Orthopedic Implants Used as Drug Delivery Systems: Numerical, in Vitro and in Vivo Studies

Total Hip Replacement (THR) is today a routine procedure executed more than 800’000 times per year worldwide. THR gives generally satisfactory results, although the 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. These patients have more demanding physical activity resulting in a significant increased failure rate of the implants. In particular for these patients, the desired service life of the implant should be extended. Proximal peri-implant bone loss is generally observed during the first two years following the implantation. This bone loss may lead to aseptic loosening, the major cause of THR failure. In order to control peri-implant bone remodeling and in particular the proximal bone loss, we developed the innovative concept of using the orthopedic implant as drug delivery system (DDS). The cementless stem of a hip implant would be coated with hydroxyapatite (HA) and bisphosphonate, a drug affecting bone resorption. The basic idea is to biologically reduce the initial peri-implant bone loss by decreasing the osteoclastic bone resorption activity. This approach could significantly increase the THR outcome. Pre-clinical tests were performed to numerically validate this new concept. An existing bone remodeling model was modified to take into account the bisphosphonate effect. The outcome of a THR was evaluated with different simulated bisphosphonate concentrations. Results of the simulations showed that the implant used as a drug delivery system would increase bone density around the implant and decrease, at the same time, the micromovements between the implant and the surrounding bone tissue. Therefore, the evolution towards peri-implant bone loss and fibrous tissue development at the bone-implant interface would be delayed, which could positively influence the THR outcome. Pre-clinical tests allowed us to verify that a partial proximal coating of the stem would result in a homogeneous bone remodeling, a situation biomechanically more favorable than the simulated situation obtained with a full 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 affected with the intermediate simulated bisphosphonate concentration. Based on these positive pre-clinical results, in vitro and in vivo experiments were performed to further validate the concept of orthopedic implant used as drug delivery system. As bisphosphonates were developed for systemic delivery, little information was available regarding the bisphosphonate concentrations which could be safely used for a local delivery application. It was especially important to quantify the bisphosphonate concentration osteoblasts could be exposed to without harmful effect for the bone formation process. We challenged osteoblasts from human and murine origins to different concentrations of the choosen bisphosphonate (Zoledronate from Novartis). As wear particles are inevitably present in the peri-implant bone, we also added titanium particles to quantify the eventual synergetic negative effect between Zoledronate and