CONTROLLED RELEASE OF OSTEOTROPIC MOLECULES STIMULATES IN VITRO CELLULAR ACTIVITY AND IN VIVO LOCAL BONE REGENERATION

Bone defects treatment and reconstructive surgery continues to increase at a significant rate. Current bone defect treatments are autotransplantation, allograft, and xenografts create many problems such as, inflammation, infection and chronic pain. Moreover, allografts and xenografts arouse immune rejection. These problems have led to development of controlled release system for use as alternatives to autografts, allografts and xenografts in bone repair. There have been many approaches for sustained drug delivery in local bone regeneration using biodegradable polymers and osteotropic biomolecules. This dissertation presents new approaches that apply intermittent drug delivery for local bone regeneration. In the first, the osteotropic molecules simvastatin (Sim) or parathyroid hormone (PTH) were released with intermittent profiles. In the second, alternating delivery of Sim and PTH as well as alternating release of the antimicrobial agent cecropin B (CB) with Sim or PTH. An association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used for the delivery vehicle. Each device showed discrete peaks in release profiles and lasted more than 10 days. Release profiles could be controlled by altering surface area exposed to aqueous environment, number of layers, loading, and blending ratios. Cells were cultured with sustained or intermittent exposure to Sim or PTH at various concentrations, and alternating exposure to CB and Sim or PTH and to Sim and PTH at different concentrations. Low dose Sim and PTH treatments stimulated higher osteoblastic activity than observed in control cultures. Furthermore, intermittent delivery was more effective than sustained exposure. In vivo, newly formed bone was found in animals implanted with both blank Sim-loaded devices. However, a greater anabolic effect was seen for Sim release devices. Further, intermittent release devices stimulated the greatest woven bone thickness, total bone area, and lamellar bone area. These results suggest that intermittent release devices containing a single molecule, Sim or PTH, and alternating release devices containing multiple molecules, CB with Sim or PTH, possess promising potential as a treatment for local bone regeneration