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GSK3 Inhibitor-Induced Dentinogenesis Using a Hydrogel

Research output: Contribution to journalArticlepeer-review

A. Alaohali, C. Salzlechner, L. K. Zaugg, F. Suzano, A. Martinez, E. Gentleman, P. T. Sharpe

Original languageEnglish
Pages (from-to)46-53
Number of pages8
JournalJournal of Dental Research
Volume101
Issue number1
Early online date21 Jun 2021
DOIs
Accepted/In press2021
E-pub ahead of print21 Jun 2021
PublishedJan 2022

Bibliographical note

Funding Information: We thank all the CCRB laboratory technicians for their support. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A. Alaohali was funded by the Medical Services Division of the Ministry of Defense in Saudi Arabia and Saudi Cultural Bureau in London. C. Salzlechner acknowledges support from the Diana Trebble Fund. E. Gentleman and C. Salzlechner received support from the Rosetrees Trust. L.K. Zaugg was funded by the Swiss National Science Foundation (Ref P300PB_167807). Funding from the NIHR GSTFT/KCL Biomedical Research Centre is acknowledged. Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A. Alaohali was funded by the Medical Services Division of the Ministry of Defense in Saudi Arabia and Saudi Cultural Bureau in London. C. Salzlechner acknowledges support from the Diana Trebble Fund. E. Gentleman and C. Salzlechner received support from the Rosetrees Trust. L.K. Zaugg was funded by the Swiss National Science Foundation (Ref P300PB_167807). Funding from the NIHR GSTFT/KCL Biomedical Research Centre is acknowledged. Publisher Copyright: © International & American Associations for Dental Research 2021.

King's Authors

Abstract

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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