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

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Anterior cruciate ligament (ACL) reconstruction with the hamstring tendon graft takes a long time, as the tendon graft needs to heal at the site of the bone-tendon integration in the created bone tunnels. Several reports have shown the therapeutic effects of simvastatin on bone formation with neovascularization. The aim of this study was to test the hypothesis that enhanced angiogenesis and osteogenesis by locally applied simvastatin promotes tendon-bone healing after ACL reconstruction. Rabbits received ACL reconstruction with hamstring tendon graft and were implanted with either simvastatin-conjugated gelatin hydrogel or gelatin hydrogel alone in their bone tunnels, and then bone regeneration and neovascularization at tendon-bone interface and biomechanical properties were assessed. Histological analysis at week 2 demonstrated that tendon-bone healing was significantly greater with angiogenesis and osteogenesis in the simvastatin-treated group than in the control group. Computed tomography at weeks 2 and 4 showed a significantly smaller tibial bone tunnel in the simvastatin-treated group. Biomechanical testing at week 2 demonstrated a significant increase in ultimate failure load in the simvastatin-treated group. This study suggested that local administration of low-dose simvastatin-conjugated gelatin hydrogel promotes the tendon-bone healing via its effect on both angiogenesis and osteogenesis at an early phase in a rabbit model, but does not affect biomechanical property in long-term after ACL reconstruction.

The objective of this study is to design biodegradable hydrogels for the controlled release of low-molecular-weight heparin (LMWH) and evaluate the biological activity. Gelatin was cationized by chemically introducing ethylene diamine into the carboxyl groups in different conditions to obtain cationized gelatins. The cationized gelatin was mixed with the LMWH in aqueous solution to form the complex. Gelatin, together with the complex of LMWH and cationized gelatin, was dehydrothermally cross-linked for different time periods to prepare the gelatin hydrogel-incorporating complex. The hydrogel-incorporating complex was neither degraded in phosphate-buffered saline solution (PBS) at 37 °C nor did it release the LMWH complex. When placed in PBS containing collagenase, the hydrogel was enzymatically degraded to release the LMWH complex. The time profile of hydrogel degradation and the LMWH release depended on the condition of hydrogel cross-linking. The longer the cross-linking time period, the slower the hydrogel degradation and the subsequent LMWH release. The half-life period of LMWH release was in good correspondence with that of hydrogel degradation. It is possible that the LMWH was released as the result of hydrogel degradation. When applied to the mouse model of abdominal membrane fibrosis, the hydrogel system of LMWH release showed a promising anti-fibrotic effect.

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