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丧失，慢性疼痛和永久性残疾。神经损伤除了对患者及其家属造成严重影响外，还通过降低生产力（神经损伤主要影响年轻人）以及增加医疗保健和康复费用对社会造成经济影响。切除的周围神经有可能在手术修复后再生，但对于损伤部位bb0 3cm存在严重限制，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获取自体神经移植物，但供体部位的发病率、有限的可用性和不良的结果意味着临床显然需要开发有效的替代方法。组织工程和干细胞技术的进步为工程人工神经替代组织提供了有希望的途径，但进展有限，部分原因是缺乏对如何在空间中安排材料和细胞以最大化神经再生的共识。由于时间和成本的限制，对实验测试的依赖使这种情况更加复杂。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，解决这一瓶颈问题，为神经修复方法带来范式转变。NerveDesign将专注于化学和物理刺激，促进血管的生长，并通过受损的神经部位再生神经。将开发包含起作用的关键机制的数学模型-这些机制将通过精心设计的实验在实验室中进行量化测试。利用计算机模拟测试了不同的潜在周围神经修复结构设计，并制造出领先的候选结构进行测试。这种神经修复的多学科方法是完全新颖的，并描绘了一种雄心勃勃的方法，对人类健康有重大影响。为了便于临床医生采用该方法，NerveDesign将创建并测试一个用户友好的软件工具，使最终用户能够根据个人修复要求设置结构设计参数。所有的计算模型都将用系统生物学标记语言进行表述，并在我们的网站上发布（与一个示例实验数据集一起），以鼓励它们在一系列神经组织工程应用中得到应用。最后，NerveDesign将与其临床和商业项目合作伙伴直接接触患者群体，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.