Titanium (Ti)-based alloys are widely used in tissue regeneration with advantages of improved biocompatibility, high mechanical strength, corrosion resistance, and cell attachment. To obtain bioactive bone–implant interfaces with enhanced osteogenic capacity, various methods have been developed to modify the surface physicochemical properties of bio-inert Ti and Ti alloys. Nano-structured hydroxyapatite (HA) formed by micro-arc oxidation (MAO) is a synthetic material, which could facilitate osteoconductivity, osteoinductivity, and angiogenesis on the Ti surface. In this paper, we applied MAO and steam–hydrothermal treatment (SHT) to produce HA-coated Ti, hereafter called Ti–M–H. The surface morphology of Ti–M–H1 was observed by scanning electron microscopy (SEM), and the element composition and the roughness of Ti–M–H1 were analyzed by energy-dispersive X-ray analysis, an X-ray diffractometer (XRD), and Bruker stylus profiler, demonstrating the deposition of nano-HA particles on Ti surfaces that were composed of Ca, P, Ti, and O. Then, the role of Ti–M–H in osteogenesis and angiogenesis in vitro was evaluated. The data illustrated that Ti–M–H1 showed a good compatibility with osteoblasts (OBs), which promoted adhesion, spreading, and proliferation. Additionally, the secretion of ALP, Col-1, and extracellular matrix mineralization was increased by OBs treated with Ti–M–H1. Ti–M–H1 could stimulate endothelial cells to secrete vascular endothelial growth factor and promote the formation of capillary-like networks. Next, it was revealed that Ti–M–H1 also suppressed inflammation by activating macrophages, while releasing multiple active factors to mediate osteogenesis and angiogenesis. Finally, in vivo results uncovered that Ti–M–H1 facilitated a higher bone-to-implant interface and was more attractive for the dendrites, which promoted osseointegration. In summary, MAO and SHT-treated Ti–M–H1 not only promotes in vitro osteogenesis and angiogenesis but also induces M2 macrophages to regulate the immune environment, which enhances the crosstalk between osteogenesis and angiogenesis and ultimately accelerates the process of osseointegration in vivo.

Osteosarcoma has a relatively high incidence rate among primary malignant tumors, and the survival rate is low. Clinically, surgical resection and chemotherapy are mainly used, which are difficult to utilize to treat metastatic or recurrent osteosarcoma. The combination of chemotherapy and immunotherapy can achieve a better tumor treatment effect. M1 macrophages (M1 Mø) can kill tumor cells and have tumor-targeting and phagocytosis ability, which are an ideal tool for tumor-targeted drug delivery. However, as carriers, living cells have the disadvantages of uncontrollable size, poor tissue permeability, and poor stability. In this study, the M1 macrophage membrane (M1M) was used as the carrier and loaded with MMP-2 (matrix metalloproteinase-2)-sensitive drug-loaded liposomes (GL) to prepare a complex nanovesicle drug delivery system M1M (GL/DOX/TPI-1), with a tumor active targeting function, for combined chemical and immune therapy from doxorubicin (DOX) and tyrosine phosphatase inhibitor 1 (TPI-1). The complex nanovesicles not only retain the tumor-targeting ability from the M1 macrophage membrane but also have the advantages of controllable size, responsive drug release, and high stability. The results of in vivo efficacy test show that the drug delivery system realizes active targeted enrichment in osteosarcoma tissue. Under the response of MMP-2, the internally encapsulated antitumor drugs DOX and TPI-1 from the system are released. This drug delivery system combined with chemical and immune treatment can effectively achieve the aim of the treatment of osteosarcoma.