Naturally derived injectable hydrogels with ROS-scavenging property to protect transplanted stem cell bioactivity for osteoarthritic cartilage repair

Chondrocytes are responsible for the maintenance of the articular cartilage. A loss of homeostasis in cartilage contributes to the development of osteoarthritis (OA) when the synthetic capacity of chondrocytes is overwhelmed by processes that promote matrix degradation. There is evidence for an age-related imbalance in reactive oxygen species (ROS) production relative to the anti-oxidant capacity of chondrocytes that plays a role in cartilage degradation as well as chondrocyte cell death. The ROS produced by chondrocytes that have received the most attention include superoxide, hydrogen peroxide, the reactive nitrogen species nitric oxide, and the nitric oxide derived product peroxynitrite. Excess levels of these ROS not only cause oxidative-damage but, perhaps more importantly, cause a disruption in cell signaling pathways that are redox-regulated, including Akt and MAP kinase signaling. Age-related mitochondrial dysfunction and reduced activity of the mitochondrial superoxide dismutase (SOD2) are associated with an increase in mitochondrial-derived ROS and are in part responsible for the increase in chondrocyte ROS with age. Peroxiredoxins (Prxs) are a key family of peroxidases responsible for removal of H2O2, as well as for regulating redox-signaling events. Prxs are inactivated by hyperoxidation. An age-related increase in chondrocyte Prx hyperoxidation and an increase in OA cartilage has been noted. The finding in mice that deletion of SOD2 or the anti-oxidant gene transcriptional regulator nuclear factor-erythroid 2- related factor (Nrf2) result in more severe OA, while overexpression or treatment with mitochondrial targeted anti-oxidants reduces OA, further support a role for excessive ROS in the pathogenesis of OA. Therefore, new therapeutic strategies targeting specific anti-oxidant systems including mitochondrial ROS may be of value in reducing the progression of age-related OA.

Osteoarthritis (OA), a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden that increases greatly as populations age. Yet no approved pharmacological intervention, biologic therapy or procedure prevents the progressive destruction of the OA joint. Mesenchymal stem cells (MSCs)-multipotent precursors of connective tissue cells that can be isolated from many adult tissues, including those of the diarthrodial joint-have emerged as a potential therapy. Endogenous MSCs contribute to maintenance of healthy tissues by acting as reservoirs of repair cells or as immunomodulatory sentinels to reduce inflammation. The onset of degenerative changes in the joint is associated with aberrant activity or depletion of these cell reservoirs, leading to loss of chondrogenic potential and preponderance of a fibrogenic phenotype. Local delivery of ex vivo cultures of MSCs has produced promising outcomes in preclinical models of joint disease. Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus, paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation. Several early-stage clinical trials, initiated or underway in 2013, are testing the delivery of MSCs as an intra-articular injection into the knee, but optimal dose and vehicle are yet to be established.