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| REVIEW ARTICLE |
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| Year : 2013 | Volume
: 3
| Issue : 3 | Page : 151-158 |
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An update on remineralizing agents
Shashi Prabha Tyagi, Paridhi Garg, Dakshita Joy Sinha, Udai Pratap Singh
Department of Conservative Dentistry and Endodontics, Kothiwal Dental College and Research Centre, Moradabad, Uttar Pradesh, India
| Date of Web Publication | 21-Apr-2014 |
Correspondence Address:
Paridhi Garg
Department of Conservative Dentistry and Endodontics, Kothiwal Dental College and Research Centre, Moradabad, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2229-5194.131200
 Abstract | | |
Modern dentistry aims to manage non-cavitated carious lesions non-invasively through remineralization in an attempt to prevent disease progression, and to improve form, function, strength and esthetics of teeth. The emphasis currently is being laid upon new technologies for enamel remineralization. Further studies are required on biomimetic molecules involved in calcium fluoride phosphate stabilization and nucleation that may provide further improvements in the development of novel remineralization treatments. The aim of this paper is to review the contemporary remineralizing systems available for remineralization therapy and their implementation into clinical practice. A search of articles from "Pubmed" and "Medline" with the keywords Remineralization- demineralization, Casein derivatives, fluoridated remineralizing agents and non-fluoridated remineralizing agents was conducted. A total of 810 abstracts were collected, of which 351 articles that discussed the current technologies of remineralizing agents were read and 71 most relevant articles were included in this paper.
Clinical Relevance to Interdisciplinary Dentistry
- All work in the health field is aimed at conservation of the human body and its function; similarly, dentistry's goal should be to preserve healthy, natural tooth structure. Modern dentistry aims to manage non-cavitated carious lesions non-invasively through remineralization. Remineralizing agents can also find its application in other fields of dentistry like pedodontics, periodontics and orthodontics. It can help in mineralization and management of hypocalcified lesions. It can be used for desensitization of exposed dentine affected by dental erosion. It can be used after debonding of brackets in lieu of completion of orthodontic treatment.
Keywords: Caries, demineralization, enamel, remineralization, remineralizing agents
How to cite this article:
Tyagi SP, Garg P, Sinha DJ, Singh UP. An update on remineralizing agents. J Interdiscip Dentistry 2013;3:151-8 |
| Introduction | |  |
Remineralization is defined as the process whereby calcium and phosphate ions are supplied from a source external to the tooth to promote ion deposition into crystal voids in demineralized enamel to produce net mineral gain. [1]
"Extension for Prevention" has given way to the new paradigm of minimally invasive dentistry. The minimally invasive approach to treat dental caries incorporates the dental signs of detecting, diagnosing, intercepting and treating dental caries on the microscopic level. [2]
The principles of minimal intervention in the management of dental caries (adopted by the FDI General Assembly, 1 st October, 2002, Vienna) are:
- Modification of oral flora
- Patient education
- Remineralization of cavitated lesions of enamel and dentin
- Minimal intervention of cavitated lesions
- Repair of defective restorations.
The purpose of this review is to have an in-depth knowledge of the natural phenomenon of enamel demineralization and remineralization while discussing the clinical relevance of remineralizing products aiming to treat early carious lesions [Table 1]. [3],[4]
| Demineralization and Remineralization | | |
Demineralization occurs by disassociation of lactic acid, produced by bacterial carbohydrate metabolism, with tooth mineral. The reaction leads to release of mineral ions into the solution:
Ca 10 (PO 4 ) 6 (OH) 2 + 14 H + → 10 Ca + + 6 H 2 PO 4 - + H 2 O
The extent to which tooth mineral dissolves in a given solution is governed by the thermodynamic ion activity product (IAP):
IAP = (Ca 2+ ) 10 (PO 4 3- ) 6 (OH - ) 2
When the IAP equals a constant called the solubility product constant of Ksp, the solution is in equilibrium with the solid and is said to be saturated with respect to the solid. [5] The only requirement for dimeralization to occur is that the IAP in the demineralizing solution should be less than the Ksp.
(Ca 2+ ) 10 (PO 4 3- ) 6 (OH - ) 2 < Ksp (tooth mineral)
The sub-surface lesion is reversible via a remineralization process. The increase in oral fluid calcium and phosphate drives the remineralization process.
| Requirements OFA Remineralizing Agent | | |
- Should deliver calcium and phosphate into the sub-surface
- Should not deliver any excess of calcium
- Should not favor calculus formation
- Should work at an acidic pH so as to stop demineralization during a carious attack
- Should be able to work in xerostomic patients as saliva cannot effectively stop the carious process
- Should be able to boost the remineralizing properties of saliva
- The novel materials should be able to show some benefits over fluoride. [6]
| Indications | | |
- An adjunct preventive therapy to reduce caries in high-risk patients
- Reduce dental erosion in patients with gastric reflux or other disorders
- To reduce decalcification in orthodontic patients
- To repair enamel in cases involving white-spot lesions
- Orthodontic decalcification or fluorosis or before and after teeth whitening and to desensitize sensitive teeth. [7]
| Fluorides | | |
The first theories concerning the mechanism of action of fluoride were based exclusively on its pre-eruptive effect. Arnold, in 1957, was the first author to mention the post-eruptive effect of fluoride in the drinking water and the ability of topical fluoride to reduce the incidence of caries. [8]
The mechanism by which fluoride increases caries resistance may arise from both systemic and topical applications of fluoride and can be broadly grouped as follows - increased enamel resistance, increased rate of maturation, remineralization of incipient caries, interference with micro-organisms and improved tooth morphology. [8]
Enamel is dissolved by lowering of pH in dental plaque due to acid production every time sugar is ingested. However, if F - is present in the biofilm fluid, and the pH is not lower than the critical pH, hydroxyapatite (HA) is dissolved and at the same time fluorapatite is formed. Furthermore, FA is deposited on the surface layer of enamel while HA is dissolved from the subsurface. This indirect effect of F - in reducing enamel demineralization when the pH drops is complemented by its natural effect on remineralization when the pH rises enhancing the redeposition of Ca 2+ and PO4 3- present in the biofilm fluid on demineralized enamel. [9] Its ability to promote net remineralization is limited by the availability of calcium and phosphate ions. Hence, this can be the limiting factor. [10] Also, fluoride might be highly effective on smooth surface caries but its effect is limited on pit and fissure caries. Overexposure of fluoride can also cause fluorosis. All these limitations have prompted researchers to look for non-fluoridated alternatives for remineralization.
| Casein Phosphopeptide - Amorphous Calcium Phosphate | | |
The casein phosphopeptides (CPPs) are produced from the tryptic digest of casein, aggregated with calcium phosphate and purified through ultrafiltration. [6] Casein has the ability to stabilize calcium and phosphate ions by releasing small sequences of peptides (CPPs) through partial enzymic digestion that led to the development of a remineralization technology based on casein phosphopeptide-stabilized amorphous calcium phosphate complexes (CPP-ACP) and casein phosphopeptide-stabilized amorphous calcium fluoride phosphate complexes (CPP-ACFP). [10],[11],[12]
This technology was developed by Eric Reynolds, Australia. CPPs contain the cluster sequence of -Ser (P)-Ser (P)-Ser (P)-Glu-Glu from casein. [13],[14] This protein nanotechnology combines the precise ratio of 144 calcium ions plus 96 phosphate ions and six peptides of CPP. The nanocomplexes form over a pH range of 5.0-9.0. Under neutral and alkaline conditions, the CPPs stabilize calcium and phosphate ions, forming metastable solutions that are supersaturated, which increase as the pH increases. A 1% CPP solution at pH 7.0 can stabilize 60 mM calcium and 36 mM phosphate. [15],[16] Calcium interacts with CPP through the negatively charged residues of the peptides. [17] However, CPPs bind more calcium and phosphate ions than can be attributed to just the calcium-binding motif -Ser (P)-Ser (P)-Ser (P)-Glu-Glu-, indicating that other acidic residues of the phosphopeptide sequence also contribute to the stabilization of calcium phosphate, preventing the growth of the calcium and phosphate ion clusters to a critical size required for nucleation and phase transformations. [17]
The size and electroneutrality of the CPP nanocomplexes allows them to diffuse down the concentration gradient into the body of the sub-surface lesion. [10],[12] Once present in the enamel sub-surface lesion, the CPP-ACP releases the weakly bound calcium and phosphate ions, [17],[18],[19] depositing them into crystal voids. The CPPs have a high binding affinity for apatite; [20] thus, on entering the lesion, the CPPs binds to the more thermodynamically favored surface of an apatite crystal face.
It is pH responsive, i.e. with increasing pH, the level of bound ACP increases, stabilizing free calcium and phosphate and thus providing an anti-calculus action. [14] The anti-caries action influences the properties and behavior of dental plaque through (1) binding with adhesion molecules on mutans Streptococci, impairing their incorporation into plaque, (2) elevating plaque calcium ion levels to inhibit plaque fermentation and (3) providing protein and phosphate buffering of plaque fluid pH to suppress overgrowth of aciduric species when fermentable carbohydrate is in excess.
Tooth crèmes using CPP-ACP (Recaldent technology) such as MIPaste and ToothMousse [21] recognize the importance of the neutral ion species, gaining access to the sub-surface lesion through a porous enamel surface. This is the reason why arrested white spot lesions should have a surface etching treatment before remineralization with Recaldent products, unlike fluoride treatments with conventional dentifrices (1000 ppm) that deposit surface mineral but do not eliminate a white-spot lesion. [22]
CPP-ACP is a useful cario-static agent for the control of dental caries. [7] A dentifrice containing CPP-ACP with fluoride will provide remineralization, which is superior to both CPP-ACP alone and to conventional and high fluoride dentifrices. [23] Reynolds and colleagues found a reduction of 15% and 46%, respectively, in 0.1% and 1.0% w/v CPP-ACP. [24]
Thus, it is evident that other than for fluoride, the strongest level of clinical evidence for remineralization is for the CPP-based Recaldent technology, with both long-term large-scale clinical trials and randomized controlled clinical trials to support its efficacy.
| Bioactive Glass | | |
Bioactive glass (Bioglass ® ) was invented by Dr. Larry Hench in1960s. It acts as a biomimetic mineralizer matching the body's own mineralizing traits while also affecting cell signals in a way that benefits the restoration of tissue structure and function. [25]
Bioglass ® in an aqueous environment immediately begins surface reaction in three phases, leaching and exchange of cations, network dissolution of SiO 2 and precipitation of calcium and phosphate to form an apatite layer. The critical stages for glass surface reactions are the initial Na + and H + /H3 O + ion exchange and de-alkalinization of the glass surface layer is quite rapid, within minutes of implantation and exposure to body fluids. [26] The net negative charge on the surface and loss of sodium causes localized breakdown of the silica network with the resultant formation of (silanol) Si (OH) groups, which then repolymerize into a silica-rich surface layer. [27] Within 3-6 h in vitro, the calcium phosphate layer will crystallize into the carbonated hydroxyapatite (CAP) layer, which is essentially the bonding layer. Chemically and structurally, this apatite is nearly identical to bone and tooth mineral. These Bioglass ® surface reactions from implantation to formation of 100-150 μm CAP layer takes 12-24 h. [26],[28]
Bioactive glass formulation commonly used in research studies contains 45 wt% SiO 2 4.5 wt% Na 2 O and CaO and 6 wt% P 2 O5 . The network breakdown of silica depends upon the concentration of SiO 2 and is time dependent. Thus, keeping the silica below 60 wt% and maintaining a high CaO/P 2 O5 ratio guarantees a highly reactive surface.
Novamin ® , a trade name for bioactive glass, is manufactured by Novamin Technologies Inc. (Alachua, FL, USA). It has been demonstrated that fine particulate bioactive glasses (<90 μm) incorporated into an aqueous dentifrice have the ability to clinically reduce the tooth hypersensitivity through the occlusion of dentinal tubules by the formation of the CAP layer. [29] Investigators using bioactive glass compositions have demonstrated a significant anti-microbial effect toward caries pathogens (S. mutans, S. sanguis) upon exposure to bioactive glass powders as well as solutions and extracts. [30]
Caries can also result from inadequate saliva, without which fluoride is of limited value. [31] Thus, individuals who experience reduced calcium, phosphate and fluoride ions caused by hyposalivation can benefit from the use of bioactive glass. In addition, women are at increased caries risk due to inadequate salivary calcium levels at different points in their lives, including ovulation, pregnancy and post-menopause, resulting in the same net effect as reduced saliva fluoride efficacy.
Thus, the use of bioactive glass (Novamin Technology) in remineralization of enamel is quite promising, especially in patients with systemic problems, but further research needs to be undertaken to prove its efficacy.
| Tri-Calcium Phosphate {Clinpro tooth crθme} | | |
TCP is a new hybrid material created with a milling technique that fuses beta tricalcium phosphate (ί-TCP) and sodium lauryl sulfate or fumaric acid. This blending results in a "functionalized" calcium and a "free" phosphate, designed to increase the efficacy of fluoride remineralization. [32],[33] ί-TCP is similar to apatite structure and possesses unique calcium environments capable of reacting with fluoride and enamel. While the phosphate floats free, these exposed calcium environments are protected, preventing the calcium from prematurely interacting with fluoride. [34] TCP provides catalytic amounts of calcium to boost fluoride efficacy and may be well designed to coexist with fluoride in a mouthrinse or dentifrice because it will not react before reaching the tooth surface. [34] When TCP finally comes into contact with the tooth surface and is moistened by saliva, the protective barrier breaks down, making the calcium, phosphate and fluoride ions available to the teeth. The fluoride and calcium then react with weakened enamel to provide a seed for enhanced mineral growth relative to fluoride alone.
Products available with TCP include a 5000 ppm sodium fluoride dentifrice and a 5% sodium fluoride varnish. Studies have concluded that TCP provided superior surface and sub-surface remineralization compared with a 5000 ppm fluoride and CPP-ACP. [35] There has been no significant research about TCP added to fluoride varnish. All published studies supporting this material have been in vitro studies. The potential of TCP is promising, but more studies are needed, including clinical trials supporting its efficacy in boosting remineralization.
| ACP Technology {Enamelon, Enamel Care} | | |
The ACP technology requires a two-phase delivery system to keep the calcium and phosphorous components from reacting with each other before use. The current sources of calcium and phosphorous are two salts, calcium sulfate and dipotassium phosphate. When the two salts are mixed, they rapidly form ACP that can precipitate on to the tooth surface. This precipitated ACP can then readily dissolve into the saliva and can be available for tooth remineralization. [36]
The ACP technology was developed by Dr. Ming S. Tung. In 1999, ACP was incorporated into toothpaste called Enamelon and later reintroduced in 2004 as EnamelCare toothpaste. [37] There is a modest evidence for Enamelon™ for its caries inhibitory action. [38]
An inherent technical issue with Enamelon™ is that calcium and phosphate are not stabilized, allowing the two ions to combine into insoluble precipitates before they come into contact with saliva or enamel. This is unlike Recaldent™, which has the casein phosphoproteins to stabilize calcium and phosphate.
| Xylitol {Spry} | | |
Xylitol is a non-cariogenic five-carbon sugar alcohol that occurs naturally in plants and is used as a substitute for sugar. Sources are fruits, berries, mushrooms, lettuce, hardwoods and corn on the cob. The dental significance of xylitol was discovered in Finland in the early 1970s. Xylitol has the ability to:
- Reduce dental plaque formation
- Make plaque less adhesive
- Neutralize plaque acids by decreasing the production of lactic acid
- Reduce the levels of S. mutans
- Reduce cavities by up to 80%
- Demonstrate significant long-term reduction in caries (88-93%)
- Assist in the remineralization of tooth enamel
- Reduce gum tissue inflammation
- Help with dry mouth and bad breath.
Xylitol has been employed for many years as a non-acidogenic sweetener in numerous applications as it cannot be fermented by plaque bacteria.
It works by interfering with the metabolism of S. mutans. When S. mutans is transported into a cell, xylitol makes it to bind to proteins. This bond is unbreakable and the transport protein is unable to go out of the cell and bring more glucose into the cell. Because the bacteria are bound, they are unable to produce the sticky extracellular polysaccharides that bind bacteria together. As a result, there is less plaque buildup and the decay-causing bacteria cannot stick to the enamel. [39]
Xylitol also stimulates salivary flow. Increased salivary flow offers protection to both the oral soft tissues and the teeth. [40]
It has also been shown that a combination of fluoride and xylitol is more effective than fluoride alone. [41],[42],[43],[44]
The recommended dose varies upon its intended action. For the maximum prevention of dental caries, 7-20 g/day is given, divided into several doses in candies or chewing gum. The best time to use xylitol is immediately after eating and clearing the mouth by swishing with water. One of its advantages is that it does not raise blood pressure or blood glucose levels as most sugar substitutes do. Thus, it has been proven to be an effective remineralizing agent in conjunction with fluoride, or even otherwise.
| Remineralization of Dentin | | |
The collagen fibrils in dentin serve as a scaffold for mineral crystallites that reinforce the matrix, supporting the surrounding enamel. From a biomechanical perspective, the mineralized dentin matrix preserves tooth function by helping to prevent propagation of cracks from the brittle enamel through the dentin-enamel junction into the dentin [45] thus preventing fracturing of the enamel crown. Although previous investigations have suggested the importance of the mechanical recovery of dentin after remineralization, [46] there is a lack of information in the current literature with regard to this phenomenon.
When the carious lesion reaches the dentin matrix, it progresses much more rapidly as compared with the enamel thus creating different zones that reflect differences of mineral content, mechanical properties and optical appearance. [47] Remineralization of carious dentin can occur either by a spontaneous incorporation of ions (calcium, phosphate and fluoride) from the oral fluid on to the remnant crystallites in the demineralized tissue [48] or by treatments that incorporate the same ions from external sources.
Remineralization of dentin can occur either by precipitation of mineral between collagen fibrils or functionally, bound to its structure. Therefore, simple precipitation of mineral into the loose demineralized dentin matrix, the so-called net remineralization, provides an increased mineral content, but may not necessarily provide an optimal interaction with the organic components of the dentin matrix. Hydration is significant in the evaluation of the mechanical response of the tissue after remineralizing treatments. In the absence of the intrafibrillar mineral and an optimal interaction of the granular precipitate within the collagen fibrils, the dentin matrix can incorporate more water and tends to swell more than the sound tissue. As a result, the compressive stresses that consolidated the mineral lying between the collagen fibrils no longer exist, and the elastic constants become largely determined by the highly deformable organic network and are therefore quite low. The net effect may be one of relatively high mineral content, but very low mechanical properties. Hence, in agreement with our previous hypothesis, [49] we suggest that changes in the mineral content alone do not necessarily result in recovery of the mechanical properties of remineralized dentin.
Ideally, the regrowth of intrafibrillar and extrafibrillar mineral between the fibrils would lead to the full mechanical recovery of the demineralized dentin. This would yield properties comparable to normal dentin and indicate successful functional remineralization. In this situation, the collagen fibrils become reinforced by the reincorporated mineral, which facilitates the transfer of load on to the extrafibrillar mineral. A remineralized tissue that has restored its mechanical properties under hydration is an indication that mineral crystallites are in tight association or perhaps chemically bound to the collagenous matrix.
More detailed determinations of biological, microstructural and other biomechanical changes of remineralized dentin will perhaps provide us with a broader understanding of the overall functionality of treated tissues. These developments should be encouraged so that better future strategies for remineralization of dentin can be designed.
| Grape Seed Extract | | |
Root caries is especially prevalent among the elderly population due to gingival recession and the exposure of susceptible root surface. [50] Dentin mineral is dissolved by acid produced from the oral bacterial biofilm and the demineralized dentin matrix is further degraded, allowing bacteria to infiltrate the intertubular area. [51] The preservation and stability of dentin collagen may be essential during the remineralization process, because it acts as a scaffold for mineral deposition. It has also been suggested that the presence of an organic matrix may reduce the progression of erosion in dentin. [52],[53] One of the important strategies regarding preventive therapies for root caries is to promote remineralization of demineralized dentin. [54],[55],[56],[57]
Polyphenols are plant-derived substances that have antioxidant and anti-inflammatory properties. [58],[59],[60] They interact with microbial membrane proteins, enzymes and lipids, thereby altering cell permeability and permitting the loss of proteins, ions and macromolecules. One such polyphenol is proanthocyanidin (PA), which is a bioflavanoid-containing benzene-pyran-phenolic acid molecular nucleus. [60] The PA accelerates the conversion of soluble collagen to insoluble collagen during development and increases collagen synthesis. [58]
Grape seed extract (GSE) has a high PA content. PA-treated collagen matrices are non-toxic and inhibit the enzymatic activity of glucosyl transferase, F-ATPase and amylase. glucosyl transferases, which are produced by S. mutans that polymerize the glucosyl moiety from sucrose and starch carbohydrates into glucans. This constitutes the sucrose-dependent pathway for S. mutans to establish on the tooth surface and is of central importance in plaque formation and development of caries. The adherent glucan also contributes to the formation of dental plaque, in which accumulation of acids leads to localized decalcification of the enamel surface by facilitating bacterial adherence to the tooth surfaces, interbacterial adhesion and accumulation of biofilms. Hence, inhibition of glucosyl transferases by PA in turn inhibits caries. [59],[61],[62]
GSE can act as a potential adjunct or alternative to fluoride in the treatment of root caries during minimally invasive therapy, although further research is warranted.
| Challenges in Implementation of Remineralization | | |
Active white-spot lesions have been shown to have a greater likelihood of regression (remineralization) compared with inactive lesions [63] as they have a more porous surface layer that allows for better penetration of the ions required for remineralization. Possible approaches that have been suggested include: Micro-abrasion, [64] acid etching, [65] bleaching/deproteination [66],[67] or a combination approach such as bleaching and etching. [68]
Another approach is to improve the biomimetic peptides used to stabilize, deliver and control remineralization. With modern peptide synthetic approaches, [69] it is possible to incorporate additional phosphoseryl residues.
Another problem is that pre-clinical models may not necessarily be predictive of clinical performance for all the non-fluoride agents and the new agents still require direct clinical validation to ensure efficacy.
| Conclusion | | |
A goal of modern dentistry is the non-invasive management of non-cavitated caries lesions involving remineralization systems to repair the enamel with fluorapatite or fluorhydroxyapatite.
With a clearer understanding of the implementation of these remineralizing agents, we can create a more favorable relationship in which remineralization can occur. It is important for dental professionals to be aware that it takes significant time to establish the bonafides of a new technology. [70],[71]
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