Valence State Manipulation of Cerium Oxide Nanoparticles on a Titanium Surface for Modulating Cell Fate and Bone Formation

Abstract

Understanding cell–biomaterial interactions is critical for the control of cell fate for tissue engineering and regenerative medicine. Here, cerium oxide nanoparticles (CeONPs) are applied at different Ce4+/Ce3+ ratios (i.e., 0.46, 1.23, and 3.23) to titanium substrate surfaces by magnetron sputtering and vacuum annealing. Evaluation of the cytotoxicity of the modified surface to cultured rat bone marrow mesenchymal stem cells (BMSCs) reveals that the cytocompatibility and cell proliferation are proportional to the increases in Ce4+/Ce3+ ratio on titanium surface. The bone formation capability induced by these surface modified titanium alloys is evaluated by implanting various CeONP samples into the intramedullary cavity of rat femur for 8 weeks. New bone formation adjacent to the implant shows a close relationship to the surface Ce4+/Ce3+ ratio; higher Ce4+/Ce3+ ratio achieves better osseointegration. The mechanism of this in vivo outcome is explored by culturing rat BMSCs and RAW264.7 murine macrophages on CeONP samples for different durations. The improvement in osteogenic differentiation capability of BMSCs is directly proportional to the increased Ce4+/Ce3+ ratio on the titanium surface. Increases in the Ce4+/Ce3+ ratio also elevate the polarization of the M2 phenotype of RAW264.7 murine macrophages, particularly with respect to the healing‐associated M2 percentage and anti‐inflammatory cytokine secretion. The manipulation of valence states of CeONPs appears to provide an effective modulation of the osteogenic capability of stem cells and the M2 polarization of macrophages, resulting in favorable outcomes of new bone formation and osseointegration.

Effects of Programmed Local Delivery from a Micro/Nano‐Hierarchical Surface on Titanium Implant on Infection Clearance and Osteogenic Induction in an Infected Bone Defect

“…For instance, alkali‐treatment coating could be used as a scaffold to allow for the sustainable release of the therapeutic agents, particularly inorganic bioactive elements such as Sr, and other trace elements. However, these studies rendered multifunctional surfaces by loading different factors into single release system . Such single release system released different agents simultaneously and independent release program was not shown.…”

“…The following biological behaviors could therefore be regulated through cell recruitment, antigen presentation, and immunoregulation . It has been proved that macrophages are vital to the initial tissue healing process . Sun et al reported the positive function of osteo macrophages in skeletal remodeling .…”

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

“…The increase in M2 percentage could increase the production of anti-inflammatory cytokines. 128 Also, the high Ce 4+ presented a higher catalase activity, but a lower peroxidase activity. Results of protein adsorption and conformation indicated that the exposed cell-binding sites of fibronectin and subsequent cell morphology were associated with the Ce valence state.…”

Harnessing Inorganic Nanoparticles to Direct Macrophage Polarization for Skeletal Muscle Regeneration

“…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 ].…”