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

IF 3.4 3区 医学 Q1 ORTHOPEDICS JOR Spine Pub Date : 2023-09-07 DOI:10.1002/jsp2.1279
Emily E. McDonnell, Niamh Wilson, Marcos N. Barcellona, Tara Ní Néill, Jessica Bagnall, Pieter A. J. Brama, Gráinne M. Cunniffe, Stacey L. Darwish, Joseph S. Butler, Conor T. Buckley
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引用次数: 1

Abstract

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.

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椎间盘修复的临床前转化:物种特异性规模、代谢和基质合成率对细胞再生的影响。
背景:潜在的细胞治疗的一个重要障碍是植入细胞的后续存活和再生能力。尽管许多令人兴奋的进展已经在临床前证明了前景,但基于细胞的椎间盘退变治疗未能转化为同等的临床疗效。目的:这项工作旨在从解剖规模及其细胞代谢和再生潜力的角度,通过实验研究和比较小型和大型动物模型与人类的临床相关性。材料和方法:首先,这项工作实验研究了大鼠、山羊和人类椎间盘细胞在三维微信息素配置中的物种特异性几何尺度、天然细胞密度、营养代谢和基质合成率。其次,这些参数在计算机中用于阐明物种特异性营养微环境,并预测动物模型之间时间再生的差异。结果:这项工作提出了在动物再生能力方面与临床前文献有良好相关性的计算机模型,并预测营养受损在小动物椎间盘中不是一个重大挑战。相反,它强调了在不加剧人类微环境生态位的情况下,通过从头开始的基质沉积进行足够修复的足够细胞剂量之间的非常好的临床平衡。讨论:总的来说,这项工作旨在为理解细胞注射次数对营养微环境的影响以及临床前动物模型和大型人类IVD之间的“再生时间”提供一条途径。虽然这些发现有助于解释有希望的临床前数据的翻译失败以及目前临床试验产生的有限结果,但它们也使研究领域和临床医生能够管理对基于细胞再生的期望。结论:最终,这项工作为临床试验的设计提供了一个平台,随着未来计算能力和软件能力的提高,可以想象,生成特定于患者的模型可以用于患者评估以及术前和术中规划。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
JOR Spine
JOR Spine ORTHOPEDICS-
CiteScore
6.40
自引率
18.90%
发文量
42
审稿时长
10 weeks
期刊最新文献
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