Paul Sharpe, a bioengineer at King’s College London, and his colleagues discovered a new way regenerate teeth in mice. They have made even more progress that edges this experimental procedure closer to human clinical trials.
If the teeth regeneration treatment eventually becomes part of the dentist’s standard toolkit, then it would easily be one of the field’s most important advances in 50 years.
They drilled holes into the molars of mice, mimicking cavities. They then soaked tiny collagen sponges in various drugs known to stimulate Wnt signaling, including tideglusib, a compound that has been investigated in clinical trials for its potential to treat Alzheimer’s and other neurological disorders. The scientists then placed these drug-soaked sponges in the drilled mouse molars, sealed them up and left them for four to six weeks. The teeth treated with these drugs produced significantly more dentin than ones untreated or stuffed with an unsoaked sponge or typical dental fillers. In most cases they restored the mice teeth completely.
The restoration of dentine lost in deep caries lesions in teeth is a routine and common treatment that involves the use of inorganic cements based on calcium or silicon-based mineral aggregates. The carrier sponge is degraded over time, dentine replaces the degraded sponge leading to a complete, effective natural repair. This simple, rapid natural tooth repair process could thus potentially provide a new approach to clinical tooth restoration.
Modern dental practice for carious lesions aims to remove decay and restore tooth structure by using mineral aggregate filling materials. Preservation of undamaged dentine forms an integral part of this practice since maintenance of as much of the natural mineral as possible is deemed important for tooth vitality. Mineral aggregates such as MTA and Biodentine are reported to aid the formation of tertiary dentine, although the deposition of this dentine is not at the sites of damage but rather internal in the pulp space. In addition the non-biodegradeable nature of these materials means that the full mineral volume is never restored. If a simple method can be developed that acts to enhance the natural processes of dentine restoration by stimulating tertiary dentine formation, then large injuries that would certainly lead the dental pulp to undergo necrosis could be repaired by enabling reparative dentine to be formed at the site of damage. The activation of Wnt/βCat signalling as a universal immediate-early response to tissue damage provides a potential route for enhancing natural repair by overstimulating this pathway30. Wnt/βcatenin signalling has thus emerged as a major target in tissue regeneration and repair and this pathway activity can be stimulated in a number of different ways. We chose small molecule agonists as a simple, cost-effective method that is supported by substantial existing experimental data and clinical use. In our damage model system we did not observe any effects of MTA on the enhancement of Wnt signaling activity and although it may be acting via other pathways it seems likely that any positive action on mineralization is a result of providing mineral ions. We developed a method that uses an already clinically-approved biomaterial (collagen sponge – Kolspon) as a delivery vehicle for small molecule GSK-3 inhibitors that act as Wnt agonists. Both BIO and CHIR99021 have been extensively used experimentally to elevate Wnt activity while Tideglusib is in clinical trials for systemic use in the treatment of neurological disorders include Alzheimers disease. Since upregulated Wnt activity in response to damage is an immediate early response we aimed to achieve rapid release of small molecule agonists and reasoned a sponge was the most effective way of ensuring this. All three agonists showed significantly increased mineralisation at the site of damage compared to the use of the sponge alone or MTA treatment. More significantly the localization of the reparative dentine formed indicated that with the treatments, the mineral replaced the biodegradable sponge and restored the cavity in the dentine made by the burr. With MTA the cavity remains permanently filled with mineral aggregate and this non-degradable material can only affect reparative dentine formation on the pulp chamber aspect.
An important consideration is the effect Wnt agonists may have following their release into the circulation. The small localised doses of these agonists used were effective at increasing the formation of reparative dentine to the extent that almost complete repair of the lesion was observed after 6 weeks. These doses are substantially lower that those used in clinical trials of Tideglusib where 500–1000 mg were delivered systemically daily for 26 weeks20. We used a maximum of 21 pg of Tideglusib on the sponges and thus even if 100% of the drug on the sponge is released within a few hours, the maximum systemic concentration, assuming all the drug enters the circulation, would be no more than 21 pg in 1.5 ml. Mouse blood volume is approximately 3000 times smaller than that of a human and thus the mouse dosage in the circulation is equivalent to 63 ng in the human circulation, or 1000 times lower than used in clinical trials. Extrapolating the size of a mouse first molar to that of a human suggests that an equivalent lesion would require around 10 times more reparative dentine formation and thus the anticipated concentrations of Tideglusib required for human tooth repair would be well below that already tested in clinical trials.
Small molecule Wnt signaling agonists delivered via a biodegradable collagen sponge provide an effective repair of experimentally-induced deep dental lesions by promotion of reparative dentine formation. The simplicity of this approach makes it ideally translatable into a clinical dental product for treatments requiring dentine restoration and pulp protection that are currently treated with non-organic cements.