ORTHOPEDIC IMPLANTS USED AS DRUG DELIVERY SYSTEMS: NUMERICAL, IN VITRO AND IN VIVO STUDIES

Abstract Total Hip Replacement (THR) is today a routine procedure executed more than800’000 times per year worldwide. THR gives generally satisfactory results, althoughthe quality of outcome is inversely proportional to the age of the patient. In parallel,there is a trend to propose cementless THR to patients younger than 60 years. Thesepatients have more demanding physical activity resulting in a signiﬁcant increasedfailure rate of the implants. In particular for these patients, the desired service lifeof the implant should be extended.Proximal peri-implant boneloss isgenerally observed during theﬁrsttwo years follow-ing the implantation. This bone loss may lead to aseptic loosening, the major causeof THR failure. In order to control peri-implant bone remodeling and in particularthe proximal bone loss, we developed the innovative concept of using the orthopedicimplant as drug delivery system (DDS). The cementless stem of a hip implant wouldbe coated with hydroxyapatite (HA) and bisphosphonate, a drug aﬀecting bone re-sorption. The basic idea is to biologically reduce the initial peri-implant bone lossby decreasing the osteoclastic bone resorption activity. This approach could signiﬁc-antly increase the THR outcome.Pre-clinical tests were performed to numerically validate this new concept. An ex-isting bone remodeling model was modiﬁed to take into account the bisphosphonateeﬀect. The outcome of a THR was evaluated with diﬀerent simulated bisphosphonateconcentrations. Results of the simulations showed that the implant used as a drugdelivery system would increase bone density around the implant and decrease, atthe same time, the micromovements between the implant and the surrounding bonetissue. Therefore, the evolution towards peri-implant bone loss and ﬁbrous tissuedevelopment at the bone-implant interface would be delayed, which could positivelyinﬂuence the THR outcome. Pre-clinical tests allowed us to verify that a partialproximal coating of the stem would result in a homogeneous bone remodeling, a situ-ation biomechanically more favorable than the simulated situation obtained with afull coating of the stem. Despite a numerically observed positive concentration eﬀect,it was noted that the decrease of peri-implant bone loss was most notably aﬀectedwith the intermediate simulated bisphosphonate concentration. Based on these pos-itive pre-clinical results, in vitro and in vivo experiments were performed to furthervalidate the concept of orthopedic implant used as drug delivery system.As bisphosphonates were developed for systemic delivery, little information was avail-able regarding the bisphosphonate concentrations which could be safely used for alocal delivery application. It was especially important to quantify the bisphosphon-ate concentration osteoblasts could be exposed to without harmful eﬀect for the boneformation process. We challenged osteoblasts from human and murine origins to dif-ferent concentrations of the choosen bisphosphonate (Zoledronate from Novartis). Aswear particles are inevitably present in the peri-implant bone, we also added titaniumparticles to quantify the eventual synergetic negative eﬀect between Zoledronate and