Silica-drug delivery systems: From prolonged drug release to wound dressings and orthopedic applications

Wounds and orthopedic implants afflicted with methicillin resistant Staphylococcus aureus (MRSA) infections and their biofilms are recalcitrant to treatment. Silica (SiO2) could be used as a carrier in delivery systems for targeting drugs (silver and gentamicin) to potentially prevent the growth of bacteria and treat bacterial infections in wound dressings and orthopedic applications. Publication [1] presents the prolonged rapid initial release of silver (Ag) from a SiO2-Ag nanocomposite delivery system over the first 24 h (~38.2%) from the stock suspension of the nanocomposite, followed by a slower sustained release after 48 (~46.9%) and 72 h (~49.1%), favorable for wound dressing applications. The nanocomposite was impregnated in gauze and compared with a commercial silver-containing (CSD) dressing, and demonstrated to have better prolonged antibacterial effects than the CSD. The underlying mechanisms of action of the nanocomposite in MRSA were putatively attributed to silver ions released from the nanocomposite, resulting at the end in the loss of bacterial membranes. Publication [2] demonstrates a prolonged rapid initial release of gentamicin from the SiO2-gentamicin nanohybrids delivery system over the first 24 h (~21.4%) from the stock suspension of the nanohybrids, followed by a slower sustained release after 120 h (~43.9%), which is essential in orthopedic surgery. Publication [3] examines the in vitro toxicities of SiO2-gentamicin nanohybrids to human osteoblast-like SaOS-2 cells, and demonstrates a significant decrease of the viability of SaOS-2 cells treated with SiO2-gentamicin nanohybrids (250 μg/mL) in a time-dependent manner (68 ± 0% after 24 h; 25 ± 5% after 5 days), demonstrating severe cytotoxicity, and a significant reduction of the expression of alkaline phoshphatase (i.e., reaching < 1/3 of the control group). Publication [4] shows the potential of SiO2-gentamicin nanohybrids to kill planktonic MRSA cells that are commonly encountered in orthopedic infections, and to eradicate Escherichia coli cells in biofilms (i.e., minimum biofilm eradication concentration of 250 μg/mL) via a complete deformation of the shape, wrinkling of the cell walls, and the reduction of the size of E. coli cells. The in vivo toxicities of SiO2-gentamicin delivery systems were also assessed, in Publication [4], in zebrafish embryos, demonstrating non-significant mortality rates and the biocompatibility of the nanohybrids at concentrations as high as 500 and 1000 μg/mL. The thesis illustrates the complexities of safety issues associated with future orthopedic applications of SiO2-gentamicin nanohybrids, resulting from discrepancies in the toxicities recorded in vitro and in vivo