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

描述（由申请人提供）：这是母RO 1的竞争性更新申请的重新提交，其主要目标是了解人类小腿三头肌复合体的结构设计特征如何定义其体内功能特性。新型器械和成像技术的发展允许对影响功能的关键解剖特征进行无创体内测量。这些一致地揭示了发生沿着腱膜、肌腱和肌束的不均匀应变以及沿肌肉长度沿着的机械齿轮比的变化。基于这些数据的后续有限元建模清楚地表明，目前的人体神经肌肉在体内功能的模型是不够的。现在很明显，复杂的肌内力学在活动肌肉中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，相对于肌肉体积的损失，力的不成比例的降低，我们假设：（1）一致且可靠的特定张力（力/PCSA）可以通过在多尺度维度上定义肌肉骨骼组织的力学异质性来导出;和（2）在这些肌肉骨骼组织内和之间的这种机械复合体的选定成分的变化显著地导致了在“废用性”萎缩中发生的肌肉力潜力的损失。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，通过单侧肢体悬吊诱导受控萎缩，然后进行康复。一系列高度集成的成像技术将全面表征这些受试者和8例跟腱断裂恢复患者在正常、萎缩和不同恢复阶段的小腿多组分肌肉骨骼（MSK）结构和功能。特定目标（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、腱膜和肌内结缔组织的分布，（C）整个肌肉的肌纤维方向和（D）总MVC。SA-2将定义由于以下原因引起的萎缩引起的变化对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）组件水平和（B）多尺度、多组件系统水平模型将用于预测应变分布、踝关节位移和总关节力。预测的模型的总关节力和其他输出变量的敏感性，从正常和萎缩状态之间的各个阶段所产生的材料特性的变化将与SA-2的实验观察进行比较。根据PA-07-279的指导方针，将采用“多学科综合、系统方法”来理解复杂肌肉结构-功能相互作用的“重要生物学、生物工程问题”。这对于肌肉骨骼疾病患者的定制管理具有广泛的临床潜力，例如慢性肌肉废用、肌肉萎缩症和痉挛。 公共卫生相关性：在本竞争性更新的父R 01中，我们研究了典型肌肉骨骼系统的结构和功能设计特征，这些特征可以解释当前肌肉行为描述中的明显矛盾。本建议调查的可能性，异质性的结构和生理系统可能是主要原因小于传统预期的强制输出从肢体和萎缩后急剧减少。这种对复杂肌肉结构-功能相互作用的基本生理学理解对于患有肌肉骨骼疾病（诸如慢性肌肉废用、肌肉萎缩症和痉挛状态）的受试者的管理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. PUBLIC HEALTH RELEVANCE: In the parent R01 of this Competitive Renewal, we investigated the structural and functional design features of a typical musculoskeletal system that could account for apparent paradoxes in current descriptions of muscle behavior. The present proposal investigates the possibility that heterogeneity in structure and physiology of the system may be the primary reason for less than conventionally expected forced output from the limb and its drastic reduction after atrophy. Such basic physiological understanding of the complex muscle structure-function interactions has far ranging clinical potential for the management of subjects with musculoskeletal disease such chronic muscle disuse, muscular dystrophy and spasticity.