Phytomolecule icaritin incorporated PLGA/TCP scaffold for steroid-associated osteonecrosis: Proof-of-concept for prevention of hip joint collapse in bipedal emus and mechanistic study in quadrupedal rabbits

Abstract

Steroid-associated osteonecrosis (SAON) may lead to joint collapse and subsequent joint replacement. Poly lactic-co-glycolic acid/tricalcium phosphate (P/T) scaffold providing sustained release of icaritin (a metabolite of Epimedium-derived flavonoids) was investigated as a bone defect filler after surgical core-decompression (CD) to prevent femoral head collapse in a bipedal SAON animal model using emu (a large flightless bird). The underlying mechanism on SAON was evaluated using a well-established quadrupedal rabbit model. Fifteen emus were established with SAON, and CD was performed along the femoral neck for the efficacy study. In this CD bone defect, a P/T scaffold with icaritin (P/T/I group) or without icaritin (P/T group) was implanted while no scaffold implantation was used as a control. For the mechanistic study in rabbits, the effects of icaritin and composite scaffolds on bone mesenchymal stem cells (BMSCs) recruitment, osteogenesis, and anti-adipogenesis were evaluated. Our efficacy study showed that P/T/I group had the significantly lowest incidence of femoral head collapse, better preserved cartilage and mechanical properties supported by more new bone formation within the bone tunnel. For the mechanistic study, our in vitro tests suggested that icaritin enhanced the expression of osteogenesis related genes COL1α, osteocalcin, RUNX2, and BMP-2 while inhibited adipogenesis related genes C/EBP-ß, PPAR-γ, and aP2 of rabbit BMSCs. Both P/T and P/T/I scaffolds were demonstrated to recruit BMSCs both in vitro and in vivo but a higher expression of migration related gene VCAM1 was only found in P/T/I group in vitro. In conclusion, both efficacy and mechanistic studies show the potential of a bioactive composite porous P/T scaffold incorporating icaritin to enhance bone defect repair after surgical CD and prevent femoral head collapse in a bipedal SAON emu model.

Icariin-Functionalized Coating on TiO2 Nanotubes Surface to Improve Osteoblast Activity In Vitro and Osteogenesis Ability In Vivo

“…Apart from the drug reservoir of TiO 2 nanotubes layer, a local controlled and sustained drug delivery system is also needed to avoid drug toxicity caused by burst release and extend the duration of the drug's action [32]. Among the various coating materials, PLGA is well accepted for its good degradability and strong drug-loading capacity compared with chitosan when used as a scaffold material [33,34]. The previous study showed that TiO 2 nanotubes coated with a PLGA polymer layer have extended release duration and higher level of burst release than TiO 2 nanotubes coated with chitosan [35].…”

Biodegradable Magnesium‐Based Implants in Orthopedics—A General Review and Perspectives

“…Although histological analysis was not performed to assess the graft structure, this work developed the framework for future in vivo studies to assess the potential use of this novel ring to repair ruptured ACLs. Among the large animal models, the bipedal emu with steroid‐induced osteonecrosis has been recognized as a unique model for replicating the collapsed femoral head in patients 93. This model proposes a novel tool to develop Mg‐based hollow screws with holes allowing the injection of bone cement to promote new bone formation in the necrotic regions (Figure 7C).…”

Icaritin promotes tumor T‐cell infiltration and induces antitumor immunity in mice

“…Icaritin is a hydrolytic product of icariin isolated from the traditional Chinese herbal medicine genus Epimedium . Previous studies showed that icaritin possesses a wide range of pharmacological properties, including neuron and cardiac protection , attenuation of lipopolysaccharide‐induced inflammation, and osteogenesis and bone defect repair promotion . Based on its potent therapy effects for human malignancies, icaritin has been entered into clinical trials for the treatment of PD‐L1 positive advanced hepatocellular carcinoma (phase III, ClinicalTrials.gov Identifier: NCT03236649), hepatocellular carcinoma (phase III, ClinicalTrials.gov Identifier: NCT03236636), advanced solid tumors (phase Ib, completed, ClinicalTrials.gov Identifier: NCT02496949), and advanced breast cancer (phase I, ClinicalTrials.gov Identifier: NCT01278810).…”