The process of cavity preparation has a deciding influence on the quality of outcome and the longevity of composite resin restorations. Proper cavity design and suitably completed preparation require thorough consideration of the different biomechanical and esthetic aspects of the tooth in concern, as well as the influencing factors of the oral environment. Nevertheless, full recognition of the extent of the carious lesion and the amount of remaining sound tooth structure is crucial. In this regard, effective rubber dam isolation before cavity preparation is mandatory whenever possible to assure adequate visibility, sound judgement and accurate fulfillment. An appropriately prepared cavity is a prerequisite for optimum bonding, good adaptation, and an effective marginal seal ^[1][19].

The European Organization of Caries Research (ORCA) and the International Association of Dental Research (IADR) have recently discussed and agreed on the most appropriate definitions related to caries based on the present concepts and modern understanding of dental caries and associated managements ^[2][20]. Accordingly, primary caries is a carious lesion in a previously sound tooth surface, while secondary or recurrent caries is a carious lesion that has developed adjacent to a restoration, and residual caries is a demineralized carious tissue left in place before the restoration is placed ^[1][19].

Secondary or recurrent caries are two interchangeably used terms describing carious lesions that are principally divided into two categories: surface and wall lesions. The old concept of complete or non-selective caries removal to hard dentin requires the excavation of caries to hard dentin in the entire cavity ^[2][20]. The removal of all carious tissues and extending cavity margins to presumably less caries-prone areas of the tooth surface to prevent caries recurrence is currently considered an unjustifiable and radical approach that sacrifices the biomechanical and esthetic integrity of the tooth structure. Conversely, more conservative approaches are adopted that minimize surface extensions to a minimal intervention approach, while at the same time limiting caries excavation to infected dentin, leaving behind the affected remineralizable dentin ^[2][20].

This paradigm shift in dental caries management has been widely accepted to replace the old concept of “extension for prevention”. A current scale of recommendations and options exists to treat extensive carious lesions, limiting removal to heavily infected and necrotic dentin and maintaining the remineralizable caries-affected dentin. The objective is to preserve the vitality of the pulp and extend the life span of the tooth as a functioning unit in the dental arch ^[1][2][19,20]. Strong evidence of systematic reviews, meta-analyses and clinical trial studies have demonstrated the high success rate of selective or partial caries removal procedures over complete caries removal. Cumulating evidence continues to support incomplete caries removal and discourage complete caries removal in deep cavities. Regardless of the controversy over whether or not residual infected caries is arrested in cavities sealed with restorations, it is more important to create effective and reliable restorations than to completely remove caries ^[3][21]. In a recent clinical study, it was found that the bacterial load under restorations was initially lower with complete versus selective caries removal, but was similar in both cases three months after the cavities were sealed with restorations ^[4][22].

Modern conservative deep caries treatment comprises two techniques: partial caries removal and stepwise caries removal. Partial caries removal is a procedure by which dentin caries is removed from the outer zones of a deep cavitated caries lesion (excavated to hard dentin), followed by the partial removal of soft dentin from the pulpal wall with a hand excavator or round bur. Treatment is indicated for deep dentin lesions to avoid pulp exposure ^[1][19]. In partial caries removal there is no second visit, and initial caries removal is followed by sealing the restoration with a final restoration ^[5][23].

Stepwise caries removal, on the other hand, is caries excavation in two (or more) steps, with a time interval between the steps to stimulate mineral deposition in the dentin prior to final excavation. In the first visit, the surrounding cavity walls are excavated until hard dentin is reached, while only the necrotic, disorganized dentin is removed at sites of proximity to the pulp until the level of soft dentin is reached. The cavity is then sealed with a provisional restoration over a period of 6 weeks to 12 months. The first step is partial caries excavation followed by additional caries removal to a firm or leathery dentin in the later visit, before insertion of the final restoration ^[2][20]. The literature shows some evidence that the success rate of one-visit partial caries removal is higher than stepwise caries excavation ^[6][7][24,25].

Although partial caries removal involves leaving a layer of infected dentin for the sake of preserving the vitality of the pulp in deep caries with a high risk of pulp exposure, cariogenic bacteria beneath clinically reliable restorations will eventually die or become markedly inactive ^[6][24].

The clinical identification of caries zones, where texture correlates with the degree of infection and the viability of dentin tissue, remains a crucial guideline for conservative caries management. Soft caries is similar to cottage cheese in texture, readily deforms upon pressing with a hand instrument, and can be easily peeled off with excavators indicating infected dentin with dissembled collagen framework cross-links ^[8][26]. Leathery dentin does not yield upon pressing and needs higher pressure to be removed with an excavator and lays in the middle of the range between soft and firm dentin. On the other hand, firm dentin is more resistant to physical pressure and needs more pressure for lifting by hand excavators. Leathery/firm dentin indicates caries-affected dentin with sound remineralizable collagen plexus configurations ^[8][26]. Hard dentin is a sound healthy dentin that requires a sharp cutting edge or a bur to be removed and has a scratchy sound of “cri dentaire” upon probing ^[9][27].

A main challenge of partial and stepwise caries removal procedures is the clinical endpoint of dentin caries excavation that frequently relies on the subjective tactile sensation of the soft, leathery, firm, and hard dentin with a lack of exact correlation with the actual histopathological features of dentin caries ^{[2][10][11][12]}[2,20,28,29].

In a survey performed in three European countries in 2016, most dentists found dentin color inadequate as a criterion of caries removal, reporting that they rely on dentin hardness to assess dentin caries excavation with an aim of reaching hard dentin in proximity to pulp ^[13][30]. On the other hand, a survey conducted in 2015 found a wide range of variety between dental schools’ programs regarding the management of deep caries and the exact definition of caries remaining at deep cavity sites. The study indicated the need to establish consistency between cumulating evidence and teaching, as well as the calibration of examiners upon evaluating cavities with deep caries ^[14][31].

Evidence-based reports recommend two possible clinical endpoints of dentin caries excavation in partial caries removal procedures. The first one is selective caries removal to soft dentin, which is indicated in deep caries that has progressed to the inner third of dentin with a high risk of pulp exposure upon complete caries removal. HIn this caserein, a limited layer of infected soft dentin is left behind near the pulp to avoid pulp exposure and maintain pulp vitality. The second is selective caries removal to leathery/firm dentin (physically resistant to hand excavation). This is indicated in moderate-depth lesions that have not reached the inner third of the dentin. In all cases, however, the surrounding walls of the cavity should be excavated to hard sound dentin ^[15][32].

Using liners of calcium hydroxide or resin-modified glass ionomer after partial caries removal in deep carious lesions may not be an essential prerequisite for the clinical success of the procedure ^[16][33]. Conversely, calcium hydroxide and glass ionomer liners proved successful in reducing the number of viable bacteria remaining and the quality of residual caries left behind after partial caries removal ^[17][34]. To arrest residual caries and enhance remineralization in deep carious lesions managed by partial caries removal, ozone and silver diamine fluoride treatments were suggested ^[18][19][20][35,36,37]. Further studies are needed to confirm procedural effectiveness, any adverse effects on bonding, biocompatibility, or deep penetration, and esthetic consequences ^[21][38].

A liner of glass ionomer can impart a required antibacterial potential because of the fluoride content. On the other hand, the use of cavity cleansers in cases of partial caries removal procedures can provide antibacterial and antiproteolytic activities, thus improving resin–dentin bond stability and reducing the number of viable bacteria remaining in dentin. On the other hand, materials such as MTA and calciumhydroxyde are effective as pulp-capping materials for their therapeutic effect in inducing reparative dentin formation. Therefore, it is recommended to use them when direct or indirect pulp capping is needed ^{[22][23][24][25]}[39,40,41,42].

The rationale in conservative deep caries management is to achieve an intelligent balance between the protection of pulp vitality and the avoidance of pulp exposure due to overzealous caries excavation from one side and attaining reliable bonding and a tight seal by excavating an adequate amount of carious dentin on the other side. A proper diagnosis of the pre-existing status of the pulp, adequate history taking, pulp sensibility testing, a percussion test, and radiographic examination are essential to confirm normal vital pulp before deep caries management procedures take place ^[26][43]. For the successful minimally invasive management of deep carious lesions, effective marginal seal and reliable bonding must be achieved.

Based on the new understanding of caries as biofilm-induced rather than an infectious disease, residual or remaining dentin caries beneath an existing restoration are not considered a failure since a peripheral well-sealed restoration is more clinically relevant ^[10][27][28][2,13,44]. In this regard, the presence of radiolucent zones beneath composite restorations are not considered a justification for restoration replacement ^[29][45].

Systematic reviews, meta-analyses and clinical trials reveal that evaluating partial and stepwise caries removal are based on collecting symptoms of pain and the assessment of clinical signs of adverse pulp reactions. Clinical procedures of inspecting the presence of swelling or fistulous tract, pulp testing, palpation and percussion tests, in addition to radiographic examination, are usually employed. However, there is inadequate evidence regarding the risk of the future failure of restorations with incomplete and stepwise caries removal ^[30][46]. Moreover, there is a lack of exact consistency between subjective clinical signs and symptoms and the actual histopathological status of the pulp tissue. Pulp reaction to dental caries starts as early as enamel caries and advances as caries progresses. Therefore, a careful clinical evaluation of pulp status is mandatory in deep caries evaluation ^[12][31][32][3,29,47].

Well-designed long-term clinical studies are needed to validate the future risk of restoration failure and the development of irreversible adverse pulp consequences following these procedures ^[33][48]. This is particularly true with high-caries-risk individuals. An exact distinction between new recurrent caries and residual caries beneath an old restoration is missing. The sensitivity and specificity to radiolucent lines beneath a resin composite restoration was less than 80% ^[29][45].

Research displayed that bacteria remain in the dentinal tubules after cavity preparation without indicating that the remaining bacteria predispose the progression of caries or restorative failure. The natural defense mechanism of dentin sclerosis in slowly progressing caries and laying down tertiary dentin on the pulpal side of deep lesions helps prevent further bacterial invasion. Nevertheless, the number of bacteria in the superficial zones of caries is much greater than in deeper caries zones, indicating the judicious removal of heavily infected non-viable degenerated dentin ^[32][47]. Longitudinal research indicates that the proper isolation of cariogenic bacteria from nutritional resources by an integrated restoration carries no risk of future caries progression. The use of cavity disinfectants such as glutaraldehyde and chlorohexidine is of limited or no benefit if clinically significant marginal gaps and evident microleakage are encountered ^[6][34][24,49].

Several techniques could help in decision-making for the endpoint of caries removal in selective caries excavation ^[35][36][50,51]. Caries detection dyes, polymeric and ceramic burs, and chemomechanical caries removal are among the suggested mechanisms. Fluorescence-aided caries excavation (FACE) uses orange–red fluorescence as a sign of heavy bacterial infection and a barometer for caries removal until the level of green sound dentin fluorescence ^[31][37][38][3,52,53]. FACE is an effective tool to assess residual caries in vivo ^[39][54]. FACE and polymer burs are currently employed by undergraduate students in some dental schools to treat teeth with deep caries. A clinical and microbiological assessment found polymeric burs more efficient in deep caries excavation than a chemomechanical technique ^[40][55]. Caries removal with the self-limiting polymer bur does not interfere with effective bonding to dentin ^[41][56]. The bonding performance to residual dentin caries varies between caries removal techniques regardless of the reported improvements in bond strength values of different bonding agents. Moreover, there is no completely reliable diagnostic tool for assessing the fate of residual caries ^[35][50].

In vitro FACE is more effective in caries removal than a caries detector dye and conventional caries excavation when considering the quantity of remaining bacteria ^[42][57]. The use of DIAGNOdent light fluorescence technology to guide caries removal using an Er:YAG laser with a threshold reading of 7 for circum-pulpal dentin left behind dentin collagen with intact links denoting vital dentin ^[43][44][58,59].

Determining an optimum endpoint upon deep caries removal in teeth with normal vital pulp is a focus of interest for researchers and clinicians. It has been recommended to use anatomical and histopathological knowledge together with caries detection dyes and light fluorescence. The objective is to preserve pulp vitality and limit deep caries removal to heavily infected layers. Preventing the progress of residual caries in partial and stepwise caries removal mandates durably effective bonding to dentin and tightly sealed margins with prepared cavities of peripheral hard dentin walls and sound non-carious enamel ^[45][60]. The successful management of deep caries should consider that bonding to caries-affected dentin is 33% weaker than bonding to hard dentin due to the adverse resin penetrability of the decreased mineral content of caries-affected dentin. Infected dentin, on the other hand, has a weak disorganized structure and exhibits 78% less bond strength than hard dentin ^[46][61].

To determine an objective clinical endpoint during dentin caries removal and to assess the clinical effectiveness of some conservative minimal intervention caries excavation techniques, a microCT study was conducted. The studied techniques included round tungsten carbide bur, tungsten carbide bur with caries detection dye, an air scaler with oscillating tungsten carbide tips, Carisolv chemomechanical caries removal with a mac-tips Carisolv instrument, CeraBur ceramic bur with a self-limiting ability endpoint, a Er:YAG laser, and three suggested experimental methods using hand metallic or plastic excavators. The study found the Er:YAG laser aided by laser-induced fluorescence to be most effective as a selective caries removal technique and that rotary burs with or without caries detection dye are aggressive methods of caries removal ^[47][62]. On the other hand, CeraBur and Carisolv were even more conservative, indicating that chemomechanical caries removal is superior to selective caries removal with the preservation of hard sound dentin ^[47][62]. Educational programs in different dental colleges around the world still face controversy in teaching and in the clinical assessment of students regarding the management of deep carious lesions. An increasing trend towards the conservative management of deep carious lesions in different dental educational programs is evident ^[14][41][48][31,56,63].

Papain-based chemomechanical caries removal gel has encouraging potential to effectively and more conservatively remove caries than conventional mechanical caries excavation methods ^[49][64]. However, a cell culture study found papain-based gels with some cytotoxicity to dental pulp cells ^[50][65]. A recent clinical trial compared two chemomechanical caries removal agents, sodium hypochlorite and a papain-based enzymatic gel Brix 3000 with conventional low-speed burs for caries removal. Both gels perform significantly better than conventional caries removal, with a similar performance ^[51][66].

A systematic review and meta-analysis conducted in 2016 found almost one-half of dentists refuse the evidence-based recommendations of selective/incomplete removal of caries. The study recommended progressive investigation with qualitative elements for a deeper understanding of the barriers against the broader implementation of less invasive deep caries management ^[52][67].

The diagnosis of recurrent caries at its early stage is crucial to avoid failed restoration. A clinical review and meta-analysis found that although recurrent caries is an obvious dental health problem, its detection has been investigated by a limited number of studies with little information about the validity and appropriateness for clinical use. The study concluded that visual, radiographic and laser fluorescence might be valuable diagnostic measures of recurrent caries and that the appropriateness of tactile monitoring and quantitative light-induced fluorescence needs further confirmation ^[53][68].

In vitro, cone beam computed tomography (CBCT) is effective at detecting secondary caries in occlusal resin composite restorations with less reliability in MOD restorations ^[54][69]. Moreover, in MOD resin composite restorations, CBCT is more effective in the detection of recurrent caries than digital radiography ^[55][70]. There is a poor-to-moderate agreement between evaluators of CBCT for recurrent caries detection in extracted teeth, although it is more effective than digital radiography ^[56][71]. Furthermore, CBCT’s higher radiation dose than digital radiography adds to the impracticality of using it clinically for recurrent caries diagnosis ^[27][13]. In vitro, swept-source optimum coherence tomography (OCT) could detect caries beneath composites with a limited depth of imaging and inaccuracy in examining deep restorations ^[57][72]. Near-infrared transillumination and reflection at wavelengths from 1300 to 1700 nm showed potential for detecting secondary caries in the first in vitro studies ^[58][73]. Presently, there is a shortage of consensus and reliable standards and strategies for the accurate diagnosis of recurrent caries.

2. Polymerization Shrinkage and Adverse Consequences of Marginal and Internal Gaps

Resin composites are composed of an organic polymeric matrix, inorganic filler particles, and silane coupling agents ^[59][79]. As a result of a polymerization reaction, monomers bond into a three-dimensional network of polymeric chains filled with inorganic fillers. The polymerization reaction is accompanied by volumetric shrinkage as the polymer’s chains form. Upon initiation of the polymerization reaction, the C=C double bonds in the dimethacrylate monomer molecules that form the organic phase of most dental composites convert into a C-C single bond with polymer chain formation as additional polymerization reaction progresses ^[60][61][80,81]. During polymerization, when a resin composite is restricted from contraction by the surrounding cavity wall confinements following bonding procedures, interfacial contraction stresses develop at the interface. Marginal and interfacial contraction gaps can arise when these stresses surpass the interfacial bond strength ^[62][82]. Interfacial gaps may predispose to recurrent caries in the form of wall lesions. In in vivo study models, caries does not develop in perfect composite–adhesive–dentin bonding, but wall lesions caries occur in all sites of faulty bonding with interfacial gaps ^[63][83]. Microleakage due to contraction gaps may also lead to post-restoration hypersensitivity, marginal discoloration, and adverse pulp reactions. Moreover, polymerization contraction stresses may induce pulling action on cusps and the cracking of tooth structure ^[64][84]. Not all marginal and interfacial gaps can cause recurrent caries, and there is no general agreement on an exact threshold of gap size for the incidence of recurrent caries ^[65][66][11,85]. However, interfacial gaps larger than 60 μm might lead to interfacial demineralization ^[27][13]. In all cases, the patient’s caries risk status is a critical decision-making factor when recurrent caries is considered ^[66][85]. The interfacial stresses due to the volumetric polymerization shrinkage of composites against bonded side walls of the cavity are influenced by many factors. These include the type of resin composite, the chemistry of the organic matrix, the technique of insertion, cavity configuration factor (C-factor), the type of adhesive bonding agent, and the nature of the substrate, i.e., tooth surface enamel or dentin. The cavity configuration factor (or C-factor) accounts for the ratio between bonded to free surfaces ^[67][86]. Increasing the number of confining constraints of bonded surfaces predisposes the patient to higher polymerization contraction stresses and an increased risk of marginal and interfacial gap development. However, the correlation between C-factor and polymerization contraction stresses should consider the compliance of the prepared tooth structure that varies at different cavity locations ^[62][82]. The non-destructive assessment of resin composite polymerization shrinkage, shrinkage vectors, and interfacial gaps was facilitated using a hybrid technology of microCT scanning and digital image analysis. This opened the door for studying the shrinkage patterns of various resin composites and bonding agents with different cavity boundaries, cavity configurations and material insertion techniques ^{[68][69][70][71]}[87,88,89,90]. In large occlusal cavities with undermined enamel, debonding from the cavity floor is observed due to shrinkage away from the cavity floor ^[72][91]. Even different composite application methods influence the shrinkage patterns and vector length values. Bulk applications yield larger shrinkage vectors than incremental applications, but material-related factors such as the volumetric shrinkage, shrinkage stresses and time to gelation should be considered ^{[68][73][74][75]}[87,92,93,94].

2.1. Protocols to Improve Marginal SEAL and Interfacial Bonding

A biomechanically and esthetically reliable resin composite restoration should be able to restore hard tooth structure defects effectively and durably. Moreover, it should bioactively integrate with the tooth hierarchical complex and surrounding environment, mimicking natural tooth structure construction and physiological biofunction ^[76][77][95,96]. The literature shows several protocols to improve the performance of resin composite restorations and minimize the future risk of recurrent caries. Ongoing research is based on a modern understanding of dental caries, bonding and resin composite material technology, as well as contemporary approaches to biomimetic restorative dentistry and bioactive integration. In resin composite restorations, an effective and long-term peripheral and internal seal preventing or minimizing marginal and interfacial gaps calls for two basic strategies of clinical protocols. These are maximizing bond effectiveness and reducing the development of interfacial stresses ^[78][97]. Resin composites are technique-sensitive materials. Maximizing bonding effectiveness and minimizing interfacial stresses requires meticulous attention to the details of the bonding procedure. Full recognition of the individual oral environmental factors is instrumental. It is the responsibility of the restorative dentist to select the most suitable resin composite material and restoration technique, and choose between etch-and-rinse, self-etch and selective (enamel etching) strategies. ItThe aim is to provide clinically effective tooth–resin composite adhesive junctional complexes with long-term stability ^[70][79][89,98]. Different techniques can improve bonding, reduce interfacial polymerization contraction stresses and improve adaptation at the critical cervical margin of class II resin composites. This includes assuring an adequate degree of conversion of light cure materials. A poor degree of conversion of resin composite restorative materials and bonding agents deteriorates the physicochemical properties of the material, leads to poor bonding, and increases the risk of future caries recurrence ^[80][99]. Ideally, the light-curing tip should be close, less than 1 mm away from the surface of the resin composite. The greater this distance, the less light energy that reaches the material to produce an adequate degree of conversion. At greater than 5 mm cavity depth, such as in deeply inserted resin composite increments in deep cavity locations, extra care should be given during light curing. In locations such as the gingival seat of class II cavities or in core build-ups, curing light exposure time should be increased or a dual-cure resin composite might be preferable to assure an adequate degree of conversion ^[81][82][83][100,101,102]. For adequate curing light energy, an incremental insertion of a maximum 2 mm thick increment of a conventional composite is recommended. Alternatively, bulk-fill composites can be cured as a bulk insertion with a 4–5 mm thick increment. Manufacturers of bulk-fill composites recommend using a light-curing unit with a minimum energy output of 1000 mW/cm² to attain adequate curing at the deep proximal parts of class II cavities for 40 s. Three-directional curing by providing an occlusal light-curing exposure for 40 s followed by a second one from a buccal direction and a third one from a lingual direction can also help to attain an adequate degree of conversion at gingival locations of class II cavities ^[84][85][103,104]. Moreover, the light-curing source should be perpendicular to the curing surface of the composite to assure direct access and avoid the shadowing effect of intervening tooth structure ^[86][105]. To reduce interfacial contraction stresses, the use of lower curing rates such as soft-start curing to maintain the ability of the material to have an extended pre-gel stage to flow and deform during contraction is advocated. Lower light curing rates, however, should not interfere with attaining an adequate degree of curing. The use of low shrinkage composite is another option to reduce interfacial contraction stresses ^[87][106]. The adequate curing of resin bonding agents is essential for effective and stable bonding. The initial light curing of bonding agents is boosted by applying a layer of a flowable composite of less than 1 mm thickness at the gingival wall of class II cavities in open or closed sandwich techniques, or as an initial thin liner on the pulpal, axial, and gingival walls of class II cavities (cavity floor). Light passing through this layer facilitates further curing of the subjacent bonding agent, particularly for the air-inhibited surface layer of the resin bonding agent. Moreover, this flowable composite layer provides a zone of resilience during curing and flexibly yields during polymerization contraction of the higher stiffness composite of the subsequent increments ^[74][75][88][93,94,107]. The use of resin-modified glass ionomer liners is another alternative sandwich technique, with debates regarding the durability and degradation vulnerability ^[89][108]. The use of bulk-fill composites furnishes the advantages of reduced time and efforts of application, in addition to avoiding the incorporation of air voids during conventional incremental application with adverse influences on material properties. Bulk-fill composites have higher translucency and different photo-initiator systems to assure an adequate degree of conversion in increased thickness in comparison to conventional incremental composites. Moreover, the resin matrix of many bulk-fill composites contains contraction stress-absorbing resins to reduce the interfacial contraction stresses ^[84][103]. Flowable bulk-fill composites used as dentin replacement materials might produce a better marginal seal, particularly when the gingival margin of class II resin composites is at a deeper location gingivally ^[84][103]. Conversely, out of 140 in vitro studies and 14 in vivo investigations, a recent systematic review and meta-analysis concludes that using an intermediate layer of flowable composite cervically in the proximal box of class II resin composites does not provide an advantage in effectiveness. Upon data search and analysis, the authors favored bond strength investigations over microleakage studies. Further studies are recommended before a clear-cut conclusion can be drawn due to wide variations in the employed techniques and testing methodology of the analyzed studies ^[90][109]. Preheating the resin composite and inserting the material under sonic vibrations are reported among the suggested insertion techniques. Although these techniques improve the degree of curing, reduce internal voids, and improve strength, controversies exist regarding their validity to promote adaptation with different resin composites ^{[91][92][93][94]}[110,111,112,113]. Since all resin composites show inherent limitations of unavoidable volumetric polymerization contraction, indirect restorative options might be advisable in large-size cavities so that shrinkage would take place outside of the prepared cavity. Evidence indicates that ceramic and resin composite inlays and onlays, including those for CAD/CAM technology, have excellent long-term clinical performance and can constitute better alternatives to direct composites in extensive cavities ^[95][96][114,115]. Immediate dentin sealing is a procedure where etch-and-rinse or self-etch adhesive resin is applied on freshly cut dentin surfaces before impression-taking in indirect restorations. The technique facilitates stress-free dentin bonds, preventing bacterial leakage and sensitivity during the temporization phase. Although the procedure improves the bonding quality and reliability of indirect restorations and elicits a better in vitro adaptation of ceramic inlays, it increases the marginal gap width of ceramic laminate veneers ^[97][98][116,117].

2.2. Biodegradation of Resin Bonds and Hybrid Layer

2.2.1. Mechanisms of Biodegradation of Resin Bonds to Dentin

The oral cavity constitutes a challenging complexity that adversely affects all dental restorative materials, leading to a time-dependent gradual deterioration in restoration performance and clinical reliability. Unavoidable conditions of humidity and moisture, as well as fluctuations in functional loading, thermal and pH cycling normally occur in the oral cavity. Furthermore, natural oral habitats of microorganisms of more than 700 different species with their complicated biochemical activities, acidic and enzymatic products ordinarily exist ^[99][118]. These influencing factors act together to compete and gradually degrade dental restorations and interfacial attachment complexes ^[100][101][4,119]. Resin bonding to dentin is a routine practice in restorative dentistry for direct and indirect restorations ^[102][120]. The procedure involves either etch-and-rinse or self-etch approaches. Postoperatively, gradual time-dependent hydrolytic degradation of the resin adhesives that have infiltrated the collagen plexus of the hybrid layer takes place with the leaching of resin adhesive degradational products. The process is more pronounced with poorly polymerized resin adhesives and becomes aggravated as the resin adhesive progressively degrades, exposing the previously infiltrated collagen. Water penetration and movement across the exposed collagen plexus of the hybrid layer progressively increase, creating water-filled channels and the vulnerability of denuded collagen to enzymatic proteolysis ^[103][121]. Endogenous collagenolytic enzyme MMPs and cysteine cathepsins are bound in mineralized dentin. The acidic treatment of the dentin surface activates the MMPs present in the dentin matrix in an inactive form, which becomes responsible for the degradation of collagen in the hybrid layer, together with cysteine cathepsins ^[104][122]. With the etch-and-rinse approach, the incomplete penetration of the collagen plexus leaves a denuded collagen layer at the bottom of the hybrid layer with vulnerability to the MMPs’ degradational activities ^[105][123]. Self-etch adhesive procedures involve synchronized etching and the resin infiltration of dentin collagen, avoiding incomplete resin infiltration. However, self-etch adhesives act as a water-permeable membrane, creating a water-treeing reticular fashion of water penetration leading to a characteristic nanoleakage pattern of self-etch adhesives predisposed to biodegradation ^[103][106][121,124]. The long-term deterioration of resin dentin interfacial bonds can be due to the degradation of the hybrid layer collagen fibrils and the hydrolytic degradation of the resin component of the hybrid layer, as well as due to endogenous host proteases and exogenous proteases produced by bacterial metabolic activities. The possible clinical adverse consequence of such deterioration includes increased hypersensitivity, recurrent caries, marginal discoloration, and the development of reversible and irreversible pulpitis ^[107][108][7,125]. This enzymatic degradation is further aggravated by the adverse influences of functional loading, thermal and pH cycling, and the humidity of the oral environment ^{[109][110][111]}[126,127,128].

2.2.2. MMPs Inhibitors

Four TIMPs (1, 2, 3, 4) are isolated from human tissues and fluids. These natural endogenous MMP inhibitors regulate and control MMPs’ expression and function. Each has a specific gene regulation pattern, expression profile, and binding affinity to specific MMPs ^[112][129]. Several attempts suggest inhibiting MMPs to control caries ^[113][130] and/or maintain the effectiveness of resin adhesive bonds to dentin ^[114][115][131,132]. One of the most widely used MMP inhibitors is chlorohexidine, which effectively and nonspecifically reduces collagen degradation via MMPs and other collagenolytic enzymes such as cysteine cathepsins. Chlorohexidine is used to control caries, to treat the dentin surface after acid etching, or is incorporated into the bonding agent to boost bonding effectiveness and longevity ^[113][130]. Different studies and systematic reviews indicate that chlorohexidine improves the long-term stability of resin bonds to dentin, with some limitations concerning the test aging periods and the need for more supportive clinical data ^[114][131]. In an experimental study, pH-sensitive nanocarriers of mesoporous silica loaded with chlorohexidine are incorporated in an experimental resin bonding agent to provide MMPs’ inhibiting effect in an acidic microenvironment produced by acid etching and dental caries ^[116][133]. The controlled release of chlorohexidine at the dentin surface by adding clays to dentin bonding agents is found to improve the durability of resin bonds to dentin ^[117][134]. Another strategy modifies resin adhesives by adding doxycycline-loaded nanotubes which inhibit MMPs without cytotoxicity or compromising the physicomechanical properties of the bonding agent ^[118][135]. Ethylene-diamine-tetra-acetic acid, tetracyclines, galardin, batmastarti, benzalkonium chloride, quaternary ammonium silane, alcohols and quaternary ammonium compounds have MMP-inhibiting potential. The application of different cross-linking agents tries to inhibit MMPs in dental caries and increase the resistance of dentin collagen degradation and improve resin dentin bond longevity. In this respect, proanthocyanidin, glutaraldehyde, riboflavin, reservaratol, and quercetin are recommended. Competing for the active sites in collagen molecules with zinc-containing compounds such as zinc oxide or zinc chloride in the resin adhesive is also proposed. Natural extracts such as carbodiimide and epigallocatechin-3-gallate are applied to the dentin surface as pretreatments before bonding procedures to induce a dual function by competing for the active sites in collagen and providing collagen cross-linking effects ^[119][120][136,137]. Remineralization potentials of the denuded collagen plexus using different remineralizing agents such as fluorides in fluoridated bonding agents or the incorporation of nanoparticles such as zinc oxide, silver, and copper improve the bond stability and collagen degradation resistance. Using laser treatment for dentin and modifying bonding procedures by applying a layer of hydrophobic resin are also advocated ^{[107][121][122][123][124]}[7,138,139,140,141].entin ^[125][126][146,147].