1. GSK3 Inhibitor-Induced Dentinogenesis Using a Hydrogel
- Author
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Ana Martínez, F. Suzano, Paul T. Sharpe, Christoph Salzlechner, Lucia K. Zaugg, Abeer Alaohali, Eileen Gentleman, Ministry of Defence (Saudi Arabia), Saudi Arabia Cultural Bureau in London, Diana Trebble Fund, Rosetrees Trust, Swiss National Science Foundation, NIHR Biomedical Research Centre (UK), Alaohali, A. [0000-0002-7148-6090], Martínez, Ana [0000-0002-2707-8110], Gentleman, E. [0000-0003-0447-5137], Alaohali, A., Martínez, Ana, and Gentleman, E.
- Subjects
0301 basic medicine ,Drug ,Mineralization ,media_common.quotation_subject ,Context (language use) ,Stem cells ,Pharmacology ,Dentin, Secondary ,dentine ,03 medical and health sciences ,chemistry.chemical_compound ,Glycogen Synthase Kinase 3 ,0302 clinical medicine ,Tissue engineering ,stomatognathic system ,GSK-3 ,stem cells ,Hyaluronic acid ,Thiadiazoles ,Humans ,mineralization ,General Dentistry ,media_common ,Chemistry ,Biomaterials & Bioengineering ,Dentine ,Research Reports ,Hydrogels ,Dentinogenesis ,Wnt signaling ,Dental pulp ,stomatognathic diseases ,030104 developmental biology ,tissue engineering ,Self-healing hydrogels ,Pulp (tooth) ,dental pulp ,030217 neurology & neurosurgery - Abstract
8 p.-4 fig., 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., 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.
- Published
- 2021