Hyaluronan-based hydrogel delivering glucose to mesenchymal stem cells intended to treat osteoarthritis

[Display omitted] Mesenchymal stem cell (MSC) therapy shows promise in regenerative medicine. For osteoarthritis (OA), MSCs delivered to the joint have a temporal window in which they can secrete growth factors and extracellular matrix molecules, contributing to cartilage regeneration and cell proliferation. However, upon injection in the non-vascularized joint, MSCs lacking energy supply, starve and die too quickly to efficiently deliver enough of these factors. To feed injected MSCs, we developed a hyaluronic acid (HA) derivative, where glucose is covalently bound to hyaluronic acid. To achieve this, the glucose moiety in 4-aminophenyl-β-D-glucopyranoside was linked to the HA backbone through amidation. The hydrogel was able to deliver glucose in a controlled manner using a trigger system based on hydrolysis catalyzed by endogenous ß-glucosidase. This led to glucose release from the hyaluronic acid backbone inside the cell. Indeed, our hydrogel proved to rescue starvation and cell mortality in a glucose-free medium. Our approach of adding a nutrient to the polymer backbone in hydrogels opens new avenues to deliver stem cells in poorly vascularized, nutrient-deficient environments, such as osteoarthritic joints, and for other regenerative therapies.