Steroid-induced osteonecrosis of the femoral head (SONFH), a serious disease caused by excessive glucocorticoid use, can impair the blood vessels of the femoral head and inhibit osteogenic activity (Fang et al., 2022, Zha et al., 2018). Current clinical strategies, such as core decompression (CD) and bone grafting, do not effectively promote angiogenesis and osteogenesis in the femoral head, thus leading to femoral head collapse and secondary osteoarthritis (Fu et al., 2019). Although total hip arthroplasty (THA) is effective for treating SONFH, complications such as dislocation, infection, and loosening are difficult to avoid (Bergh et al., 2014, Dale et al., 2012). Thus, THA cannot be considered the preferred therapeutic method for SONFH—particularly in relatively young patients. Therefore, it is necessary to develop effective methods for the treatment of SONFH.

Several recent studies have revealed that oxidative stress is a vital pathogenic factor in SONFH (Fan et al., 2021, Chen et al., 2020, Ichiseki et al., 2011). High concentrations of glucocorticoids can significantly increase the levels of reactive oxygen species (ROS) and create an oxidative stress microenvironment in the femoral head, leading to the apoptosis and necrosis of osteogenic and angiogenic cells (Zhang et al., 2021). In addition, excess ROS can suppress the survival of implanted cells and reduce the efficiency of tissue engineering in SONFH (Zhang et al., 2020). Several studies have indicated that the suppression of oxidative stress is effective for treating SONFH (Deng et al., 2018b, Bosco et al., 2018, Huang et al., 2016). As antioxidants with low toxicity, selenium nanoparticles (SeNPs) have been successfully used to treat SONFH because they scavenge ROS and suppress oxidative stress (Deng et al., 2018a). However, existing antioxidant strategies for SONFH therapy are all systemic administration, which may significantly reduce the ROS-scavenging efficiency in the femoral head. Therefore, we propose that the local transplantation of SeNPs-releasing biomaterials into the femoral head may represent an ideal strategy for treating SONFH. In addition, the molecular mechanisms underlying the treatment effect of Se in SONFH have not yet been studies. So far, this is the first study to investigate the treatment mechanisms of SeNPs in SONFH.

Several molecular mechanisms have been reported to underlie SONFH. Among them, the Wnt/β‐catenin signaling pathway is of particular concern. Evidence suggests that the inhibition of the Wnt/β-catenin signaling pathway can lead to SONFH by promoting the apoptosis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) (Zhang et al., 2019, Wu et al., 2019). In addition, downregulation of the Wnt/β‐catenin signaling pathway is closely related to the inhibition of angiogenesis (Pei et al., 2017). Thus, the activation of the Wnt/β-catenin pathway is an effective strategy for treating SONFH. Recent research has indicated that SeNPs can activate the Wnt/β-catenin signaling pathway and promote nerve regeneration under oxidative stress conditions (Liu et al., 2022). However, whether SeNPs can activate the Wnt/β-catenin signaling pathway in the femoral head during SONFH treatment remains largely unexplored.

As carriers loading and delivering drugs, proper hydrogels can retain the biological activity of drugs and realize their sustained release. Alginate (Alg) is a common natural polymer that has been used in various fields such as food and pharmaceutical industry (Jain and Bar-Shalom, 2014). Alg is often used to load drugs because it can easily cross-link in the presence of divalent cations such as Ca2+. Carboxymethyl chitosan (CMC) is a chitosan derivative, which has improved biological and physicochemical properties, such as biodegradability, biocompatibility and water solubility at neutral pH (Upadhyaya et al., 2013). It was reported that hydrogels prepared by combination of Alg and CMC had better characteristics such as swelling and drug controlled release compared with Alg hydrogels (Lin et al., 2005). In this study, we integrated SeNPs into a CMC/Alg hydrogel, which we previously prepared (Xu et al., 2021) to realize the sustained release of SeNPs, and then transplanted the SeNPs/CMC/Alg hydrogel into the femoral head after CD surgery to treat SONFH. The main objectives of this study were to assess the therapeutic effect of the SeNPs/CMC/Alg hydrogel on SONFH and to investigate the mechanism of action by examining the levels of ROS and activation of the Wnt/β-catenin signaling pathway in the femoral head.