Therapeutic effect of local administration of low-dose simvastatin-conjugated gelatin hydrogel for fracture healing

Abstract

Several reports have shown the therapeutic effect of statins on bone formation and neovascularization. However, the effect of the systemic administration of statins is limited due to its metabolism in the liver and clearance in the digestive system. In addition, highdose administration may cause adverse side effects. To avoid low-efficacy/frequent side effects of high-dose statin treatment, we utilized biodegradable gelatin hydrogel as a drug delivery system of statin for fracture healing. A femoral fracture was created in rats with periosteum cauterization leading to nonunion at 8 weeks postfracture. Rats received local administration of either simvastatinconjugated gelatin hydrogel (ST-Gel group) or gelatin hydrogel alone (Gel group). Approximately 70% of animals in the ST-Gel group achieved fracture union radiographically and histologically, while only 7% of animals achieved fracture healing in the Gel group. Functional bone healing was also significantly greater with increased angiogenesis-and osteogenesis-related growth factor expressions in periosteal granulation tissue in the ST-Gel group than in the Gel group. Simvastatin locally applied with gelatin hydrogel to fracture sites at a dose similar to that used in clinical settings successfully induced fracture union in a rat unhealing bone fracture model via its effect on both angiogenesis and osteogenesis. ß

Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions

“…The network component of a hydrogel is usually a polymer network and for aquagel is a colloidal network. Hydrogels are highly absorbent natural or synthetic polymeric networks and possess a degree of flexibility comparable to natural tissue [13,30,38,39]. Synthetic and natural hydrogels are routinely produced, using the same biomaterials used for manufacturing the solid scaffolds [5,13,128].…”

“…Hybrid hydrogels are highly hydrated polymeric networks, either physically or covalently cross-linked together and/or with HPFs (e.g. drugs), nanoparticles or nanostructures [6,38]. Hydrogel systems have attracted increasing attention as TERM scaffolds and for the sustained release of drugs [13,30,38,39].…”

“…), hydrogels (liquid materials with viscoelastic properties) or a combination of them as a sustained delivery systems [6,75,119,127]. Based on the type of carrier, the carrier-statin construct can be directly injected in the injured area by a single injection (the liquid and foamy forms of carriers) or can be surgically implanted in LBDs (the solid forms of carriers) [6,13,21,38,39,128,129]. …”

Role of Biological Scaffolds, Hydro Gels and Stem Cells in Tissue Regeneration Therapy

“…Local administration of either simvastatin-conjugated gelatin hydrogel (STGel group) or gelatin hydrogel alone (Gel group) in experimental animals induce functional bone healing significantly with increased angiogenesis-and osteogenesis-related growth factor expressions in periosteal granulation tissue. 80 Collagen hydrogel is used as a matrix to generate engineered hepatic units to reconstitute three-dimensional, vascularized hepatic tissue in vivo. The engineered hepatic tissue has the ability to respond to the regenerative stimulus.…”

Release properties of atelocollagen-gelatin complexes as carriers for local administration of fluvastatin

“…However, simple direct administration of statins to the affected sites is not effective for osteoinduction because the drug diffuses into the surrounding tissues [5][6][7] . Accordingly, controlled release systems for statins are required for local administration of statins with carriers, such as gelatin, atelocollagen sponge (Teruplug ® ), α-TCP, β-TCP, HA, and PLGA [8][9][10][11] . In particular, gelatin is widely used as a drug carrier because of desirable characteristics including (1) proven safety, (2) wide application of this biodegradable material for clinical purposes, (3) different physical properties by chemical modification, and (4) ease of attaching to drugs [12][13][14][15] .…”