Synergy between rhBMP-2 and IKK-Inhibitor PS-1145 Delivered via a Porous Biodegradable Polymer Implant

Abstract

Critical-sized bone defects, whether caused by congenital malformation, tumor resection, trauma, or implant loosening, remain a major challenge for orthopaedic management. In this study we describe a bone tissue engineering approach in mice for the co-delivery of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) and the IKK inhibitor PS-1145. Scaffold implants were manufactured from poly(lactide-co-glycolide)(PLGA) by Thermally-Induced Phase Separation (TIPS), with rhBMP-2 (10 μg) and the IKK inhibitor PS-1145 (0 μg, 40 μg or 80 μg) incorporated into the polymer. These scaffolds were then surgically implanted into the hind limb muscle of C57BL6/J mice. One group of mice also received systemic 50 mg/kg PS-1145 (days 11-20). Specimens were harvested at week 3 for X-ray and microCT analyses and descriptive histology. Local and systemic delivery PS-1145 both significantly increased the net rhBMP-2 induced bone at 3 weeks. A maximal response was seen with the 40 μg PS-1145 group, although there was no significant difference between the 40 μg and 80 μg PS-1145 regimens. No local cytotoxicity was seen with either dose of PS-1145. In summary, local co-delivery of rhBMP-2 and PS-1145 via a porous PLGA scaffold represents a new tissue engineering approach for maintaining new bone in an unloaded environment.