BACKGROUND: The cholesterol-lowering drug simvastatin promotes bone formation in cell cultures and animal models. In previous studies, devices for the controlled, localized delivery of simvastatin hydroxyacid enhanced osteoblastic activity in vitro. The objective of this investigation was to determine bioactivity of the delivery system in vivo. METHODS: Devices for sustained or intermittent release of simvastatin hydroxyacid were formed using a blend of cellulose acetate phthalate and a poly(ethylene oxide) and poly(propylene oxide) block copolymer, and they were implanted directly over the calvarium of young male rats. Drug-free devices were used as controls. After 9, 18, or 28 days, specimens were histologically evaluated for new bone formation. RESULTS: All three groups showed some level of new bone formation, but the extent of osteogenesis depended on the type of implant. Devices delivering simvastatin hydroxyacid were associated with a 77.5% to 133% increase in new woven bone thickness compared to control devices without a drug (P<0.05). Furthermore, intermittent release stimulated a 32.3% greater response in bone thickness and a 74.1% greater bone area than did sustained delivery (P<0.05). Although a minimal thickness of woven bone was formed directly under the device (up to 36 microm), a significantly thicker layer was observed at the periphery (up to 205 microm), implying mechanical and/or chemical effects directly under the implant. The percentage of lamellar bone area for intermittent and sustained release was higher than that for the control group (P<0.05). CONCLUSION: Based on the present results of enhanced bone formation, these devices for the intermittent delivery of simvastatin hydroxyacid merit further attention for localized osteogenesis.
BACKGROUND: The cholesterol-lowering drug simvastatin promotes bone formation in cell cultures and animal models. In previous studies, devices for the controlled, localized delivery of simvastatin hydroxyacid enhanced osteoblastic activity in vitro. The objective of this investigation was to determine bioactivity of the delivery system in vivo. METHODS: Devices for sustained or intermittent release of simvastatin hydroxyacid were formed using a blend of cellulose acetate phthalate and a poly(ethylene oxide) and poly(propylene oxide) block copolymer, and they were implanted directly over the calvarium of young male rats. Drug-free devices were used as controls. After 9, 18, or 28 days, specimens were histologically evaluated for new bone formation. RESULTS: All three groups showed some level of new bone formation, but the extent of osteogenesis depended on the type of implant. Devices delivering simvastatin hydroxyacid were associated with a 77.5% to 133% increase in new woven bone thickness compared to control devices without a drug (P<0.05). Furthermore, intermittent release stimulated a 32.3% greater response in bone thickness and a 74.1% greater bone area than did sustained delivery (P<0.05). Although a minimal thickness of woven bone was formed directly under the device (up to 36 microm), a significantly thicker layer was observed at the periphery (up to 205 microm), implying mechanical and/or chemical effects directly under the implant. The percentage of lamellar bone area for intermittent and sustained release was higher than that for the control group (P<0.05). CONCLUSION: Based on the present results of enhanced bone formation, these devices for the intermittent delivery of simvastatin hydroxyacid merit further attention for localized osteogenesis.
Authors: Sharath C Sundararaj; Mark V Thomas; Rebecca Peyyala; Thomas D Dziubla; David A Puleo Journal: Biomaterials Date: 2013-08-12 Impact factor: 12.479