Dental caries is a highly prevalent diet-related disease and is a major public health problem. A goal of modern dentistry is to manage non-cavitated caries lesions non-invasively through remineralization in an attempt to prevent disease progression and improve aesthetics, strength, and function. 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. Recently, a range of novel calcium-phosphate-based remineralization delivery systems has been developed for clinical application. These delivery systems include crystalline, unstabilized amorphous, or stabilized amorphous formulations of calcium phosphate. These systems are reviewed, and the technology with the most scientific evidence to support its clinical use is the remineralizing system utilizing casein phosphopeptides to stabilize and deliver bioavailable calcium, phosphate, and fluoride ions. The recent clinical evidence for this technology is presented and the mechanism of action discussed. Biomimetic approaches to stabilization of bioavailable calcium, phosphate, and fluoride ions and the localization of these ions to non-cavitated caries lesions for controlled remineralization show promise for the non-invasive management of dental caries.

Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) nanocomplexes incorporated into sugar-free chewing gum have been shown to remineralize enamel subsurface lesions in situ. The aim of this study was to compare the ability of CPP-ACP, with that of other forms of calcium, to be retained in supragingival plaque and remineralize enamel subsurface lesions in situ when delivered in a mouthrinse or sugar-free gum in randomized, double-blind trials. In the mouthrinse study, only the CPP-ACP-containing mouthrinse significantly increased plaque calcium and inorganic phosphate levels, and the CPP were immunolocalized to the surfaces of bacterial cells as well as the intercellular matrix. In the chewing gum studies, the gum containing the CPP-ACP, although not containing the most calcium per piece of gum, produced the highest level of enamel remineralization independent of gum-chewing frequency and duration. The CPP could be detected in plaque extracts 3 hrs after subjects chewed the CPP-ACP-containing gum. The results showed that CPP-ACP were superior to other forms of calcium in remineralizing enamel subsurface lesions.

Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) slows the progression of caries and remineralizes enamel subsurface lesions. The aim of this study was to determine the ability of CPP-ACP to increase the incorporation of fluoride into plaque and to promote enamel remineralization in situ. Randomized, double-blind, cross-over studies involved mouthrinses and dentifrices containing CPP-ACP and fluoride. The mouthrinses were used for 60 sec, three times/day for 5 days, and supragingival plaque was collected and analyzed for F. The dentifrices were rinsed as a water slurry for 60 sec four times/day for 14 days in an in situ model. The addition of 2% CPP-ACP to the 450-ppm-F mouthrinse significantly increased the incorporation of fluoride into plaque. The dentifrice containing 2% CPP-ACP produced a level of remineralization similar to that achieved with a dentifrice containing 2800 ppm F. The dentifrice containing 2% CPP-ACP plus 1100 ppm F was superior to all other formulations.

Casein phosphopeptide-amorphous calcium phosphate nanocomplexes (CPP-ACP) exhibit anticariogenic potential in laboratory, animal, and human in situ experiments. The aim of this study was to determine the ability of CPP-ACP in sugar-free chewing gum to remineralize enamel subsurface lesions in a human in situ model. Thirty subjects in randomized, cross-over, double-blind studies wore removable palatal appliances with six human-enamel half-slabs inset containing sub-surface demineralized lesions. The appliances were inserted immediately before gum-chewing for 20 min and then retained for another 20 min. This was performed four times per day for 14 days. At the completion of each treatment, the enamel half-slabs were paired with their respective demineralized control half-slabs, embedded, sectioned, and subjected to microradiography and densitometric image analysis, for measurement of the level of remineralization. The addition of CPP-ACP to either sorbitol- or xylitol-based gum resulted in a dose-related increase in enamel remineralization, with 0.19, 10.0, 18.8, and 56.4 mg of CPP-ACP producing an increase in enamel remineralization of 9, 63, 102, and 152%, respectively, relative to the control gum, independent of gum weight or type.

Casein phosphopeptide stabilised amorphous calcium phosphate (CPP-ACP) and amorphous calcium fluoride phosphate (CPP-ACFP) solutions have been shown to remineralise enamel subsurface lesions. The aim of this study was to determine the effect of ion composition of CPP-ACP and CPP-ACFP solutions on enamel subsurface lesion remineralisation in vitro. CPP-bound and free calcium, phosphate and fluoride ion concentrations in the solutions were determined after ultrafiltration. The ion activities of the free ion species present were calculated using an iterative computational program. The mineral deposited in the subsurface lesions was analysed using transverse microradiography and electron microprobe. CPP was found to stabilise high concentrations of calcium, phosphate and fluoride ions at all pH values (7.0–4.5). Remineralisation of the subsurface lesions was observed at all pH values tested with a maximum at pH 5.5. The CPP-ACFP solutions produced greater remineralisation than the CPP-ACP solutions at pH 5.5 and below. The mineral formed in the subsurface lesions was consistent with hydroxyapatite and fluorapatite for remineralisation with CPP-ACP and CPP-ACFP, respectively. The activity gradient of the neutral ion pair CaHPO₄⁰ into the lesion was significantly correlated with remineralisation and together with HF⁰ were identified as important species for diffusion.