Armoring Enamel: New Paradigms for Combating Dental Decay

Feb 21, 2014 | Contact Author | By: Steven Isaacman, PhD, and Michael Isaacman, PhD, Nanometics LLC; and Kent Kirshenbaum, PhD, and Peter Smith, New York University
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Title: Armoring Enamel: New Paradigms for Combating Dental Decay
enamelx remineralizationx calciumx phosphatex ionsx salivax acidsx proteinsx fluoridex nanocomplexesx peptidomimeticsx
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Keywords: enamel | remineralization | calcium | phosphate | ions | saliva | acids | proteins | fluoride | nanocomplexes | peptidomimetics

Abstract: To protect enamel, new mechanisms in classic oral care continue to be uncovered, while modern advances mimic and enhance natural protective systems. New approaches to enamel repair include augmenting natural remineralization by creating reservoirs of ions and applying saliva biomimetics. Such technologies, described here, represent significant advances for repairing and protecting teeth noninvasively.

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S Isaacman, M Isaacman, K Kirshenbaum and P Smith, Armoring Enamel: New Paradigms for Combating Dental Decay, Cosm & Toil 129(2) 38 (2014)

The tough yet thin outer layer of the tooth is composed of dental enamel, which protects teeth from the daily assault of physical and chemical wear of chewing, grinding, food and drink. Dental caries, known as cavities, are the primary cause of enamel degradation, leading to tooth decay and yellowing. Although the body has mechanisms for natural enamel repair and protection, improving enamel health is a major objective of dentistry and public health concern. Furthermore, the maintenance of healthy enamel is critical for enhancing teeth strength and appearance.

Unlike bone, which is composed of living cells capable of regeneration, dental enamel is constructed largely of mineral hydroxyapatite, Ca10(PO4)6(OH)2.1 The oral environment endures a constant cycle of mineral loss and gain, and the calcium phosphate crystals in enamel can dissolve when exposed to acids from foods or oral bacteria—a process known as demineralization. Remineralization works to restore calcium and phosphate ions to enamel, and the structure of hydroxyapatite allows for ion substitutions in the crystal lattice during this process. Maintaining appropriate levels of calcium and phosphate ions in saliva is essential for oral health, and the interface of enamel and saliva is of key importance since it is where both demineralization and remineralization processes occur (see Figure 1).

Saliva represents the major component for protecting and maintaining healthy teeth. It provides an environment that is supersaturated with respect to hydroxyapatite and other calcium phosphate minerals, which helps to deter dissolution of enamel.2 Furthermore, saliva provides a source of calcium and phosphate ions, enabling remineralization to occur and repairing damaged teeth. Saliva hosts a wide range of proteins and peptides that function to protect the oral cavity. Most important to enamel protection are salivary statherin and acidic proline-rich proteins, which aid in oral care by preserving the supersaturated state of calcium and phosphate ions in saliva.3, 4 These proteins inhibit the precipitation of calcium phosphate salts out of solution, thereby preventing demineralization and providing solubilized ions for remineralization.

Fluoride Treatment

Fluoride has been known to exhibit a cavity-preventive effect for teeth, and has been utilized extensively in oral care for decades. Despite the widespread use of fluoride in reducing the prevalence of dental caries, the mechanism of action is still under debate. Previously, the benefits of fluoride were attributed to modifications of surface enamel from hydroxyapatite to fluorapatite—a harder mineral that is more resistant to decay due to its low solubility properties of fluorapatite.5 Moreover, fluoride adsorbs onto the surface of enamel and attracts calcium ions, promoting remineralization. A significant contributor to the onset of caries is the production of acids by oral bacteria, which increases the solubility of enamel and causes demineralization.

New research suggests that fluoride treatment is also capable of reducing bacterial adhesion to teeth, which limits acid production while maintaining a stable environment for enamel.6 Fluoride treatment for protection against dental caries is highly effective, though there are slight drawbacks. In order for fluoride to provide lasting protection, repeated use is necessary to maintain the protective fluorapatite film on the surface of enamel hydroxyapatite.7 Unfortunately, extensive fluoride treatment can lead to dental fluorosis, which is characterized by white streaks on enamel. Extensive treatment can also threaten the maturation of dental enamel.8

Advanced technologies aim to work synergistically with fluoride treatment or serve as an alternative to it. These systems can provide a healthy environment for enamel and encourage remineralization, allowing for rapid repair of damaged enamel. They also can be used to treat dental hypersensitivity. The use of amorphous calcium phosphate (ACP) is a simple method of introducing calcium and phosphate ions to the surface of enamel for repair. These ions are delivered separately in saliva, allowing the formation of ACP precipitates. In this newly formed unstable phase, the ACP acts as a source of calcium and phosphate ions that can be utilized for enamel remineralization before they are transformed to more stable salts.9 Thus, ACP increases the calcium and phosphate content of saliva, albeit only for a brief period.

Nanocomplexes of Calcium Phosphate

The use of nanoparticles or similar materials can overcome the brevity of ACP efficacy by encapsulating the calcium and phosphate ions and acting as a delivery platform. The presence of ACP nanoparticles at the surface of enamel creates a continuous release of ions that contribute to remineralization.10 Additionally, these nanocomposites possess acid-neutralizing properties, which aid in preventing enamel demineralization.

Another approach to stabilize calcium and phosphate ions for delivery to enamel is through the use of peptides. This technique takes inspiration from salivary statherin and acidic proline-rich proteins, which, as noted, stabilize calcium and phosphate ions in saliva. However, when saliva is deficient in these proteins, calcium phosphate salts will precipitate out of the supersaturated state, hindering the remineralization of enamel. For the oral care industry, the mechanisms of action of these proteins are an encouraging target. Small-chain peptide mimics, an area known as peptidomimetics, can be utilized to copy the functions of this natural system in order to protect teeth while also providing added benefits such as resistance to proteolytic degradation.

Phosphopeptides derived from casein can mimic these salivary proteins and create nanocomplexes of stabilized ACP (see Figure 2).9 The acidic residues of these peptides, especially the phosphate groups, bind ions in ACP. This interaction stabilizes ACP by preventing the nucleation and growth of ACP clusters into more stable calcium phosphate salts that do not make the ions available for remineralization. These nanocomplexes extend the exposure time of damaged enamel to ACP by preventing the growth of calcium phosphate crystal clusters. Numerous clinical studies have been conducted with this technology, and results show both prevention and regression of dental caries.11

Bioactive Glasses

Micro- and nanoscale silicate materials also have proven useful in a variety of medical applications. These bioactive glasses can be utilized for bone substitution, bone tissue engineering, dentistry and drug delivery.12 Minor modifications to the composition of bioactive glasses enable the tailoring of this diverse set of applications, and can even add further benefits such as antimicrobial activity.

The use of bioactive glasses in dentistry has been pursued successfully with calcium sodium phosphosilicate. This material reacts with saliva at the surface of enamel to release calcium, sodium and phosphate ions, which then form a hydroxyapatite-like mineral layer.13 Again, ions are delivered to damaged enamel to facilitate remineralization processes. By this mechanism, bioactive glass also can be used to repair dentin, the tissue beneath enamel, and occlude dental tubules to provide relief from hypersensitivity14—extending tooth repair beyond the surface to provide numerous benefits.

Conclusion

New mechanisms in classic treatments continue to be uncovered in oral care, while more modern advances search for better ways to mimic and enhance the natural protective systems already in place. These new repair systems aim to augment natural remineralization by creating reservoirs of ions. Exciting new materials make tooth repair feasible; however, these methods pose the risk of excess mineralization, leading to dental calculus. Nonetheless, the use of these materials as saliva biomimetics represents significant advances for repairing and protecting teeth noninvasively.

References

  1. JM ten Cate and JDB Featherstone, Mechanistic aspects of the interactions between fluoride and dental enamel, Critical Reviews in Oral Biology and Medicine 2, 283 (Jan 1, 1991)
  2. P Grøn, Saturation of human saliva with calcium phosphates, Archives of Oral Biology 18, 1385 (1973)
  3. S Schwartz, D Hay and S Schluckebier, Inhibition of calcium phosphate precipitation by human salivary statherin: Structure-activity relationships, Calcified Tissue International 50, 511 (Jun 1, 1992)
  4. DI Hay, ER Carlson, SK Schluckebier, EC Moreno and DH Schlesinger, Inhibition of calcium phosphate precipitation by human salivary acidic proline-rich proteins: Structure-activity relationships, Calcified Tissue International 40, 126 (May 1, 1987)
  5. JDB Featherstone, Prevention and reversal of dental caries: Role of low level fluoride, Community Dentistry and Oral Epidemiology 27, 31 (1999)
  6. P Loskill et al, Reduced adhesion of oral bacteria on hydroxyapatite by fluoride treatment, Langmuir 29, 5528 (May 7, 2013)
  7. NH de Leeuw, Resisting the onset of hydroxyapatite dissolution through the incorporation of fluoride, J Phys Chem B 108, 1809 (Feb 1, 2004)
  8. T Aoba and O Fejerskov, Dental fluorosis: Chemistry and biology, Critical Reviews in Oral Biology and Medicine 13, 155 (Mar 1, 2002)
  9. NJ Cochrane, F Cai, NL Huq, MF Burrow and EC Reynolds, Critical review in oral biology and medicine: New approaches to enhanced remineralization of tooth enamel, J Dental Res 89, 1187 (2010)
  10. MD Weir, LC Chow and HHK Xu, Remineralization of demineralized enamel via calcium phosphate nanocomposite, J Dental Res 91, 979 (Oct 1, 2012)
  11. NJ Cochrane and EC Reynolds, Calcium phosphopeptides—Mechanisms of action and evidence for clinical efficacy, Adv in Dental Res 24, 41 (Sep 1, 2012)
  12. M Erol-Taygun, K Zheng and AR Boccaccini, Nanoscale bioactive glasses in medical applications, Intl J Applied Glass Sci 4, 136 (2013)
  13. AK Burwell, LJ Litkowski and DC Greenspan, Calcium sodium phosphosilicate (NovaMin): Remineralization potential, Advan Dental Res 21, 35 (Aug 1, 2009)
  14. S Hedge et al, Evaluation of the efficacy of a 5% calcium sodium phosphosilicate (Novamin) containing dentifrice for the relief of dentinal hypersensitivity: A clinical study, Indian J Dental Res 23, 363 (May/Jun 2012)
 

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Figure 1. A constant cycle of enamel demineralization and remineralization with calcium and phosphate ions occurs in the oral environment.

Figure 1. A constant cycle of enamel demineralization and remineralization with calcium and phosphate ions occurs in the oral environment

Maintaining appropriate levels of calcium and phosphate ions in saliva is essential for oral health, and the interface of enamel and saliva is of key importance since it is where both demineralization and remineralization processes occur (see Figure 1).

Figure 2. Primary structure of salivary statherin N-terminal hexamer; casein phosphopeptides mimic this anionic fragment by stabilizing amorphous calcium phosphate with acidic residues.

Figure 2. Primary structure of salivary statherin N-terminal hexamer; casein phosphopeptides mimic this anionic fragment by stabilizing amorphous calcium phosphate with acidic residues.

Phosphopeptides derived from casein can mimic these salivary proteins and create nanocomplexes of stabilized ACP (see Figure 2).9

Biography: Steven Isaacman, PhD, Nanometics LLC

Steven Isaacman, PhD, earned a master’s degree in organic chemistry from Stony Brook University, and a Master of Science and doctorate in physical organic chemistry from New York University, where his research involved the design and fabrication of single molecule magnets, chiral molecular switches and self-assembling nano-architectures. In 2006, he founded Nanometics LLC and is the principal investigator on two small business innovation research awards from the National Institutes of Health. In addition, he is a visiting scholar at the Albert Einstein College of Medicine and New York University. As founder and CEO at Nanometics, he leads the research team in designing novel small molecules, polymers and materials for the personal care and pharmaceutical markets.

Biography: Michael Isaacman, PhD, Nanometics, LLC

Michael Isaacman, PhD, graduated from the University of California, Santa Barbara. His research focuses on the synthesis and self-assembling dynamics of silicone-based amphiphilic block copolymers. As an expert in silicone chemistry, he has pioneered novel methodologies for the design and fabrication of silicone polymers for use in drug delivery and personal care. A consultant for the personal care and pharmaceutical industry, he has published in the fields of natural product synthesis, pollutant metal detection and polymer chemistry.

Biography: Kent Kirshenbaum, PhD

Kent Kirshenbaum, PhD

Kent Kirshenbaum, PhD, studied chemistry at Reed College and obtained his doctorate in pharmaceutical chemistry from the University of California, San Francisco. Following post-doctoral studies at Caltech, Kirshenbaum joined the faculty at New York University, where he is an associate professor of chemistry. His research integrates oligomeric molecules in pursuit of new antibiotics and cancer therapeutics.

Biography: Peter Smith

Peter Smith

Peter Smith is currently a fourth-year undergraduate student at New York University, where his research is focused on the design and synthesis of bioactive peptidomimetics. He has developed new methods to utilize these functionalized oligomers as both antimicrobial agents and inhibitors of crystal growth. Smith is the recipient of multiple New York University undergraduate research grants, and his work has extended into personal care with research at Nanometics LLC.

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