Enhancing Bone-Titanium integration through hydrogel coating mediated sequential M1/M2 polarization of interfacial macrophages

[Display omitted] •Sequential release of sophoridine and luteolin from Ti surface through pH mediated conformational transition of boronic acid ester bond.•Promoting bone-Ti integration through inducing sequential M1/M2 polarization of macrophages.•The rationale behind macrophage polarization being identified to be related to PI3K-AKT signaling. Regulating phenotypes of in situ macrophages (Mφ) is a cutting-edge strategy for promoting bone-Titanium (Ti) integration, but what is the most rational modulation manner has long been controversial. Short-term inducing in situ M1 Mφ polarization or inducing in situ M2 Mφ polarization have proven to be capable of promoting osseointegration. However, an increasing number of researches have claimed that sequentially inducing in situ M1/M2 Mφ polarization, compared to the above-mentioned two strategies, could further enhance osseointegration. In this work, we compared the capability of the three different modulation manners to promote osseointegration. Briefly, we anchored a homogeneous Poly(HEMA-co-3APBA)/LUT/SOP hydrogel coating, which could sequentially release pro-inflammatory sophoridine (SOP) molecules and anti-inflammatory luteolin (LUT) molecules through pH mediated conformational transition of phenylboronic acid ester bonds, on the surface of Ti implants. Ti implants coated with the Poly(HEMA-co-3APBA)/SOP hydrogel or the Poly(HEMA-co-3APBA)/LUT hydrogel, which merely released SOP molecules and LUT molecules respectively, were utilized as controls. In vitro Mφ co-culture assays proved the immunoregulation functions of different hydrogel coatings in inducing Mφ polarization, and the rationale behind which was identified to be related to the PI3K-AKT signaling pathways. In addition, the immunoregulation mediated osteogenic differentiation behaviors of bone marrow mesenchymal stem cells (BMSCs) were also investigated. Implantation of as-prepared Ti nails to a rat femur defect model followed by evaluations of H&E staining, Masson staining, immunohistochemical staining, etc. proved the stronger capability to enhance osseointegration of inducing sequential M1/M2 Mφ polarization than short-term inducing in situ M1 Mφ polarization or inducing in situ M2 Mφ polarization. This work not only reported a novel Ti implant with superior osseointegration capability but also will inspire corresponding researches in the future.