Mathematical Modelling Led Design of Tissue-Engineered Constructs: A New Paradigm for Peripheral Nerve Repair (NerveDesign)

周围神经损伤使人衰弱，导致感觉和肌肉控制的丧失、慢性疼痛和永久性残疾。除了对患者及其家庭的严重影响外，神经损伤还通过降低生产力（神经损伤主要影响年轻人）以及医疗保健和康复成本来影响社会经济。横断的周围神经在手术修复后具有再生的潜力，但对于>3cm的损伤部位存在严重的限制，因为再生需要支持性微环境。目前最好的选择是从患者身体的另一部分收获的自体神经移植物，但供体部位发病率，有限的可用性和不良结果意味着有一个明确的临床需要开发有效的替代品。组织工程与干细胞技术的进展为工程化活的人工神经替代组织提供了有前途的途径，但进展有限，部分原因是缺乏关于如何在空间中安排材料和细胞以最大限度地促进神经再生的共识。由于时间和成本的限制，实验测试排除了详细的研究，这使得NerveDesign将通过首次将数学建模与最先进的体外和体内实验相结合来解决这一僵局，从而实现神经修复方法的范式转变。NerveDesign将专注于促进血管生长和通过受损神经部位再生神经的化学和物理刺激。将开发数学模型，其中包括发挥作用的关键机制-这些机制将通过精心设计的实验进行量化，在实验室中进行测试。计算机模拟，然后被用来测试不同的潜在周围神经修复结构设计，和领先的竞争者将被制造，然后进行测试。这种多学科的神经修复方法是完全新颖的，并描绘了一个雄心勃勃的方法与人类健康的影响显着的潜力。为了促进临床医生的方法的吸收，NerveDesign将创建和测试一个用户友好的软件工具，使最终用户能够设置根据个人修复要求的结构设计参数。所有的计算模型都将用系统生物学标记语言制定，并在我们的网站上发布（以及示例实验数据集），以鼓励它们在一系列神经组织工程应用中的应用。最后，NerveDesign将与其临床和商业项目合作伙伴合作，直接参与患者群体，并为新修复结构设计的翻译和商业化铺平道路。

Peripheral nerve injury is debilitating, causing loss of sensation and muscle control, chronic pain and permanent disability. In addition to the serious impact on patients and their families, nerve injuries impact society economically through reduced productivity (nerve injuries predominantly affect young people) as well as the cost of healthcare and rehabilitation. Transected peripheral nerves have the potential to regenerate following surgical repair, but there are serious limitations for injury sites >3cm, because regeneration requires a supportive microenvironment. The current best option is a nerve autograft harvested from another part of the patient's body, but donor site morbidity, limited availability and poor outcome mean there is a clear clinical need to develop effective alternatives. Advances in tissue engineering together with stem cell technologies provide promising routes for engineering living artificial nerve replacement tissues, but progress is limited due in part to a lack of consensus on how to arrange materials and cells in space to maximize nerve regeneration. This is compounded by a reliance on experimental testing, which precludes elaborate investigations due to time and cost limitations.NerveDesign will address this log-jam, by combining mathematical modelling with state-of-the-art in vitro and in vivo experimentation for the first time, to bring about a paradigm shift in the approach used for neural repair. NerveDesign will focus on the chemical and physical stimuli that promote growth of blood vessels and regenerating nerves through a damaged nerve site. Mathematical models will be developed that incorporate the key mechanisms at play - these mechanisms will be quantified through carefully designed experiments that test them in the laboratory. Computer simulations with then be used to test different potential peripheral nerve repair construct designs, and the leading contenders will be fabricated and then tested. This multidisciplinary approach to nerve repair is entirely novel, and delineates an ambitious approach with significant potential for human health impact.To facilitate the uptake of the approach by clinicians, NerveDesign will create and test a user-friendly software tool that enables end users to set construct design parameters according to individual repair requirements. All computational models will be formulated in Systems Biology Mark-Up Language, and published on our websites (alongside an example experimental dataset) to encourage their uptake in a range of nerve tissue engineering applications. Finally, NerveDesign will work with its clinical and commercial Project Partners to directly engage patient groups, and pave the way for translation and commercialisation of the new repair constructs designs.