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<p>Orthodontic-induced gingival enlargement (OIGE) affects approximately 15–30% of patients undergoing orthodontic treatment and remains largely unpredictable, often relying on subjective clinical assessments made after irreversible tissue changes have occurred. S100A4 is a well-characterized marker of activated fibroblasts involved in pathological tissue remodeling. This was a cross-sectional precision biomarker study that analyzed gingival tissue samples from three groups: healthy controls (<i>n</i> = 60), orthodontic patients without gingival enlargement (<i>n</i> = 31), and patients with clinically diagnosed OIGE (<i>n</i> = 61). Immunohistochemical analysis quantified S100A4-positive fibroblasts, type I collagen synthesis, and microvascular density. Advanced statistical analyses included multivariate logistic regression, machine learning–based validation, causal mediation analysis, and survival modeling for risk stratification. The density of S100A4-positive fibroblasts was significantly higher in OIGE patients (245.8 ± 38.7 cells/mm<sup>2</sup>) compared to orthodontic controls (165.3 ± 29.4 cells/mm<sup>2</sup>) and healthy individuals (98.2 ± 18.5 cells/mm<sup>2</sup>) (<i>p</i> &lt; 0.001; <i>η</i><sup>2</sup> = 0.891). Multivariate analysis confirmed S100A4 as an independent predictor of OIGE (OR = 1.028 per cell/mm<sup>2</sup>; 95%CI 1.021–1.035; <i>p</i> &lt; 0.001). Machine learning validation demonstrated high predictive accuracy (AUC = 0.946). Survival analysis identified distinct risk strata: individuals with S100A4 densities &gt; 180 cells/mm<sup>2</sup> had a 78% probability of developing OIGE within 24&#xa0;months, compared to 12% for those with &lt; 130 cells/mm<sup>2</sup>. S100A4 demonstrates 95% predictive accuracy for OIGE, supporting its role in personalized risk stratification and early preventive interventions during a defined therapeutic window. This study presents the first validated precision biomarker in orthodontics with the potential to prevent an estimated 180,000–360,000 OIGE cases globally each year.</p>

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Early prediction of orthodontic gingival enlargement using S100A4: a biomarker-based risk stratification model

  • 期刊论文

  • 发表日期：

    2025年9月10日

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  • Víctor Simancas-Escorcia,
  • Jaime Plazas-Román,
  • Antonio Díaz-Caballero,
  • Adel Martínez-Martínez,
  • Carlos M. Ardila

摘要

Orthodontic-induced gingival enlargement (OIGE) affects approximately 15–30% of patients undergoing orthodontic treatment and remains largely unpredictable, often relying on subjective clinical assessments made after irreversible tissue changes have occurred. S100A4 is a well-characterized marker of activated fibroblasts involved in pathological tissue remodeling. This was a cross-sectional precision biomarker study that analyzed gingival tissue samples from three groups: healthy controls (n = 60), orthodontic patients without gingival enlargement (n = 31), and patients with clinically diagnosed OIGE (n = 61). Immunohistochemical analysis quantified S100A4-positive fibroblasts, type I collagen synthesis, and microvascular density. Advanced statistical analyses included multivariate logistic regression, machine learning–based validation, causal mediation analysis, and survival modeling for risk stratification. The density of S100A4-positive fibroblasts was significantly higher in OIGE patients (245.8 ± 38.7 cells/mm2) compared to orthodontic controls (165.3 ± 29.4 cells/mm2) and healthy individuals (98.2 ± 18.5 cells/mm2) (p < 0.001; η2 = 0.891). Multivariate analysis confirmed S100A4 as an independent predictor of OIGE (OR = 1.028 per cell/mm2; 95%CI 1.021–1.035; p < 0.001). Machine learning validation demonstrated high predictive accuracy (AUC = 0.946). Survival analysis identified distinct risk strata: individuals with S100A4 densities > 180 cells/mm2 had a 78% probability of developing OIGE within 24 months, compared to 12% for those with < 130 cells/mm2. S100A4 demonstrates 95% predictive accuracy for OIGE, supporting its role in personalized risk stratification and early preventive interventions during a defined therapeutic window. This study presents the first validated precision biomarker in orthodontics with the potential to prevent an estimated 180,000–360,000 OIGE cases globally each year.