Spatiotemporal regulation of neutrophil-mediated immune cascades via engineered PEEK surfaces restores osseointegration in diabetes.

Abstract

Diabetes mellitus compromises bone regeneration and increases implant failure rates, posing persistent challenges in orthopedic and dental therapies. Although macrophage-centered immunomodulation has been widely investigated, the role of neutrophils, particularly under diabetic conditions, remains insufficiently defined. Here, we identify neutrophil dysfunction, characterized by impaired chemotaxis and elevated oxidative stress, as a critical upstream driver of impaired osseointegration in diabetes. We demonstrate that dietary flavonoid quercetin restores neutrophil redox homoeostasis in association with reactivation of Nrf2/HO-1 signaling, attenuates pathological neutrophil extracellular trap formation, and promotes MerTK-associated efferocytosis by macrophages. Efferocytosis of quercetin-treated neutrophils subsequently reprograms macrophage toward an anti-inflammatory, pro-regenerative M2-like phenotype, therefore establishing a microenvironment favorable for angiogenesis and osteogenesis. Based on these insights, we engineer a biodegradable tri-layered coating on polyetheretherketone (PEEK) implant, comprising an osteoconductive nano-hydroxyapatite base layer, a quercetin-rich antioxidant intermediate layer, and an outermost surface functionalized with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP) to actively recruit neutrophils. In a diabetic rat model, this rationally designed interface enables temporal coordination of innate immune responses, leading to substantially improved vascularized bone regeneration and implant osseointegration. These findings highlight neutrophils as key therapeutic targets in diabetic bone repair and propose an immunomodulatory biomaterials strategy that addresses upstream immune dysregulation in compromised metabolic conditions.