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Adv Drug Deliv Rev. 2018 Dec 31. pii: S0169-409X(18)30319-3. doi: 10.1016/j.addr.2018.12.015. [Epub ahead of print]

Articular fibrocartilage - Why does hyaline cartilage fail to repair?

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AO, Research Institute Davos, 7270 Davos, Platz, Switzerland. Electronic address: angela.armiento@aofoundation.organgela.
AO, Research Institute Davos, 7270 Davos, Platz, Switzerland. Electronic address:
AO, Research Institute Davos, 7270 Davos, Platz, Switzerland. Electronic address:


Once damaged, articular cartilage has a limited potential to repair. Clinically, a repair tissue is formed yet it is often mechanically inferior fibrocartilage. The use of monolayer expanded versus naïve cells may explain one of the biggest discrepancies in mesenchymal stromal cell (MSC) based cartilage regeneration. Namely, studies utilizing monolayer expanded MSCs, as indicated by numerous in vitro studies, report the main limitation as induction of type X collagen and hypertrophy, a phenotype associated with endochondral bone formation. However, marrow stimulation and transfer studies report a mechanically inferior collagen I/ II fibrocartilage as the main outcome. Therefore, this review will highlight the collagen species produced during the different therapeutic approaches. New developments in scaffold design and delivery of therapeutic molecules will be described. Potential future directions towards clinical translation will be discussed. New delivery mechanisms are being developed and they offer new hope in targeted therapeutic delivery. This review aims to: 1. Report the challenges that still need to be addressed to achieve the goal of hyaline cartilage regeneration by focusing on the shortcoming of the repair tissue generated after traumatic injury or biological therapy; 2. Discuss the state of the art in cartilage-targeting therapeutic delivery; and 3. Highlight some of the emerging technologies and strategies that the authors believe to hold great promise.


A disintegrin and metalloproteinase with thrombospondin motifs; AAV; ACI; ADAMTS; ALK; Activin receptor like kinase; Adeno-associated virus; Autologous chondrocyte implantation; BMAC; BMP; Basic fibroblast growth factor; Bone marrow aspirate concentrate; Bone morphogenetic protein; CD; COMP; Cartilage oligomeric matrix protein; Chondrocytes; Cluster of differentiation; Col; Collagen; Cross-linked elastin-like polypeptide; DMOAD; DNA; Deoxyribonucleic acid; Disease modifying OA drug; ECM; EV; Extracellular matrix; Extracellular vesicle; GAG; GDF-5; GMP; Glycosaminoglycan; Good manufacturing practice; Growth differentiation factor-5; HA; HGF; Hepatocyte growth factor; Hyaluronan; IGF-1; IHH; IL; IL-1Ra; Indian hedgehog; Insulin growth factor binding protein-1; Interleukin; Interleukin-1 receptor antagonist; List of abbreviations; MMP; MSCs; MV; Matrix metalloproteinase; Mesenchymal stromal/stem cells; Messenger RNA; MicroRNA; Microvesicle; NK; NO; Natural killer; Nitric oxyde; OA; Osteoarthritis; PBS; PEG; PEMF; PGE2; PLGA; PLGF2; PTHrP; Parathyroid hormone-related protein; Phosphate buffered saline; Placenta growth factor – 2; Poly(lactide-co-glycolide); Poly-ethylene glycol; Prostaglandin E2; Pulsed electromagnetic field; RNA; Ribonucleic acid; SDF-1; SLRPs; Small leucin-rich proteoglycans; Stromal cell derived factor-1; TGF-β; TNF; Transforming growth factor-beta; Tumor necrosis factor; VEGF; Vascular endothelial growth factor; bFGF; cartilage; chondrogenesis; cytokines; differentiation; gene therapy; mRNA; mesenchymal stem cells; miRNA; paracrine; secretome; xELP

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