Design strategies of biomaterial-based intra-articular drug delivery system for osteoarthritis therapy

Osteoarthritis (OA), the most prevalent degenerative joint disorder, is emerging as a significant medical and socioeconomic burden worldwide, representing a major challenge in the field of public health for the coming decades. Although intra-articular drug administration remains a cornerstone of OA treatment, its therapeutic efficacy is substantially constrained by multiple barriers posed by intricate joint anatomy, including rapid joint clearance, poor tissue penetration, non-specific biodistribution, and suboptimal pharmacokinetics. Recently, biomaterials have surfaced as promising platforms for advanced drug delivery in OA management. Through appropriate design strategies, biomaterial-based drug delivery systems (DDSs) can significantly prolong intra-articular retention while enabling spatiotemporal control over drug release with optimized pharmacokinetics. These enhancements help overcome the barriers of conventional intra-articular drug delivery, potentially revolutionizing OA treatment paradigms. Herein, this review first describes the anatomical structure of OA joints and elucidates the associated intra-articular drug delivery barriers arising from cartilage, synovial membrane and synovial fluid characteristics. Subsequently, this review delves into the corresponding cutting-edge biomaterial-based DDSs design strategies to overcome these barriers, including size modulation, targeted delivery, stimulus-responsive systems, and multifunctional platforms. Finally, a comprehensive discussion about the current limitations and future directions toward the design and development of advanced biomaterial-based intra-articular DDSs was sketched out. This review establishes a systematic barrier-strategy matching paradigm for biomaterial-based DDSs development, providing actionable insights to address this urgent global health burden of OA.