Mathematical Modelling to Define a New Design Rationale for Tissue-Engineered Peripheral Nerve Repair Constructs

周围神经损伤是由创伤、手术或反复压迫引起的，其影响范围从严重(导致重大功能丧失或顽固性神经病理性疼痛)到轻度(一些感觉和/或运动障碍影响生活质量)。目前临床上修复神经缺损区3 cm的最佳方法是用患者的移植物修复损伤部位，但这需要额外的时间、费用和对健康神经的损伤，供体神经的数量有限，主要损伤的功能恢复只有50%左右。出于这些原因，研究集中在开发人工神经导管来替代移植物，但到目前为止，可用于临床的人工神经导管只能弥补较短的缺口(&lt；3厘米)，并且不包含移植物中发现的活细胞。干细胞技术为设计活的人工神经替代组织提供了治疗细胞的来源，但进展有限，部分原因是对于工程组织中细胞的空间排列与植入后的生存结果之间的微妙相互作用缺乏共识。细胞需要一个关键的氧气浓度来维持它们的功能；在缺氧的情况下，细胞产生化学信号(生长因子)来促进血液网络进入组织的生长，这是修复过程的重要组成部分。更密集的细胞群体将诱导更多的氧气剥夺和相关的生长因子，具有更高的生成血液供应的潜力；然而，氧气剥夺的增加也可能导致细胞死亡，因此是次优结构。纯粹从实验上解决这种敏感的平衡需要不切实际、代价高昂、在伦理上有问题的动物实验；这项提议的目的是建立一个关于氧合、细胞活性和血液供应增长之间的紧张关系的数学模型，为在神经修复管道内分布细胞和材料提供合理的设计基础。上述目标将通过精心设计的数学模型和实验相结合来实现。数学工作将由受雇的PDRA完成，而UCL机械工程将资助一名博士生进行实验工作。例如，数学模型将跟踪不同细胞群体的密度，以及神经修复结构中氧气和相关生长因子的浓度场。必须量化关键的生物学关系，这些模型才能具有预测能力；例如，细胞群体的摄氧率，以及由此产生的细胞增殖率。建模和实验之间的相互作用是该提案的一个关键特征。信息的流动是一个双向的过程：数学模型将利用实验得出的数据，但也将通过突出将产生最有意义数据的实验以及通过预测待测试的细胞分布和化学/物理梯度来为实验工作提供信息。由此产生的实验参数数学模型将预测氧合作用、细胞活力和血管生长之间的敏感相互作用，提供对生物学的重要洞察，这是在孤立的实验方法下不可能实现的。该数学模型将告知结构中细胞和材料的空间分布，从而促进细胞存活和血管供应的生长。这些结构设计将为未来产生新的修复设备提供一个平台，开发的建模-实验框架将成熟应用于细胞治疗领域的一系列修复场景。

Peripheral nerve injuries result from traumatic injury, surgery or repetitive compression, and their impact ranges from severe (leading to major loss of function or intractable neuropathic pain) to mild (some sensory and/or motor deficits affecting quality of life). The current clinical best practice for nerve gaps > 3 cm is to bridge the site of injury with a graft taken from the patient; however, this involves additional time, cost and damage to a healthy nerve, the amount of donor nerve is limited, and functional recovery of the main injury only occurs in ~50% of cases. For these reasons, research has focused on developing artificial nerve conduits to replace grafts, but to-date those available for clinical use can only bridge short (<3 cm) gaps and don't contain the living cells found in grafts. Stem cell technology provides a source of therapeutic cells for engineering living artificial nerve replacement tissue, but progress is limited due in part to a lack of consensus on the subtle interplay between the spatial arrangement of cells in engineered tissue and their survival outcome when implanted. Cells require a critical oxygen concentration to retain their function; under oxygen-deprivation, cells produce chemical cues (growth factors) to promote the growth of a blood network into the tissue, and this is an essential component of the repair process. A denser population of cells will induce greater oxygen deprivation and associated growth factors with higher potential to generate a blood supply; however, the increase in oxygen deprivation may also induce cell death, and therefore a sub-optimal construct. Resolving this sensitive balance purely experimentally would require an unrealistic, costly and ethically-questionable level of animal experimentation; the aim of this proposal is to develop a mathematical model of the tension between oxygenation, cell viability and growth of a blood supply, providing a rational design base for distributing cells and materials within nerve repair conduits. The above aim will be achieved through a carefully designed combination of mathematical modelling and experimentation. The mathematical work will be performed by the hired PDRA, whilst UCL Mechanical Engineering will fund a PhD student to perform the experimental work. The mathematical models will track, for example, the density of different cell populations, and the concentration field of oxygen and related growth factors in a nerve repair construct. Key biological relationships must be quantified for these models to have predictive capabilities; examples include the rate of oxygen uptake by a cell population, and the resulting proliferation rate of the cells. The interplay between modelling and experiment is a key feature of the proposal. The flow of information is a two-way process: the mathematical models will utilise experimentally-derived data, but will also inform the experimental work by highlighting the experiments that will produce the most meaningful data, and by predicting the cell distributions and chemical/ physical gradients to be tested. The resulting experimentally-parameterised mathematical model will predict the sensitive interplay between oxygenation, cellular viability and blood vessel growth, providing significant insight into the biology that would not be possible using an experimental approach in isolation. The mathematical model will inform spatial distributions of cells and materials in a construct, that promote cell survival and growth of a vascular supply. These construct designs will provide a platform to underpin generation of new repair devices in the future, and the modelling-experimental framework developed will be ripe for application to a host of repair scenarios in the cell therapy field.