Supramolecular hydrogels based on MPEG-grafted hyaluronic acid and α-CD containing HP-β-CD/simvastatin enhance osteogenesis in vivo

Simvastatin (SIM) accelerates new bone formation both in vitro and in vivo by enhancing the expression of recombinant human bone morphogenetic protein-2 (rhBMP-2). In this study, we evaluated the effect of water-solubility of SIM on new bone formation by preparing two types of supramolecular hydrogels: pseudopolyrotaxanes (PPRXs) based on metoxy polyethyleneglycol-grafted hyaluronic acid (MPEG-g-HA) and α-cyclodextrin (α-CD) containing water-soluble hydroxypropyl β-cyclodextrin/simvastatin inclusion complex (HP-β-CD-ic-SIM; MPEG-g-HA/α-CD/HP-β-CD-ic-SIM) or only SIM (MPEG-g-HA/α-CD/SIM). As compared to MPEG-g-HA/α-CD/SIM, SIM was more rapidly released from MPEG-g-HA/α-CD/HP-β-CD-ic-SIM in a sustained manner owing to increased water-solubility. New bone actively formed at the calvarial defect site in a rabbit model 4 weeks after implantation, as examined by micro computed tomography (micro CT), hematoxylin and eosin (H&E) staining, and Goldner's trichrome staining. The results showed that the water-solubility of SIM plays a significant role in enhancing new bone formation in vivo.