Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora

Abstract

Statins, a class of naturally-occurring compounds that inhibit HMG-CoA reductase, are known to increase endogenous bone morphogenetic protein-2 (BMP-2) expression. Local administration of statins has been shown to stimulate fracture repair in in vivo animal experiments. However, the ability of statins to heal more challenging critical-sized defects at the mid-diaphyseal region in long bones has not been investigated. In this study, we examined the potential of injectable lovastatin microparticles combined with biodegradable polyurethane (PUR) scaffolds in preclinical animal models: metaphyseal small plug defects and diaphyseal segmental bone defects in rat femora. Sustained release of lovastatin from the lovastatin microparticles was achieved over 14 days. The released lovastatin was bioactive, as evidenced by its ability to stimulate BMP-2 gene expression in osteoblastic cells. Micro-computed tomography (CT) and histological examinations showed that lovastatin microparticles, injected into PUR scaffolds implanted in femoral plug defects, enhanced new bone formation. Furthermore, bi-weekly multiple injections of lovastatin microparticles into PUR scaffolds implanted in critical-sized femoral segmental defects resulted in increased new bone formation compared to the vehicle control. In addition, bridging of the defect with newly formed bone was observed in four of nine defects in the lovastatin microparticle treatment group, whereas none of the defects in the vehicle group showed bridging. These observations suggest that local delivery of lovastatin combined with PUR scaffold can be an effective approach for treatment of orthopaedic bone defects and that multiple injections of lovastatin may be useful for large defects.