• Exposure-anchored framework evaluates ion-releasing biomaterials under realistic use • Design-of-Mixtures resolves composition–interaction effects on functional properties • Antibacterial efficacy is non-monotonic and tunable without dose escalation • Safety positioned as a primary design variable via ISO 10993-17 risk mapping • Defines a transferable safety–efficacy window for transient ion delivery systems Soluble ion-releasing materials intended for transient, dilution-limited use must achieve functional performance while maintaining safety under repeated exposure. This study presents a clinically parameterized framework for the design of multi-ion, soluble glasses for toothpaste applications by integrating a Design-of-Mixtures composition space with brushing-relevant extraction conditions. Glasses within a constrained Ag 2 O–NaF–CaO design domain were synthesized, characterized, and evaluated using 2-min aqueous extracts to quantify dissolution behavior, multi-element ion release, and antibacterial activity against Streptococcus mutans at clinically plausible dilutions. By maintaining a constant extraction ratio across the mixture space, compositional effects on early-time dissolution and ion speciation were isolated under exposure conditions relevant to transient plaque pH challenges. Composition–response modeling demonstrated that calcium release establishes a thermodynamically constrained, remineralization-relevant baseline, whereas silver-mediated antibacterial activity is non-monotonic and highly composition-dependent, indicating that antibacterial potency can be engineered through controlled dissolution rather than increased silver loading. Ag 2 O–NaF interaction effects consistent with speciation-sensitive co-release were identified, supporting strategies that preserve fluoride availability while optimizing antimicrobial performance. An ISO 10993-17-aligned toxicological risk assessment was applied as a conservative, exposure-based screening tool to map efficacy–safety relationships across the design space and prioritize dose-efficient compositions. Together, this workflow provides a safety-constrained framework for evaluating antibacterial ion-releasing glasses and for assessing transient, multi-ion delivery materials under realistic exposure conditions.
Andrea et al. (Fri,) studied this question.