Low back pain is a widespread disorder that creates much patient suffering and exerts a tremendous economic burden on society. While this condition is multifactorial, intervertebral disc degeneration is one of its main causes. Degeneration starts in the compressible core of the intervertebral disc (i.e. the nucleus pulposus, NP). It is characterized by the inability of the resident cells to keep the NP tissue intact due to a change of their phenotype and their decreasing number. Actual treatments are only symptomatic (aimed at alleviating pain) and new therapies able to reverse the degenerative process are crucially needed. Thus, delivery of exogenous cells, such as mesenchymal stem cells (MSCs), has been proposed to help to NP repair. These cells, however, had only a limited success, with disc degeneration inhibited but not reversed. Because of its avascular nature, the intervertebral disc relies solely on diffusion for its nutrient supply. As a result, NP cells are physiologically exposed to hypoxia, nutrient deprivation and low pH. As degeneration progresses some of these environmental factors worsen. This challenging environment may explain the loss of function of NP cells as well as the sub-optimal results obtained with MSCs. In fact, some studies already begun to look at the effects of low oxygen and glucose levels on NP cells and MSCs and they showed that glucose, rather than oxygen, was critical for cell survival. Providing an adequate glucose supply to a degenerated disc can, therefore, help to promote tissue repair by resident NP cells as well as by exogenous MSCs. The SLiGRIv project proposes to improve native NP cell and exogenous MSC survival and functions in degenerative discs by its improving glucose supply with injectable glucose delivery systems. The first step of the project (WP1) will test two strategies to increase local concentration of glucose either by enzymatic degradation of a glucose polymer or by glucose diffusion from hydrogels with increased viscosity. Hydrogel compositions will be optimized for a sustain delivery of physiological doses of glucose. Hydrogels will also be tested for their injecting properties and for their effects on disc mechanical properties. In the second step of the project (WP2), the optimized hydrogels will be tested on human degenerated NP samples, using an explant culture system. Their effects on NP cell viability and phenotype and NP matrix turn-over will be evaluated. The third step of the project (WP3) will, then, evaluate the potential benefit of combining the optimized hydrogels with exogenous MSCs to promote NP repair using the same NP explant system and same analysis methods than in WP2. If adding MSCs improves NP repair, WP3 will also try to elucidate the mechanisms beyond this effect (i.e. via MSC differentiation or via MSC paracrine effects). Finally, the last step of the project (WP4) will provide the in vivo proof-of-concept that glucose delivery can promote NP repair, with or without the addition of exogenous MSCs, in an animal model of disc degeneration. The ability of the proposed therapy to restore disc height, hydration and mechanical properties will be assessed. The SLiGRIv project will provide an innovative strategy to overcome hurdles encountered by regenerative therapies for the intervertebral disc degeneration.