“Sandwich” structured nanorods for timely antibiosis, immunoregulation and neuroangiogenesis to accelerate osteogenesis of Zn-based implants in diabetics

Abstract

Pathological microenvironment of diabetes predisposes to induce bacterial infection, sustained inflammatory response, and impaired neuroangiogenesis, impeding fracture repair. Zn-based implants have great potential to replace conventional Ti implants as temporary fixations, but their osseointegration ability needs improvement. In this work, “sandwich” structured nanorods were constructed on Zn substrate with ZnO nanorods as core, riboflavin-encapsulated ZIF-8 as intermediate layer and HA as outer shell. Under normal physiological condition, ZIF-8 and HA reduce degradation of Zn substrate, decreasing Zn²⁺ release. ZIF-8 and riboflavin scavenge extracellular and intracellular ROS, respectively, achieving antioxidant therapy and establishing anti-inflammatory microenvironment via promoting M1 macrophages to polarize toward M2 phenotype. The synergistic effect of Zn²⁺, riboflavin as well as cytokines secreted by macrophages up-regulates the vitality and biological functions of BMSCs, HUVECs and PC-12 cells in vitro. When bacteria invade, they secrete hyaluronidase and organic acids to decompose HA and ZIF-8 sequentially, releasing a mass of Zn²⁺, which increases bacterial membrane permeability and induces intracellular ROS production and protein leakage, leading to bacterial death. The comprehensive effects of the “sandwich” structured nanorods on antibiosis, anti-inflammatory and neuroangiogenesis to accelerate osseointegration are further confirmed in an infected diabetic model, exhibiting great promise for Zn-based implants in clinical application.