Bisphosphonate-Conjugated Photo-Crosslinking Polyanionic Hyaluronic Acid Microbeads for Controlled BMP2 Delivery and Enhanced Bone Formation Efficacy

초록

Background: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) superfamily and act as bone-inducing autocrine molecules for embryogenesis, bone formation, and remodeling processes in the body. Among BMPs, BMP2 is the only approved drug by the US Food and Drug Administration for the treatment of single-level anterior lumbar interbody fusion (ALIF), tibial nonunion, and oral maxillofacial reconstruction. One of the major challenges of BMP2 therapy is the optimized delivery system that can exactly apply the titrated dose to the bone defects and also can release the BMP2 at the site of implantation without devastating leakage to other tissues. Methodology: In this study, we designed bisphosphonate-conjugated polyanionic hyaluronic acid microbeads for the controlled delivery of BMP2. Microbeads (MBs) were prepared via the photo-crosslinking of bisphosphonates (alendronate)-conjugated methacryl hyaluronic acid (Alen-MHA). Principal Findings: The polyanionic Alen-MHA MBs actively absorbed cationic BMP2 up to 91.0% of loading efficacy and displayed a sustained release of BMP2 for 10 days. BMP2/Alen-MHA MBs induced osteogenic-related genes in cellular experiments and showed the highly increased bone formation efficacy in thigh muscle injection and rat spinal fusion animal models. Conclusion: BMP2/Alen-MHA MBs provide a promising opportunity to improve the delivery efficiency of BMP2. Significant: Alen-MHA MBs may address the safety issues of scaffold-based BMP2 delivery systems. Hence, BMP2/Alen-MHA MBs could be a potent platform design for BMP2 related orthopedic procedures.