Long-term delivery of rhIGF-1 from biodegradable poly(lactic acid)/hydroxyapatite@Eudragit double-layer microspheres for prevention of bone loss and articular degeneration in C57BL/6 mice

Abstract

Insulin-like growth factor (IGF-1) has encouraged researchers to investigate its various potential therapeutic uses such as in the treatment of osteoporosis and repair of articular cartilage. The purpose of this study was to develop core–shell double-layer structural microspheres for the long-term delivery of rhIGF-1 for the prevention of bone loss and articular degeneration. rhIGF-1-loaded poly(lactic acid)/hydroxyapatite@Eudragit (PLA/HA@Eu) double-layer microspheres with a core–shell structure were formulated using poly(lactic acid) and hydroxyapatite by an oil-in-water-in-oil (w/o/w) technique. The in vitro release profiles of rhIGF-1 and the surface morphology and cytocompatibility of microspheres were investigated. In vitro release of rhIGF-1 from PLA/HA@Eu microspheres was maintained over 180 days. In vivo experiments were performed on male C57BL/6 mice with two different ages: adult mice (three months old) and old mice (ten months old). PLA/HA@Eu microspheres containing 1 mg rhIGF-1 were subcutaneously implanted into the back of mice. The rhIGF-1 amounts in the sera, livers and bones of mice were monitored for 6 months. The in vivo rhIGF-1 release patterns were similar to those observed from in vitro release. By analyzing the effects of rhIGF-1-loaded microspheres on bone mass in adult mice and cartilage in old mice via micro-CT and histological measurements, we observed beneficial trends. These results suggest that PLA/HA@Eu double-layer microspheres providing long-term delivery of rhIGF-1 were effective in systemic preventive therapy of bone loss in adult mice and delaying the progressive degeneration of articular cartilage in old mice. The long-term delivery strategy demonstrated herein may be a promising therapeutic approach for delaying osteoporosis and articular degeneration.