In situ sustained release of icariin from injectable thermosensitive PLGA-PEG-PLGA hydrogels combined with core decompression for steroid-induced osteonecrosis of femoral head

Yingxing Xu¹Kaige Xu²Zehua Wang²Xinyu Tang²Tao Li^2*Yaping Jiang^2*

• ¹First Affiliated Hospital of Kunming Medical University, Kunming, China
• ²The Affiliated Hospital of Qingdao University, Qingdao, China

Background: Icariin (ICA) has showed the beneficial effects on preventing the occurrence of steroid-induced osteonecrosis of the femoral head (SONFH) through enhancing bone formation and remodeling. The present study was first designed to observe the effect of ICA on dexamethasone (Dex)-induced BMSCs and further reveal the relevant molecular mechanism. Furthermore, the sustained-release ICA delivery system co-loaded thermosensitive PLGA-PEG-PLGA hydrogels was constructed, and the efficiency of this drug delivery system in rats model with SONFH was evaluated. Methods: The anti-apoptotic effect of ICA on the Dex-induced BMSCs was observed by crystal violet staining, Hoechst 33342 staining and flow cytometry analysis. Meanwhile, the expression of Akt/Bad/Bcl-2 signaling pathway were detected by western blotting. Moreover, the sustained-release ICA delivery system co-loaded thermosensitive PLGA-PEG-PLGA hydrogels was constructed, and the sol-gel transition, in vitro degradation, as well as the sustained release of ICA from this drug delivery system was evaluated by a high performance liquid chromatography (HPLC) system. Ultimately, the sustained-release 2000μM ICA delivery system co-loaded 25 wt% thermosensitive PLGA-PEG-PLGA hydrogels was injected into the femoral head and medullary cavity after core decompression (CD) to assess the efficiency of this drug delivery system in rats model with SONFH by MRI, Micro-CT and histological analysis. Results: ICA could rescue BMSCs from Dex-induced apoptosis through promoting the phosphorylation of Akt/Bad/Bcl-2 signaling pathway. Furthermore, the degradation of copolymer was related to the ICA concentration, and the sustained-release effect of this delivery system in vitro was influenced by the drug and gel concentration. Importantly, the local injection of the sustained-release ICA delivery system co-loaded thermosensitive PLGA-PEG-PLGA hydrogels combined with CD could significantly relieve the bone marrow edema, augment the trabeculae bone, reduce the empty lacunae, and decrease the accumulation of adipocyte while increasing the expression of Runx-2 and inhibiting the expression of PPAR-γ in the femoral head. Conclusion: Our data showed that local injection of this sustained-release drug delivery system combined with CD could significantly relieve osteonecrosis in the rats model with SONFH by increasing the residence time of ICA in the necrotic area of femoral head to maximize the anti-apoptotic, pro-osteogenic and anti-adipogenic effects of ICA.