# Targeting the AMPK pathway to enhance dentin repair with novel metformin-releasing dental cements

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $193,125

## Abstract

PROJECT SUMMARY
The normal structure and function of the dentin-pulp complex in adult permanent teeth can be affected by the exposure of
a vital pulp following deep caries removal, traumatic injuries, or accidental restorative procedures. To stimulate dentin
repair, preserve pulp vitality and avoid more invasive and costly procedures, vital pulp therapy relies on direct pulp-capping
agents. These are mainly composed of inorganic hydraulic calcium-silicate cements, where mineral trioxide aggregate
(MTA) is often considered the gold standard. Despite its well-accepted therapeutic value, it remains unclear which specific
underlying signaling mechanisms orchestrate reparative dentinogenesis through the differentiation of dental pulp stem cells
(DPSCs) into odontoblast-like cells. Also, common drawbacks associated with MTA include long setting times and high
cost. Thus, enhancing dentin repair through novel, substantially more affordable bioactive formulations with improved
physico-mechanical properties that molecularly target the pulp cells responsible for its synthesis could translate into truly
beneficial and highly cost-effective therapeutic outcomes. We provide the first evidence supporting the development of a
novel biomaterial formulated with calcium phosphate cement/chitosan (CPCC) and metformin (Met), that triggered a
significant upregulation in the expression of odontoblastic differentiation markers and mineral synthesis in DPSCs. Met is
a widely used, safe and low-cost oral anti-diabetic biguanide drug, and potent activator of the AMP-activated protein kinase
(AMPK) signaling pathway, a master sensing mechanism of cellular bioenergetics. These promising preliminary data imply
that Met could be safely repurposed within locally delivered formulations to enhance reparative dentin by molecularly
targeting AMPK. In the proposed studies, we seek to maximize dentin repair by developing a new Met-CPCC pulp-capping
agent with similar mechanical and flowability properties like MTA but with a substantial, several folds of reduction in
setting time and cost. This innovative formulation relies on Met to induce AMPK activation and odontoblastic differentiation
in DPSCs, and CPCC to provide the alkaline, ionic building blocks for hydroxyapatite formation. To that end, we will test
the central hypothesis that dentin repair following vital pulp exposure is significantly potentiated by a Met-releasing CPCC
bioactive pulp-capping agent through AMPK activation and delivery of mineralized tissue-building ions. In vitro and in
vivo studies will expand our initial findings through two specific aims. Aim 1 will test the hypothesis that in DPSCs, a novel
Met-CPCC pulp-capping agent induces odontogenic responses in an AMPK-dependent manner. In Aim 2, we will test the
hypothesis that Met-CPCC pulp-capping agent significantly enhances dentin repair and increases the hardness and elastic
modulus of new dentin in a rat dentin injury model with pulp exposure in vivo. The...

## Key facts

- **NIH application ID:** 10505282
- **Project number:** 1R21DE032139-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Abraham Schneider
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,125
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505282

## Citation

> US National Institutes of Health, RePORTER application 10505282, Targeting the AMPK pathway to enhance dentin repair with novel metformin-releasing dental cements (1R21DE032139-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10505282. Licensed CC0.

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