Ze Zhao,1,* Peng Dong,1,* Haochen Wang,1 Jianbang Su,1 Minghao Yu,1 Haoyan Shi,1 Tianqi Gao,1 Qian Zhang,1 Wenzheng Chen,1 Jingyu Yang,2 Huijie Zhang,3 Yingliang Wei1 

1Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2School of Business Administration, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China; 3Department of Gynaecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yingliang Wei, Department of Orthopedics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People’s Republic of China, Tel +86-024-96615-36311, Email ylwei@cmu.edu.cn Huijie Zhang, Department of Gynaecology and Obstetrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People’s Republic of China, Tel +86-024-96615-42211, Email 824458519@qq.com

Abstract: Intra-articular therapy has long been a key focus in the treatment of osteoarthritis (OA), with both intra-articular drug injection and cell therapy offering significant advantages over systemic administration due to their superior local therapeutic efficacy. However, several challenges remain, including difficulties in maintaining effective drug concentrations within the joint cavity, limited survival and functionality of injected cells, and the inability to accurately target drugs or cells to diseased tissues. To address these issues, hydrogel-based microsphere systems have recently been developed as carriers for drugs, cells, and bioactive factors, enabling more precise and efficient intra-articular therapies. This review summarizes recent advances in hydrogel microspheres for intra-articular injection and classifies them according to their functional properties. From the perspective of drug delivery, we discuss their roles in sustained release, cartilage penetration and targeting, stimulus-responsive release mechanisms, and inherent pharmacological activity. From the perspective of cell therapy, we explore their applications in cell delivery and cartilage tissue engineering, including their ability to enhance cell viability, maintain stemness, and enable the co-delivery of bioactive molecules. In conclusion, hydrogel microspheres represent a promising strategy for improving the efficacy of intra-articular treatments in osteoarthritis.

Keywords: osteoarthritis, microspheres, drug delivery, cartilage tissue engineering