Overcoming Intra-Articular Delivery Barriers in Cartilage Regeneration: Emerging Controlled-Release Strategies

Abstract

Articular cartilage has a limited capacity for self-repair due to its avascular nature, dense extracellular matrix, and low cellularity. Current treatments for cartilage injury and osteoarthritis (OA) often provide temporary symptom relief but do not restore native tissue structure or function. Intra-articular (IA) administration enables localized delivery of therapeutic agents; however, its effectiveness is limited by rapid clearance from the joint, poor cartilage penetration, and insufficient tissue retention. Controlled-release systems, including scaffolds, hydrogels, nanoparticles, and stimuli-responsive platforms, have been developed to address these barriers by prolonging local therapeutic exposure and enabling sustained or targeted delivery. Preclinical studies have demonstrated the potential of these systems to reduce inflammation and support cartilage protection and repair. However, clinical evidence remains limited, and further studies are required to determine whether these delivery advantages translate into sustained disease-modifying or regenerative outcomes in patients. This review discusses the biological barriers that limit effective IA delivery and summarizes recent advances in controlled-release strategies, with particular attention to their ability to improve joint retention, cartilage penetration, and sustained therapeutic exposure. The advantages and limitations of the different delivery platforms are critically discussed, together with the translational challenges that currently limit their progression from preclinical studies to clinical application.