Development of a Bisphosphonate Delivering Hydrogel for the Augmentation of Impaired Peri-Implant Bone

Osteoporosis is a major health problem in our aging society. This metabolic disease, which is characterized by a deterioration of the bone microarchitecture and a significant loss of bone mass, is affecting a rising number of mostly elderly patients. The main clinical consequences are typical fragility fractures resulting in severe pain, morbidity, and mortality for affected patients. Osteoporosis does not only cause fractures, but also complicates fracture treatment, as implants are difficult to anchor in the impaired bone structure. Therefore, many mechanical and pharmaceutical approaches have been developed over the last decades to target this issue and improve implant anchorage in osteoporotic bone. The overall goal of the present PhD thesis was the development of a bisphosphonate (BP) releasing hydrogel that can enhance implant fixation in osteoporotic bone. The project was divided into three major sections: the investigation of the BP effect on peri-implant bone, the development and testing of the drug delivering biomaterial, and the evaluation of its efficiency in terms of implant fixation improvement. An ovariectomized rat model of postmenopausal osteoporosis was utilized for the investigation of the spatio-temporal effect of locally released Zoledronate, the BP used in this study. The drug was delivered from a biodegradable hyaluronic acid (HyA) hydrogel matrix to the bone stock surrounding screws that were implanted in the femoral condyles of the rats. Static and dynamic bone histomorphometric parameters were monitored in four concentric bone layers around the screw with time-lapsed in vivo microCT scans. With this study, we were able to demonstrate a significant enhancement of early bone formation rate accompanied by an efficient inhibition of peri-implant bone resorption in a large range around the screw. In a second in vivo study, we incorporated Zoledronate-loaded hydroxyapatite nanoparticles in the HyA hydrogel resulting in an unexpected rapid mineralization of the hydrogel within 10 days after implantation. Histology performed 2 months after implantation revealed granule-shaped mineralized spots within the peri-implant bone serving as scaffolds for new bone formation. When using Zoledronate-loaded particles, we could demonstrate a strong inhibitory effect on both peri-implant bone resorption and mineralized hydrogel degradation. Finally, we used the in vivo microCT scans of the first animal study to create micro-finite element models for the analysis of the screw fixation time course. We were able to show that Zoledronate locally delivered from the hyaluronic acid hydrogel improved screw fixation significantly as soon as 17 days after implantation when compared to an untreated control group. This difference persisted until the end of the study at day 58. Taken together, the studies performed for the present PhD thesis demonstrated an excellent suitability of HyA hydrogels for the local delivery of BPs intended to improve implant fixation in impaired bone. A Zoledronate triggered enhancement of screw fixation occurred early and persisted over a prolonged period, an important aspect considering that osteosynthesis implants need a reliable bone anchorage from the time of implantation until complete fracture healing. Furthermore, it could be shown that an addition of hydroxyapatite particles to the HyA resulted in a rapid in vivo mineralization of the hydrogel, a promising feature for bone defect repair applications.