Supramolecular Hydrogels Based on MPEG-Grafted Hyaluronic Acid and .ALPHA.-CD Containing HP-.BETA.-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 alpha-cyclodextrin (alpha-CD) containing water-soluble hydroxypropyl beta-cyclodextrin/simvastatin inclusion complex (HP-beta-CD-ic-SIM; MPEG-g-HA/alpha-CD/HP-beta-CD-ic-SIM) or only SIM (MPEG-g-HA/alpha-CD/SIM). As compared to MPEG-g-HA/alpha-CD/SIM, SIM was more rapidly released from MPEG-g-HA/alpha-CD/HP-beta-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.