Addressing translational barriers in intra-articular drug delivery for cartilage regeneration

Despite growing interest in regenerative therapies for osteoarthritis (OA), clinical translation remains limited by biological and biophysical barriers that restrict target engagement within human cartilage. The recent identification of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition as a strategy for restoring cartilage regeneration in experimental OA has renewed interest in regenerative disease-modifying osteoarthritis drugs (DMOADs), yet overcoming translational barriers likely requires looking beyond molecular-target engagement alone. This Review proposes that responsiveness to 15-PGDH inhibition depends on a biologically defined, cartilage-competent ("index-responder") phenotype-one retaining regenerative plasticity despite structural disease progression. It further advances the hypothesis that 15-PGDH activity is enriched in deep cartilage, creating a depth-dependent enzymatic barrier to target accessibility. Integrating current knowledge of cartilage biology, intra-articular (IA) drug transport, and joint mechanobiology, this study examines the multiscale transport processes governing therapeutic exposure, including synovial clearance, interfacial mass-transfer resistance, matrix diffusion, and depth-dependent target engagement. Collectively, these processes are proposed to generate a clearance-diffusion mismatch in which rapid IA elimination outpaces penetration into cartilage, potentially resulting in incomplete inhibition of deep-zone targets despite apparently adequate joint exposure. To address this challenge, a spatiotemporal pharmacomechanical framework is introduced in which regenerative therapy is conceptually segmented into preconditioning, delivery, and retention/remodeling phases. Within this framework, joint biomechanics act as active determinants of drug transport, target engagement, and signaling persistence rather than passive background variables. The central hypothesis is that successful cartilage regeneration depends on the coordinated alignment of molecular mechanisms, transport dynamics, spatial target accessibility, and biomechanical state. Together, these concepts provide experimentally testable predictions and a translational roadmap for the development of regenerative OA therapies.