Chondroitin sulfate immobilized on a biomimetic scaffold modulates inflammation while driving chondrogenesis

Costs associated with degenerative inflammatory conditions of articular cartilage are exponentially increasing in the aging population, and evidence shows a strong clinical need for innovative therapies. Stem cell-based therapies represent a promising strategy for the treatment of innumerable diseases. Their regenerative potential is undeniable, and it has been widely exploited in many tissue-engineering approaches, especially for bone and cartilage repair. Their immune-modulatory capacities in particular make stemcell-based therapeutics an attractive option for treating inflammatory diseases.However, because of their great plasticity, mesenchymal stem cells (MSCs) are susceptible to different external factors. Biomaterials capable of concurrently providing physical support to cells while acting as synthetic extracellular matrix have been established as a valuable strategy in cartilage repair. Here we propose a chondroitin sulfate-based biomimetic scaffold that recapitulates the physicochemical features of the chondrogenic niche and retains MSC immunosuppressive potential in vitro, either in response to a proinflammatory cytokineor in thepresenceof stimulatedperipheralbloodmononuclear cells. Inboth cases, a significant increase in the production ofmolecules associated with immunosuppression (nitric oxide and prostaglandins), as well as in the expression of their inducible enzymes (iNos, Pges, Cox-2, and Tgf-b). When implanted subcutaneously in rats, our scaffold revealed a reduced infiltration of leukocytes at 24 hours, which correlated with a greater upregulation of genes involved in inflammatory cell apoptotic processes. In supportof its effectiveuse in tissue-engineeringapplications of cartilagerepair, thepotential of the proposed platform to drive chondrogenic and osteogenic differentiation of MSC was also proven.