Modelling-informed cell-seeded nerve repair construct designs for treating peripheral nerve injuries.
Modelling-informed cell-seeded nerve repair construct designs for treating peripheral nerve injuries.
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DOI：
10.1371/journal.pcbi.1009142
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发表时间：
2021-07
影响因子：
4.3
通讯作者：
Shipley RJ
中科院分区：
文献类型：
--
作者：
Coy R;Berg M;Phillips JB;Shipley RJ
全世界有数百万人受到周围神经损伤（PNI）的影响，涉及数十亿美元的医疗费用。患者的常见结果包括瘫痪和感觉丧失，通常导致终身疼痛和残疾。工程神经组织（EngNT）正在开发作为目前治疗大间隙PNI的替代方法，这些治疗在许多情况下显示出令人印象深刻的功能恢复。EngNT修复结构由稳定的水凝胶圆柱体组成，由材料鞘包围，以模拟神经组织的特性。该技术还能够在水凝胶中空间接种治疗细胞，以促进神经再生。鉴定导致最大神经再生和功能恢复的机制是EngNT修复结构设计中的核心挑战。单独使用体内实验是昂贵且耗时的，对给定修复结构的性能的潜在机制提供了有限的见解。为了弥合这一差距，我们推导出一个细胞溶质模型，并将其应用到与治疗细胞接种的EngNT修复构建体的情况下，该治疗细胞在低氧条件下产生血管内皮生长因子（VEGF），以促进构建体中的血管化。该模型包括一组耦合的非线性扩散-反应方程，其描述了在移植到神经损伤部位后的前24小时期间进化的细胞群体沿着其与氧和VEGF场的相互作用。该模型使我们能够评估广泛的修复构建体设计（例如细胞接种策略，鞘材料，培养条件），其想法是在短时间内表现良好的设计可以入围体内试验。特别是，我们的研究结果表明，无论考虑何种情况，超过一定密度阈值的细胞接种都是有害的，为未来的神经组织工程开辟了新的途径。数学模型在生物医学科学中越来越受到重视，特别是在外周神经修复中。这些模型可以帮助揭示损伤后神经再生的潜在机制，并为新的修复策略的设计提供信息，同时通过实验和临床数据不断改进。特别是，细胞溶质模型提供了灵活的，计算效率高的框架，使访问时空信息难以达到体内神经修复的情况。在这项工作中，我们推导出这样一个模型，并将其应用于神经损伤部位移植后的工程神经组织修复结构的情况。这种修复结构的一个关键特征是能够产生促进神经再生的信号分子的治疗细胞的空间接种。我们模拟这些细胞的活性，并在24小时后评估一系列神经修复构建体设计的细胞存活和信号分子输出。潜在的假设是，在如此短的时间内表现良好的设计可以入围体内试验，后者是昂贵和耗时的。我们的研究结果表明，无论考虑何种情况，超过一定密度阈值的细胞接种都是有害的，为未来的神经修复结构设计开辟了新的途径。
Millions of people worldwide are affected by peripheral nerve injuries (PNI), involving billions of dollars in healthcare costs. Common outcomes for patients include paralysis and loss of sensation, often leading to lifelong pain and disability. Engineered Neural Tissue (EngNT) is being developed as an alternative to the current treatments for large-gap PNIs that show underwhelming functional recovery in many cases. EngNT repair constructs are composed of a stabilised hydrogel cylinder, surrounded by a sheath of material, to mimic the properties of nerve tissue. The technology also enables the spatial seeding of therapeutic cells in the hydrogel to promote nerve regeneration. The identification of mechanisms leading to maximal nerve regeneration and to functional recovery is a central challenge in the design of EngNT repair constructs. Using in vivo experiments in isolation is costly and time-consuming, offering a limited insight on the mechanisms underlying the performance of a given repair construct. To bridge this gap, we derive a cell-solute model and apply it to the case of EngNT repair constructs seeded with therapeutic cells which produce vascular endothelial growth factor (VEGF) under low oxygen conditions to promote vascularisation in the construct. The model comprises a set of coupled non-linear diffusion-reaction equations describing the evolving cell population along with its interactions with oxygen and VEGF fields during the first 24h after transplant into the nerve injury site. This model allows us to evaluate a wide range of repair construct designs (e.g. cell-seeding strategy, sheath material, culture conditions), the idea being that designs performing well over a short timescale could be shortlisted for in vivo trials. In particular, our results suggest that seeding cells beyond a certain density threshold is detrimental regardless of the situation considered, opening new avenues for future nerve tissue engineering. Mathematical models are increasingly gaining traction in biomedical sciences in general and in peripheral nerve repair in particular. These models can both help to unveil mechanisms underlying nerve regeneration post-injury and inform the design of new repair strategies, while continuously being improved through experiments and clinical data. In particular, cell-solute models provide flexible, computationally-efficient frameworks that enable access to spatio-temporal information difficult to reach in vivo in nerve repair scenarios. In this work, we derive such a model and apply it to the case of Engineered Neural Tissue repair constructs after their transplant into the nerve injury site. One key feature of such repair constructs is the spatial seeding of therapeutic cells capable of producing signalling molecules that promote nerve regeneration. We simulate the activity of such cells and evaluate, after 24h, cell survival and signalling molecule output for a range of nerve repair construct designs. The underlying hypothesis is that designs performing well at such short timescales could be shortlisted for in vivo trials, the latter being costly and time-consuming. Our results suggest that seeding cells beyond a certain density threshold is detrimental regardless of the situation considered, opening new avenues for future nerve repair construct design.
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影响因子：
3.3
作者：
Coy RH;Evans OR;Phillips JB;Shipley RJ
通讯作者：
Shipley RJ
量化工程三维培养模型中空间定义的氧梯度与细胞命运之间的相关性。
DOI：
10.1098/rsif.2014.0501
发表时间：
2014-09-06
期刊：
Journal of the Royal Society, Interface
影响因子：
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作者：
Ardakani AG;Cheema U;Brown RA;Shipley RJ
通讯作者：
Shipley RJ
影响因子：
4.1
作者：
Ezra, Mindy;Bushman, Jared;Kohn, Joachim
通讯作者：
Kohn, Joachim
影响因子：
14
作者：
Chamberlain, LJ;Yannas, IV;Spector, M
通讯作者：
Spector, M
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.