Despite the caries decline over the last five decades in many countries,^1,2 dental caries is still the most prevalent disease in the world.^2,3 Caries occurs when an imbalance between re- and demineralization takes place at the site of loss of minerals in hard dental tissue. Therefore, the classic “treatment” of cavities by drilling and filling constitutes repair of the damage, but does not treat the disease itself (see Chapter 1). “Real” caries treatment would consist of shifting the equilibrium to remineralization, for instance by improving the daily oral hygiene regime and fluoride utilization. Furthermore, the traditional invasive restorative interventions lead to destruction of healthy tooth tissue, destabilizing the tooth structure and leading to a cycle of new restorations, more removal of dental tissue to replace existing restorations by larger ones, and so on.

The caries decline and a subsequently slow progression of caries lesions allow the use of preventive treatment strategies instead of restorative treatments.⁴

Based on the new understanding of caries kinetics, monitoring the de-/remineralization equilibrium is the first step in applying and controlling measures for correcting the mineralization balance. In the early stages of caries, prior to the cavitation of the enamel surface, many non- and minimally invasive treatments have been suggested to avoid placing a restoration. The primary aim of noninvasive treatments is to inactivate or arrest the caries (see Chapter 1). This can be achieved by diet control and plaque removal, which allow the caries lesions to remineralize naturally through saliva,⁵ as described in other chapters of this book. The presence of fluorides clearly enhances remineralization and prevents further demineralization,^6–8 but this is less effective in manifest cavities (see Chapter 3).^9,10

Thus, most preventive approaches rely on changes in the patient’s behavior. A possible alternative is mechanically sealing caries risk surfaces,¹¹ but sealants are prone to microleakage and subsequent caries in the long run.¹²

Regenerative medicine enables the replacement of damaged or diseased tissues. The shift from reparative to regenerative dentistry reflects the current trend in medicine,¹³ and also mirrors the new understanding of caries as a chronic disease.¹ Similar to the guided regeneration of bone and periodontal tissue (long-established procedures in dentistry), the subsurface caries lesion presents a unique compartment, in which a biomimetic scaffold can support natural hard tissue formation through saliva,¹⁴ resulting in guided enamel regeneration (GER) analogous to guided tissue regeneration (GTR) and guided bone regeneration (GBR).^15,16

Biomimetic remineralization follows this concept in the treatment of dental caries, as it aims to remineralize initial caries lesions instead of sealing or infiltrating them with resin.

The new biomimetic approach endeavors mimicry of the enamel matrix proteins using a self-assembling peptide (SAP) system to form a three-dimensional (3D) matrix within the subsurface caries lesion.^17,18 In vitro studies showed that this matrix has a high affinity for hydroxyapatite (HA) and possesses binding sites on its surface that provide a template for HA formation.^14,19 These properties support the body’s own regeneration process by saliva to remineralize larger lesions, as saliva delivers Ca²⁺ and PO₄³⁻ to the lesion body for mineralization.²⁰

Biomimetic remineralization using a SAP presents a novel possibility for dental practitioners to predictively treat early caries as a disease, healing the enamel tissue. In comparison with amelogenin-based experimental therapies,¹⁸ the advantage of SAPs is the ability to form a biomimetic scaffold within the subsurface caries lesion.^14,21 In turn, the biomimetic scaffold relies on saliva to mineralize around the matrix; the mechanism of action is displayed in Fig 13-1.

Self-assembling peptide P11-4

The SAP P11-4 is clinically available as Curodont Repair (Credentis; Fig 13-2). It has the chemical structure: Ace-Gln-Gln-Arg-Phe-Glu-Trp-Glu-Phe-Glu-Gln-Gln-NH₂. The P11-4 is formulated in a low-salt Tris-buffer preventing self-assembly to take place and contains 1% trehalose for preservation. It is fully synthetic and manufactured under current good manufacturing practices (cGMP). It contains no human- or animal-derived components.

P11-4 undergoes under specific physicochemical conditions, and above a critical concentration, a hierarchical self-assembly to form tapes and ribbons within seconds, and fibrils and fibers within the following 24 hours (Fig 13-3).^21–24 These resulting SAP fibers forming the 3D self-assembling peptide matrix (SAPM) can grow to a significant length. If the conditions for self-assembly are given, the assembly process cannot be stopped at the intermediates unless no more monomeric peptides are available. Physical factors such as pH and ionic strength can be used to control the assembly process.²⁵

Biocompatibility studies (according to ISO 10993 or equivalent) have shown that P11-4 did not raise any cytotoxic effects or any immunologic response.^26–28 P11-4 has been proven safe in animals and patients in vivo. No adverse device effects have been reported so far.²⁹

In vitro studies

Confocal microscopy and mass spectroscopy showed that monomeric P11-4 diffuses through the pores of demineralized enamel, where fiber formation is triggered and the 3D matrix is formed.³⁰ Furthermore, C-labeled P11-4 indicated that about 35% of P11-4 remained within artificial caries lesions,³⁰ being available for de novo HA crystal formation. Two studies^31,32 used the microtomography (microCT) analysis of remineralized specimens and found a remineralization of up to 90% of the original enamel density.

A series of in vitro studies revealed the high affinity of the P11-4 matrix for Ca²⁺ ions and its action as a nucleator for de novo HA formation.^14,21,30,33 Furthermore, the P11-4 fibers bind to the already existing Ca²⁺ ions of the HA lattice of the tooth enamel,²¹ enabling stable bridge binding of the new regenerated enamel to the tooth hard tissue.

A study by Kind et al³⁰ investigated the diffusion of P11-4 into a caries lesion by time-resolved confocal microscopy pictures. The results showed that the P11-4 diffuses beyond the volume of the caries lesion into the enamel layer below that is defined as the caries lesion, on a microradiograph. After the formation of fibers is complete, the formed fibers seem to occupy the observed lesion.

In vivo and clinical studies

Huang et al³⁴ used a self-assembling bioactive matrix to investigate the ability to induce ectopic formation of enamel at chosen sites adjacent to a mouse incisor cultured in vivo under the kidney capsule. The resulting material revealed a highly organized, hierarchical structure of HA crystallites similar to native enamel.

SAP for treatment of occlusal caries

To investigate the safety and clinical efficacy of P11-4 for treatment of initial caries, a randomized controlled single-blind study was conducted by Alkilzy et al^29,35 on children aged from 5 years old with visible active early caries on erupting permanent molars. Subjects were randomized to either the test group (P11-4 + fluoride varnish) or the control group (fluoride varnish alone). Caries lesions were assessed at baseline and at 3 and 6 months posttreatment per laser fluorescence, a visual analog scale (VAS), the International Caries Detection and Assessment System (ICDAS), and Nyvad caries activity criteria. Safety and clinical feasibility of the treatment approaches were also assessed. The P11-4 (Curodont Repair) was applied according to the instructions of the manufacturer (Fig 13-4). Compared with the control group, the test group showed clinically and statistically significant improvement in all outcomes at the 3- and 6-month follow-ups. The laser fluorescence readings (odds ratio [OR] = 3.5, P = .015) and VAS scores (OR = 7.9, P < .0001) were significantly lower for the test group, and they showed regression in the ICDAS caries index (OR = 5.1, P = .018; Fig 13-5) and conversion from active to inactive lesions according to Nyvad criteria (OR = 12.2, P < .0001; Fig 13-6). No adverse events occurred. This study showed that the biomimetic mineralization facilitated by P11-4 in combination with fluoride application is a simple, safe, and effective noninvasive treatment for early caries lesions that is superior to the presently used gold standard of fluoride alone.

SAP for treatment of buccal caries and white spots

Bröseler et al³⁶ compared in a prospective, randomized, split-mouth, clinical trial the efficacy of the SAP P11-4 to that of fluoride varnish in the treatment of early buccal caries lesions. Subjects with at least two clinically affected teeth were treated at day (D) 1 and D90 with P11-4 (test) or fluoride varnish (control). At D180, fluoride varnish was applied on all study lesions. Standardized photographs were taken at D0, D30, D90, D180, and D360 and the decrease in size between test and control groups was blindly morphometrically assessed. The results showed a significant difference between test and control groups, indicating a decrease in test lesions and stabilization of control lesions size (P = .001). The authors concluded that the size of early caries lesions treated with P11-4 was significantly reduced, and this size reduction was superior to that of fluoride varnish treat-ment.

SAP for treatment of proximal caries

A study by Schlee et al³⁷ investigated the clinical performance of SAP P11-4 on noncavitated initial proximal caries lesions 12 months after treatment. Twenty-six patients with 35 caries lesions were included in a practice-based case series. The radiographs of the proximal lesions at baseline and at D360 were evaluated pairwise in a randomized and blinded manner with respect to the time point. The 1-year results showed a predominant shift toward regression of the initial lesions, with 20 of 28 lesions showing total or partial regression, four unchanged, and four progressing. The authors suggested that the initial proximal caries lesions can regress after treatment with P11-4, but additional factors might influence the overall treatment outcome.

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