Consolidating and re-evaluating the human disc nutrient microenvironment

Abstract

Background: Despite exciting advances in regenerative medicine, cell-based strategies for treating degenerative disc disease remain in their infancy. To maximize the potential for successful clinical translation, a more thorough understanding of the in vivo microenvironment is needed to better determine and predict how cell therapies will respond when administered in vivo. Aims: This work aims to reflect on the in vivo nutrient microenvironment of the degenerating IVD through consolidating what has already been measured together with investigative in silico models. Materials and methods: This work uses in silico modeling, underpinned by more recent experimentally determined parameters of degeneration and nutrient transport from the literature, to re-evaluate the current knowledge in terms of grade-specific stages of degeneration. Results: Through modeling only the metabolically active cell population, this work predicts slightly higher glucose concentrations compared to previous in silico models, while the predicted results show good agreement with previous intradiscal pH and oxygen measurements. Increasing calcification with degeneration limits nutrient transport into the IVD and initiates a build-up of acidity; however, its effect is compensated somewhat by a reduction in diffusional distance due to decreasing disc height. Discussion: This work advances in silico modeling through a strong foundation of experimentally determined grade-specific input parameters. Taken together, pre-existing measurements and predicted results suggest that metabolite concentrations may not be as critically low as commonly believed, with calcification not appearing to have a detrimental effect at stages of degeneration when cell therapies are an appropriate intervention. Conclusion: Overall, our initiative is to provoke greater deliberation and consideration of the nutrient microenvironment when performing in vitro cell culture and cell therapy development. This work highlights urgency for robust experimental glucose measurements in healthy and degenerating IVDs, not only to validate in silico models but to significantly advance the field in fully elucidating the nutrient microenvironment and refining in vitro techniques to accelerate clinical translation.