, drug delivery, and self-repair capacity [138,139,140]. Stimuli-responsive polymers release remineralizing agents like calcium (Ca2+), phosphate (PO43−), and fluoride (F−) in response to acidic conditions caused by bacterial activity, promoting enamel repair and caries resistance [25,28,100]. Self-healing polymers based on vitrimer chemistry enable dynamic bond exchange reactions, allowing the adhesive layer to reorganize and repair microcracks generated by mechanical or thermal stress. This maintains interfacial integrity and extending the longevity of restorations [141,142,143].
Hydrogels, composed of hydrophilic polymer networks, offer excellent biocompatibility and the ability to mimic the extracellular matrix, making them ideal for interactions with the dentin–pulp complex [144]. They can also act as drug delivery reservoirs, providing sustained release of antimicrobials (e.g., chlorhexidine [145], silver nanoparticles [98]), enzymes [146], or growth factors [147]. Thermo-responsive hydrogels, such as PNIPAAm, undergo physical state transitions at body temperature, enhancing adhesive adaptability and curing efficiency [148,149].
Functionalized hydrogels like GelMA (gelatin methacryloyl) and PNIPAAm were being explored for dual-curing capabilities and temperature responsiveness [150,151]. Chitosan-based hydrogels further contribute antimicrobial activity and mucoadhesive properties, improving tissue contact and reducing bacterial colonization while enabling controlled drug release [43]. Injectable and enzyme-responsive hydrogels enable precision in minimally invasive procedures and allow targeted therapeutic release triggered by specific enzymatic activity at infection sites [11,152,153,154]. Moreover, amorphous calcium phosphate (ACP)/Nano-HA hydrogels facilitate calcium and phosphate ion delivery at the adhesive interface, enhancing remineralization and reducing dentin hypersensitivity, key factors that contribute to long-term restoration success [19,155].

5.3. Enzymatic Inhibitors Incorporated Bioactive Dental Adhesives

The incorporation of enzymatic inhibitors into bioactive dental adhesives has represented a critical advancement aimed at enhancing the durability and integrity of resin-dentin bonds. Enzymatic degradation, particularly by host-derived matrix metalloproteinases (MMPs), significantly contributes to the breakdown of the hybrid layer over time, leading to adhesive failure and restoration loss. These enzymes are activated during acid-etching or through bacterial activity and gradually degrade the exposed collagen matrix. To mitigate this, dental adhesives have been formulated with enzyme-inhibiting agents that stabilize the hybrid layer and protect the collagen framework from proteolytic attack [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157].
Matrix metalloproteinase inhibitors, such as chlorhexidine [48], galardin [158], and benzalkonium chloride [49,159], are among the most extensively studied compounds for this purpose. These inhibitors can be incorporated directly into primers or adhesives, where they act by chelating the zinc ions required for MMP activity or by modifying enzyme conformation. Cysteine cathepsin inhibitors, including epigallocatechin gallate (EGCG) and tannic acid, offer complementary protection by targeting additional enzymatic pathways involved in dentin degradation [160,161]. Notably, the use of synthetic peptides and enzyme-inhibiting polymers is also being explored to provide more targeted, controlled, and long-lasting inhibition within the adhesive interface [152].
Table 2. Advanced Components in Bioactive Dental Adhesives: Nanomaterials, Smart Polymers, Hydrogels, and Enzymatic Inhibitors.
Table 2. Advanced Components in Bioactive Dental Adhesives: Nanomaterials, Smart Polymers, Hydrogels, and Enzymatic Inhibitors.
TypesAgentsTarget FunctionsAdded Benefits
Nanomaterials Nano-Hydroxyapatite (n-HAp) [76,94,110,111,112] Biomimetic remineralization Facilitates mineral deposition and reduces hypersensitivity
Nano-Silica (SiO2) [113,114,115,116] Mechanical reinforcement Boosts bond strength, wear resistance, and marginal seal
Nano-Zirconia (ZrO2) [117,118,119] Toughening agent Enhances fracture toughness and mechanical stability
Titanium Dioxide (TiO2) [117,120] Mechanical reinforcement Increases bond strength; reduces microleakage and microbial adhesion
Silver Nanoparticles (NAg) [123,124] Antimicrobial Suppresses biofilm; prevents recurrent caries
Zinc Oxide Nanoparticles [23,46] Antimicrobial and anti-inflammatory Inhibits microbial colonization; modulates inflammation
Copper Oxide Nanoparticles [125,126,127] Antimicrobial Boosts antimicrobial activity and bond durability
Chitosan Nanoparticles [128,129] Antimicrobial; drug delivery carrier Facilitates healing with controlled drug release
Dendrimers [130,131] Self-healing Enables pH-driven ion release and self-repair of microcracks
Nanogels [132,133,134] Smart delivery system Enables pH-responsive ion and drug release
Nanotubes (e.g., Halloysite) [135,136,137] Therapeutic agent reservoirs Enables prolonged antimicrobial release
Smart Polymers
/Hydrogels		pH-Responsive Polymers [25,100] Ion release in acidic pH Promotes remineralization and acid protection
Diels–Alder/Self-Healing Polymers [142,143] Autonomous microcrack repair Improves longevity and strength at the adhesive interface
Enzyme-Responsive Systems [146] Targeted therapeutic release Release agents in response to bacterial enzymatic action
Gelatin Methacryloyl (GelMA) [150] Light-curable hydrogel matrix Enables moisture-resistant curing and tissue bonding
Thermoresponsive Hydrogels (PNIPAAm) [151] Thermoresponsive viscosity Facilitates handling and better intraoral adaptation
Chitosan-Based Hydrogels [43] Antimicrobial, drug delivery carrier Inhibits microbe; facilitates prolonged therapeutic delivery.
ACP/nano-HAp Hydrogels [19,155] Calcium/phosphate delivery Enhances remineralization; decreases hypersensitivity
Enzymatic
Inhibitors 		MMP Inhibitors (e.g., Chlorhexidine, Galardin) [49,158,159] Inhibits matrix metalloproteinases Preserves hybrid layer; reduces adhesive degradation
Cathepsin Inhibitors (e.g., EGCG, Tannic Acid) [160,161] Blocks collagen-degrading cathepsins Strengthens bond over time; protects interface integrity
Peptide-Based Inhibitors (e.g., Synthetic MMP-inhibitory peptides) [152] Selective MMP inhibition Provides sustained enzyme inhibition with low toxicity
Bioactive Fillers + Inhibitors (e.g., n-HAp + ACP) [162,163]. Dual action: remineralization and enzymatic inhibition Reinforces framework and inhibits enzymatic degradation
Moreover, these enzymatic inhibitors have often been synergistically combined with bioactive fillers like nano-hydroxyapatite or calcium phosphate to provide dual functionality, enzymatic protection, and remineralization [162,163]. This combination promotes both mechanical stability and biological healing of the tooth structure. While these innovations offer promising benefits, such as reduced marginal leakage, enhanced bond longevity, and decreased postoperative sensitivity, several challenges remain. These include ensuring sustained inhibitor activity, preventing interference with polymerization, and maintaining biocompatibility. Ongoing research focuses on optimizing delivery methods, such as microencapsulation and polymer-bound inhibitors, to achieve sustained and controlled release without compromising the adhesive’s mechanical properties.

5.4. Clinical Performance Studies

Clinical performance studies are essential for validating the real-world efficacy, durability, and therapeutic impact of bioactive dental adhesives. Unlike in vitro evaluations, these studies assessed how adhesives perform in the complex oral environment, accounting for variables such as saliva, pH fluctuations, patient habits, and operator techniques. The key metrics investigated include bond strength longevity, caries prevention, antimicrobial efficacy, and patient-reported outcomes such as postoperative sensitivity and esthetic satisfaction.
Long-term bond strength was a primary focus, with studies indicating that bioactive dental adhesives can maintain adhesion to enamel and dentin over several years due to ongoing ion release and hybrid layer stabilization [164]. Materials incorporating bioactive glass (BAG) and nano-hydroxyapatite (nHAp) have demonstrated promising results in promoting remineralization, sealing dentinal tubules, and reducing marginal microleakage [165,166,167,168]. These benefits have been translated into better marginal integrity, helping to prevent secondary caries and extend the functional life of restorations. Clinical trials also showed that the sustained release of fluoride, calcium, and phosphate ions contributed to a reduction in postoperative sensitivity and enhanced biocompatibility [169,170,171,172]. Additionally, adhesives with embedded antimicrobial agents like zinc oxide or silver nanoparticles showed reduced bacterial colonization at the restoration interface [173,174].
However, variability in outcomes due to patient-specific factors (e.g., oral hygiene, cavity location, moisture control) remains a challenge. Comparative studies continued to examine how bioactive dental adhesives stack up against traditional systems, with most reported superior or equivalent performance in high-risk environments. These findings supported their growing adoption in clinical practice, though further long-term, multicenter trials are necessary to fully establish their efficacy and optimize application protocols.
Dental adhesives have evolved from passive bonding agents to multifunctional materials that actively enhance restoration longevity, resist degradation, and promote maintenance of tooth structure. Advances in nanotechnology, smart polymers, enzymatic inhibitors, and clinical validation have collectively improved bond strength, antimicrobial action, and remineralization capacity. However, future research should focus on enhancing the durability and responsiveness of these systems under dynamic oral conditions. Developing multifunctional adhesives with precise, stimuli-responsive release of therapeutic agents will further improve clinical outcomes. Integration of regenerative technologies like peptides or stem cell-compatible matrices holds great promise. Standardized in vitro and long-term clinical studies are essential to ensure safety, efficacy, and practical adoption in clinical settings.
Table 3. Evaluation of Bioactive Dental Adhesives: Clinical Functionality and Performance Parameters.
Table 3. Evaluation of Bioactive Dental Adhesives: Clinical Functionality and Performance Parameters.
Engineered PerformanceExperimental OutcomesClinical Benefits
Remineralization [165] BAG and nHAp induce apatite formation, restoring mineral content in dentin/enamel Aids tooth preservation and repair
Postoperative Sensitivity [169] Ion release mitigates dentinal hypersensitivity in deep cavities Improves comfort and compliance.
Secondary Caries Prevention [169] Fluoride/calcium ions prevent demineralization and bacterial ingress Strengthens caries defense at margins
Biocompatibility [172] Safe and well-tolerated; fluoride and BAG offer low-toxicity therapeutic effects Enables safe application in pulp and deep cavities
Bond Strength [175] Strong initial bond; ion release boosts durability in moist conditions Ensures reliable adhesion in challenging clinical settings
Marginal Integrity [176] Minimizes microleakage with enhanced sealing and adaptation Prevents bacterial ingress and recurrent caries
Longevity [177] Stable adhesion for 5+ years, dependent on hygiene and site Minimizes long-term replacement needs

6. Current Challenges and Limitations in Advanced Bioactive Dental Adhesive Systems

Compatibility of bioactive additives with resin networks is a major challenge in the development and clinical application of bioactive dental adhesives These fillers often differ significantly from the resin in surface chemistry, polarity, and reactivity, which can interfere with polymerization, disrupt network formation, and compromise adhesive performance [178,179]. Incompatibility can lead to nanoparticle agglomeration, poor dispersion, or phase separation, resulting in heterogeneous structures with weak interfacial bonding. This undermines critical properties such as mechanical strength, dimensional stability, and water resistance. Additionally, some bioactive components may react with initiators or free radicals during light curing, reducing the degree of conversion and yielding unstable polymer networks [180,181,182]. To address these issues, surface functionalization techniques such as silanization and methacrylate grafting are used to improve filler–resin interaction. Resin formulation strategies, including the use of compatible co-monomers and optimized monomer-to-filler ratios, further enhance dispersion and interfacial adhesion without compromising bioactivity [183,184]. Therefore, it is essential to achieve uniform distribution and stable integration of bioactive agents to maintain mechanical integrity and ensure sustainable ion release, antimicrobial action, and remineralization. Furthermore, enhancing the intermolecular chemistry between fillers and resins remains a key priority for developing sustainable and medically effective bioactive dental adhesives.
Enhancing the bioactivity of dental adhesives often involves incorporating inorganic fillers or hydrophilic agents that promote ion release and remineralization. However, these additives can compromise mechanical properties such as tensile strength, flexural modulus, fracture toughness, and wear resistance by increasing water sorption and introducing matrix heterogeneity, which weakens structural integrity and durability [132,178]. Striking an optimal balance between therapeutic functionality and mechanical performance remains a key challenge in materials science. While bioactive components enhance antimicrobial effects and support tissue remineralization, they may also reduce bond strength and resistance to mechanical stresses. Current research focuses on optimizing filler size, concentration, and surface modification techniques to preserve adhesive durability while retaining bioactive benefits.
The long-term success of bioactive dental adhesives depends on their ability to resist hydrolytic and enzymatic degradation while maintaining strong, stable bonds. While ion-releasing dental adhesives show promise in dentin remineralization and hybrid layer preservation, their durability under the complex conditions of the oral environment remains a major concern. Factors such as thermal cycling, enzymatic activity (particularly from matrix metalloproteinases and cathepsins), and repeated mechanical loading contribute to collagen matrix degradation within the hybrid layer. This leads to reduced bond strength, increased microleakage, and ultimately, restoration failure [185,186,187]. Therefore, the development of dental adhesives that can sustain both mechanical and biological functions while resisting hydrolysis and enzymatic breakdown is essential for improving long-term restoration performance and clinical reliability.
Another key limitation of many bioactive dental adhesives is their compatibility with established clinical protocols and the lack of randomized controlled trials to substantiate their clinical efficacy. These formulations often require modifications to standard procedures such as etching, priming, or curing, which can complicate chairside application and increase the learning curve for practitioners. For instance, some may demand longer curing times, specific handling techniques, or alternative solvent systems to maintain bioactivity without compromising bond strength. Such deviations from conventional workflows can hinder clinical efficiency and limit widespread adoption [9,57]. Therefore, developing user-friendly bioactive dental adhesives that integrate seamlessly into existing protocols without requiring significant procedural changes is essential for ensuring clinician acceptance and translating laboratory advances into routine dental practice.

7. Conclusions and Future Perspective

Advances in dental adhesive technology are driving the development of multifunctional systems that not only achieve strong and durable adhesion but also deliver therapeutic benefits such as remineralization and antimicrobial protection. Key strategies include incorporating functional bioactive monomers like 10-MDP for chemical bonding to tooth calcium, ion-releasing fillers for sustained mineral delivery, and enzyme inhibitors to preserve the collagen network within the hybrid layer. Emerging approaches, such as stimuli-responsive and self-healing materials, offer the potential to adapt to the oral environment and repair microdamage, further enhancing longevity. Future work should optimize formulations for controlled ion release and validate their performance through long-term in vivo trials, especially in high-caries-risk populations. To address the current lack of clinical data, well-designed randomized controlled trials (RCTs) and longitudinal cohort studies are needed, with clear endpoints including restoration survival, secondary caries incidence, and biological effects at the adhesive–tooth interface. Standardized methodologies and consistent outcome measures will be crucial for generating comparable, high-quality evidence. Bio-mimetic designs that mimic natural remineralization and form a sealed, acid-neutralizing, antimicrobial interface hold promise for preventing bacterial colonization, reducing microleakage, and mitigating secondary caries. Collectively, these innovations aim to extend restoration lifespan and improve long-term oral health outcomes, providing a clear roadmap for translating bioactive adhesive research into clinical practice.

Author Contributions

Conceptualization, M.Z.I.N., A.J. and J.S.; methodology, M.Z.I.N., A.J. and J.S.; validation, M.Z.I.N., A.J., Q.M., S.J.L. and J.S.; formal analysis, M.Z.I.N., A.J. and J.S.; investigation, M.Z.I.N., A.J. and J.S.; resources, Q.M., S.J.L. and J.S.; data curation, Q.M., S.J.L. and J.S.; writing—original draft preparation, M.Z.I.N. and A.J.; writing—review and editing, M.Z.I.N., A.J., Q.M., S.J.L. and J.S.; visualization, M.Z.I.N. and J.S.; supervision, J.S.; project administration, J.S.; funding acquisition, M.Z.I.N., A.J., Q.M., S.J.L. and J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research is supported by the National Institute of Dental and Craniofacial Research (NIDCR), under grants RM1DE034233, R01DE033442A, and the NIDCR training grant R90DE027638.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing does not apply to this article.

Conflicts of Interest

Qiang Ma is an employee of the company BISCO Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Chan, K.H.; Mai, Y.; Kim, H.; Tong, K.C.; Ng, D.; Hsiao, J.C. Resin composite filling. Materials 2010, 3, 1228–1243. [Google Scholar] [CrossRef]
  2. Spencer, P.; Ye, Q.; Park, J.; Topp, E.M.; Misra, A.; Marangos, O.; Wang, Y.; Bohaty, B.S.; Singh, V.; Sene, F. Adhesive/dentin interface: The weak link in the composite restoration. Ann. Biomed. Eng. 2010, 38, 1989–2003. [Google Scholar] [CrossRef]
  3. Demarco, F.F.; Corrêa, M.B.; Cenci, M.S.; Moraes, R.R.; Opdam, N.J. Longevity of posterior composite restorations: Not only a matter of materials. Dent. Mat. 2012, 28, 87–101. [Google Scholar] [CrossRef] [PubMed]
  4. Opdam, N.; Van De Sande, F.; Bronkhorst, E.; Cenci, M.; Bottenberg, P.; Pallesen, U.; Gaengler, P.; Lindberg, A.; Huysmans, M.; Van Dijken, J. Longevity of posterior composite restorations: A systematic review and meta-analysis. J. Dent. Res. 2014, 93, 943–949. [Google Scholar] [CrossRef]
  5. Shah, Y.R.; Shiraguppi, V.L.; Deosarkar, B.A.; Shelke, U.R. Long-term survival and reasons for failure in direct anterior composite restorations: A systematic review. J. Conserv. Dent. Endod. 2021, 24, 415–420. [Google Scholar] [CrossRef] [PubMed]
  6. Yamauchi, S.; Wang, X.; Egusa, H.; Sun, J. High-performance dental adhesives containing an ether-based monomer. J. Dent. Res. 2020, 99, 189–195. [Google Scholar] [CrossRef]
  7. Price, R.; Roulet, J. The value of consensus conferences: Peer review by 50 key opinion leaders! Stoma 2020, 7, 1–80. [Google Scholar] [CrossRef]
  8. Ferracane, J.L.; Sidhu, S.K.; Melo, M.A.S.; Yeo, I.-S.L.; Diogenes, A.; Darvell, B.W. Bioactive dental materials: Developing, promising, confusing. JADA Found. Sci. 2023, 2, 100022. [Google Scholar]
  9. Melo, M.A.S.; Garcia, I.M.; Mokeem, L.; Weir, M.D.; Xu, H.H.K.; Montoya, C.; Orrego, S. Developing Bioactive Dental Resins for Restorative Dentistry. J. Dent. Res. 2023, 102, 1180–1190. [Google Scholar] [CrossRef]
  10. Cocco, A.R.; da Rosa, W.L.d.O.; da Silva, A.F.; Lund, R.G.; Piva, E. A systematic review about antibacterial monomers used in dental adhesive systems: Current status and further prospects. Dent. Mater. 2015, 31, 1345–1362. [Google Scholar] [CrossRef]
  11. Münchow, E.A.; da Silva, A.F.; Piva, E.; Cuevas-Suárez, C.E.; de Albuquerque, M.T.P.; Pinal, R.; Gregory, R.L.; Breschi, L.; Bottino, M.C. Development of an antibacterial and anti-metalloproteinase dental adhesive for long-lasting resin composite restorations. J. Mater. Chem. B 2020, 8, 10797–10811. [Google Scholar] [CrossRef]
  12. Tay, F.R.; Pashley, D.H. Dental adhesives of the future. J. Adhes. Dent. 2002, 4, 91–103. [Google Scholar]
  13. Cadenaro, M.; Josic, U.; Maravić, T.; Mazzitelli, C.; Marchesi, G.; Mancuso, E.; Breschi, L.; Mazzoni, A. Progress in dental adhesive materials. J. Dent. Res. 2023, 102, 254–262. [Google Scholar] [CrossRef]
  14. Tung, M.S. Amorphous Calcium Phosphates for Tooth. Compendium 2004, 25, 9–13. [Google Scholar] [PubMed]
  15. National Cancer Institute. NCI Dictionary of Cancer Terms; National Cancer Institute: Bethesda, MD, USA, 2023. [Google Scholar]
  16. Arifa, M.K.; Ephraim, R.; Rajamani, T. Recent advances in dental hard tissue remineralization: A review of literature. Inter. J. Clin. Pediatr. Dent. 2019, 12, 139. [Google Scholar] [CrossRef] [PubMed]
  17. Quigley, R.M.; Kearney, M.; Kennedy, O.D.; Duncan, H.F. Tissue engineering approaches for dental pulp regeneration: The development of novel bioactive materials using pharmacological epigenetic inhibitors. Bioact. Mater. 2024, 40, 182. [Google Scholar] [CrossRef]
  18. Schmalz, G.; Hickel, R.; Price, R.B.; Platt, J.A. Bioactivity of dental restorative materials: FDI policy statement. Inter. Dent. J. 2023, 73, 21–27. [Google Scholar] [CrossRef] [PubMed]
  19. Tao, S.; He, L.; Xu, H.H.K.; Weir, M.D.; Fan, M.; Yu, Z.; Zhang, M.; Zhou, X.; Liang, K.; Li, J. Dentin remineralization via adhesive containing amorphous calcium phosphate nanoparticles in a biofilm-challenged environment. J. Dent. 2019, 89, 103193. [Google Scholar] [CrossRef]
  20. Kim, H.J.; Jang, J.H.; Woo, S.U.; Choi, K.K.; Kim, S.Y.; Ferracane, J.L.; Lee, J.H.; Choi, D.; Choi, S.; Kim, S.; et al. Effect of Novel Bioactive Glass-Containing Dentin Adhesive on the Permeability of Demineralized Dentin. Materials 2021, 14, 5423. [Google Scholar] [CrossRef]
  21. Alhussein, A.; Alsahafi, R.; Balhaddad, A.A.; Mokeem, L.; Schneider, A.; Jabra-Rizk, M.-A.; Masri, R.; Hack, G.D.; Oates, T.W.; Sun, J. Novel bioactive nanocomposites containing calcium fluoride and calcium phosphate with antibacterial and low-shrinkage-stress capabilities to inhibit dental caries. Bioengineering 2023, 10, 991. [Google Scholar] [CrossRef]
  22. Zhang, K.; Melo, M.A.; Cheng, L.; Weir, M.D.; Bai, Y.; Xu, H.H. Effect of quaternary ammonium and silver nanoparticle-containing adhesives on dentin bond strength and dental plaque microcosm biofilms. Dent. Mater. 2012, 28, 842–852. [Google Scholar] [CrossRef]
  23. Garcia, I.M.; Balhaddad, A.A.; Ibrahim, M.S.; Weir, M.D.; Xu, H.H.K.; Collares, F.M.; Melo, M.A.S. Antibacterial response of oral microcosm biofilm to nano-zinc oxide in adhesive resin. Dent. Mater. 2021, 37, e182–e193. [Google Scholar] [CrossRef]
  24. Boutsiouki, C.; Frankenberger, R.; Lücker, S.; Krämer, N. Effect of Chlorhexidine-containing Etch-and-Rinse Adhesives on Dentin Microtensile Bond Strength after Biological Loading. J. Adhes. Dent. 2023, 25, 13–22. [Google Scholar]
  25. Ibrahim, M.S.; Balhaddad, A.A.; Garcia, I.M.; Collares, F.M.; Weir, M.D.; Xu, H.H.K.; Melo, M.A.S. pH-responsive calcium and phosphate-ion releasing antibacterial sealants on carious enamel lesions in vitro. J. Dent. 2020, 97, 103323. [Google Scholar] [CrossRef]
  26. He, Y.; Vasilev, K.; Zilm, P. pH-responsive biomaterials for the treatment of dental caries—A focussed and critical review. Pharmaceutics 2023, 15, 1837. [Google Scholar] [CrossRef] [PubMed]
  27. Kachoei, M.; Divband, B.; Rahbar, M.; Esmaeilzadeh, M.; Ghanizadeh, M.; Alam, M. A Novel Developed Bioactive Composite Resin Containing Silver/Zinc Oxide (Ag/ZnO) Nanoparticles as an Antimicrobial Material against Streptococcus mutans, Lactobacillus, and Candida albicans. Evid. Based. Complement. Alternat. Med. 2021, 2021, 4743411. [Google Scholar] [CrossRef] [PubMed]
  28. Shi, Y.; Liang, J.; Zhou, X.; Ren, B.; Wang, H.; Han, Q.; Li, H.; Cheng, L. Effects of a Novel, Intelligent, pH-Responsive Resin Adhesive on Cariogenic Biofilms In Vitro. Pathogens 2022, 11, 1014. [Google Scholar] [CrossRef]
  29. Tjäderhane, L.; Nascimento, F.D.; Breschi, L.; Mazzoni, A.; Tersariol, I.L.; Geraldeli, S.; Tezvergil-Mutluay, A.; Carrilho, M.R.; Carvalho, R.M.; Tay, F.R.; et al. Optimizing dentin bond durability: Control of collagen degradation by matrix metalloproteinases and cysteine cathepsins. Dent. Mater. 2013, 29, 116–135. [Google Scholar] [CrossRef] [PubMed]
  30. Abbassy, M.A.; Bakry, A.S.; Alshehri, N.I.; Alghamdi, T.M.; Rafiq, S.A.; Aljeddawi, D.H.; Nujaim, D.S.; Hassan, A.H. 45S5 Bioglass paste is capable of protecting the enamel surrounding orthodontic brackets against erosive challenge. J. Orthod. Sci. 2019, 8, 5. [Google Scholar] [CrossRef]
  31. Zhang, R.; Qi, J.; Gong, M.; Liu, Q.; Zhou, H.; Wang, J.; Mei, Y. Effects of 45S5 bioactive glass on the remineralization of early carious lesions in deciduous teeth: An in vitro study. BMC Oral Health 2021, 21, 576. [Google Scholar] [CrossRef]
  32. Juntavee, A.; Juntavee, N.; Sinagpulo, A.N. Nano-Hydroxyapatite Gel and Its Effects on Remineralization of Artificial Carious Lesions. Int. J. Dent. 2021, 2021, 7256056. [Google Scholar] [CrossRef] [PubMed]
  33. Kunert, M.; Piwonski, I.; Hardan, L.; Bourgi, R.; Sauro, S.; Inchingolo, F.; Lukomska-Szymanska, M. Dentine remineralisation induced by “Bioactive” materials through mineral deposition: An in vitro study. Nanomaterials 2024, 14, 274. [Google Scholar] [CrossRef]
  34. Lertwisitphon, P.; Worapasphaiboon, Y.; Champakanan, N.; Toneluck, A.; Naruphontjirakul, P.; Young, A.M.; Chinli, R.; Chairatana, P.; Sucharit, S.; Panpisut, P. Enhancing elemental release and antibacterial properties of resin-based dental sealants with calcium phosphate, bioactive glass, and polylysine. BMC Oral Health 2025, 25, 96. [Google Scholar] [CrossRef]
  35. Jia, A.; Wang, P.; Tong, F.; Chen, Z.; Deng, Y.; Yao, H.; Wang, L.; Liu, Y.; Ge, H. Developing a Novel Enamel Adhesive with Amorphous Calcium Phosphate and Silver Nanoparticles to Prevent Demineralization during Orthodontic Treatment. J. Funct. Biomater. 2023, 14, 77. [Google Scholar] [CrossRef]
  36. Zhang, L.; Weir, M.D.; Hack, G.; Fouad, A.F.; Xu, H.H. Rechargeable dental adhesive with calcium phosphate nanoparticles for long-term ion release. J. Dent. 2015, 43, 1587–1595. [Google Scholar] [CrossRef]
  37. Li, S.; Qi, L.; Liu, Z. Antimicrobial properties and bonding durability of pH-responsive dentin adhesives with chlorhexidine-load mesoporous silica nanoparticles. Front. Mater. 2024, 11, 1379941. [Google Scholar] [CrossRef]
  38. Lobo, M.M.; Goncalves, R.B.; Pimenta, L.A.F.; Bedran-Russo, A.K.B.; Pereira, P.N. In vitro evaluation of caries inhibition promoted by self-etching adhesive systems containing antibacterial agents. J. Biomed. Mater. Res. Part. B Appl. Biomater. 2005, 75, 122–127. [Google Scholar] [CrossRef] [PubMed]
  39. Lopes, S.R.; Matuda, A.G.; Campos, R.P.; Mafetano, A.P.V.; Barnabe, A.H.M.; Chagas, G.S.; Barcellos, D.C.; Niu, L.-N.; Tay, F.R.; Pucci, C.R. Development of an antibacterial dentin adhesive. Polymers 2022, 14, 2502. [Google Scholar] [CrossRef]
  40. Zhang, K.; Wang, S.; Zhou, X.; Xu, H.H.; Weir, M.D.; Ge, Y.; Li, M.; Wang, S.; Li, Y.; Xu, X.; et al. Effect of antibacterial dental adhesive on multispecies biofilms formation. J. Dent. Res. 2015, 94, 622–629. [Google Scholar] [CrossRef]
  41. Thaweboon, S.; Saito, T.; Mateekusontan, S.; Thaweboon, B. Antimicrobial Effect of Dental Adhesive on Cariogenic Multi-Species Biofilm. Key Eng. Mater. 2024, 977, 129–134. [Google Scholar] [CrossRef]
  42. Luiz, M.T.; di Filippo, L.D.; Dutra, J.A.P.; Viegas, J.S.R.; Silvestre, A.L.P.; Anselmi, C.; Duarte, J.L.; Calixto, G.M.F.; Chorilli, M. New technological approaches for dental caries treatment: From liquid crystalline systems to nanocarriers. Pharmaceutics 2023, 15, 762. [Google Scholar] [CrossRef]
  43. Elsaka, S.E. Antibacterial activity and adhesive properties of a chitosan-containing dental adhesive. Quintessence Int. 2012, 43, 603–613. [Google Scholar]
  44. Wang, S.; Zhang, K.; Zhou, X.; Xu, N.; Xu, H.H.; Weir, M.D.; Ge, Y.; Wang, S.; Li, M.; Li, Y.; et al. Antibacterial effect of dental adhesive containing dimethylaminododecyl methacrylate on the development of Streptococcus mutans biofilm. Int. J. Mol. Sci. 2014, 15, 12791–12806. [Google Scholar] [CrossRef]
  45. Thomas, R.; Snigdha, S.; Bhavitha, K.; Babu, S.; Ajith, A.; Radhakrishnan, E. Biofabricated silver nanoparticles incorporated polymethyl methacrylate as a dental adhesive material with antibacterial and antibiofilm activity against Streptococcus mutans. 3 Biotech 2018, 8, 404. [Google Scholar] [CrossRef]
  46. Saffarpour, M.; Rahmani, M.; Tahriri, M.; Peymani, A. Antimicrobial and bond strength properties of a dental adhesive containing zinc oxide nanoparticles. Braz. J. Oral Sci. 2016, 15, 66–69. [Google Scholar] [CrossRef]
  47. Betancourt, D.; Baldion, P.; Castellanos, J. Resin-dentin bonding interface: Mechanisms of degradation and strategies for stabilization of the hybrid layer. Int. J. Biomater. 2019, 2019, 5268342. [Google Scholar] [CrossRef]
  48. Hebling, J.; Pashley, D.H.; Tjäderhane, L.; Tay, F.R. Chlorhexidine arrests subclinical degradation of dentin hybrid layers in vivo. J. Dent. Res. 2005, 84, 741–746. [Google Scholar] [CrossRef] [PubMed]
  49. Sabatini, C.; Patel, S.K. Matrix metalloproteinase inhibitory properties of benzalkonium chloride stabilizes adhesive interfaces. Eur. J. Oral Sci. 2013, 121, 610–616. [Google Scholar] [CrossRef]
  50. Osorio, R.; Yamauti, M.; Osorio, E.; Ruiz-Requena, M.; Pashley, D.; Tay, F.; Toledano, M. Zinc reduces collagen degradation in demineralized human dentin explants. J. Dent. 2011, 39, 148–153. [Google Scholar] [CrossRef]
  51. Yoshida, Y.; Nagakane, K.; Fukuda, R.; Nakayama, Y.; Okazaki, M.; Shintani, H.; Inoue, S.; Tagawa, Y.; Suzuki, K.; De Munck, J. Comparative study on adhesive performance of functional monomers. J. Dent. Res. 2004, 83, 454–458. [Google Scholar] [CrossRef] [PubMed]
  52. Prosthodontics, A.O. The Glossary of Prosthodontic Terms; Mosby: Maryland Heights, MO, USA, 1999. [Google Scholar]
  53. Van Landuyt, K.L.; Snauwaert, J.; De Munck, J.; Peumans, M.; Yoshida, Y.; Poitevin, A.; Coutinho, E.; Suzuki, K.; Lambrechts, P.; Van Meerbeek, B. Systematic review of the chemical composition of contemporary dental adhesives. Biomaterials 2007, 28, 3757–3785. [Google Scholar] [CrossRef]
  54. Kowalska, A.; Sokolowski, J.; Bociong, K. The photoinitiators used in resin based dental composite—A review and future perspectives. Polymers 2021, 13, 470. [Google Scholar] [CrossRef]
  55. Yoshida, K.; Greener, E.H. Effect of photoinitiator on degree of conversion of unfilled light-cured resin. J. Dent. 1994, 22, 296–299. [Google Scholar] [CrossRef]
  56. Rueggeberg, F.A.; Craig, R.G. Correlation of parameters used to estimate monomer conversion in a light-cured composite. J. Dent. Res. 1988, 67, 932–937. [Google Scholar] [CrossRef] [PubMed]
  57. Carrilho, E.; Cardoso, M.; Marques Ferreira, M.; Marto, C.M.; Paula, A.; Coelho, A.S. 10-MDP based dental adhesives: Adhesive interface characterization and adhesive stability—A systematic review. Materials 2019, 12, 790. [Google Scholar] [CrossRef]
  58. Cheng, L.; Weir, M.D.; Zhang, K.; Arola, D.D.; Zhou, X.; Xu, H.H. Dental primer and adhesive containing a new antibacterial quaternary ammonium monomer dimethylaminododecyl methacrylate. J. Dent. 2013, 41, 345–355. [Google Scholar] [CrossRef]
  59. Imazato, S.; Torii, Y.; Takatsuka, T.; Inoue, K.; Ebi, N.; Ebisu, S. Bactericidal effect of dentin primer containing antibacterial monomer methacryloyloxydodecylpyridinium bromide (MDPB) against bacteria in human carious dentin. J. Oral. Rehabil. 2001, 28, 314–319. [Google Scholar] [CrossRef]
  60. Breschi, L.; Mazzoni, A.; Ruggeri, A.; Cadenaro, M.; Di Lenarda, R.; Dorigo, E.D.S. Dental adhesion review: Aging and stability of the bonded interface. Dent. Mater. 2008, 24, 90–101. [Google Scholar] [CrossRef]
  61. Hill, R.G.; Stevens, M.M. Bioactive Glass. US20090208428A1, 20 August 2009. [Google Scholar]
  62. de Souza Balbinot, G.; Leitune, V.C.B.; Montenegro, S.D.; Collares, F.M. Silver core-shells particles as antibacterial filler for adhesive resins. Int. J. Adhes. Adhes. 2025, 138, 103916. [Google Scholar] [CrossRef]
  63. Su, M.; Yao, S.; Gu, L.; Huang, Z.; Mai, S. Antibacterial effect and bond strength of a modified dental adhesive containing the peptide nisin. Peptides 2018, 99, 189–194. [Google Scholar] [CrossRef] [PubMed]
  64. Schmidlin, P.R.; Zehnder, M.; Göhring, T.N.; Waltimo, T.M. Glutaraldehyde in bonding systems disinfects dentin in vitro. J. Adhes. Dent. 2004, 6, 61–64. [Google Scholar]
  65. Jing, D.; Wang, L. Effect of Chlorhexidine on the Bonding Effect of an Etch-and-Rinse Adhesive to Pretreatment Dentin. Int. J. Periodontics Restor. Dent. 2023, 43, s146–s155. [Google Scholar] [CrossRef]
  66. Dorozhkin, S.V. Amorphous calcium (ortho) phosphates. Acta biomater. 2010, 6, 4457–4475. [Google Scholar] [CrossRef]
  67. Ionescu, A.C.; Degli Esposti, L.; Iafisco, M.; Brambilla, E. Dental tissue remineralization by bioactive calcium phosphate nanoparticles formulations. Sci. Rep. 2022, 12, 5994. [Google Scholar] [CrossRef] [PubMed]
  68. Maillard, M.; Bandiaky, O.N.; Maunoury, S.; Alliot, C.; Alliot-Licht, B.; Serisier, S.; Renard, E. The effectiveness of calcium phosphates in the treatment of dentinal hypersensitivity: A systematic review. Bioengineering 2023, 10, 447. [Google Scholar] [CrossRef]
  69. Zhao, J.; Liu, Y.; Sun, W.-b.; Yang, X. First detection, characterization, and application of amorphous calcium phosphate in dentistry. J. Den. Sci. 2012, 7, 316–323. [Google Scholar] [CrossRef]
  70. Hegde, M.N.; Moany, A. Remineralization of enamel subsurface lesions with casein phosphopeptide-amorphous calcium phosphate: A quantitative energy dispersive X-ray analysis using scanning electron microscopy: An: In vitro: Study. J. Conserv. Dent. 2012, 15, 61–67. [Google Scholar] [CrossRef]
  71. Nozari, A.; Haji Abbas Oghli, F.; Parvizi, F.; Jowkar, Z.; Pakniyat Jahromi, M.; Hamidi, S.A. Impact of Casein Phosphopeptide Amorphous Calcium Phosphate and Proanthocyanidin on Bond Strength of Universal Adhesives to Caries-Affected Dentin in Primary Teeth: An In Vitro Study. Clin. Exp. Dent. Res. 2025, 11, e70131. [Google Scholar] [CrossRef] [PubMed]
  72. Iafisco, M.; Degli Esposti, L.; Ramírez-Rodríguez, G.B.; Carella, F.; Gómez-Morales, J.; Ionescu, A.C.; Brambilla, E.; Tampieri, A.; Delgado-López, J.M. Fluoride-doped amorphous calcium phosphate nanoparticles as a promising biomimetic material for dental remineralization. Sci. Rep. 2018, 8, 17016. [Google Scholar] [CrossRef] [PubMed]
  73. Xu, H.H.; Moreau, J.L.; Sun, L.; Chow, L.C. Nanocomposite containing amorphous calcium phosphate nanoparticles for caries inhibition. Dent. Mater. 2011, 27, 762–769. [Google Scholar] [CrossRef]
  74. Bordea, I.R.; Candrea, S.; Alexescu, G.T.; Bran, S.; Băciuț, M.; Băciuț, G.; Lucaciu, O.; Dinu, C.M.; Todea, D.A. Nano-hydroxyapatite use in dentistry: A systematic review. Drug Metab. Rev. 2020, 52, 319–332. [Google Scholar] [CrossRef]
  75. Anil, A.; Ibraheem, W.I.; Meshni, A.A.; Preethanath, R.S.; Anil, S. Nano-hydroxyapatite (nHAp) in the remineralization of early dental caries: A scoping review. Int. J. Environ. Res. Public Health 2022, 19, 5629. [Google Scholar] [CrossRef]
  76. Sadat-Shojai, M.; Atai, M.; Nodehi, A.; Khanlar, L.N. Hydroxyapatite nanorods as novel fillers for improving the properties of dental adhesives: Synthesis and application. Dent. Mater. 2010, 26, 471–482. [Google Scholar] [CrossRef] [PubMed]
  77. Wu, V.M.; Huynh, E.; Tang, S.; Uskoković, V. Calcium phosphate nanoparticles as intrinsic inorganic antimicrobials: Mechanism of action. Biomed. Mater. 2020, 16, 015018. [Google Scholar] [CrossRef]
  78. Skaria, S.; Berk, K.J. Experimental dental composites containing a novel methacrylate-functionalized calcium phosphate component: Evaluation of bioactivity and physical properties. Polymers 2021, 13, 2095. [Google Scholar] [CrossRef]
  79. Al-Qarni, F.; Weir, M.; Melo, M.A.; Al-Dulaijan, Y.; Almulhim, K.S.; Xu, H.H. Novel calcium phosphate ion-rechargeable and antibacterial adhesive to inhibit dental caries. Clin. Oral Investig. 2022, 26, 313–323. [Google Scholar] [CrossRef]
  80. Crovace, M.C.; Souza, M.T.; Chinaglia, C.R.; Peitl, O.; Zanotto, E.D. Biosilicate®—A multipurpose, highly bioactive glass-ceramic. In vitro, in vivo and clinical trials. J. Non-Cryst. Solids 2016, 432, 90–110. [Google Scholar] [CrossRef]
  81. Hench, L.L. Introduction to Bioceramics, An; World Scientific Publishing Company: Singapore, 2013. [Google Scholar]
  82. Xu, Y.-T.; Wu, Q.; Chen, Y.-M.; Smales, R.J.; Shi, S.-Y.; Wang, M.-T. Antimicrobial effects of a bioactive glass combined with fluoride or triclosan on Streptococcus mutans biofilm. Arch. Oral Biol. 2015, 60, 1059–1065. [Google Scholar] [CrossRef] [PubMed]
  83. Kido, H.W.; Oliveira, P.; Parizotto, N.A.; Crovace, M.C.; Zanotto, E.D.; Peitl-Filho, O.; Fernandes, K.P.; Mesquita-Ferrari, R.A.; Ribeiro, D.A.; M. Renno, A.C. Histopathological, cytotoxicity and genotoxicity evaluation of Biosilicate® glass–ceramic scaffolds. J. Biomed. Mater. Res. Part A 2013, 101, 667–673. [Google Scholar] [CrossRef]
  84. Suzuki, T.Y.U.; Gallego, J.; Assunção, W.G.; Briso, A.L.F.; Dos Santos, P.H. Influence of silver nanoparticle solution on the mechanical properties of resin cements and intrarradicular dentin. PLoS ONE 2019, 14, e0217750. [Google Scholar] [CrossRef]
  85. Hardan, L.; Bourgi, R.; Cuevas-Suárez, C.E.; Zarow, M.; Kharouf, N.; Mancino, D.; Villares, C.F.; Skaba, D.; Lukomska-Szymanska, M. The bond strength and antibacterial activity of the universal dentin bonding system: A systematic review and meta-analysis. Microorganisms 2021, 9, 1230. [Google Scholar] [CrossRef]
  86. Melo, M.A.S.; Cheng, L.; Zhang, K.; Weir, M.D.; Rodrigues, L.K.; Xu, H.H. Novel dental adhesives containing nanoparticles of silver and amorphous calcium phosphate. Dent. Mater. 2013, 29, 199–210. [Google Scholar] [CrossRef]
  87. Gonzalez-Bonet, A.; Kaufman, G.; Yang, Y.; Wong, C.; Jackson, A.; Huyang, G.; Bowen, R.; Sun, J. Preparation of Dental Resins Resistant to Enzymatic and Hydrolytic Degradation in Oral Environments. Biomacromolecules 2015, 16, 3381–3388. [Google Scholar] [CrossRef]
  88. Takahashi, M.; Nakajima, M.; Hosaka, K.; Ikeda, M.; Foxton, R.M.; Tagami, J. Long-term evaluation of water sorption and ultimate tensile strength of HEMA-containing/-free one-step self-etch adhesives. J. Dent. 2011, 39, 506–512. [Google Scholar] [CrossRef]
  89. Park, J.G.; Ye, Q.; Topp, E.M.; Misra, A.; Spencer, P. Water sorption and dynamic mechanical properties of dentin adhesives with a urethane-based multifunctional methacrylate monomer. Dent. Mater. 2009, 25, 1569–1575. [Google Scholar] [CrossRef] [PubMed]
  90. Melo, M.A.; Guedes, S.F.; Xu, H.H.; Rodrigues, L.K. Nanotechnology-based restorative materials for dental caries management. Trends Biotechnol. 2013, 31, 459–467. [Google Scholar] [CrossRef] [PubMed]
  91. Singer, L.; Fouda, A.; Bourauel, C. Biomimetic approaches and materials in restorative and regenerative dentistry: Review article. BMC Oral Health 2023, 23, 105. [Google Scholar] [CrossRef]
  92. Padovani, G.C.; Feitosa, V.P.; Sauro, S.; Tay, F.R.; Durán, G.; Paula, A.J.; Durán, N. Advances in Dental Materials through Nanotechnology: Facts, Perspectives and Toxicological Aspects. Trends Biotechnol. 2015, 33, 621–636. [Google Scholar] [CrossRef]
  93. da Costa, K.N.B.; Veras, N.P.; Carvalho, C.N.; de Oliveira Bauer, J.R.; Loguercio, A.D.; Cardenas, A.F.M.; de Siqueira, F.S.F.; Ferreira, M.C. Adhesive system containing Bioglass 45S5 particles in teeth affected by molar-incisor hypomineralization and quality of life impact: Study protocol for a randomized clinical trial. Trials 2025, 26, 151. [Google Scholar] [CrossRef] [PubMed]
  94. AlQhtani, F.; Abdulla, A.M.; Kamran, M.A.; Luddin, N.; Abdelrahim, R.K.; Samran, A.; AlJefri, G.H.; Niazi, F.H. Effect of adding sodium fluoride and nano-hydroxyapatite nanoparticles to the universal adhesive on bond strength and microleakage on caries-affected primary molars. J. Clin. Pediatr. Dent. 2024, 48, 79–85. [Google Scholar]
  95. AlFawaz, Y.F.; Almutairi, B.; Kattan, H.F.; Zafar, M.S.; Farooq, I.; Naseem, M.; Vohra, F.; Abduljabbar, T. Dentin Bond Integrity of Hydroxyapatite Containing Resin Adhesive Enhanced with Graphene Oxide Nano-Particles-An SEM, EDX, Micro-Raman, and Microtensile Bond Strength Study. Polymers 2020, 12, 2978. [Google Scholar] [CrossRef]
  96. Aljamhan, A.S.; Alrefeai, M.H.; Alhabdan, A.; Alhusseini, S.A.; Farooq, I.; Vohra, F.; Naseem, M.; Alkhudhairy, F. Influence of ER-CR-YSGG Laser and Photodynamic Therapy on the Dentin Bond Integrity of Nano-Hydroxyapatite Containing Resin Dentin Adhesive: SEM-EDX, Micro-Raman, Micro-Tensile, and FTIR Evaluation. Polymers 2021, 13, 1903. [Google Scholar] [CrossRef] [PubMed]
  97. Wang, J.; Jiang, W.; Liang, J.; Ran, S. Influence of silver nanoparticles on the resin-dentin bond strength and antibacterial activity of a self-etch adhesive system. J. Prosthet. Dent. 2022, 128, 1363.e1–1363.e10. [Google Scholar] [CrossRef] [PubMed]
  98. Wang, Y.; Ding, Y.; Deng, J.; Nie, R.; Meng, X. Antibacterial one-step self-etching dental adhesive with silver nanoparticles synthesized in situ. J. Dent. 2023, 129, 104411. [Google Scholar] [CrossRef]
  99. Aguiar, J.D.; Pedrosa, M.D.S.; Toma, S.H.; Araki, K.; Marques, M.M.; Medeiros, I.S. Antibacterial effect, cytotoxicity, and bond strength of a modified dental adhesive containing silver nanoparticles. Odontology 2023, 111, 420–427. [Google Scholar] [CrossRef]
  100. Liang, J.; Liu, F.; Zou, J.; Xu, H.H.K.; Han, Q.; Wang, Z.; Li, B.; Yang, B.; Ren, B.; Li, M.; et al. pH-Responsive Antibacterial Resin Adhesives for Secondary Caries Inhibition. J. Dent. Res. 2020, 99, 1368–1376. [Google Scholar] [CrossRef] [PubMed]
  101. Dionysopoulos, D. Effect of digluconate chlorhexidine on bond strength between dental adhesive systems and dentin: A systematic review. J. Conserv. Dent. Endod. 2016, 19, 11–16. [Google Scholar] [CrossRef]
  102. Pupo, Y.M.; Farago, P.V.; Nadal, J.M.; Esmerino, L.A.; Maluf, D.F.; Zawadzki, S.F.; Michél, M.D.; Santos, F.A.d.; Gomes, O.M.M.; Gomes, J.C. An innovative quaternary ammonium methacrylate polymer can provide improved antimicrobial properties for a dental adhesive system. J. Biomater. Sci. Polym. Ed 2013, 24, 1443–1458. [Google Scholar] [CrossRef]
  103. Ribeiro, R.C.; Silva, E.M.; Carvalho, C.M.; Miranda, M.; Portela, M.B.; Amaral, C.M. Characterization and Anti-Caries Effect of an Experimental Adhesive Containing Natural Antimicrobial Agents. J. Adhes. Dent. 2021, 23, 527–537. [Google Scholar]
  104. Sarikaya, R.; Song, L.; Yuca, E.; Xie, S.X.; Boone, K.; Misra, A.; Spencer, P.; Tamerler, C. Bioinspired multifunctional adhesive system for next generation bio-additively designed dental restorations. J. Mech. Behav. Biomed. Mater. 2021, 113, 104135. [Google Scholar] [CrossRef]
  105. Schröter, F.-J.; Moldovan, M.; Sarosi, C.; Ilie, N. Enhancing dentin bonding through new adhesives formulations with natural polyphenols, tricalcium phosphate and chitosan. Dent. Mater. 2024, 40, 276–284. [Google Scholar] [CrossRef]
  106. Cheng, L.; Zhang, K.; Weir, M.D.; Melo, M.A.S.; Zhou, X.; Xu, H.H. Nanotechnology strategies for antibacterial and remineralizing composites and adhesives to tackle dental caries. Nanomedicine 2015, 10, 627–641. [Google Scholar] [CrossRef]
  107. Nassif, M.; El Askary, F. Nanotechnology and nanoparticles in contemporary dental adhesives. In Nanobiomaterials in Clinical Dentistry; Elsevier: Amsterdam, The Netherlands, 2019; pp. 163–198. [Google Scholar]
  108. Nagano, F.; Selimovic, D.; Noda, M.; Ikeda, T.; Tanaka, T.; Miyamoto, Y.; Koshiro, K.-i.; Sano, H. Improved bond performance of a dental adhesive system using nano-technology. BioMed. Mater. Eng. 2009, 19, 249–257. [Google Scholar] [CrossRef] [PubMed]
  109. Stape, T.H.S.; Mutluay, M.M.; Tjäderhane, L.; Uurasjärvi, E.; Koistinen, A.; Tezvergil-Mutluay, A. The pursuit of resin-dentin bond durability: Simultaneous enhancement of collagen structure and polymer network formation in hybrid layers. Dent. Mater. 2021, 37, 1083–1095. [Google Scholar] [CrossRef] [PubMed]
  110. Lezaja, M.; Jokic, B.M.; Veljovic, D.N.; Miletic, V. Shear bond strength to dentine of dental adhesives containing hydroxyapatite nano-fillers. J. Adhes. Sci. Technol. 2016, 30, 2678–2689. [Google Scholar] [CrossRef]
  111. Mutar, M.A.; Mahdi, M.S. Synthesis and characterization of novel nanocomposites with nanofillers particles and their applications as dental materials. Period. Eng. Nat. Sci. (PEN) 2019, 7, 1512–1538. [Google Scholar] [CrossRef]
  112. Shekofteh, K.; Boruziniat, A.; Moghaddas, M.-J.; Namdar, F.; Zahabi, E.; Bagheri, H. Formulation and mechanical characterization of a semi-crystalline nano-fluorine hydroxyapatite-filled dental adhesive. J. Aust. Ceram. Soc. 2018, 54, 731–738. [Google Scholar]
  113. Mazloom-Jalali, A.; Taromi, F.A.; Atai, M.; Solhi, L. Dual modified nanosilica particles as reinforcing fillers for dental adhesives: Synthesis, characterization, and properties. J. Mech. Behav. Biomed. Mater. 2020, 110, 103904. [Google Scholar] [CrossRef]
  114. Solhi, L.; Atai, M.; Nodehi, A.; Imani, M. On the properties of nanosilicate-based filled dental adhesives: Synthesis, characterization, and optimized formulation. J. Mech. Behav. Biomed. Mater. 2021, 119, 104498. [Google Scholar] [CrossRef]
  115. Jahromia, S.F.; Naimi-Jamala, M.; Ataib, M. Preparation of dental polymeric nano-adhesives with silica nano-porous (MCM-41) as novel fillers for improving the adhesive mechanical properties: Synthesis and application. In Proceedings of the The 18th International Electronic Conference on Synthetic Organic Chemistry, Bergen, Norway, 1–6 August 2010; MDPI: Basel, Switzerland, 2014. [Google Scholar]
  116. Sabir, M.; Muhammad, N.; Siddiqui, U.; Khan, A.S.; Syed, M.R.; Rahim, A.; Liaqat, S.; Shah, A.T.; Sharif, F.; Khan, M.A. Effect of nanocrystalline cellulose/silica-based fillers on mechanical properties of experimental dental adhesive. Polym. Bull. 2023, 80, 9131–9148. [Google Scholar]
  117. Felemban, N.H.; Ebrahim, M.I. The influence of adding modified zirconium oxide-titanium dioxide nano-particles on mechanical properties of orthodontic adhesive: An in vitro study. BMC Oral Health 2017, 17, 1–8. [Google Scholar] [CrossRef]
  118. Lohbauer, U.; Wagner, A.; Belli, R.; Stoetzel, C.; Hilpert, A.; Kurland, H.-D.; Grabow, J.; Müller, F.A. Zirconia nanoparticles prepared by laser vaporization as fillers for dental adhesives. Acta Biomater. 2010, 6, 4539–4546. [Google Scholar] [CrossRef]
  119. Alkhudhairy, F.; Vohra, F. Adhesive bond strength and compressive strength of a novel bulk fill composite with zirconia nano-hybrid filler. J. Adhes. Sci. Technol. 2017, 31, 450–463. [Google Scholar] [CrossRef]
  120. Florez, F.L.E.; Hiers, R.D.; Larson, P.; Johnson, M.; O’Rear, E.; Rondinone, A.J.; Khajotia, S.S. Antibacterial dental adhesive resins containing nitrogen-doped titanium dioxide nanoparticles. Mater. Sci. Eng. C 2018, 93, 931–943. [Google Scholar] [CrossRef] [PubMed]
  121. Scribante, A.; Dermenaki Farahani, M.R.; Marino, G.; Matera, C.; Rodriguez y Baena, R.; Lanteri, V.; Butera, A. Biomimetic Effect of Nano-Hydroxyapatite in Demineralized Enamel Before Orthodontic Bonding of Brackets and Attachments: Visual, Adhesion Strength, and Hardness in In Vitro Tests. BioMed Res. Int. 2020, 2020, 6747498. [Google Scholar] [CrossRef] [PubMed]
  122. Kavrik, F.; Kucukyilmaz, E. Effect of Nano-sized Hydroxyapatite Filler on Remineralization Efficacy of an Adhesive Resin: An in vitro study. J. Adhes. Sci. Technol. 2024, 38, 1334–1352. [Google Scholar] [CrossRef]
  123. Peralta, L.C.F.; Almeida, N.L.M.; Pontes, F.M.L.; Rinaldo, D.; Carneiro, C.A.; Neppelenbroek, K.H.; Lara, V.S.; Porto, V.C. Silver nanoparticles in denture adhesive: An antimicrobial approach against Candida albicans. J. Dent. 2023, 131, 104445. [Google Scholar] [CrossRef]
  124. Dutra-Correa, M.; Leite, A.A.; de Cara, S.P.; Diniz, I.M.; Marques, M.M.; Suffredini, I.B.; Fernandes, M.S.; Toma, S.H.; Araki, K.; Medeiros, I.S. Antibacterial effects and cytotoxicity of an adhesive containing low concentration of silver nanoparticles. J. Dent. 2018, 77, 66–71. [Google Scholar] [CrossRef] [PubMed]
  125. Gutiérrez, M.F.; Malaquias, P.; Hass, V.; Matos, T.P.; Lourenço, L.; Reis, A.; Loguercio, A.D.; Farago, P.V. The role of copper nanoparticles in an etch-and-rinse adhesive on antimicrobial activity, mechanical properties and the durability of resin-dentine interfaces. J. Dent. 2017, 61, 12–20. [Google Scholar] [CrossRef]
  126. Argueta-Figueroa, L.; Scougall-Vilchis, R.J.; Morales-Luckie, R.A.; Olea-Mejía, O.F. An evaluation of the antibacterial properties and shear bond strength of copper nanoparticles as a nanofiller in orthodontic adhesive. Aust. Orthod. J. 2015, 31, 42–48. [Google Scholar] [CrossRef]
  127. Gutiérrez, M.F.; Alegría-Acevedo, L.F.; Méndez-Bauer, L.; Bermudez, J.; Dávila-Sánchez, A.; Buvinic, S.; Hernández-Moya, N.; Reis, A.; Loguercio, A.D.; Farago, P.V. Biological, mechanical and adhesive properties of universal adhesives containing zinc and copper nanoparticles. J. Dent. 2019, 82, 45–55. [Google Scholar] [CrossRef]
  128. Neves, J.; Marcato, P.; e Silva, F.d.P.; Mantovani, C.; Prado, H.; Aires, C.; Massaro, T.; Borsato, M. Synthesis and characterization of an experimental primer containing chitosan nanoparticles–Effect on the inactivation of metalloproteinases, antimicrobial activity and adhesive strength. Arch. Oral Biol. 2021, 127, 105148. [Google Scholar] [CrossRef]
  129. Sodagar, A.; Bahador, A.; Jalali, Y.F.; Gorjizadeh, F.; Baghaeian, P. Effect of chitosan nanoparticles incorporation on antibacterial properties and shear bond strength of dental composite used in orthodontics. Iran J. Orth.o 2016, 21, 81–88. [Google Scholar]
  130. Cai, X.; Wang, X. Chlorhexidine-loaded poly (amido amine) dendrimer and a dental adhesive containing amorphous calcium phosphate nanofillers for enhancing bonding durability. Dent. Mater. 2022, 38, 824–834. [Google Scholar] [CrossRef] [PubMed]
  131. Tao, S.; Yang, X.; Liao, L.; Yang, J.; Liang, K.; Zeng, S.; Zhou, J.; Zhang, M.; Li, J. A novel anticaries agent, honokiol-loaded poly (amido amine) dendrimer, for simultaneous long-term antibacterial treatment and remineralization of demineralized enamel. Dent. Mater. 2021, 37, 1337–1349. [Google Scholar] [CrossRef] [PubMed]
  132. Gotti, V.B.; Correr, A.B.; Lewis, S.H.; Feitosa, V.P.; Correr-Sobrinho, L.; Stansbury, J.W. Influence of nanogel additive hydrophilicity on dental adhesive mechanical performance and dentin bonding. Dent. Mater. 2016, 32, 1406–1413. [Google Scholar] [CrossRef]
  133. Morães, R.; Garcia, J.; Wilson, N.; Lewis, S.; Barros, M.; Yang, B.; Pfeifer, C.; Stansbury, J. Improved dental adhesive formulations based on reactive nanogel additives. J. Dent. Res. 2012, 91, 179–184. [Google Scholar] [CrossRef]
  134. Trivedi, R.; Gautam, D.; Kehe, G.M.; Escobedo, H.D.; Patel, K.; Stansbury, J.W.; Schurr, M.J.; Nair, D.P. Synthesis, characterization and evaluation of azobenzene nanogels for their antibacterial properties in adhesive dentistry. Eur. J. Oral Sci. 2022, 130, e12832. [Google Scholar] [CrossRef] [PubMed]
  135. Balhaddad, A.A.; Garcia, I.M.; Mokeem, L.; Alsahafi, R.; Collares, F.M.; Sampaio de Melo, M.A. Metal oxide nanoparticles and nanotubes: Ultrasmall nanostructures to engineer antibacterial and improved dental adhesives and composites. Bioengineering 2021, 8, 146. [Google Scholar] [CrossRef]
  136. Garcia, I.M.; Araújo-Neto, V.G.; Balbinot, G.; Souza, V.S.; Mokeem, L.; Scholten, J.D.; Melo, M.A.S.; Giannini, M.; Collares, F.M. Dental adhesives incorporated with alkyl trimethyl ammonium bromide-loaded titanium oxide nanotubes for sustained bioactive and anti-biofilm protection. Dent. Mater. 2025, 41, 721–729. [Google Scholar] [CrossRef]
  137. Degrazia, F.W.; Genari, B.; Leitune, V.C.B.; Arthur, R.A.; Luxan, S.A.; Samuel, S.M.W.; Collares, F.M.; Sauro, S. Polymerisation, antibacterial and bioactivity properties of experimental orthodontic adhesives containing triclosan-loaded halloysite nanotubes. J. Dent. 2018, 69, 77–82. [Google Scholar] [CrossRef]
  138. Amirthalingam, S.; Rajendran, A.K.; Moon, Y.G.; Hwang, N.S. Stimuli-responsive dynamic hydrogels: Design, properties and tissue engineering applications. Mater. Horiz. 2023, 10, 3325–3350. [Google Scholar] [CrossRef]
  139. Wei, Y.; Zheng, L.; Xie, X.; Yang, X.; Liao, J. Recent advances in stimuli responsive hydrogels for oral disease treatment. Mater. Des. 2024, 112817. [Google Scholar] [CrossRef]
  140. Liu, J.; Du, C.; Huang, W.; Lei, Y. Injectable smart stimuli-responsive hydrogels: Pioneering advancements in biomedical applications. Biomater. Sci. 2024, 12, 8–56. [Google Scholar] [CrossRef] [PubMed]
  141. Wu, J.; Weir, M.D.; Melo, M.A.S.; Strassler, H.E.; Xu, H.H.K. Effects of water-aging on self-healing dental composite containing microcapsules. J. Dent. 2016, 47, 86–93. [Google Scholar] [CrossRef]
  142. Carbonell-Blasco, M.P.; Moyano, M.A.; Hernández-Fernández, C.; Sierra-Molero, F.J.; Pastor, I.M.; Alonso, D.A.; Arán-Aís, F.; Orgilés-Calpena, E. Polyurethane Adhesives with Chemically Debondable Properties via Diels–Alder Bonds. Polymers 2023, 16, 21. [Google Scholar] [CrossRef]
  143. Yu, F.; Cao, X.; Du, J.; Wang, G.; Chen, X. Multifunctional hydrogel with good structure integrity, self-healing, and tissue-adhesive property formed by combining Diels–Alder click reaction and acylhydrazone bond. ACS Appl. Mater. Interfaces 2015, 7, 24023–24031. [Google Scholar] [CrossRef] [PubMed]
  144. Sadeghian, A.; Kharaziha, M.; Khoroushi, M. Dentin extracellular matrix loaded bioactive glass/GelMA support rapid bone mineralization for potential pulp regeneration. Int. J. Biol. Macromol 2023, 234, 123771. [Google Scholar] [CrossRef]
  145. Wang, Z.; Han, X.; Xiao, W.; Wang, P.; Wang, J.; Zou, D.; Luo, X.; Shi, L.; Wu, J.; Guo, L.; et al. Mussel-inspired adhesive drug-loaded hydrogels for oral ulcers treatment. Acta Biomater. 2024, 187, 98–109. [Google Scholar] [CrossRef] [PubMed]
  146. Ikeda, Y.; Holcroft, J.; Ikeda, E.; Ganss, B. Amelotin Promotes Mineralization and Adhesion in Collagen-Based Systems. Cell Mol. Bioeng. 2022, 15, 245–254. [Google Scholar] [CrossRef]
  147. An, Y.H.; Yu, S.J.; Kim, I.S.; Kim, S.H.; Moon, J.M.; Kim, S.L.; Choi, Y.H.; Choi, J.S.; Im, S.G.; Lee, K.E. Hydrogel functionalized Janus membrane for skin regeneration. Adv. Healthc. Mater. 2017, 6, 1600795. [Google Scholar] [CrossRef]
  148. Basak, S.; Bandyopadhyay, A. Solvent responsive shape memory polymers-evolution, current status, and future outlook. Macromol. Chem. Phys. 2021, 222, 2100195. [Google Scholar] [CrossRef]
  149. Zhao, H.; Akiba, N.; Tanimoto, H.; Yoshizaki, T.; Yalikun, K.; Minakuchi, S. Effects of temperature-responsive hydrogel on viscosity of denture adhesives. Dent. Mater. J. 2016, 35, 210–215. [Google Scholar] [CrossRef]
  150. Alia, A.; Gao, F.; Mitchell, J.C.; Gasiorowski, J.; Ciancio, M.; Kuppast, B.; Pfeifer, C.; Carrilho, M.R. Dentin primer based on a highly functionalized gelatin-methacryloyl hydrogel. Dental Materials 2023, 39, 192–203. [Google Scholar] [CrossRef]
  151. Mohamed, M.; Wahied, D.M.; Mohsen, R.; El Wakeel, A.M. The Effect of Poly (N-Isopropylacrylamide) Based Microgel Application on the Microtensile Bond Strength to Dentin: An In Vitro Study. Egypt. Dent. J. 2024, 70, 2753–2765. [Google Scholar] [CrossRef]
  152. Xie, S.X.; Boone, K.; VanOosten, S.K.; Yuca, E.; Song, L.; Ge, X.; Ye, Q.; Spencer, P.; Tamerler, C. Peptide Mediated Antimicrobial Dental Adhesive System. Appl. Sci. 2019, 9, 557. [Google Scholar] [CrossRef]
  153. Purcell, B.P.; Lobb, D.; Charati, M.B.; Dorsey, S.M.; Wade, R.J.; Zellars, K.N.; Doviak, H.; Pettaway, S.; Logdon, C.B.; Shuman, J.A.; et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 2014, 13, 653–661. [Google Scholar] [CrossRef] [PubMed]
  154. Muntean, A.; Sarosi, C.; Petean, I.; Cuc, S.; Carpa, R.; Chis, I.A.; Ilea, A.; Delean, A.G.; Moldovan, M. Developing Bioactive Hydrogels with Peptides for Dental Application. Biomedicines 2024, 12, 694. [Google Scholar] [CrossRef] [PubMed]
  155. Tao, S.; Su, Z.; Xiang, Z.; Xu, H.H.; Weir, M.D.; Fan, M.; Yu, Z.; Zhou, X.; Liang, K.; Li, J. Nano-calcium phosphate and dimethylaminohexadecyl methacrylate adhesive for dentin remineralization in a biofilm-challenged environment. Dent. Mater. 2020, 36, e316–e328. [Google Scholar] [CrossRef] [PubMed]
  156. Almahdy, A.; Koller, G.; Sauro, S.; Bartsch, J.; Sherriff, M.; Watson, T.; Banerjee, A. Effects of MMP inhibitors incorporated within dental adhesives. J. Dent. Res. 2012, 91, 605–611. [Google Scholar] [CrossRef]
  157. Zheng, P.; Chen, H. Evaluate the effect of different mmps inhibitors on adhesive physical properties of dental adhesives, bond strength and mmp substarte activity. Sci. Rep. 2017, 7, 4975. [Google Scholar] [CrossRef]
  158. Breschi, L.; Martin, P.; Mazzoni, A.; Nato, F.; Carrilho, M.; Tjäderhane, L.; Visintini, E.; Cadenaro, M.; Tay, F.R.; Dorigo, E.D.S. Use of a specific MMP-inhibitor (galardin) for preservation of hybrid layer. Dent. Mater. 2010, 26, 571–578. [Google Scholar] [CrossRef]
  159. Oguz Ahmet, S.; Mutluay, M.M.; Seyfioglu Polat, Z.; Seseogullari Dirihan, R.; Bek, B.; Tezvergil-Mutluay, A. Addition of benzalkonium chloride to self-adhesive resin-cements: Some clinically relevant properties. Acta Odontol. Scand 2014, 72, 831–838. [Google Scholar] [CrossRef]
  160. Khamverdi, Z.; Rezaei-Soufi, L.; Rostamzadeh, T. The effect of epigallocatechin gallate on the dentin bond durability of two self-etch adhesives. J. Dent. 2015, 16, 68. [Google Scholar]
  161. Bedran-Russo, A.; Yoo, K.; Ema, K.; Pashley, D. Mechanical properties of tannic-acid-treated dentin matrix. J. Dent. Res. 2009, 88, 807–811. [Google Scholar] [CrossRef]
  162. Zhang, J.; He, X.; Yu, S.; Zhu, J.; Wang, H.; Tian, Z.; Zhu, S.; Cui, Z. A novel dental adhesive containing Ag/polydopamine-modified HA fillers with both antibacterial and mineralization properties. J. Dent. 2021, 111, 103710. [Google Scholar] [CrossRef] [PubMed]
  163. Melo, M.A.S.; Cheng, L.; Weir, M.D.; Hsia, R.C.; Rodrigues, L.K.; Xu, H.H. Novel dental adhesive containing antibacterial agents and calcium phosphate nanoparticles. J. Biomed. Mater. Res. Part. B Appl. Biomater. 2013, 101, 620–629. [Google Scholar] [CrossRef]
  164. Gou, Y.-P.; Meghil, M.M.; Pucci, C.R.; Breschi, L.; Pashley, D.H.; Cutler, C.W.; Niu, L.-n.; Li, J.-y.; Tay, F.R. Optimizing resin-dentin bond stability using a bioactive adhesive with concomitant antibacterial properties and anti-proteolytic activities. Acta Biomater. 2018, 75, 171–182. [Google Scholar] [CrossRef]
  165. Seifi, M.; Eskandarloo, F.; Amdjadi, P.; Farmany, A. Investigation of mechanical properties, remineralization, antibacterial effect, and cellular toxicity of composite orthodontic adhesive combined with silver-containing nanostructured bioactive glass. BMC Oral Health 2024, 24, 650. [Google Scholar] [CrossRef] [PubMed]
  166. Elasser, D.M.; Niazy, M.A.; Elsharkawy, D.A.; Mansour, M.S. The remineralizing potential of nano bioactive glass versus nanohydroxyapatite on dentine as affected by pH cycling. Al-Azhar Dent. J. Girls 2018, 5, 327–334. [Google Scholar] [CrossRef]
  167. Khvostenko, D.; Hilton, T.; Ferracane, J.; Mitchell, J.; Kruzic, J. Bioactive glass fillers reduce bacterial penetration into marginal gaps for composite restorations. Dent. Mater. 2016, 32, 73–81. [Google Scholar] [CrossRef]
  168. Farooq, I.; Moheet, I.A.; AlShwaimi, E. In vitro dentin tubule occlusion and remineralization competence of various toothpastes. Arch. Oral Biol. 2015, 60, 1246–1253. [Google Scholar] [CrossRef]
  169. Aboelenein, A.Z.; Riad, M.I.; Haridy, M.F. Effect of a self-etch adhesive containing nanobioglass on postoperative sensitivity of posterior composite restorations-a randomized trial. Maced. J. Med. Sci. 2019, 7, 2313. [Google Scholar] [CrossRef] [PubMed]
  170. Samir, N.K.M.; El-Hoshy, A.; Helal, H.; Sayed, Y. One-Year Clinical Evaluation of a Fluoride, Calcium and Phosphate-Releasing New Bioactive Material versus a Fluoride-Releasing Hybrid Restorative Material in Cervical Lesions: A Randomized Clinical Trial. Adv. Dent. J. 2025, 7, 457–472. [Google Scholar] [CrossRef]
  171. Machado, A.C.; Maximiano, V.; Yoshida, M.L.; Freitas, J.G.; Mendes, F.M.; Aranha, A.C.C.; Scaramucci, T. Efficacy of a calcium-phosphate/fluoride varnish and ionomeric sealant on cervical dentin hypersensitivity: A randomized, double-blind, placebo-controlled clinical study. J. Oral Rehabil. 2022, 49, 62–70. [Google Scholar] [CrossRef] [PubMed]
  172. De Caluwé, T.; Vercruysse, C.; Declercq, H.; Schaubroeck, D.; Verbeeck, R.; Martens, L. Bioactivity and biocompatibility of two fluoride containing bioactive glasses for dental applications. Dent. Mater. 2016, 32, 1414–1428. [Google Scholar] [CrossRef]
  173. Bahador, A.; Ayatollahi, B.; Akhavan, A.; Pourhajibagher, M.; Kharazifard, M.J.; Sodagar, A. Antimicrobial efficacy of silver nanoparticles incorporated in an orthodontic adhesive: An animal study. Front. Dent. 2020, 17, 14. [Google Scholar] [CrossRef]
  174. Ekrikaya, S.; Yilmaz, E.; Arslan, S.; Karaaslan, R.; Ildiz, N.; Celik, C.; Ocsoy, I. Dentin bond strength and antimicrobial activities of universal adhesives containing silver nanoparticles synthesized with Rosa canina extract. Clin. Oral Investig. 2023, 27, 6891–6902. [Google Scholar] [CrossRef]
  175. Cascales, Á.F.; Moscardó, A.P.; Toledano, M.; Banerjee, A.; Sauro, S. An in-vitro investigation of the bond strength of experimental ion-releasing dental adhesives to caries-affected dentine after 1 year of water storage. J. Dent. 2022, 119, 104075. [Google Scholar] [CrossRef]
  176. Tohidkhah, S.; Kermanshah, H.; Ahmadi, E.; Jalalian, B.; Ranjbar Omrani, L. Marginal microleakage and modified microtensile bond strength of Activa Bioactive, in comparison with conventional restorative materials. Clin. Exp. Dent. Rese. 2022, 8, 329–335. [Google Scholar] [CrossRef]
  177. Oltramare, R.; Par, M.; Mohn, D.; Wiedemeier, D.B.; Attin, T.; Tauböck, T.T. Short-and long-term dentin bond strength of bioactive glass-modified dental adhesives. Nanomaterials 2021, 11, 1894. [Google Scholar] [CrossRef] [PubMed]
  178. Farooq, I.; Ali, S.; Al-Saleh, S.; AlHamdan, E.M.; AlRefeai, M.H.; Abduljabbar, T.; Vohra, F. Synergistic effect of bioactive inorganic fillers in enhancing properties of dentin adhesives—A review. Polymers 2021, 13, 2169. [Google Scholar] [CrossRef]
  179. Almulhim, K.S.; Syed, M.R.; Alqahtani, N.; Alamoudi, M.; Khan, M.; Ahmed, S.Z.; Khan, A.S. Bioactive inorganic materials for dental applications: A narrative review. Materials 2022, 15, 6864. [Google Scholar] [CrossRef]
  180. Kreutz, M.; Kreutz, C.; Kanzow, P.; Tauböck, T.T.; Burrer, P.; Noll, C.; Bader, O.; Rohland, B.; Wiegand, A.; Rizk, M. Effect of Bioactive and Antimicrobial Nanoparticles on Properties and Applicability of Dental Adhesives. Nanomaterials 2022, 12, 3862. [Google Scholar] [CrossRef]
  181. Abedin, F.; Ye, Q.; Good, H.J.; Parthasarathy, R.; Spencer, P. Polymerization- and solvent-induced phase separation in hydrophilic-rich dentin adhesive mimic. Acta Biomater. 2014, 10, 3038–3047. [Google Scholar] [CrossRef]
  182. Belli, R.; Kreppel, S.; Petschelt, A.; Hornberger, H.; Boccaccini, A.R.; Lohbauer, U. Strengthening of dental adhesives via particle reinforcement. J. Mech. Behav. Biomed. Mater. 2014, 37, 100–108. [Google Scholar] [CrossRef]
  183. Aydınoğlu, A.; Yoruç, A.B.H. Effects of silane-modified fillers on properties of dental composite resin. Mater. Sci. Eng. C 2017, 79, 382–389. [Google Scholar] [CrossRef] [PubMed]
  184. Li, W.; Wang, K.; Wang, Z.; Li, B. Optimal resin monomer ratios for light-cured dental resins. Heliyon 2022, 8, e10554. [Google Scholar] [CrossRef] [PubMed]
  185. Mokeem, L.S.; Garcia, I.M.; Melo, M.A. Degradation and Failure Phenomena at the Dentin Bonding Interface. Biomedicines 2023, 11, 1256. [Google Scholar] [CrossRef]
  186. Xie, Y.; Chen, R.; Yao, W.; Ma, L.; Li, B. Synergistic effect of ion-releasing fillers on the remineralization and mechanical properties of resin-dentin bonding interfaces. Biomed. Phys. Eng. Express 2023, 9, 062001. [Google Scholar] [CrossRef]
  187. Frassetto, A.; Breschi, L.; Turco, G.; Marchesi, G.; Di Lenarda, R.; Tay, F.R.; Pashley, D.H.; Cadenaro, M. Mechanisms of degradation of the hybrid layer in adhesive dentistry and therapeutic agents to improve bond durability—A literature review. Dent. Mater. 2016, 32, e41–e53. [Google Scholar] [CrossRef] [PubMed]
Jfb 16 00418 g001
Figure 1. Key Functional Components of Bioactive Adhesives Preventing Recurrent Caries.
Figure 1. Key Functional Components of Bioactive Adhesives Preventing Recurrent Caries.
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Nizami, M.Z.I.; Jindarojanakul, A.; Ma, Q.; Lee, S.J.; Sun, J. Advances in Bioactive Dental Adhesives for Caries Prevention: A State-of-the-Art Review. J. Funct. Biomater. 2025, 16, 418. https://doi.org/10.3390/jfb16110418

AMA Style

Nizami MZI, Jindarojanakul A, Ma Q, Lee SJ, Sun J. Advances in Bioactive Dental Adhesives for Caries Prevention: A State-of-the-Art Review. Journal of Functional Biomaterials. 2025; 16(11):418. https://doi.org/10.3390/jfb16110418

Chicago/Turabian Style

Nizami, Mohammed Zahedul Islam, Apissada Jindarojanakul, Qiang Ma, Sang J. Lee, and Jirun Sun. 2025. "Advances in Bioactive Dental Adhesives for Caries Prevention: A State-of-the-Art Review" Journal of Functional Biomaterials 16, no. 11: 418. https://doi.org/10.3390/jfb16110418

APA Style

Nizami, M. Z. I., Jindarojanakul, A., Ma, Q., Lee, S. J., & Sun, J. (2025). Advances in Bioactive Dental Adhesives for Caries Prevention: A State-of-the-Art Review. Journal of Functional Biomaterials, 16(11), 418. https://doi.org/10.3390/jfb16110418

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