Effect of collagen cross-linkers on the bonding performance of resin-dentin interfaces: A systematic review and meta-analysis of in vitro studies.

STATEMENT OF PROBLEM: Collagen cross-linkers have great potential for enhancing dentin bond strength, but their types are diverse, and the existing evidence requires systematic review. PURPOSE: The purpose of this study was to systematically evaluate the effects of collagen cross-linkers on the immediate bonding strength and long-term stability of the resin-dentin interface, providing evidence for their experimental and potential clinical applications. MATERIAL AND METHODS: English-language studies published between January 2015 and September 2025 were retrieved from the PubMed, Web of Science, Embase, and Cochrane databases. In vitro studies assessing the effects of cross-linkers on dentin using microtensile bond strength (µTBS) were included. Subgroup analyses were conducted according to cross-linker type and application method. A random-effects model was used to pool effect sizes, and the standardized mean difference with 95% confidence intervals was calculated. RESULTS: A total of 63 studies were included. Aldehyde-, chitosan-, riboflavin-, polyphenol-, and carbodiimide-based cross-linkers were found to enhance immediate or long-term bonding strength under specific conditions, with more consistent effects when used as pretreatment with the etch-and-rinse system. Evidence for chitosan- and siloxane-based cross-linkers was limited, and their reinforcing effects remain unconfirmed. Bonding efficacy depended on cross-linker type, application mode, and adhesive strategy. Most studies had medium bias, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence was low to very low, with significant publication bias in aged subgroups of aldehyde- and polyphenol-based pretreatments. CONCLUSIONS: Current in vitro evidence indicated that certain collagen cross-linkers may help enhance the bonding properties of the resin-dentin interface. However, their effectiveness was influenced by the material type, application strategy, and adhesive system. High heterogeneity, medium risk of bias, and low-quality evidence warrant cautious interpretation.