Strontium (Sr) has shown strong osteogenic potential and thereby been widely incorporated into dental and orthopedic implants. However, the improved osseointegration of strontium-modified titanium implants through regulation of angiogenesis and macrophage polarization is still beginning to be explored. Here, we demonstrated that the angiogenic capacity of human umbilical vein endothelial cells on the Sr-incorporated micro/nano titanium (SLA-Sr) surface was also significantly improved through the up-regulated expression of the HIF-1α protein and Erk1/2 phosphorylation. Meanwhile, SLA-Sr not only switched macrophage polarization towards the M2 phenotype, but also expressed a high level of pro-angiogenic platelet-derived growth factor. Furthermore, macrophage secretion induced by SLA-Sr was also capable of enhancing angiogenesis of human umbilical vein endothelial cells. In vivo experimental results also showed early vascularized implant osseointegration of SLA-Sr with the type H vessel formation around the SLA-Sr implant. This study emphasized the synergistic role of Sr in the regulation of macrophage polarization and angiogenesis, and therefore depicted the therapeutic potential of SLA-Sr for rapidly vascularized osseointegration.

Recruitment of endogenous bone marrow-derived mesenchymal stem cells (BMSCs) has been widely discussed as an alternative strategy for bone regeneration. Strontium (Sr) is known to direct the BMSCs’ commitment to the bone lineage and encourage bone formation; however, the underlying mechanisms remain elusive. In this study, an Sr-incorporated micro/nano rough titanium surface (MNT-Sr) was fabricated by hydrothermal treatment in an attempt to facilitate BMSCs’ recruitment and their osteogenic differentiation to enhance rapid osseointegration. Micro rough titanium (MT) was set as the control biomaterial. In vitro, MNT-Sr and its extracts promoted the migration and osteogenic differentiation of BMSCs. In animal studies, green fluorescent protein (GFP)-labeled BMSCs were intravenously injected into wild-type rats for tracing before tibial implantation surgery. The GFP⁺BMSC recruitment to the implantation site was successfully triggered by MNT-Sr implantation. A trend for increased bone area (BA%), bone–implant contact (BIC%) and removal torque values (RTVs) was observed for the MNT-Sr implant compared to that observed for MT at 2 weeks. Advanced mechanism analysis indicated that Sr²⁺ enhanced the SDF-1α/CXCR4 signaling pathway both in vitro and in vivo. Taken together, these findings suggest that MNT-Sr has promising therapeutic potential for future use in dental implants by homing endogenous stem cells to stimulate bone regeneration.

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C ⁺ CCR2^hi monocytes, and S100a8^hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1^hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of ‘osteoimmune-smart’ biomaterials in the bone regeneration field.