Objectives Wnt/β-catenin signalling plays important roles in regeneration, particularly in hard tissues such as bone and teeth, and can be regulated by small molecule antagonists of glycogen synthase kinase 3 (GSK3); however, small molecules can be difficult to deliver clinically. Lithium (Li) is also a GSK3 antagonist and can be incorporated into bioactive glasses (BG), which can be used clinically in dental and bone repair applications and tuned to quickly release their constituent ions. Methods Here, we created phosphate (P)- and borate (B)-based BG that also contained Li (LiPBG and LiBBG) and examined their ion release kinetics and the toxicity of their dissolution ions on mouse 17IA4 dental pulp cells. Results We found that although LiPBG and LiBBG can both quickly release Li at concentrations known to regulate Wnt/β-catenin signalling, the P and B ions they concomitantly release are highly toxic to cells. Only when relatively low concentrations of LiPBG and LiBBG were placed in cell culture medium were their dissolution products non-toxic. However, at these concentrations, LiPBG and LiBBG’s ability to regulate Wnt/β-catenin signalling was limited. Significance These data suggest that identifying a BG composition that can both quickly deliver high concentrations of Li and is non-toxic remains a challenge.

Small-molecule drugs targeting glycogen synthase kinase 3 (GSK3) as inhibitors of the protein kinase activity are able to stimulate reparative dentine formation. To develop this approach into a viable clinical treatment for exposed pulp lesions, we synthesized a novel, small-molecule noncompetitive adenosine triphosphate (ATP) drug that can be incorporated into a biodegradable hydrogel for placement by syringe into the tooth. This new drug, named NP928, belongs to the thiadiazolidinone (TDZD) family and has equivalent activity to similar drugs of this family such as tideglusib. However, NP928 is more water soluble than other TDZD drugs, making it more suitable for direct delivery into pulp lesions. We have previously reported that biodegradable marine collagen sponges can successfully deliver TDZD drugs to pulp lesions, but this involves in-theater preparation of the material, which is not ideal in a clinical context. To improve surgical handling and delivery, here we incorporated NP928 into a specifically tailored hydrogel that can be placed by syringe into a damaged tooth. This hydrogel is based on biodegradable hyaluronic acid and can be gelled in situ upon dental blue light exposure, similarly to other common dental materials. NP928 released from hyaluronic acid–based hydrogels upregulated Wnt/β-catenin activity in pulp stem cells and fostered reparative dentine formation compared to marine collagen sponges delivering equivalent concentrations of NP928. This drug-hydrogel combination has the potential to be rapidly developed into a therapeutic procedure that is amenable to general dental practice.

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