Ethylenediaminetetraacetic Acid and Other Dentine Bioactive Molecule‐Releasing Agents for Regenerative Endodontic Procedures: A Systematic Review
Arwa Al‐Maswary, Xiaoxuan Deng, Haizal M. Hussaini, Lara T. Friedlander, Paul R. CooperABSTRACT
Background
The bioactive molecules released from dentine are key to stem‐cell recruitment, proliferation and differentiation in regenerative endodontics. However, there is limited and conflicting information regarding current and potential agents for releasing dentine bioactive molecules for regenerative endodontic procedures.
Objectives
To answer a focused and PICOS‐designed question: are there any available experimental agents [Intervention (I)] comparable to EDTA [Comparison/Control (C)] in releasing bioactive molecules [Outcome (O)] from dentine [Population (P)] for regenerative endodontic procedures?
Method
A systematic search was conducted (PubMed, Web of Science, Scopus, Medline [Ovid], Embase [Ovid], ProQuest Central, Google Scholar and citation searching: backwards and forwards), from inception until August 2025. The selection process followed the PICOS model to define inclusion and exclusion criteria. Original studies investigating experimental agents for the release of bioactive molecules from the dentine, compared with EDTA, were included. The risk of bias was strictly assessed using the QUIN tool for in vitro dental studies. Qualitative analysis was performed, while meta‐analysis was not possible.
Results
Out of the 1364 studies screened, 32 were included. These studies from 2000 to 2025 investigated 23 experimental agents in comparison with EDTA. All were in vitro; of the studies, two had a low risk of bias, 25 had a moderate risk (11 with the minimum score) and five had a high risk of bias. A lack of methodological rigour was identified in approximately 80% of the included studies, including omissions of pH measurements for experimental groups, deficiencies in data assessment or normalisation to account for potential inter‐sample variability and deficiencies in validation against detection limits. The qualitative analysis indicated that 9% etidronic acid (known as HEBP), 1% phytic acid, chitosan and 10% citric acid released TGF‐β1 and/or VEGF levels as effectively as both 10% and 17% EDTA.
Conclusion
Qualitative analysis suggested that 9% etidronic acid (HEBP), 1% phytic acid, chitosan and 10% citric acid might serve as alternatives to 17% EDTA use for releasing bioactive molecules from dentine. However, the methodological issues and lack of robust evidence limit the strength and comparability of the findings, highlighting the need for further well‐designed and rigorous studies before clinical translation.
Registration
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