About 160,000 primary hip or knee replacement procedures were performed in England and Wales in 2013 and about 1,000,000 in the USA. Orthopedic bone cement is employed to provide a rapid and strong bond between bone and medical devices. Antibiotic laden bone cement are routinely used to prevent infections. Unfortunately, uneven distribution and uncontrolled release of the antibiotic are serious drawbacks associated with the mixing of antibiotics in the bone cement dough. Post-orthopedic operatory infections have an incidence of about 7-10 % depending on the type of surgery and they are estimated to cost between 15,000$ and 30,000$. In order to control and sustain the antibiotic release from bone cement, and consequently extend the antimicrobial activity, we have developed silica nanocarriers containing gentamicin as a drug delivery system to be mixed in bone cement. Gentamicin has been conjugated directly to amino functionalized particles or to succinylated amino functionalized particles. Alternatively, direct entrapment of gentamicin in the nanoparticles during synthesis has been accomplished; moreover adsorptions on: amino functionalized, succinylated and un-functionalized silica nanocarriers has been performed. Furthermore, the antibiotic (naturally positively charged) has been deposited on the silica nanoparticles using the Layer-by-layer technique, sandwiching the drug between alginate layers. The direct entrapment provided the highest antibiotic load (12% w/w) but the release was completed after 4 hours, whilst the adsorption on un-functionalized silica particles returned the lowest amount of antibiotic load (＜1 % w/w). For all other conjugated and adsorbed nanocarriers, gentamicin load was about (4% w/w) and the release was observed over a period of at least 2 days in all cases without significant differences among the synthetic route and pH. Using the LbL self-assembly approach the released was sustained for at least 3 weeks; the use of multiple double layers (up to 4) of gentamicin and alginate did not improve the release profile or extended it. 0 Once encapsulated in PMMA bone cement, the silica nanoparticles did not negatively affect the cytotoxicity and mechanical properties of the material. The release of gentamicin from silica nanocarriers prepared through entrapment, adsorption or conjugation occurred for no more than 2-3 days hence this approach did not appear suited for bone cement application. On the other hand, the LbL preparation achieved the longer release windows because of the presence of the electrolyte that protects the antibiotic from direct contact with the liquid phase. Our results therefore, show that silica nanocarriers of antibiotics can be embedded in bone cement and extend the antimicrobial activity. Depending on the preparation route, the release can be controlled; for prolonged activity in order of many weeks, the coating of silica nanoparticles with antibiotic through LbL appear the most promising technique.
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