Collagen Cross-Linkers for Dentin Bonding: A Systematic Review and Meta-Analysis of In Vitro Studies

Abstract

Background: The durability of the resin-dentin bond remains a major challenge in adhesive dentistry. Collagen cross-linking agents are promising biomodification strategies that improve bond durability by stabilizing the collagen matrix and inhibiting enzymatic degradation.
Objectives: To systematically evaluate the effect of collagen cross-linking agents on resin-dentin bond strength, nanoleakage, and failure modes, with emphasis on natural versus synthetic agents.
Methods: PubMed, Web of Science, Scopus, and Cochrane Library were searched from 2015 to 2026. In vitro studies evaluating collagen cross-linkers for dentin bonding were included. Random-effects meta-analysis was performed using standardized mean differences (SMD) with 95% confidence intervals (CI).
Results: Twenty-eight studies were included in the qualitative synthesis, of which 22 provided sufficient data for meta-analysis. Collagen cross-linker pretreatment significantly improved immediate bond strength (SMD = 0.82, 95% CI: 0.54–1.10, P < 0.001) and long-term bond strength after aging (SMD = 0.68, 95% CI: 0.41–0.95, P < 0.001). Nanoleakage was significantly reduced in cross-linker groups (SMD = −0.75, 95% CI: −1.12 to −0.38, P < 0.001). Propolis showed relatively large estimated effects across several evaluated outcomes, although direct superiority between cross-linker types could not be established
Conclusions: Collagen cross-linking agents effectively improve resin-dentin bond performance. Natural agents, particularly propolis, show promising results comparable to synthetic alternatives. Standardization of application protocols is necessary for clinical translation.