In Vivo Imaging-Based Multiscale Modeling of Normal and Atrophied Human Lower Leg

描述（由申请人提供）：这是母RO1的竞争性更新申请的再提交，其主要目标是了解人类三头肌肌复合体的结构设计特征如何定义其体内功能特性。新型设备和成像技术的发展使得对影响功能的关键解剖特征进行无创体内测量成为可能。这些结果一致地揭示了沿腱膜、肌腱和肌束发生的异质应变以及沿肌肉长度机械齿轮比的变化。随后基于这些数据的有限元建模清楚地表明，目前的人类神经肌肉在体内功能模型是不充分的。现在很明显，复杂的肌内力学在活动肌肉产生的肌肉力量中起着关键作用。为了解释在萎缩和类似病理的临床病例中相对于肌肉体积损失的不成比例的力下降，我们假设：(1)通过定义肌肉骨骼组织在多尺度上的机械异质性，可以推导出一致和可靠的人体骨骼肌的比张力（每PCSA的力）；(2)在这些肌肉骨骼组织内部和之间，这种机械复合体的选定成分的变化显著地导致了“废用”萎缩中肌肉力量潜力的丧失。将对30名正常受试者进行成像，从中选择12名肌肉形状范围最广的受试者进行单侧肢体悬吊诱导控制萎缩，然后进行康复治疗。高度集成的成像技术阵列将全面表征这些受试者在正常，萎缩和不同恢复阶段的小腿多成分肌肉骨骼（MSK）结构和功能，以及8例从跟腱断裂恢复的患者。Specific Aim (SA)-1将测量MSK参数：(A)肌肉复合体的3D体积渲染图像，(B)肌腱、腱膜和肌肉内结缔组织的分布，(C)整个肌肉的肌纤维方向，(D)总MVC。SA-2将定义由于萎缩引起的变化导致的扭矩损失的相对贡献：(A)肌肉变形，(B)肌纤维应变，(C)腱膜应变和剪切，(D)肌腱偏移和(E)跟骨位移。（SA-3）受试者特定图像驱动的无网格(A)组件级和(B)多尺度、多组件系统级模型将用于预测应变分布、踝关节位移和关节总力。模型预测的总联合力和其他输出变量对正常状态和萎缩状态之间不同阶段产生的材料性能变化的敏感性将与SA-2的实验观察结果进行比较。遵循PA-07-279的指导方针，将应用“多学科综合系统方法”来“理解（重要的）生物、生物工程问题”，即复杂的肌肉结构-功能相互作用。这在针对慢性肌肉失用、肌肉萎缩和痉挛等肌肉骨骼疾病患者的量身定制管理方面具有广泛的临床潜力。

DESCRIPTION (provided by applicant): This is the resubmission of a Competitive Renewal application of a parent RO1 whose primary goal was to understand how the structural design features of the human Triceps Surae Complex define its functional properties in vivo. Development of novel devices and imaging techniques allowed non-invasive in-vivo measurement of critical anatomical features that affect function. These consistently revealed heterogeneous strain occurring along the aponeurosis, tendon and muscle fascicles and variation of mechanical gear ratio along the length of the muscle. Subsequent finite element modeling based on these data clearly demonstrated that current models of human neuromuscular in vivo function are inadequate. It is now evident that complex intramuscular mechanics play a critical role in the muscle forces generated in active muscles. To explain the disproportionate decrease in force relative to loss of muscle volume in clinical cases of atrophy and similar pathologies, we hypothesize that: (1) A consistent and reliable specific tension (force per PCSA) of human skeletal muscle can be derived by defining the mechanical heterogeneity of musculoskeletal tissues over multi-scale dimensions; and (2) Changes in selected components of this mechanical complex within and among these musculoskeletal tissues contribute significantly to the loss of muscle force potential as occurs in "disuse" atrophy. 30 normal subjects will be imaged from which 12 with the broadest range of muscle shapes will be chosen for inducement of controlled atrophy by Unilateral Limb Suspension followed by rehabilitation. A highly integrated array of imaging techniques will characterize comprehensively, the multi- component musculoskeletal (MSK) architecture and function of the lower leg, in normal, atrophied and at various stages of recuperation in these subjects and in 8 patients recovering from Achilles Tendon Rupture. Specific Aim (SA)-1 will measure the MSK parameters: (A) 3D volume rendered images of the muscle complex, (B) Distribution of tendon, aponeurosis and intra-muscular connective tissues, (C) Muscle fiber orientation throughout the muscles and (D) total MVC. SA-2 will define the relative contribution to losses of torque due to atrophy-induced changes from: (A) Muscle deformation, (B) Muscle fiber strain, (C) Aponeurosis strain and shear, (D) Tendon excursion and, (E) Calcaneus displacement. (SA-3) Subject-specific image-driven mesh-free (A) Component Level, and (B) Multi- scale, multi-component Systems Level models will be used to predict strain distribution, ankle joint displacement and total joint force. Predictions of the model as to the sensitivity of the total joint force and other output variables to changes in material properties arising from various stages between normal and atrophied states will be compared with the experimental observations in SA-2. Following the guidelines of PA-07-279, a "multi-disciplinary integrative, systems approach" will be applied "to understand (the) important biological, bioengineering problem" of the complex muscle structure-function interactions. This has far ranging clinical potential for tailored management of patients with musculoskeletal disease such as chronic muscle disuse, muscular dystrophy and spasticity.