Articular fibrocartilage - Why does hyaline cartilage fail to repair?

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.