Synergistic release of copper and lithium components in biodegradable zinc alloy for osteoimmunomodulation

Zinc (Zn)-based alloys have emerged as promising bioresorbable metals for orthopedic implants because of their favorable combination of moderate degradation rates, good mechanical properties, and biocompatibility. In addition, the performance of bone implants relies heavily on their osteointegration ability, which is closely related to the immune responses triggered after implantation. In this study, two Zn-based alloys, Zn–2Cu and Zn–2Cu–0.8Li were developed, to improve the comprehensive properties of Zn implants. The introduction of copper (Cu) and lithium (Li) via alloying improved the hardness and localized corrosion resistance of Zn-based specimens. Both the Zn alloys exhibited enhanced adhesion, proliferation, and osteogenic differentiation behaviors when tested with MC3T3-E1 cells. Importantly, the immune response of RAW264.7, mediated by the two Zn alloys, with pure Zn as a control was systematically investigated. The results demonstrated that the synergistic release of Cu²⁺ and Li⁺ played a pivotal role in promoting the anti-inflammatory and osteoimmunomodulatory properties of degradable Zn. By alloying with Cu and Li, we achieved sequential and sustained ion release, resulting in the synergistic enhancement of osteoimmunomodulation through the modulation of the JAK-STAT signaling pathway. Finally, the Zn-based specimens were evaluated in vivo using rat mandibular defect models. After 8 weeks, the Zn–2Cu–0.8Li group exhibited significantly higher bone regeneration than the Zn–2Cu and pure Zn groups. These findings highlight the beneficial immune response and potential of Zn–Cu–Li alloys as novel biodegradable materials for orthopedic implants.