Incorporation of cerium oxide into hydroxyapatite coating regulates osteogenic activity of mesenchymal stem cell and macrophage polarization

Abstract

Biomedical coatings for orthopedic implants should facilitate osseointegration and mitigate implant-induced inflammatory reactions. Cerium oxide (CeO) ceramics possess anti-oxidative properties and can be used to decrease mediators of inflammation, which makes them attractive for biomedical applications. In our work, two kinds of CeO incorporated hydroxyapatite coatings (HA-10Ce and HA-30Ce) were prepared via plasma spraying technique and the effects of CeO addition on the responses of bone mesenchymal stem cells (BMSCs) and RAW264.7 macrophages were investigated. An increase in CeO content in the HA coatings resulted in better osteogenic behaviors of BMSCs in terms of cell proliferation, alkaline phosphatase (ALP) activity and mineralized nodule formation. RT-PCR and western blot analysis suggested that the incorporation of CeO may promote the osteogenic differentiation of BMSCs through the Smad-dependent BMP signaling pathway, which activated Runx2 expression and subsequently enhanced the expression of ALP and OCN. The expression profiles of macrophages cultured on the CeO modified coating revealed a tendency toward a M2 phenotype, because of an upregulation of M2 surface markers (CD163 and CD206), anti-inflammatory cytokines (TNF-α and IL-6) and osteoblastogenesis-related genes (BMP2 and TGF-β1) as well as a downregulation of M1 surface markers (CCR7 and CD11c), proinflammatory cytokines (IL-10 and IL-1ra) and reactive oxygen species production. The results suggested the regulation of BMSCs behaviors and macrophage-mediated responses at the coating's surface were associated with CeO incorporation. The incorporation of CeO in HA coatings can be a valuable strategy to promote osteogenic responses and reduce inflammatory reactions.

<p>The Advances of Ceria Nanoparticles for Biomedical Applications in Orthopaedics</p>

“…Li et al [96][97][98] prepared CeO 2 -HA composite coatings by plasma spraying technique and conducted considerable research to testify the coatings' application. Because of the antioxygenic property of CeO 2 , the increase of CeO 2 content in the coatings can improve the cell viability and reduce the cell apoptosis, but decrease the chemical stability slightly.…”

“…96 In the study on the inflammatory response, the results found that the increase of CeO 2 content in HA coatings enhanced the osteogenic activity of BMSC through the Smad-dependent-BMP signaling pathway. 97 The addition of CeO 2 also endowed HA coatings with anti-inflammatory effect. HA-30Ce, by inducing a drift towards an M2 phenotype, presented an ideal effect on macrophage polarization.…”

Harnessing Inorganic Nanoparticles to Direct Macrophage Polarization for Skeletal Muscle Regeneration

“…In 2013, topical application of CeO 2 NPs was reported to accelerate the healing of dermal wounds in mice, enhancing proliferation and migration of fibroblasts, keratinocytes, and vascular endothelial cells [ 62 ]. More recently, CeO 2 NPs incorporated into hydroxyapatite coating, via the plasma spraying technique, induced polarization of murine RAW264.7 macrophages towards the M2 phenotype, as demonstrated by the upregulation of the M2 surface markers CD163 and CD206, promoting an osteogenic behavior of bone mesenchymal stem cells (BMSCs) [ 53 ]. The improved osteogenic differentiation ability of BMSCs was further found to be proportional to the surface Ce 4+ /Ce 3+ ratio; indeed, the higher ratio achieved better osseointegration in vivo, and enhanced murine macrophages polarization towards the M2 phenotype, increasing the levels of anti-inflammatory cytokines [ 54 ].…”

The Impact of Metallic Nanoparticles on Stem Cell Proliferation and Differentiation

“…The incorporation of nanoceria into a hydroxyapatite coating led to the promotion of proliferation and osteogenic induction, which was attributed to the activation of BMP signaling [ 168 ]. In addition, nanoceria showed potent anti-inflammatory activity in RAW264.7 macrophages [ 168 ].…”

“…The incorporation of nanoceria into a hydroxyapatite coating led to the promotion of proliferation and osteogenic induction, which was attributed to the activation of BMP signaling [ 168 ]. In addition, nanoceria showed potent anti-inflammatory activity in RAW264.7 macrophages [ 168 ]. Nanoceria suppressed the adipogenic differentiation of rMSCs via the suppression of ROS-induced adipogenic differentiation induction [ 169 ].…”