Simultaneously enhanced osteogenesis and angiogenesis via macrophage-derived exosomes upon stimulation with titania...

Fulfilled angiogenesis and osteogenesis are prerequisites for achieving favorable osseointegration of the bone implants. Incremental evidences have pinpointed that macrophages (MΦs) manipulated osteoimmunomodulation plays a pivotal role in the regulation of angio-/osteo-genesis. However, the underlying mechanism of osteoimmunomodulation is still unclear. Exosomes derived from MΦs are recently recognized as a novel mediator of intercellular communication while the role in osteoimmunomodulation is unraveled yet. In the present study, titania nanotube arrays (TNAs) with diameters of 25 and 95 nm were fabricated via one-step anodization with the voltage of 10 (TNA-10) and 40 V (TNA-40). The results showed that although TNA-10 and TNA-40 have no significant effect on the adhesion, skeleton, morphology, and proliferation of MΦs compared with the pristine titanium (P-Ti), the alkaline phosphatase (ALP) activity and osteogenic-related genes expression of bone mesenchymal stem cells (BMSCs) can be significantly up-regulated after incubated with exosomes extracted from MΦs cultured on TNA-40 (TNA-40Exo). Meanwhile, TNA-40Exo can promote endothelial cells (ECs) migration and enhance the angiogenesis capacity in vitro and in vivo. miRNA sequencing analysis of the exosomes further demonstrated that MΦs-derived exosomal microRNA-3473e (miR-3473e) may be of pivotal importance in the promotion of osteo-/angio-genesis via upregulation of the Akt1 gene. The study indicated that surface morphology of the implant can significantly impact the composition of the derived exosomes, which provides a new insight into understanding immunomodulation mediated osseointegration.