The osteochondral regeneration paradox: why biomimetic scaffolds are biologically superior but injectable systems dominate the clinic

Abstract

Musculoskeletal disorders (MSDs), particularly articular cartilage injuries and the progression of osteoarthritis (OA), represent a substantial global health burden. Conventional techniques fail to consistently achieve durable regeneration, yielding biomechanically inferior fibrocartilage due to the native tissue's avascularity and complex zonal architecture. This review translates the critical biological, mechanical, and architectural requirements of the osteochondral unit into quantitative design targets and critically evaluates two major regenerative strategies: structurally precise architected biomimetic scaffolds and minimally invasive injectable hydrogels. Our analysis reveals a fundamental trade-off between technical potential and translational feasibility. Architected scaffolds, fabricated using advanced methods like 3D printing and melt electrowriting, demonstrate superior capacity to meet structural demands. They achieve precise zonal stiffness gradients, secure bone anchorage, and immediate high-load-bearing capability necessary for long-term chondrocyte phenotype stabilization and faithful tissue reconstruction. In contrast, injectable hydrogels excel in defect conformability, logistical simplicity, and microenvironmental programming (e.g., controlled growth factor release, viscoelastic tuning), offering a patient-friendly, single-stage delivery. However, clinical success is governed by a persistent paradox: the technical potential of a therapy is inversely related to its regulatory and commercial viability. Scaffold-based constructs, due to their complexity, surgical invasiveness, and customization needs, face severe regulatory hurdles (e.g., ATMP/Class III classification) and high associated costs. Conversely, the batch manufacturability and minimal invasiveness of injectable systems grant them a smoother regulatory path and broader market adoption, despite often resulting in monophasic repair with limited long-term mechanical fidelity. We conclude that the field of osteochondral regeneration is shaped by this structural asymmetry. While scaffolds represent the platforms most capable of delivering faithful structural repair, injectable systems are the primary route by which innovation reaches the patient. Future success depends on either the development of hybrid strategies that reconcile architectural control with surgical simplicity, or the evolution of regulatory frameworks to accommodate the necessary complexity for true tissue regeneration.