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Orthopedic implants used as drug delivery systems: numerical, in vitro and in vivo studies

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DOI: 10.5075/epfl-thesis-3044
Infoscience @ EPFL
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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 particles on osteoblast behavior. In this in vitro study, we showed that Zoledronate did not impair proliferation of human osteoblasts when used at concentrations lower or equal to 1 µM, while murine cells could be exposed to concentrations up to 10 µM. A concentration of 0.01% of titanium particles did not impair proliferation of either cell line. Zoledronate affected, through a chelation phenomenon, ALP activity of murine osteoblasts, whereas the presence of titanium particles strongly decreased the ALP activity of murine osteoblasts. We did not detect any synergic effect of Zoledronate and titanium particles on neither human and murine osteoblast behavior. Those results allowed us to conclude that 1 µM and 10 µM Zoledronate concentrations for human and murine respectively, could be used in the proposed drug delivery system. The basic idea behind the drug delivery system is that the bisphosphonate will stay around the implant where its effect on bone resorption is needed. Since the drug is directly brought into contact with the endosteal bone, it was necessary to study the bisphosphonate diffusion in bone. The in vitro measured Zoledronate diffusion profile in the bone showed that the bisphosphonate entered the bone and diffused from the endosteal bone towards the periosteal bone. The drug accumulated in the first millimeter of the endosteal bone. This meant that the Zoledronate would stay in the peri-implant bone and would not reach regions which are not influenced by the presence of the implant. Based on the in vitro results for Zoledronate concentrations effect on osteoblast and diffusion in bone, an in vivo experiment was designed to demonstrate the proof of concept of orthopedic implant used as drug delivery system. Several Zoledronate quantites were grafted to hydroxyapatite (HA) coatings of titanium implants. The implants were inserted in rat condyles for 3 weeks. Bone density, histomorphometric and biomechanical measurements were performed on the collected rat femurs. A concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. The Zoledronate coated implant positively influenced the structure of the trabecular bone. Biomechanical pull-out tests confirmed the higher peri-implant bone quality of Zoledronate coated implant. Interestingly, this in vivo study highlighted the existence of a window of Zoledronate coating concentration in which the mechanical fixation of the implant was increased. A similar result was suggested with the pre-clinical testing. The in vivo study allowed the demonstration of proof-of-concept for orthopedic implant used as drug delivery system to control peri-implant bone remodeling. The results obtained in this thesis might then open the way of an easy transformation of currently existing HA coated implants. By grafting bisphosphonate onto the implant HA coating, the peri-implant bone loss might be reduced which would increase the service life of a THR. This approach is especially interesting for patient younger than 60 years.


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