Supramolecular Hydrogels Based on MPEG-Grafted Hyaluronic Acid and α-CD Containing HP-β-CD/Simvastatin Enhance Osteogenesis In Vivo

Abstract

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.

Type II Collagen-Positive Embryonic Progenitors are the Major Contributors to Spine and Intervertebral Disc Development and Repair

“…Longitudinal sections of whole tail were cut at 6 μm using a cryostat followed by Goldner's trichrome staining protocol as previously described. 25 Briefly, the slides were mordanted in Bouin's Fluid solution and stained with Weigert's hematoxylin, ponceau acid fuchsin and then costained with light green respectively. Five to six mice were evaluated in each group.…”

Simvastatin-Incorporated Drug Delivery Systems for Bone Regeneration

“…Hydrogel materials are also excellent carriers for simvastatin because of their three-dimensional network structure, flexibility, and moisture content. ,, These properties give them the ability to embed bone-forming drugs such as simvastatin into their network structures. Hydrophilic hydrogel materials induce weaker local inflammatory responses than their hydrophobic counterparts because fewer protein components adsorb onto their surfaces.…”

“…In addition, increasing the systemically administered dose increases the risk of side effects such as liver damage, kidney disease, and rhabdomyolysis. − Therefore, several drug delivery system studies have been performed with the goal of directly delivering simvastatin to bone defect sites. These studies have demonstrated the ability to induce bone repair. , …”

“…These studies have demonstrated the ability to induce bone repair. 23,24 Simvastatin-loaded drug delivery systems that do not provide suitable concentrations of simvastatin have limited bone regeneration promotion effects. High local simvastatin concentrations cause inflammation in bone defects and inhibit osteoblast differentiation, thereby impairing bone repair.…”