Mechanisms of Hierarchical Topographies Tuning Bacteria and Cell Biological Responses to the Surfaces of Pure Titanium and Cu-Bearing Titanium Alloy.

The competition between cells integration and bacterial colonization determines the fate of implantations. To reveal the effects of clinical implant topographies on osteoblast differentiation and bacterial biofilm formation, a series of micron/submicron/nano-hierarchical structures were created at pure titanium surfaces (Ti-I, Ti-II, Ti-III). It was found that the hierarchical structures promoted MC3T3-E1 cell differentiation through contact guidance and Ti-II processed the best osteogenic ability. Undesirably, hierarchical surfaces further accelerated the biofilm formation due to submicron structures with low interaction. To reduce the risk of bacterial infections, hierarchical structures were prepared on the antibacterial Cu-bearing titanium alloy surfaces (TiCu-I, TiCu-II, TiCu-III). Hierarchical topographies not only endowed TiCu surfaces with antibacterial trapping characteristics due to CuO doped in the outermost oxides layer but also shifted the corrosion behavior of TiCu alloy into activation-passivation, increasing the Cu-ion release rate and further promoting the osteogenic differentiation. TiCu-III possessed excellent antibacterial trapping ability and optimal osteogenic action. Finally, in the osteomyelitis-modeled mice, hierarchical topographies aggravated the bacterial infection around Ti implants, which entirely lost the osseointegration, while all of the TiCu surfaces significantly inhibited the infection and accelerated the formation of new bone tunnels around the implants. In vivo studies successfully confirmed the tuning mechanism of hierarchical topographies on the biological responses of bacteria and cells to the Ti and TiCu alloys, which would pave the way to develop novel biofunctionalized metal implants.

Corrigendum: NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis.

[This corrects the article on p. 1301 in vol. 11, PMID: 32595631.].

NF-κB/TWIST1 Mediates Migration and Phagocytosis of Macrophages in the Mice Model of Implant-Associated Staphylococcus aureus Osteomyelitis.

Staphylococcus aureus (S. aureus) infection-induced osteomyelitis is a great challenge in clinic treatment. Identification of the essential genes and biological processes that are specifically changed in mononuclear cells at an early stage of S. aureus osteomyelitis is of great clinical significance. Based on transcriptional dataset GSE16129 available publicly, a bioinformatic analysis was performed to identify the differentially expressed genes of osteomyelitis caused by S. aureus infection. ERBB2, TWIST1, and NANOG were screened out as the most valuable osteomyelitis-related genes (OMRGs). A mice model of implant-associated S. aureus osteomyelitis was used to verify the above genes. We found significantly up-regulated expression of TWIST1 in macrophages and accumulation of macrophages around the infected implant. Meanwhile, S. aureus infection increased the expression of TWIST1, MMP9, and MMP13, and stimulated the migration and phagocytosis function of Raw 264.7 cells. Additionally, knock-down of the expression of TWIST1 by siRNA could significantly down-regulate MMP9 and MMP13 and suppress the migration and phagocytosis ability of macrophages in response to S. aureus infection. Furthermore, we found that NF-κB signaling was activated in Raw 264.7 cells by S. aureus and that inhibition of NF-κB signaling by Bay11-7082 blocked the expression of TWIST1, MMP9, and MMP13 as well as cell migration and phagocytosis evoked by S. aureus. Our findings demonstrate that NF-κB/TWIST1 is necessary for migration and phagocytosis of macrophages in response to S. aureus infection. Our study highlights the essential role of NF-κB/TWIST1 in early innate immune response to S. aureus infection in bone.

Copper-Containing Alloy as Immunoregulatory Material in Bone Regeneration via Mitochondrial Oxidative Stress.

In the mammalian skeletal system, osteogenesis and angiogenesis are closely linked by type H vessels during bone regeneration and repair. Our previous studies confirmed the promotion of these processes by copper-containing metal (CCM) in vitro and in vivo. However, whether and how the coupling of angiogenesis and osteogenesis participates in the promotion of bone regeneration by CCM in vivo is unknown. In this study, M2a macrophages but not M2c macrophages were shown to be immunoregulated by CCM. A CCM, 316L-5Cu, was applied to drilling hole injuries of the tibia of C57/6 mice for comparison. We observed advanced formation of cortical bone and type H vessels beneath the new bone in the 316L-5Cu group 14 and 21 days postinjury. Moreover, the recruitment of CD206-positive M2a macrophages, which are regarded as the primary source of platelet-derived growth factor type BB (PDGF-BB), was significantly promoted at the injury site at days 14 and 21. Under the stimulation of CCM, mitochondria-derived reactive oxygen species were also found to be upregulated in CD206hi M2a macrophages in vitro, and this upregulation was correlated with the expression of PDGF-BB. In conclusion, our results indicate that CCM promotes the evolution of callus through the generation of type H vessels during the process of bone repair by upregulating the expression of PDGF-BB derived from M2a macrophages.