Dual-temporal bidirectional immunomodulation of Cu-Zn Bi-layer nanofibrous membranes for sequentially enhancing antibacterial activity and osteogenesis

Abstract Implant-related infections (IRIs) and implant osseointegration disorders are the most common and catastrophic complications after total joint arthroplasty (TJA). Macrophages play a vital role in the development of these complications. Herein, tailored to the immunological characteristics of IRIs and implant osseointegration disorders, we proposed a sequential immunomodulatory strategy to cope with the complications, using Cu-Zn bi-layer nanofibrous membranes synthesized via a facile electrospinning process and a hot-pressed method. It was found that Cu-Zn bi-layer nanofibrous membranes exhibited a desirable controlled release of Cu2+ and Zn2+, and could sequentially regulate macrophage phenotype shift from M1 to M2 through alternately activating the MAPK and mTOR signaling pathways. Moreover, the dual-temporal bidirectional immunomodulatory effect endowed the Cu-Zn bi-layer nanofibrous membranes excellent anti-infection and osteogenic abilities in vitro and in vivo. To our knowledge, this is the first dual-temporal bidirectional immunomodulatory biomaterial specifically designed for the immune requirements of IRIs and implant osseointegration disorders. This is a meaningful attempt, which may pave a new way for exploring novel immunomodulatory biomaterials to solve the clinical challenges.