Dual-response of multi-functional microsphere system to ultrasound and microenvironment for enhanced bone defect treatment.

Using bone tissue engineering strategies to achieve bone defect repair is a promising modality. However, the repair process outcomes are often unsatisfactory. Here we properly designed a multi-functional microsphere system, which could deliver bioactive proteins under the dual response of ultrasound and microenvironment, release microenvironment-responsive products on demand, reverse bone injury microenvironment, regulate the immune microenvironment, and achieve excellent bone defect treatment outcomes. In particular, the MnO introduced into the poly(lactic-co-glycolic acid) (PLGA) microspheres during synthesis could consume the acid produced by the degradation of PLGA to protect bone morphogenetic protein-2 (BMP-2). More importantly, MnO could consume reactive oxygen species (ROS) and produce Mn and oxygen (O), further promoting the repair of bone defects while reversing the microenvironment. Moreover, the reversal of the bone injury microenvironment and the depletion of ROS promoted the polarization of M1 macrophages to M2 macrophages, and the immune microenvironment was regulated. Notably, the ultrasound (US) irradiation used during treatment also allowed the on-demand release of microenvironment-responsive products. The multi-functional microsphere system combines the effects of on-demand delivery, reversal of bone injury microenvironment, and regulation of the immune microenvironment, providing new horizons for the clinical application of protein delivery and bone defect repair.