GSK3 Inhibitor-Induced Dentinogenesis Using a Hydrogel

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.

Therapeutic approaches to activate the canonical Wnt pathway for bone regeneration

“…Hydrogels can be synthesized from natural or synthetic materials and have a wide range of applications due to their flexibility and potential for injectability (Ahmed, 2015). Many studies have employed hydrogel systems to deliver growth factors and/or cells for the promotion of bone regeneration, but few have used this approach specifically to activate Wnt signaling (Alaohali et al, 2021;Bai et al, 2018;Gresham et al, 2021). Alaohali et al used a hyaluronic acid-based hydrogel to deliver a GSK-3 inhibitor to promote bone formation in dental applications (Alaohali et al, 2021).…”

“…Many studies have employed hydrogel systems to deliver growth factors and/or cells for the promotion of bone regeneration, but few have used this approach specifically to activate Wnt signaling (Alaohali et al, 2021;Bai et al, 2018;Gresham et al, 2021). Alaohali et al used a hyaluronic acid-based hydrogel to deliver a GSK-3 inhibitor to promote bone formation in dental applications (Alaohali et al, 2021). In this application, the hydrogel was injected into a murine molar defect, crosslinked using UV light to facilitate drug encapsulation, and the drug was control released through degradation, stimulating dentine formation (Alaohali et al, 2021).…”

“…Alaohali et al used a hyaluronic acid-based hydrogel to deliver a GSK-3 inhibitor to promote bone formation in dental applications (Alaohali et al, 2021). In this application, the hydrogel was injected into a murine molar defect, crosslinked using UV light to facilitate drug encapsulation, and the drug was control released through degradation, stimulating dentine formation (Alaohali et al, 2021). Similarly, Wang et al utilized a hydrogel-based system to deliver bone targeting nanoparticles with a peptide targeting GSK-3β, showing that fracture healing was accelerated in a murine fracture model (Wang et al, 2016).…”

“…used a hyaluronic acid‐based hydrogel to deliver a GSK‐3 inhibitor to promote bone formation in dental applications (Alaohali et al., 2021 ). In this application, the hydrogel was injected into a murine molar defect, crosslinked using UV light to facilitate drug encapsulation, and the drug was control released through degradation, stimulating dentine formation (Alaohali et al., 2021 ). Similarly, Wang et al.…”

Wnt Signalling in Regenerative Dentistry

“…ReDent (Regeneration of Dentine) allows delivery of small concentration of a novel GSK3 small molecule inhibitor drug via hydrogel into tooth cavity and results in rapid stimulation of resident DPSCs to proliferate and differentiate into odontoblastlike cells that produce reparative dentine (85). LithGlass is a novel glass ionomer formulation specifically designed to rapidly release lithium ions to stimulate odontoblast activity in non-exposed pulp lesions.…”