Translational Challenges in Cartilage Regeneration for Knee Osteoarthritis: Bridging Clinical Guidelines and Animal Model Evidence

Knee osteoarthritis (OA) is a whole-joint degenerative disorder in which cartilage loss, subchondral bone remodeling, synovial inflammation, and biomechanical dysfunction restrict durable regenerative repair. This systematic translational review compared current guideline-based management of knee OA and cartilage injuries with preclinical animal-model evidence to define the gap between experimental regeneration and clinically achievable outcomes. Conducted in accordance with PRISMA 2020, the review used OARSI, AAOS, ESSKA, ICRS, and FIFA-Aspetar guidance as human clinical benchmarks and synthesized in vivo studies of OA, post-traumatic OA, and focal chondral or osteochondral defects. Interventions were grouped as cell-based therapies, cell-free biologics, biomaterial scaffolds, and gene/RNA-based approaches; outcomes were classified as symptom modifying, structure modifying, or regenerative. Clinical guidance consistently prioritizes pain relief and function, and no approved therapy has demonstrated durable disease modification or hyaline cartilage regeneration in generalized knee OA. Animal models indicate that mesenchymal stromal cells, platelet-derived products, extracellular vesicles, advanced scaffolds, and gene/mRNA therapies can reduce inflammation, enhance matrix synthesis, and partially restore cartilage and osteochondral structure. Large-animal and spontaneous OA models further show that biomechanical loading and subchondral bone strongly determine repair durability. Nevertheless, restoration of native hyaline cartilage under long-term load remains inconsistent, especially in advanced joint-wide degeneration. True cartilage and osteochondral-unit regeneration is therefore currently most achievable in selected focal defects. Future disease-modifying strategies will likely require integrated biologic, structural, and molecular approaches tested in biomechanically relevant models with long-term, clinically meaningful endpoints.