Review Article Int J Clin Prev Dent 2018;14(1):1-10ㆍhttps://doi.org/10.15236/ijcpd.2018.14.1.1 ISSN (Print) 1738-8546ㆍISSN (Online) 2287-6197 Enhanced Remineralisation of Tooth Enamel Using Casein Phosphopeptide-Amorphous Calcium Phosphate Complex: A Review Nidhi Chhabra, Anuj Chhabra Department of Dental Surgery, North DMC Medical College and Hindu Rao Hospital, Delhi, India The protective effects of milk and milk products against dental caries, due to micellar casein or caseinopeptide derivatives, have been demonstrated in various animal and human in situ studies. Among all the remineralising agents, casein phospho- peptide-amorphous calcium phosphate (CPP-ACP) technology has shown the most promising scientific evidence to support its use in prevention and reversal of carious lesions. CPP-ACP complex acts as a calcium phosphate reservoir and buffer the activities of free calcium and phosphate ions in the plaque. Calcium phosphate stabilized by CPP produces a metastable sol- ution supersaturated with respect to the amorphous and crystalline calcium phosphate phases, thereby depressing enamel demineralisation and enhancing mineralisation. CPP-ACP provides new avenue for the remineralisation of noncavitated ca- ries lesions. The objective of this article was to review the clinical trials of CPP-ACP complex and highlight its evidence based applications in dentistry. Keywords: remineralisation, casein derivatives, casein phospho peptide-amorphous calcium phosphate Introduction from an imbalance in the physiological process of remineralisa- tion/demineralisation of the tooth structure and results in the Recent scientific advances in restorative materials, techni- formation of a subsurface lesion [1]. At an early stage, the caries ques and better understanding of the etiology, pathogenicity and lesion is reversible via remineralisation process involving the prevention of caries, have led to more efficient management of diffusion of calcium and phosphate ions into the subsurface le- oral health. Dental caries is a pathological condition arising sion, to restore the lost tooth structure. Due to the presence of calcium and phosphate ions in supersaturated state, the whole human saliva has the potential to remineralise demineralised Corresponding author Nidhi Chhabra crystals of tooth structure, while preventing surface deposition Department of Dental Surgery, North DMC Medical College in the form of calculus [2]. However, net remineralisation pro- and Hindu Rao Hospital, DR. J.S. Kkaranwal Memorial duced by saliva is small and a slow process, with a tendency for Road, Near Malka Ganj, Sabji Mandi, Malka Ganj, New the mineral gain to be in the surface layer of the lesion due to Delhi, Delhi 110007, India. Tel: +91-1127471245, Fax: the low ion concentration gradient from saliva into the lesion +91-1127471245, E-mail: [email protected] [3]. Thus, if the pH challenge overcome the physiological re- https://orcid.org/0000-0002-0277-8938 mineralisation process, a therapeutic approach using the new Received February 28, 2018, Revised March 5, 2018, remineralisation system is necessary to achieve effective lesion Accepted March 9, 2018 regression. Copyright ⓒ 2018. Korean Academy of Preventive Dentistry. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1 International Journal of Clinical Preventive Dentistry Enamel Remineralising Systems ally would sequester available fluoride ions, thereby reducing their ability to promote remineralisation of subsurface enamel Fluoride has been known as a remineralising agent that inter- lesions [18,19]. acts with the oral fluids on the interface of enamel and subsur- Recent developments in the area of remineralisation include face regions of teeth, and combines with the calcium and phos- casein phosphopeptide (CPP)-ACP nanocomplexes, which are phate ions to form fluorapatite crystals [4]. Fluoride is the cor- derived from bovine milk protein, casein, calcium, and nerstone of the non-invasive management of non-cavitated ca- phosphate. ries lesions, but its ability to promote net remineralisation is lim- ited by the availability of calcium and phosphate ions in the sali- CPP-ACP va or dental plaque [5]. Various studies have shown that enamel remineralisation in situ and the retention of fluoride in plaque In the late 1950s, milk and dairy products were shown to be are dependent on the availability of calcium ions [5-8]. Hence, effective in preventing caries without any side effects on the on topical application of fluoride ions, the availability of cal- teeth [20-30]. Casein is the predominant phosphoprotein in bo- cium and phosphate ions can be the limiting factor for fluoride vine milk and accounts for almost 80% of its total protein, pri- retention and net enamel remineralisation to occur, and this is marily as calcium phosphate stabilized micellular complexes highly exacerbated under hypo-salivation conditions [5]. that can be released as small peptides (CPPs) by partial enzy- Moreover, the topical fluoride applications (particularly matic digestion. This has led to the development of a reminerali- high concentrations) promote mainly the surface remineralisa- sation technology based on CPP-stabilized ACP complexes tion of enamel [9-12]. However, remineralising agents should (CPP-ACP) (RecaldentR CASRN691364-49-5) [31,32] and supply stabilized bioavailable calcium, phosphate and fluoride CPP stabilized ACFP complexes (CPP-ACFP) [5,33,34]. The ions that favor the subsurface remineralisation rather than CPPs are approximately 10% (w/w) of the protein casein [35]. merely promoting the surface remineralisation. Also, this ele- They can be easily purified from a tryptic digest of casein by ment can cause fluorosis, and is toxic if administered in high selective precipitation, iron exchange, or ultrafiltration [36]. dosages [13,14]. Moreover, CPP does not have the limitations that are associated With the increasing focus on early detection and non-in- with the use of casein like the adverse organoleptic properties vasive management of caries, researchers have been testing and large amount required for its efficacy. The potential for a new methods to enhance the remineralisation of enamel. The specific anticariogenic activity is at least 10 times greater on a problem with applying crystalline calcium phosphate reminer- weight basis for CPP than it is for casein [37]. alising materials to promote enamel remineralisation in the oral The concept of CPP-ACP as a remineralising agent was first cavity is the poor solubility of the calcium phosphate phases, postulated in 1998 [37]. The CPP-ACP complex was patented such that the calcium and phosphate ions are unavailable for re- by the University of Melbourne, Australia, and the Victorian mineralisation at normal pH range of saliva [15]. Furthermore, Dairy Industry Authority, Abbotsford, Australia. Bonlac Foods localization of significant quantities of solid calcium phosphate Limited (an Australian company owned by 2,300 dairy farmers phases at the tooth surface is problematic [16]. in Victoria and Tasmania) has retained exclusive manufactur- The unstabilized amorphous calcium phosphate (ACP) sys- ing and marketing rights for CPP-ACP and is the owner of the tems deliver calcium ions with phosphate ions that result in im- trademark RecaldentTM [38]. The protective anticariogenic ef- mediate precipitation of ACP or, in the presence of fluoride ions, fects of CPP-calcium phosphate complexes have been shown amorphous calcium fluoride phosphate (ACFP). In the intra-or- in various laboratory, animal and human in situ studies [39-48]. al environment, these phases (ACP and ACFP) are potentially CPP-ACP complexes have been incorporated into commer- very unstable and may rapidly transform into a more thermody- cially available sugar-free chewing gum (RecaldentTM; GC namically stable, crystalline phase (e.g., hydroxyapatite [HA] Corp, Tokyo, Japan and Trident WhiteⓇ; Cadbury Adams USA, and fluorhydroxyapatite) [17]. Although some of the published Parsippany, NJ, USA), mints (Recaldent MintsTM; Cadbury papers suggest that the unstabilized ACP/ACFP technology Japan Ltd, Tokyo, Japan), topical gels (Tooth Mousse, Tooth may have efficacy in preventing caries progression, some au- Mousse Plus; GC Corp, and MI Paste and MI Paste Plus; GC thors have expressed concern with the unstabilized nature of the America, Alsip, IL, USA) and experimentally tested sports product that forms intra-orally with this technology. The un- drinks and glass ionomer cements (Figure 1) [16,45,46,49]. stabilized ACP/ACFP may transform to poorly soluble phases One of the advantages of CPP-ACP products over fluoride in the mouth, and, in so doing, may act to promote dental products is that they do not cause fluorosis of the enamel and calculus. The formation of fluoride-containing apatite intra-or- are ingestible in contrast to the topical fluoride products that 2 Vol. 14, No. 1, March 2018 Nidhi Chhabra and Anuj Chhabra：Enhanced Remineralisation of Tooth Enamel Using CPP-ACP Complex CPP-ACP release the weakly bound calcium and phosphate ions [32,52,53] which would then deposit into crystal voids. Hence, the CPPs have a role in regulating the anisotropic crystal growth and also inhibiting crystal demineralisation in the enam-