Injectable hydrogel loaded with bilayer microspheres to inhibit angiogenesis and promote cartilage regeneration for repairing growth plate injury

Lei Qiang; Minjie Fan; Yiwei Wang; Yihao Liu; Hanjie Zhuang; Ruoyi Guo; Hao Huang; Yulong Ben; Dalin Wang; Xiaoling Wu; Jinwu Wang; Jie Weng; Pengfei Zheng

doi:10.3389/fbioe.2023.1181580

Injectable hydrogel loaded with bilayer microspheres to inhibit angiogenesis and promote cartilage regeneration for repairing growth plate injury

Front Bioeng Biotechnol. 2023 May 18:11:1181580. doi: 10.3389/fbioe.2023.1181580. eCollection 2023.

Authors

Lei Qiang^{1

2}, Minjie Fan¹, Yiwei Wang¹, Yihao Liu^{1

3}, Hanjie Zhuang¹, Ruoyi Guo¹, Hao Huang², Yulong Ben¹, Dalin Wang⁴, Xiaoling Wu⁵, Jinwu Wang³, Jie Weng², Pengfei Zheng¹

Affiliations

¹ Department of Orthopaedic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
² Key Laboratory of Advanced Technologies of Materials (MOE), School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China.
³ Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing, Jiangsu, China.
⁵ School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China.

Abstract

Introduction: The repair and regeneration of growth plate injuries using tissue engineering techniques remains a challenge due to large bone bridge formation and low chondrogenic efficiency. Methods: In this study, a bilayer drug-loaded microspheres was developed that contains the vascular endothelial growth factor (VEGF) inhibitor, Bevacizumab, on the outer layer and insulin-like growth factor-1 (IGF-1), a cartilage repair factor, on the inner layer. The microspheres were then combined with bone marrow mesenchymal stem cells (BMSCs) in the gelatin methacryloyl (GelMA) hydrogel to create a composite hydrogel with good injectability and biocompatibility. Results: The in vitro drug-release profile of bilayer microspheres showed a sequential release, with Bevacizumab released first followed by IGF-1. And this hydrogel simultaneously inhibited angiogenesis and promoted cartilage regeneration. Finally, in vivo studies indicated that the composite hydrogel reduced bone bridge formation and improved cartilage regeneration in the rabbit model of proximal tibial growth plate injury. Conclusion: This bilayer microsphere-based composite hydrogel with sequential controlled release of Bevacizumab and IGF-1 has promising potential for growth plate injury repair.

Keywords: anti-angiogenesis; bilayer microspheres; chondrogenic differentiation; growth plate; hydrogel; tissue engineering.

Grants and funding

This work was supported by Jiangsu Provincial Key Research and Development Program (CN) (grant number BE2019608); Postdoctoral Research Foundation of China (2022M721685); Jiangsu Health Commission Medical Research Program (grant number 2020158); National Facility for Translational Medicine (Shanghai) Open Program (grant number TMSK-2021-304); Nanjing International Science and Technology Cooperation Program; Nanjing Medical Science and Technology Development Key Program (grant number ZKX18041); Nanjing Postdoctoral Research Funding Program.