Assessing the clinical relevance of pre-clinical models through investigating their nutrient microenvironment and regeneration capacity

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ICE Krakow

ICE Krakow

ul. Marii Konopnickiej 17 30-302 Kraków


Mc Donnell, Emily (Trinity College Dublin)


"Despite exciting advances in regenerative medicine, cell-based strategies for treating degenerative disc disease remain in their infancy. After demonstrating safety and efficacy in animal studies, many of these therapies enter a critical period between preclinical validation and clinical evaluation, where they do not appear to work to the same extent in humans. It is commonly believed that the harsh nutrient microenvironment and “hostile” nature of the degenerating intervertebral disc is linked to high failure of prospective studies [1]–[3]. Therefore, in this work we aim to investigate the species-specific nutrient microenvironment and regenerative capacity of two commonly used animal models in attempts to ascertain their scientific merit for successful clinical translation.

In-silico models have been developed using COMSOL Multiphysics to predict the local nutrient microenvironment of a small rat tail and large goat lumbar pre-clinical model, using methods published previously [4]. These models are reinforced by experimentally determined input parameters such as species-specific metabolically active cell densities, geometries, and rates of metabolism. An active cell density is determined by using MTT and DAPI counterstain. Metabolic rates are determined for disc cells in a 3-D spheroid culturing using seahorse flux analyser. In addition to the nutrient microenvironment, we developed a GAG regeneration models for rat and goat, as seen previously for human [5], [6], using experimentally determined species-specific GAG synthesis rates.

This study provides a guide for designing pre-clinical animal models through understanding differing nutrient microenvironments within intervertebral discs of different size scale. By comparing these animal models to the degenerated human condition, we can demonstrate the predicted rate of regeneration and the period needed for significant extracellular matrix repair, to assess the efficacy of rat and goat studies for successful clinical translation of cell-based therapies.

[1] D. Sakai and G. B. J. Andersson, “Stem cell therapy for intervertebral disc regeneration: Obstacles and solutions,” Nat. Rev. Rheumatol., vol. 11, no. 4, pp. 243–256, 2015.
[2] L. J. Smith et al., “Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section,” JOR Spine, no. July, p. e1036, 2018.
[3] N. Farhang, L. I. Silverman, and R. D. Bowles, “Improving Cell Therapy Survival and Anabolism in Harsh Musculoskeletal Disease Environments,” Tissue Engineering - Part B: Reviews, vol. 26, no. 4. pp. 348–366, 2020.
[4] E. E. McDonnell and C. T. Buckley, “Investigating the physiological relevance of ex vivo disc organ culture nutrient microenvironments using in silico modeling and experimental validation,” JOR Spine, 2021.
[5] Q. Zhu, X. Gao, H. T. Temple, M. D. Brown, and W. Y. Gu, “Simulation of Biological Therapies for Degenerated Intervertebral Discs,” J. Orthop. Res., vol. 34, no. 4, pp. 699–708, 2016.
[6] W. Y. Gu, Q. Zhu, X. Gao, and M. D. Brown, “Simulation of the Progression of Intervertebral Disc Degeneration Due to Decreased Nutritional Supply,” Spine (Phila. Pa. 1976)., vol. 39, no. 24, pp. 1411-1417;, 2014."

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