Royal College of Surgeons in Ireland
Preclinical to clinical translation for intervertebral disc repair.....pdf (5.49 MB)

Preclinical to clinical translation for intervertebral disc repair: effects of species-specific scale, metabolism, and matrix synthesis rates on cell-based regeneration

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posted on 2023-11-01, 17:09 authored by Emily E McDonnell, Niamh Wilson, Marcos N Barcellona, Tara Ní Néill, Jessica Bagnall, Pieter AJ Brama, Gráinne M. Cunniffe, Stacey L Darwish, Joseph S Butler, Conor BuckleyConor Buckley

Background A significant hurdle for potential cell-based therapies is the subsequent survival and regenerative capacity of implanted cells. While many exciting developments have demonstrated promise preclinically, cell-based therapies for intervertebral disc (IVD) degeneration fail to translate equivalent clinical efficacy.

Aims This work aims to ascertain the clinical relevance of both a small and large animal model by experimentally investigating and comparing these animal models to human from the perspective of anatomical scale and their cellular metabolic and regenerative potential.

Materials and Methods First, this work experimentally investigated species-specific geometrical scale, native cell density, nutrient metabolism, and matrix synthesis rates for rat, goat, and human disc cells in a 3D microspheroid configuration. Second, these parameters were employed in silico to elucidate species-specific nutrient microenvironments and predict differences in temporal regeneration between animal models.

Results This work presents in silico models which correlate favorably to preclinical literature in terms of the capabilities of animal regeneration and predict that compromised nutrition is not a significant challenge in small animal discs. On the contrary, it highlights a very fine clinical balance between an adequate cell dose for sufficient repair, through de novo matrix deposition, without exacerbating the human microenvironmental niche.

Discussion Overall, this work aims to provide a path towards understanding the effect of cell injection number on the nutrient microenvironment and the “time to regeneration” between preclinical animal models and the large human IVD. While these findings help to explain failed translation of promising preclinical data and the limited results emerging from clinical trials at present, they also enable the research field and clinicians to manage expectations on cell-based regeneration.

Conclusion Ultimately, this work provides a platform to inform the design of clinical trials, and as computing power and software capabilities increase in the future, it is conceivable that generation of patient-specific models could be used for patient assessment, as well as pre- and intraoperative planning.


European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement ERC-2019-CoG-864104; INTEGRATE)

Open access funding provided by IReL



The original article is available at

Published Citation

McDonnell E. et al. Preclinical to clinical translation for intervertebral disc repair: effects of species-specific scale, metabolism, and matrix synthesis rates on cell-based regeneration. JOR Spine. 2023;6(3):e1279

Publication Date

7 September 2023

PubMed ID



  • Amber (Advanced Material & Bioengineering Research) Centre
  • Anatomy and Regenerative Medicine
  • Tissue Engineering Research Group (TERG)


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  • Published Version (Version of Record)