With the improvement of people's living standards and the strengthening of awareness of caries prevention and control, enamel remineralization has received extensive attention. Fluoride is a commonly used remineralization agent in clinic and life, but its remineralization process depends on calcium and phosphorus ions in saliva. Therefore, several new remineralizers have been introduced to supplement and improve the repair ability of fluoride to dental minerals, such as bioactive glass, nano hydroxyapatite, casein phosphopeptide amorphous calcium phosphate (CPP-ACP), which can promote enamel remineralization to a certain extent. Casein phosphopeptide amorphous calcium phosphate (CPP-ACP), derived from milk, is a stable calcium phosphorus remineralization system, which can be used in the minimally invasive treatment of early enamel caries, and has attracted much attention in recent years. In this paper, the structure of CPP-ACP, the mechanism of remineralization and related research progress are systematically reviewed and summarized, so as to provide reference for basic research and clinical application.

Jing Wang, Yanli Mo, Yishan Liu. Research progress of CPP-ACP promoting enamel remineralization. International Journal of Frontiers in Medicine (2022), Vol. 4, Issue 9: 12-17. https://doi.org/10.25236/IJFM.2022.040903.

[1] Tüfekçi E, Pennella DR, Mitchell JC, et, al. Efficacy of a fluoride-releasing orthodontic primer in reducing demineralization around brackets: an in-vivo study. Am J Orthod Dentofacial Orthop. 2014 Aug; 146(2): 207-214.

[2] Yap J, Walsh LJ, Naser-Ud Din S, et, al. Evaluation of a novel approach in the prevention of white spot lesions around orthodontic brackets. Aust Dent J. 2014 Mar;59(1):70-80. 

[3] Kugel G, Arsenault P, Papas A. Treatment modalities for caries management, including a new resin infiltration system. Compend Contin Educ Dent. 2009. Oct;30 Spec No 3:1-10; quiz 11-2.

[4] Abou Neel EA, Aljabo A, Strange A, et al. Demineralization-remineralization dynamics in teeth and bone. Int J Nanomedicine. 2016. Sep 19; 11: 4743-4763.

[5] Li J, Xie X, Wang Y, Yin W, Antoun JS, Farella M, Mei L. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on early caries lesions in vivo: a systematic review. J Dent. 2014 Jul; 42(7): 769-777. 

[6] Wang Liyuan, Zhou Hongyan, Mei Yufeng. Progress in the remineralization of casein phosphopeptide-amorphous calcium remineralization phosphate [J]. Oral Biomedicine, 2019, 10 (01): 51-53.

[7] Indrapriyadharshini K, Madan Kumar PD, Sharma K, et al. Remineralizing potential of CPP-ACP in white spot lesions - A systematic review. Indian J Dent Res. 2018 Jul-Aug; 29(4): 487-496.

[8] Reynolds EC, Cain CJ, Webber FL, et al. Anticariogenicity of calcium phosphate complexes of tryptic casein phosphopeptides in the rat. J Dent Res. 1995 Jun; 74(6): 1272-1279. 

[9] Boskey AL. Amorphous calcium phosphate: the contents of bone. J Dent Res 1997; 76: 1433–1436.

[10] N.J. Cochrane, E.C. Reynolds, Calcium phosphopeptides -- mechanisms of action and evidence for clinical efficacy, Adv. Dent. Res. 24 (2012) 41-47.

[11] K.J. Cross, N.L. Huq, E.C. Reynolds, Casein phosphopeptide-amorphous calcium phosphate nanocomplexes: a structural model, Biochemistry 55 (2016) 4316-4325.

[12] L. Wu, K. Geng, Q. Gao, Early caries preventive effects of casein phosphopeptideamorphous calcium phosphate (CPP-ACP) compared with conventional fluorides: ameta-analysis, Oral Health Prev. Dent 17 (2019) 495-503.

[13] Xu Yu, Zou Huiru. CPP-ACP combined with fluoride for enamel remineralization research progress [J]. International Journal of Biomedical Engineering, 2021, 44 (05): 388-394.

[14] Llena C, Leyda AM, Forner L. CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early caries lesions. A prospective study [J]. Eur J Paediatr Dent, 2015, 16(3): 181-186. 

[15] Jayarajan J, Janardhanam P, Jayakumar P. Efficacy of CPP-ACP and CPP-ACPF on enamel remineralization-an in vitro study using scanning electron microscope and DIAGNOdent [J]. Indian J Dent Res, 2011, 22(1): 77-82. 

[16] Sun Yang, Gao Chengzhi. Evaluation of the effect of fluoride-coated paint with CPP-ACP or bioactive glass on root caries [J]. Shanghai Stomatology, 2020, 29 (01): 46-50.

[17] Liu Xingrong, Xu Ai, Li Yanping, et al. Effect of the casein phosphopeptide calcium-phosphate complex on the growth and acid production of S. mutans [J]. Journal of Modern Preventive Medicine, 2006, 33 (10): 1815-1817.

[18] Liao Fuqin, Li Song, Sheng Min, et al. In vitro study of casein phosphopeptide-amorphous calcium phosphate in preventing enamel demineralization in orthodontic treatment [J]. Journal of Modern Oral Medicine, 2008, 22 (5): 524-527.

[19] Li Yanping, Liu Xingrong, Xu Aai, et al. Experimental studies on the effect of casein phosphopeptide calcium phosphate fluid on acid production in L. fermentations [J]. Journal of Dental pulp Periodontology, 2006, 16 (11): 627-629.

[20] Wei Hua. Anti-caries effect of casein phosphopeptides combined with calcium and phosphorus [J]. Fudan Journal (Medical edition), 2003 (03): 297-298.

[21] Dashper SG, Shen P, Sim CPC, et, al. CPP-ACP Promotes SnF2 Efficacy in a Polymicrobial Caries Model. J Dent Res. 2019 Feb; 98(2): 218-224. 

[22] Boles J. Non-Pharmacological Strategies for Addressing Infant Pain. Pediatr Nurs. 2017 Mar-Apr; 43(2): 98-100.

[23] Hatfield LA, Hoffman RK, Polomano RC, et, al. Epigenetic Modifications Following Noxious Stimuli in Infants. Biol Res Nurs. 2018. Mar; 20(2): 137-144. 

[24] Cremillieux C, Makhlouf A, Pichot V, et, al. Objective assessment of induced acute pain in neonatology with the Newborn Infant Parasympathetic Evaluation index. Eur J Pain. 2018. Jul; 22(6): 1071-1079. 

[25] Wu Tingyun, Ruan Qiong, Li Zhi, Xu Xiaofan, Du Xiaotao, Chen Yunqiao, Peng LAN. Quantitative analysis of the effect of nanoscale tooth protectors on remineralization after enamel acid erosion [J]. Journal of Clinical Stomatology, 2022, 38 (02): 75-78.

[26] Zhao Yan, Gao Ping. In vitro experimental study of the casein calcium phosphate complex on demineralization of enamel in deciduous teeth [J]. Journal of Practical Stomatology, 2019, 35 (05): 681-684.

[27] Memarpour M, Fakhraei E, Dadaein S, et, al. Efficacy of fluoride varnish and casein phosphopeptide-amorphous calcium phosphate for remineralization of primary teeth: a randomized clinical trial. Med Princ Pract. 2015; 24(3): 231-237.

[28] Andersson A, Sköld-Larsson K, Hallgren A, et, al. Effect of a dental cream containing amorphous cream phosphate complexes on white spot lesion regression assessed by laser fluorescence. Oral Health Prev Dent. 2007; 5(3): 229-333. 

[29] Vyavhare S, Sharma DS, Kulkarni VK. Effect of three different pastes on remineralization of initial enamel lesion: an in vitro study. J Clin Pediatr Dent. 2015 Winter; 39(2): 149-60.

[30] López-García S, Guerrero-Gironés J, Pecci-Lloret MP, Pecci-Lloret MR, Rodríguez-Lozano FJ, García-Bernal D. In Vitro Biocompatibility of CPP-ACP and Fluoride-containing Desensitizers on Human Gingival Cells. Oper Dent. 2021 Nov 1;46(6): E264-E275.

[31] Mahesuti A, Duan YL, Wang G, et, al. Short-term Efficacy of Agents Containing KNO3 or CPP-ACP in Treatment of Dentin Hypersensitivity. Chin J Dent Res. 2014; 17(1): 43-47. 

[32] Ramalingam L, Messer LB, Reynolds EC. Adding casein phosphopeptide-amorphous calcium phosphate to sports drinks to eliminate in vitro erosion. Pediatr Dent. 2005 Jan-Feb; 27(1): 61-67.

[33] Cai F, Shen P, Morgan MV, et, al. Remineralization of enamel subsurface lesions in situ by sugar-free lozenges containing casein phosphopeptide-amorphous calcium phosphate. Aust Dent J. 2003 Dec; 48(4): 240-243.

[34] Fernando JR, Butler CA, Adams GG, et, al. The prebiotic effect of CPP-ACP sugar-free chewing gum. J Dent. 2019 Dec; 91: 103225. 

[35] Manton DJ, Cai F, Yuan Y, et, al. Effect of casein phosphopeptide-amorphous calcium phosphate added to acidic beverages on enamel erosion in vitro. Aust Dent J. 2010. Sep; 55(3): 275-279.

[36] Romão DA, de Lima CP, Lôbo MV, et, al. Erosive potential of powdered juice drinks on dental enamel. Gen Dent. 2021 Jan-Feb; 69(1): 44-49.

[37] Wang CP, Huang SB, Liu Y, et, al. The CPP-ACP relieved enamel erosion from a carbonated soft beverage: an in vitro AFM and XRD study. Arch Oral Biol. 2014 Mar; 59(3): 277-282. 

[38] Walker GD, Cai F, Shen P, et, al. Consumption of milk with added casein phosphopeptide-amorphous calcium phosphate remineralizes enamel subsurface lesions in situ. Aust Dent J. 2009 Sep; 54(3): 245-249.

[39] Shen P, Fernando JR, Walker GD, et, al. Addition of CPP-ACP to yogurt inhibits enamel subsurface demineralization. J Dent. 2020 Dec; 103: 103506.