Oju Jeon^{a, 1}, Su Jin Song^{a, 1}, Sun-Woong Kang^a, Andrew J. Putnam^b, Byung-Soo Kim^c

^a Department of Chemical Engineering, Hanyang University, 17 Hangdang-dong, Sungdong-gu, Seoul 133-791, Korea
^b Department of Biomedical Engineering, Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697, USA
^c Department of Bioengineering, Hanyang University, 17 Hangdang-dong, Sungdong-gu, Seoul 133-791, Korea

¹These authors contributed equally to this work.

Abstract
In this study, a heparin-conjugated poly(l-lactic-co-glycolic acid) (HP-PLGA) scaffold was developed for the sustained delivery of bone morphogenetic protein-2 (BMP-2), and then used to address the hypothesis that BMP-2 delivered from this scaffold could enhance ectopic bone formation. We found the amount of heparin conjugated to the PLGA scaffolds could be increased up to 3.2-fold by using scaffolds made from star-shaped PLGA, as compared to scaffolds made from linear PLGA, and that the release of BMP-2 from the HP-PLGA scaffold was sustained for at least 14 days in vitro. The BMP-2 released from the HP-PLGA scaffold stimulated an increase in alkaline phosphatase (ALP) activity of osteoblasts for 14 days in vitro, suggesting that the HP-PLGA scaffold delivery system releases BMP-2 in a bioactive form for a prolonged period. By contrast, BMP-2 release from unmodified (no heparin) PLGA scaffolds induced a transient increase in ALP activity for the first 3 days and a decrease thereafter. In vivo bone formation studies showed the BMP-2-loaded HP-PLGA scaffolds induced bone formation to a much greater extent than did either BMP-2-loaded unmodified PLGA scaffolds or unloaded (no BMP-2) HP-PLGA scaffolds, with 9-fold greater bone formation area and 4-fold greater calcium content in the BMP-2-loaded HP-PLGA scaffold group compared to the BMP-2-loaded unmodified PLGA scaffold group. Collectively, these results demonstrate that the HP-PLGA delivery system is capable of potentiating the osteogenic efficacy of BMP-2, and underscore its importance as a possible bone regeneration strategy.

Keywords : Bone morphogenetic protein; Bone regeneration; Poly(l-lactide-co-glycolide); Scaffold; Sustained delivery