Diagnostic in endodontics: towards a precision molecular approach

In endodontics, diagnosis traditionally relies on the patient's subjective response to thermal or electrical stimuli. These conventional methods lack objective precision to finely characterize the pulp inflammatory state. This review synthesizes advances in biomarker-based diagnostics, an emerging discipline aiming to integrate chairside precision medicine to improve the detection and management of pulpitis.

The objective of this analysis is to evaluate the potential of biological markers — notably cytokines (IL-1β, TNF-α), neuropeptides (Substance P, CGRP), matrix metalloproteinases (MMPs) and micro-RNAs — as objective diagnostic tools. The authors explore how these molecular signatures allow for the distinction between reversible and irreversible pulpitis states via non-invasive methods using dentinal fluid, gingival crevicular fluid or saliva.

The central hypothesis is based on the fact that these biomarkers present distinct profiles depending on the stage of inflammation, thus allowing for targeted interventions. The review also examines the integration of innovative technologies, such as biosensors and artificial intelligence, to facilitate longitudinal monitoring and the implementation of personalized pulp therapies in daily clinical practice.

Methodology of molecular synthesis

This systematic and narrative review (including data from Rai et al., 2025 and Mejàre et al., 2012) synthesizes the results of multiple clinical and experimental studies focusing on the diagnosis of pulp inflammation. The analysis compares biological responses between reversible pulpitis, irreversible pulpitis, and healthy tissues.

• Biological matrices: The included protocols exploit non-invasive sampling methods targeting dentinal fluid (Zehnder et al., 2011), gingival crevicular fluid (GCF) and saliva (Javaid et al., 2016).
• Biomarker groups: The evaluation focuses on four distinct molecular families: cytokines (IL-1β, TNF-α, IL-8), neuropeptides (Substance P, CGRP, Neurokinin A), matrix metalloproteinases (MMP-8, MMP-9) and micro-RNAs, notably miR-181 (Hutchison et al., 2013).
• Technological tools: The synthesis integrates data from omics technologies, microfluidics and advanced biosensors.
• Analysis criteria: The authors report the diagnostic accuracy of these markers by comparing them to conventional thermal and electrical stimuli. Predictive modeling via artificial intelligence is also examined as a lever for high diagnostic performance.

Identification and differentiation of pulpal biomarkers

The data reported in this synthesis highlight distinct molecular and cellular profiles allowing for the discrimination of inflammatory stages of the dental pulp. Unlike conventional tests (thermal or electrical) limited by patient subjectivity, biomarker analysis offers increased precision for the differential diagnosis between reversible and irreversible pulpitis.

Sampling methods and diagnostic accuracy

The study highlights the effectiveness of non-invasive or minimally invasive diagnostic methods. The analysis of biological fluids provides real-time information on the state of pulpal health:

• Dentinal fluid: Direct analysis of pulp exudate via the tubules.
• Gingival crevicular fluid (GCF): A non-invasive source reflecting systemic and local changes.
• Saliva: Use of biosensors for rapid point-of-care detection.

The integration of omics technologies and microfluidics facilitates high-throughput analysis, while artificial intelligence is used for predictive modeling of disease progression. Although the profiles are described as "distinct," the study reminds that sensitivity and cost-effectiveness remain major challenges for a full transition to routine clinical practice.

The era of molecular diagnostics: beyond the subjective response

This review highlights a major transition in endodontics: the shift from subjective conventional pulp tests (thermal, electrical) toward a precision biological approach. The clinical challenge is significant, as current methods rely on the patient's perception of pain, which is often imprecise. The use of specific biomarkers offers an objective molecular reading of the pulp's inflammatory state.

The authors highlight that molecules such as cytokines (IL-1β, TNF-α), neuropeptides (Substance P, CGRP), matrix metalloproteinases (MMPs), and micro-RNAs exhibit distinct expression profiles, allowing for the clinical differentiation between reversible and irreversible pulpitis. Accessing this information via non-invasive fluids — dentinal fluid, gingival crevicular fluid (GCF), or saliva — could transform chairside therapeutic decision-making.

Technological challenges and current limitations

Despite the potential of omics technologies and artificial intelligence for predictive modeling, this synthesis identifies persistent obstacles. The lack of standardization in sampling protocols, variable test sensitivity, and high costs still limit immediate clinical translation. Furthermore, although longitudinal monitoring via multi-marker panels is promising for personalized therapy, the integration of point-of-care devices (rapid in-office tests) still requires rigorous validation.

Compared to classic vitality tests, which only measure nerve response or blood flow indirectly, biomarkers provide a direct assessment of cellular processes. This review shows that the future lies in interdisciplinary collaboration to integrate these biological data into daily endodontic routine.

Summary of results

This review highlights that specific biomarkers, such as cytokines (IL-1β, TNF-α), neuropeptides (Substance P, CGRP), and MMPs, allow for the objective distinction between reversible pulpitis and irreversible forms. The non-invasive analysis of gingival crevicular fluid (GCF), dentinal fluid, or saliva via biosensors offers superior molecular precision compared to conventional thermal or electrical tests, which are often limited by patient subjectivity.

In concrete terms, for the practitioner:

• Go beyond subjectivity: Keep in mind that current sensitivity tests do not reflect the actual biological state of the pulp; gingival crevicular fluid (GCF) analysis represents a promising non-invasive path for confirming an inflammatory state.
• Validate your vital pulp therapies: The identification of mediators such as MMP-9 or micro-RNAs will soon help confirm whether a pulp is biologically capable of healing before opting for a pulpectomy.
• Prepare for chairside diagnostics: The evolution toward 'Point-of-Care' devices will soon allow you to standardize your clinical decisions through rapid molecular tests, making endodontics more predictable and personalized.

Technical lexicon of the study

Cytokines (IL-1β, TNF-α): Cell signaling proteins acting as mediators of inflammation. Their expression profile allows for the distinction between reversible and irreversible pulpitis stages.

Neuropeptides (Substance P, CGRP): Signaling molecules (including substance P and Calcitonin Gene-Related Peptide) released by pulpal nerve fibers, involved in pain and the regulation of neurogenic inflammation.

Matrix metalloproteinases (MMPs): A family of proteolytic enzymes responsible for the degradation of the extracellular matrix. Their measurement in biological fluids serves as an objective indicator of pulpal health status.

MicroRNAs: Small non-coding RNA molecules that regulate gene expression. They are studied as circulating biomarkers for precision molecular diagnosis.

Gingival crevicular fluid (GCF): Gingival crevicular fluid used as a non-invasive sampling medium for the analysis of molecular biomarkers of pulpal origin.

Dentinal fluid: Dentinal fluid whose analysis allows for the collection of direct biological information on the inflammatory state of the dentin-pulp complex.

Point-of-care devices: Rapid diagnostic devices usable directly at the chairside, allowing immediate analysis of biomarkers to guide clinical decision-making.

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