Thermosensitive -hydrogel-coated titania nanotubes with controlled drug release and immunoregulatory characteristics for orthopedic applications

Abstract

Although Ti is widely used in orthopedic implants, its bio-inert characteristics and poor antibacterial activity may result in implant failure. To counter this problem, in this study, we loaded simvastatin, a bioactive compound that promotes osteogenesis, in TiO₂ nanotubes and a thermosensitive chitosan-glycerin-hydroxypropyl methyl cellulose hydrogel (CGHH) was then layered on top of these nanotubes. At normal human-body temperature (37 °C), CGHH was present in a sol state, thus facilitating the controlled release of simvastatin to enhance differentiation in MC3T3-E1 osteoblasts. In vitro cell-culture studies suggested that CGHH in a gel state would induce macrophage polarization to the pro-inflammatory M1 phenotype. In vitro testing against Escherichia coli and Staphylococcus aureus indicated no antibacterial activity in CGHH in both sol and gel states. However, the results of subcutaneous infection animal models suggested that CGHH showed excellent in vivo antibacterial activity, which can be explained by the fact at high temperatures induced by an infection, CGHH transitioned into a gel state and released large amounts of glycerin. Such a high glycerin dosage induced an acute inflammatory reaction and antibacterial activity. Thus, due to their enhanced osteogenesis capacity at normal body temperature and antibacterial characteristics in the presence of infection, the newly designed simvastatin-loaded CGHH-encapsulated TiO₂ nanotubes are promising materials for application in orthopedic implants.

Keywords: Antibacterial; Immune response; Nanotubes; Osteogenesis; Simvastatin.