Frontier Engineering: Progression Grant in Modelling complex and partially identified engineering problems. Application to the musculoskeletal system.

传统的工程学忽视了几个时空尺度上的复杂相互作用，这不符合生物系统建模的背景，因为生物系统的尺度重叠，多尺度相互作用的内在复杂性无法避免。为此，在之前资助的MultiSim项目中，我们建立了一个研究肌肉骨骼疾病的计算平台，并成功地将其应用于预测骨质疏松和骨量减少女性的骨折风险，以及在动物模型中进行骨重建的临床前研究，以评估新治疗方法的效果。然而，这一平台的充分利用受到这样一个事实的限制，即大多数MultiSim活动仅围绕骨骼健康发展。MultiSim2将使我们能够扩大我们中心的重点，包括同样健壮和详细的骨骼肌模型，以预测诸如骨骼肌减少或神经退行性疾病等病理学的影响。为此，我们将开发新的方法，以更好地对肌肉及其与骨骼系统的相互作用进行成像、表征和建模。在我们的小鼠工作中，我们将专注于开发非侵入性纵向成像技术和计算模型，以支持减少和部分替代小鼠在肌肉骨骼研究中的使用。我们将使用微磁共振成像(MicroMRI)系统和先进的图像处理技术来测量肌肉特性的纵向变化，以预测组织随时间的变化。这些测量将被集成到现有工具的框架中，以利用活体微型计算机断层扫描(MicroCT)获得高分辨率的骨特性，并在空间和时间上共同登记所有获得的数据。我们将使用我们的人体模型来预测肌肉体积和质量的生理和病理变化，肌肉纤维的变化，肌腱的几何和弹性特性，以及与神经运动控制中的退化相关的变化。对患者和动物不同肌肉骨骼组织(骨骼、肌肉、肌腱)随时间的变化进行全面评估，将使我们能够创建一个实验和计算相结合的框架，以更好地了解疾病的影响并对其进行建模，并优化未来的治疗。

Traditional engineering ignores complex interactions across several space-time scales, which does not fit the context of modelling of biological systems where scales overlap and the inherent complexity of multi-scale interaction cannot be avoided. For this reason, in the previously funded MultiSim project, we established a computational platform for the investigation of musculoskeletal disorders, which we successfully applied to the prediction of the risk of fracture in osteoporotic and osteopenic women, and to the pre-clinical investigation of bone remodelling in animal models to assess the effect of new treatments. Full exploitation of this platform, however, is limited by the fact that most of the MultiSim activities evolved around skeletal health only. MultiSim2 will allow us to expand the focus of our Centre to include an equivalently robust and detailed modelling of the skeletal muscles to predict the effects of pathologies such as sarcopenia or neurodegenerative diseases. To do so, we will develop new approaches for better imaging, characterisation and modelling of the muscles and of their interaction with the skeletal system. In our murine work, we will focus on developing noninvasive longitudinal imaging techniques and computational models to support the reduction and partial replacement of the use of mice in musculoskeletal research. We will measure longitudinal changes in muscle properties by using a micro-magnetic resonance imaging (microMRI) system and advanced image processing to predict tissue changes over time. These measurements will be integrated to a framework of available tools to obtain bone properties at high resolution with in vivo micro-Computed Tomography (microCT) and to co-register all the acquired data in space and time. We will use our human models to predict physiological and pathological changes of muscle volumes and masses, variations in muscle fibres, tendon geometric and elastic properties and changes associated with degeneration in the neuromotor control. The comprehensive assessment of changes in different musculoskeletal tissues (bone, muscles, tendons) over time in both patients and animals will allow us to create a combined experimental and computational framework to better understand and model the effect of diseases and to optimise future treatments.