Relieving oxidative stress microenvironment and promoting vascularized bone formation to treat femoral head necrosis using 3D-printed scaffold with ultralong-term multienzyme-like activity

Abstract

Background

Characterized by microcirculatory disorder and oxidative stress microenvironment, the repair of bone defect after hip preservation therapy (such as core decompression) for osteonecrosis of the femoral head (ONFH) remains a clinical challenge. Thus, an ideal bone scaffold for treating ONFH should not only promote bone and vessel formation but also alleviate hypoxia and oxidative stress.

Method

We integrated manganese oxides (MnO_x) nanoparticles (NPs) with a 3D-printed poly(lactic-co-glycolic acid) (PLGA) scaffold to achieve this goal. The MnO_x NPs were synthesized using an oxidation reaction and the scaffold was 3D-printed using a fused deposition modeling method. The characterization and the enzyme-like activity of the scaffold was investigated. The biocompatibility and biofunctions of the scaffold were evaluated both in vitro and in vivo, including the antioxidant capacity, the effects on promoting bone formation and vascularization, and the therapeutic effect in animal model.

Results

The resultant MnO_x-doped PLGA scaffold could catalyze reactive oxygen species into oxygen through its superoxide dismutase (SOD)-like and catalase (CAT)-like activities. In vitro studies revealed that this multienzyme-like activity of the scaffold could be maintained for more than 30 days, thereby improving cell viability under oxidative stress. The underlying mechanism was shown to involve regulation of the antioxidant activity of cells via PI3K/AKT signaling pathway. The scaffold also significantly improved capabilities of osteogenesis and angiogenesis compared to pure PLGA scaffold. In vivo studies further demonstrated that the combination therapy of core decompression and scaffold implantation efficiently reduced osteoblast necrosis and enhanced vascularized bone formation in a clinically relevant ONFH rabbit model.

Conclusion

The 3D-printed MnO_x-doped PLGA scaffold not only relieve oxidative stress to protect osteocytes under ONFH microenvironment but also promote vascularized bone formation, showing the potential for treating ONFH.

Translational potential of this article

PLGA has been already applied in clinical bone implants. Mn is an essential trace element for the human body and MnO_x NPs offer the advantage of biocompatibility, ease of large-scale preparation, and low cost. Hence, this scaffold has the potential for clinical translation in the treatment of ONFH.