Copper-enabled biofunctional dental adhesives: A systematic review of interfacial stability, enzymatic inhibition, and clinical performance

This systematic review synthesized the available laboratory, in situ/ex vivo, and clinical evidence on copper-modified dental adhesive systems, with emphasis on antibacterial activity, resin–dentin interfacial stability, enzymatic inhibition, and clinical performance. A systematic search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library in accordance with PRISMA 2020. Experimental and clinical publications assessing copper-containing adhesive systems were included. Study selection, data extraction, and risk-of-bias assessment were performed independently by two reviewers using RoBDEMAT for laboratory studies and Risk of Bias(RoB) 2 .0 for clinical trials. Owing to substantial heterogeneity in copper formulations, adhesive systems, aging protocols, outcome measures, and partially overlapping clinical cohorts, meta-analysis was not performed and findings were synthesized narratively. Twenty-one publications were included, comprising laboratory investigations, one in situ/ex vivo model, and clinical publications derived from a limited number of independent participant cohorts. Laboratory evidence indicated that copper incorporation may reduce matrix metalloproteinase-related activity, nanoleakage, and interfacial degradation, while generally preserving immediate bond strength and polymerization-related properties. Antibacterial effects were consistently observed in vitro, although their magnitude was formulation- and concentration-dependent. In contrast, clinical evidence showed that copper-modified adhesives achieved restoration retention, marginal adaptation, marginal staining, postoperative sensitivity, and secondary caries outcomes broadly comparable to conventional adhesives over follow-up periods ranging from 4 weeks to 6 years. A short-term benefit reported for self-etch copper-containing adhesives at 18 months was not consistently maintained at longer follow-ups and should therefore be interpreted cautiously. Overall, copper-modified adhesive systems show promising mechanistic and interfacial effects, but current clinical evidence does not demonstrate consistent superiority over conventional adhesives for restoration survival, marginal integrity, or secondary caries prevention.