|Year : 2016 | Volume
| Issue : 1 | Page : 18-25
Casein phosphopeptide-amorphous calcium phosphate in dentistry: An update
GK Divyapriya, Puja C Yavagal, DJ Veeresh
Department of Public Health Dentistry, Bapuji Dental College and Hospital, Davangere, Karnataka, India
|Date of Web Publication||21-Jul-2016|
G K Divyapriya
Department of Public Health Dentistry, Bapuji Dental College and Hospital, Davangere, Karnataka
Source of Support: None, Conflict of Interest: None
Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), milk derivative helps in remineralization of the carious lesion by replenishing lost minerals like calcium, phosphate ions into the tooth structure. Several in vitro and in vivo studies have proven that CPP-ACP to be useful in the treatment of white spot lesions, early childhood caries, dental erosion, root caries, and dentin hypersensitivity. CPP-ACP is delivered in the form of oral hygiene products such as chewing gum, tooth cream, and even incorporated in dental restorative materials also.
Keywords: Casein phosphopeptide-amorphous calcium phosphate, dental caries, remineralization
|How to cite this article:|
Divyapriya G K, Yavagal PC, Veeresh D J. Casein phosphopeptide-amorphous calcium phosphate in dentistry: An update. Int J Oral Health Sci 2016;6:18-25
|How to cite this URL:|
Divyapriya G K, Yavagal PC, Veeresh D J. Casein phosphopeptide-amorphous calcium phosphate in dentistry: An update. Int J Oral Health Sci [serial online] 2016 [cited 2017 Apr 29];6:18-25. Available from: http://www.ijohsjournal.org/text.asp?2016/6/1/18/186660
| Introduction|| |
Oral diseases are the most prevalent chronic diseases worldwide, and a burden to health-care services. The treatment of dental diseases is expensive, accounting for between 5% and 10% of total health-care expenditures in industrialized countries.  Dental hard tissues are continuously undergoing cycles of demineralization and remineralization. A drop in pH of oral cavity results in demineralization which if continued leads to loss of minerals from tooth structure resulting in dental caries.  If the disease has progressed significantly, more drastic measure has to be taken, i.e., surgical intervention, where we treat the disease not the cause. It has taken over a century for dentistry to advance from the pioneering "extension for prevention" concept to a newer concept "minimum intervention." Minimum intervention as the term suggests refers to the principle of treatment in dentistry, in which early intervention minimizes tooth destruction because the disease is diagnosed prior to the destruction of the tooth. Hence, it is possible to remineralize the carious lesion. 
The ideal method of increasing remineralization is reconstructing the depleted tissues with hydroxyapatite (HA), which is the same inorganic component as the enamel. Even though fluoride has a profound effect on the reduction of caries prevalence but its exposure is related to many harmful effects like fluorosis.  Therefore, it is necessary to seek effective nonfluoride agents. At present, calcium-based phosphate system like casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) has provided a new area to preventive dentistry. Hence, this article focuses on the role of CPP-ACP, its mode of action, and clinical applications.
| Amorphous Calcium Phosphate|| |
Amorphous calcium phosphate (ACP) was first described by Aaron S Posner in the mid-1960s. It is the initial solid phase that precipitates from a highly supersaturated calcium phosphate solution and can convert readily to stable crystalline phases, such as octacalcium phosphate or apatitic products. ACP has been demonstrated to have better in vivo osteoconductivity than HA, better biodegradability than tricalcium phosphate, and good bioactivity but no cytotoxicity. ACP has been widely applied in the biomedical field due to its excellent bioactivity, high cell adhesion, adjustable biodegradation rate, and good osteoconduction. However, unstabilized ACP rapidly transforms to crystalline phases in the mouth and in doing so may act to promote dental calculus. In the presence of fluoride ions, the unstabilized ACP may produce fluorapatite. The formation of fluorapatite intraorally would sequester available fluoride ions thereby reduce the ability to remineralize subsurface enamel during acid challenge. Hence, the stability of ACP is an issue. 
| Development of Casein Phosphopeptide|| |
Mellanby found that milk and its products help to prevent dental caries in animals and in situ caries models.  The anticariogenic effect of milk products was not attributed to a change in the level of infection of streptococci but attributed to a direct chemical effect by milk components such as casein, calcium, and phosphate. The casein forms a layer on the surface of the tooth, and it attracts more calcium and phosphate ions from the saliva. However, the use of casein has not been implemented because of its adverse organoleptic properties and the large amount required for its efficacy.  However, Reynolds et al. at the University of Melbourne interested in using casein products as anticaries agents and identified that tryptic digestion of the milk protein casein when aggregated with calcium phosphate and later purified by ultrafiltration forms casein phosphopeptide (CPP). The nanocomplexes of CPP form over a pH range from 5.0 to 9.0. The amount of calcium and phosphate bound by CPP increases as pH rises. 
CPP contains the cluster sequence of Ser (P)-Ser (P)-Glu-Glu from casein. These multiple phosphor-seryl residues, markedly increase the apparent solubility of calcium phosphate by stabilizing ACP under neutral and alkaline conditions. The multiple phosphor-seryl residues of CPP bind to nanoclusters of ACP in supersaturated solutions, thereby preventing the growth to the critical size required for phase transformation and precipitation. CPP-ACP works effectively as a remineralizing agent at acidic pH levels, as well as in neutral and alkaline phosphate range. 
| Manufacturer of Casein Phosphopeptide-Amorphous Calcium Phosphate|| |
The CPP-ACP complex was patented by the University of Melbourne, Victorian Dairy Industry Authority, Abbotsford and Bonlac Foods Limited, Australia. It is generally marketed in the USA as MI Paste and MI Paste Plus and outside the USA, the products are marketed as GC Tooth Mousse™ (India) and GC Tooth Mousse plus™ (India). 
| Mechanism of Action of Casein Phosphopeptide-Amorphous Calcium Phosphate|| |
Casein phosphopeptide-amorphous calcium phosphate as calcium phosphate reservoir
As CPP-ACP has the ability to localize ACP at the tooth structure, increasing the level of calcium phosphate in plaque and hence may act as a calcium phosphate reservoir, buffering the free calcium and phosphate ion activities, thereby helping to maintain a state of supersaturation with respect to tooth enamel thereby it decreases enamel demineralization and enhances enamel remineralization. 
Similarity between salivary statherin and casein phosphopeptide-amorphous calcium phosphate
In fact, statherins in saliva, calcium phosphopeptides, and phosphoproteins share a remarkable similarity. All of these regulate the behavior of calcium and phosphate and stabilize calcium phosphate compounds. 
CPP-ACP has the ability to inhibit cariogenic streptococci to the tooth surface inducing the formation of noncariogenic plaque. CPP-ACP can be incorporated into the pellicle in exchange for albumin to inhibit the adherence of Streptococcus mutans and Streptococcus sobrinus thus producing both neutralization and enhancement of remineralization. The high extracellular free calcium concentrations may have bactericidal or bacteriostatic properties which reduce the adhesion between bacterial cells and moreover casein buffers plaque acid directly or indirectly through bacterial catabolism. This agent also releases basic amino acids which accept proton ions and act as an inert barrier preventing diffusion of protons.  An in vivo study demonstrated that CPP-ACP binds twice the affinity of the bacterial cells for calcium up to a value of 0.16 g/g wet weight cells. 
Delays biofilm formation
Immunolocalization studies indicated that incorporation of CPP-ACP into plaque by binding to the surface of bacterial cells, to components of intercellular plaque matrix, and to adsorbed proteins on tooth surfaces, thereby possibly influence the process of biofilm formation. These interactions lead to the formation of less cariogenic plaque. It is also observed that CPP-ACP reduces the fall in plaque pH following a sucrose challenge. 
The binding of ACP to CPP is pH responsive, with binding decreases as the pH falls and vice versa. It stabilizes free calcium and phosphate so that spontaneous precipitation of calcium phosphate does not occur which is an inherently anticalculus action. 
Inhibition of demineralization and promoting remineralization of enamel
The use of CPP at 0.5% w/v and 5% w/v significantly inhibited acid demineralization in a human intraoral caries model.  An in vitro model system designed to study the effect of CPP-ACP solutions on the remineralization of artificial lesions in human third molars showed that there was a substantial increase in the mineral content of test enamel sections exposed to CPP-ACP solutions.  Enamel lesions, which have been remineralized with topical exposure to CPP-ACP, have shown to be more resistant to subsequent acid challenge compared with normal remineralized enamel as CPP-ACP is able to promote the remineralization of enamel subsurface lesions with HA. In addition, the relatively low carbonate environment of the CPP-ACP treated subsurface lesions may also exhibit improved crystallinity and lower microstrain than normal tooth enamel. 
Rate of remineralization
CPP-stabilized calcium phosphate solutions can remineralize enamel subsurface lesions at the rate of 1.5-3.9 × 10−8 moles HA/m 2 /s 1 . CPP can stabilize over 100 times more calcium phosphate than is normally possible in aqueous solution at neutral and alkaline pH before spontaneous precipitation. In the process of mineralization, ACP and crystalline phase dicalcium phosphate dihydrate and octacalcium phosphate have been implicated as intermediates in the formation of HA depending on pH and degree of saturation. Assuming the deposited mineral in the remineralized lesion to be predominantly HA, the maximum average rate of remineralization was 3.9 ± 0.8 × 10−8 moles HA/m 2 for 10 day period. 
CPP-ACP reduces caries activity in a dose-dependent mechanism, and the subsequently formed mineral is more resistant to acid attack. In animal model, it showed that 0.1% w/v CPP-ACP produces 14% reduction on smooth surface caries and 1% w/v CPP-ACP produced a 55% reduction on smooth surfaces caries, and similarly 0.1% w/v CPP-ACP and 1% w/v CPP-ACP produced 15% and 46% reduction in fissure caries activity. 
Interaction of casein phosphopeptide-amorphous calcium phosphate with fluoride
The combination of CPP-ACP with fluoride resulted in localization of calcium and phosphate ions with fluoride ions at the enamel surface. The advantage of CPP-ACFP is the availability of calcium, phosphate, and fluoride in one product. Each molecule of CPP can bind up to 25 calcium ions, 15 phosphate ions, and 5 fluoride ions. The calcium phosphate in these complexes is biologically available for remineralization of subsurface lesions in tooth enamel.  Few studies suggested that combination of CPP-ACP with 900 PPM of fluoride and 250-500 PPM of fluoride exhibited higher remineralization than the CPP-ACP alone. ,
| Role of Casein Phosphopeptide in Vitamin D Deficiency|| |
The CPP are formed in vivo by normal digestion of casein and because they are relatively resistant to further proteolytic degradation, accumulate in the distal portion of the small intestine. It has been proposed that this accumulation together with the ability of the peptides to form soluble complexes with calcium phosphate are responsible for the enhanced intestinal calcium absorption that has been observed even in Vitamin D-deficient animals consuming dietary CPP. 
| Casein Phosphopeptide-Amorphous Calcium Phosphate Applications in Dentistry|| |
Remineralization of white spot lesions
White spot lesions are not unique to orthodontic patients but also observable in the children who have not received orthodontic treatment.  In vivo study investigated the effect of a dental cream containing CPP-ACP and compared with fluoride mouth rinses on remineralizing white spot lesions using laser fluorescence, where the regression of white spot lesions was seen following the application of CPP-ACP cream.  An another in vivo study done by Iijima et al. also showed that sugar-free chewing gum containing CPP-ACP has shown acid resistance and promotes remineralization of enamel. 
CPP-ACP is useful in reducing dentinal hypersensitivity by occluding dentinal tubules. CPP-ACP was proven to be effective in treating dentinal hypersensitivity which was evaluated using a visual analog scale, where at the end of 21 days an improvement was noted in hypersensitivity.  A systematic review found CPP-ACP cream to be effective in treating dentin hypersensitivity but found insufficient evidence for its efficacy. 
Dental erosion is a relatively new risk factor for dental health introduced by today's life. Demineralization of the tooth by erosion is caused by frequent contact between the tooth surface and acids. It has been suggested that both CPP-ACP and CPP-ACP fluoride (CPP-ACPF) has anti-erosive property. When the eroded enamel specimens were treated with different remineralizing agents, like CPP-ACP and CPP-ACPF, there was a significant increase in microhardness and remineralization effect of CPP-ACPF which was found to be superior to be that of CPP-ACP alone. This probably was due to the interaction of CPP-ACP with hydrogen ions leading to the formation of calcium hydrogen phosphate, thus aid in remineralization. While CPP-ACPF provides additional fluoride along with calcium and phosphate ions for remineralization, CPP-ACP also restores the center areas of the enamel prisms which are dissolved in enamel erosion and also it maintains the orientation of crystal fibrils which were confirmed by enamel surface roughness measurements. ,
Casein phosphopeptide-amorphous calcium phosphate in early childhood caries
Early childhood caries is a major public health problem worldwide, begins with white spot lesion, and caries can progress continuously, leading to complete destruction of the crown. An in vivo study showed that children who applied CPP-ACP once daily from the time of tooth emergence together with tooth brushing twice daily with 400 ppm fluoride toothpaste, showed an early childhood caries of 2% at 24 months compared to 7% of the comparison group who did not use CPP-ACP. The use of CPP-ACP offers a significant advantage in remineralization effects of decalcified tooth enamel, it can form HA crystals to repair the enamel prisms and enamel inter-prisms along c-axis, and permits a rapid return to resting calcium concentrations and allows more intermediate remineralization of enamel substrate. 
Casein phosphopeptide-amorphous calcium phosphate in root dentinal caries
Rahiotis et al. showed that application of CPP-ACP on dentine surfaces was able to prevent demineralization of dentine, suggesting thereby its use in the prevention of dental root caries which could be due to buffer capacity of this agent. 
Casein phosphopeptide-amorphous calcium phosphate with laser application
The use of laser irradiation for preventing caries is based on physical, chemical, and crystalline changes induced in enamel due to the heating of the surface. High energy laser irradiation of enamel, at a specific wavelength, has been shown to cause remineralization. Holmium-doped: yttrium lithium fluoride laser irradiation followed by CPP-ACP application allowed for incorporation of nanocomplexes of calcium onto the tooth surfaces. These numerous calcium deposits act as a reservoir to replenish the soluble calcium and phosphate ions that diffuse into the subsurface enamel.  An in vitro study conducted by Subramanian and Pandey showed that combined action of CPP-ACP and erbium, chromium: yattrium-scandium-gallium-garnet laser (2.79 μm wavelength) resulted in a significant high microhardness of primary tooth as compared to CPP-ACP alone. 
Casein phosphopeptide-amorphous calcium phosphate on bleached enamel surface
The growing demand for bleaching as an essential esthetic improvement has led to considerable development in bleaching products. However, studies demonstrated that bleaching agents create demineralization, degradation, alterations in the surface enamel roughness.  Roughness is considered as a predisposing factor for bacterial adhesion and stain adsorption. The study showed that the application of CPP-ACPF increases the surface hardness of enamel eventually after treated with bleaching agents.  CPP-ACP can increase the flexural strength of tooth surface and reverse the structural damage caused by bleaching agents. It seems to increase the calcium and phosphate content of dental tissue after bleaching and also it enhances the tooth resistance to demineralization effect of bleaching agents. 
In vivo studies in patients with xerostomia treated with CPP-ACP-based mouth rinses showed a lower rate of new caries lesions compared to patients treated with 0.05% fluoride mouth rinses. 
| Mode of Delivery of Casein Phosphopeptide-Amorphous Calcium Phosphate|| |
Sugar-free chewing gum containing CPP-ACP paste has shown to promote remineralization of caries in vivo and also it increases calcium concentration in saliva.  The addition of 10, 18.8, or 56.4 mg of CPP-ACP to either the sorbitol or xylitol based gums showed 63%, 102%, and 152% of increase in enamel remineralization, respectively.  The CPP-ACP chewing gum is marketed as GC Recaldent™ (India).
When CPP-ACP was delivered in the form of mouth rinses (2% w/v and 6% w/v, respectively), it significantly increased plaque levels, inorganic phosphate levels, and the CPP were immunolocalized to the surfaces of bacterial cells, as well as to the intracellular plaque matrix. 
When CPP-ACP was delivered in the form of lozenges, it showed an increase in remineralization of subsurface caries lesions, which is dose dependent and also increased salivary flow rate. Hence, sugar-free lozenge may be a suitable vehicle for delivery of CPP-ACP. 
The twice daily application of 10-fold diluted CPP-ACP paste resulted in preventing dentine demineralization. Enamel microabrasion together with prolonged use of CPP-ACP based paste is useful for treating white spot enamel lesions. 
Method of application
It can be applied directly with clean finger onto the teeth, smeared over all surfaces, and left in place to slowly dissolve overnight. Any material that is swallowed is completely safe and will contribute toward dietary calcium. 
The addition of 2% CPP-ACP to the 1100 ppm fluoride dentifrice increase enamel subsurface remineralization by 156% relative to that produced by 1100 ppm fluoride alone dentifrice and also the incorporation of CPP-ACP into 250-500 ppm/900 ppm of fluoride was shown to be effective in increasing enamel remineralization. The increased concentration of calcium, phosphate, and fluoride ions at the tooth surface would drive diffusion into the enamel, producing higher activities of the ions in the subsurface lesion, resulting in higher levels of remineralization and fluoride incorporation into mineral phase.  The use of CPP-ACP, along with fluoride containing dentifrice, has proved to be beneficial in reducing the demineralization around orthodontic brackets.  Owing to its additive effect with fluoride, it can be recommended that CPP-ACP should be used as a self-applied topical coating after teeth have been brushed with fluoridated toothpaste by children who have a high caries risk. 
Hay and Thomson observed moistening and lubrication action with the CPP-calcium phosphate complex mouth rinse when used as an atomized spray in the mouth. 
Adding CPP-ACP to energy drinks reduces their erosive capacity with no change in flavor when added in proportion of over 0.09% CPP-ACP, and it is an important constituent of tooth-friendly soft drink. 
Incorporation of casein phosphopeptide-amorphous calcium phosphate into glass ionomer cement
Mazzaoui et al. determined the effect of incorporation of CPP-ACP (1.56%) into self-cured glass ionomer cement GC Fuji IX™ and demonstrated significant increase in microtensile bond strength and significantly enhances the release of calcium, phosphate, and fluoride ions thereby it protects the adjacent dentin during acid challenge.  Various clinical trials incorporating CPP-ACP into oral health products shown in [Table 1]
|Table 1: Clinical trials incorporating casein phosphopeptide-amorphous calcium phosphate into various oral health products|
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Incorporation of casein phosphopeptide-amorphous calcium phosphate into noneugenol cement
Setting time was delayed with incorporation of ≤8.0% (w/w) CPP-ACP in both noneugenol cements like Freegenol™ and Temp-Bond ® NE but a progressive weakening in mean compressive and tensile strength values was found. 
Casein phosphopeptide-amorphous calcium phosphate complex and resin bonding
The application of CPP-ACP may influence the subsequent resin adhesion to dentine. The presence of CPP-ACP on the dentine surface may compromise the bonding effectiveness of the etch-and-rinse adhesive system. The enamel etching may not be inhibited by the use of CPP-ACP paste with or without prior bleaching. 
Casein phosphopeptide-amorphous calcium phosphate sealants
The solubility of ACP enables it to release supersaturating levels of calcium and phosphate ions in proportion that is favorable for HA formation. These fortified sealants have a higher remineralizing capacity with the potential to remineralize enamel subsurface lesions.  It is marketed as Aegis ® pit and fissure sealant (USA).
Safety of casein phosphopeptide-amorphous calcium phosphate
Bussadori et al. assessed the cytotoxicity of CPP-ACP in rat fibroblast culture and it showed that allowable cell viability >70% and low cytotoxicity. Hence, it is considered to be safe to use topically in dentistry.  In early 1999, the US Food and Drug Administration accepted CPP-ACP products as generally recognized as safe for its intended use in dentistry. 
Potential area of improvement
- As CPP-ACP is a milk product, it cannot be given to patients having intolerance to milk. Therefore, a suitable alternative for these patients is required
- Need to conduct cost-effectiveness studies of CPP-ACP in current situation
- Further clinical trials should be conducted to explore more detailed clinical benefits of CPP-ACP
- Need to investigate on the public perception of these agents.
| Conclusion|| |
CPP-ACP has provided a new arena to preventive dentistry. It has shown anticariogenic, anti-erosive efficiency and reduces dentine hypersensitivity. It is delivered in the form of chewing gum, mouthwashes, dentifrices, and also added in various restorative materials. Hence, it is proven as adjunctive treatment to fluorides in the noninvasive management of early caries lesion, root dentinal caries, dental erosion, and dentine hypersensitivity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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