A modified glass ionomer cement to mediate dentine repair
Introduction
The restoration of tooth mineral after caries removal is central to clinical dental practice. Current approaches are dominated by materials aimed at producing a hard, easy-to-use, and long-lasting restoration. Glass ionomer cements (GIC), which are based on an aluminosilicate glass reacting with a polymeric acid, were originally developed in the 1970s [[1], [2], [3]] because of the limitations of other restorative materials [2,[4], [5], [6], [7], [8]]. GIC are naturally bioactive as they can release a number of ions and chemically bond to dentine. GIC have better aesthetics than amalgam, gold and porcelain and so are often used for luting, lining and restoration. Modifications of cement formulations have been performed over the last decades to improve the characteristics of GIC, however GIC remain limited in their effect on the reactionary dentine formation in the tooth cavity.
Tertiary dentine forms in response to dentine and/or odontoblast damage in a natural reparative/regenerative process. In deep caries lesions that penetrate the pulp and destroy odontoblasts, resident pulp stem cells are activated and differentiate into odontoblast-like cells that produce reparative dentine. In lesions that do not expose the pulp, signals from the damaged dentine stimulate odontoblast activity to produce reactionary dentine that forms on the pulpal aspect of the resident dentine [[9], [10], [11], [12]]. A stimulus that promotes the formation of both these forms of tertiary dentine is the Wnt/β-catenin signalling pathway [13,14]. In reparative dentine formation, Wnt ligands released by damaged pulp/odontoblasts are received by local resident stem cells in the pulp that then proliferate and differentiate into odontoblast-like cells [15,16]. Genetic elevation of Wnt activity results in an enhancement of reparative dentine formation whereas complete loss of signalling prevents reparative dentine formation. In non-exposed pulp lesions, physical damage to dentine promotes odontoblast activity. The stimuli for this activity are not fully elucidated but can be mimicked by increasing Wnt/β-catenin signalling activity, although endogenous Wnt/β-catenin activity is not essential for this to occur [11]. Release of sequestered growth factors by damaged dentine has been suggested to play a role on odontoblast activation although more recent evidence suggests this role is more modulatory in nature [10,14,[16], [17], [18]]. In a clinical context, Wnt/β-catenin activity can be enhanced by the addition of small molecule drugs that promote Wnt/β-catenin activity by antagonising GSK3 activity [[19], [20], [21]]. Lithium is a naturally occurring alkali metal that can be found in food and tap water and is clinically approved for the treatment of acute mania and bipolar disorders [[22], [23], [24], [25], [26]]. Lithium ions are long established as agonists of the canonical Wnt signaling that can inhibit GSK3β activity and thereby stabilise free cytosolic β‐catenin, resulting in increased intracellular Wnt activity [[27], [28], [29], [30], [31]]. Lithium has been shown to regulate Wnt/β-catenin activity in dental pulp stem cells, induce odontoblasts differentiation, and promote dentine regeneration [29,32,33].
There are currently no clinically approved restorative dental materials that regulate a specific biological mechanism to stimulate the formation of reactionary dentine. In order to investigate the possibility of formulating a GIC that can promote intracellular Wnt activity, we incorporated lithium-containing bioactive glass in a commercial GIC so that lithium released from the GIC could naturally penetrate dentin and stimulate odontoblast activity.
Section snippets
BG synthesis
SiO2-P2O5-CaO-Na2O-Li2O BG were formed using a melt quench route. We created either conventional 45S5 BG or substituted Li2O for Na2O in 45S5 BG on a molar basis (Table S1). Glass components were melted in a platinum crucible at 1250 °C for 1 h, then at 1350 °C for an additional hour before being rapidly quenched in water. Glass frits were then crushed in a steel mortar, milled and sieved to create particles of <38 μm in diameter.
GIC formation
LithGlassGIC were formed by replacing part of the powder
Results
We first aimed to create GIC that could release lithium, a Wnt/β-catenin pathway antagonist, and thus stimulate dentine formation and improve repair in a murine molar defect model. To accomplish this, we created 45S5 BG in which all of the sodium had been replaced with lithium on a molar basis (LithGlass) [34,35]. We have previously shown by X-ray diffraction that these BG are amorphous [36]. We then formed cements by substituting part (10–40%) of the powder phase of the commercial GIC Ketac™
Discussion
GIC have been used in dental clinics as a restorative or base material for the tooth. GIC contain both glass and a polymeric acid. In this study, we aimed to form a lithium-releasing cement that can enhance dentine repair by elevation of Wnt signalling by incorporating a lithium-releasing BG. We formed stable cements with 10%–40% LithGlass substituted for the powder component of a commercial GIC.
There are several reports that show promising effects of dissolution ions from GIC in promoting
Conclusions
Taken together, these observations confirm that LithGlassGIC quickly releases lithium, stimulates Wnt/β-catenin activity, and enhances tertiary dentine formation in pulp cells in a murine molar damage model that does not expose the dental pulp. The levels of lithium released from LithGlassGIC are similar to therapeutic levels known to be safely tolerated in humans. Therefore, LithGlassGIC may find use in a range of therapeutic applications to stimulate tertiary dentine formation to repair tooth
Acknowledgements
This study is part of PhD project of Abeer Alaohali funded by the Medical Services Division of the Ministry of Defense in Saudi Arabia and the Saudi Cultural Bureau in London. We thank Dhivya Chandrasekaran for providing animal support, Chris Healy for the μCT analysis, Anne Poliard-Arias for the gift of the 171A4 cells, Abeer Alshaalan for assistance with saliva collection, Andrew Cakebread and Anna Caldwell for assistance with ICP-MS and Vitor Neves for his valuable assistance in the
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