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

Qingxu Song; Dianwei Wang; Haoyu Li; Zongliang Wang; Songjia Sun; Zhenyu Wang; Yi Liu; Sien Lin; Gang Li; Shaokun Zhang; Peibiao Zhang

doi:10.1016/j.bioactmat.2023.10.007

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

Bioact Mater. 2023 Oct 18:32:304-318. doi: 10.1016/j.bioactmat.2023.10.007. eCollection 2024 Feb.

Authors

Qingxu Song^{1

2}, Dianwei Wang², Haoyu Li^{1

2}, Zongliang Wang², Songjia Sun³, Zhenyu Wang¹, Yi Liu¹, Sien Lin⁴, Gang Li⁴, Shaokun Zhang¹, Peibiao Zhang²

Affiliations

¹ Department of Spine Surgery, The First Hospital of Jilin University, Changchun, 130021, China.
² Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
³ Department of Dermatology, Second Hospital of Jilin University, Changchun, 130022, China.
⁴ Department of Orthopaedics and Traumatology and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.

Abstract

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 MnO₂ 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, MnO₂ could consume reactive oxygen species (ROS) and produce Mn²⁺ and oxygen (O₂), 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.

Keywords: BMP-2; Bone defect repair; Bone injury microenvironment; Immune microenvironment; Multi-functional microsphere.