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

描述(由申请人提供)：这是一个父RO1的竞争性续展申请的重新提交，其主要目标是了解人类三头肌复合体的结构设计特征如何定义其在体内的功能特性。新设备和成像技术的发展使影响功能的关键解剖特征的非侵入性体内测量成为可能。这些图像始终显示出沿腱膜、肌腱和肌束发生的不均一应变，以及机械齿轮比沿肌肉长度的变化。随后基于这些数据的有限元建模清楚地表明，目前的人体神经肌肉体内功能模型是不充分的。现在很明显，复杂的肌肉内力学在活跃肌肉中产生的肌力中起着关键作用。为了解释萎缩和类似病理的临床病例中相对于肌肉体积损失的力量不成比例的减少，我们假设：(1)通过定义肌肉骨骼组织在多个尺度上的力学异质性，可以推导出一致和可靠的人类骨骼肌的比张力(每PCSA的力量)；以及(2)这些肌肉骨骼组织内和这些肌肉骨骼组织之间这种机械复合体的选定组件的变化显著地导致了肌肉力量潜力的丧失，就像在“废弃”萎缩中所发生的那样。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。一个高度集成的成像技术阵列将全面表征这些受试者和8名跟腱断裂恢复期患者小腿的多成分肌肉骨骼(MSK)结构和功能，包括正常、萎缩和不同恢复阶段。特定目标(SA)-1将测量MSK参数：(A)肌肉复合体的3D体积再现图像，(B)肌腱、腱膜和肌肉内结缔组织的分布，(C)肌肉中的肌纤维取向和(D)总MVC。SA-2将定义由于肌肉萎缩引起的变化引起的扭矩损失的相对贡献，这些变化来自：(A)肌肉变形，(B)肌肉纤维拉伤，(C)腱膜应变和剪切，(D)肌腱偏移，(E)跟骨移位。(SA-3)特定对象的图像驱动的无网格(A)组件级别，以及(B)多尺度、多组件系统级别的模型将用于预测应变分布、踝关节位移和总的关节力。模型对总结合力和其他输出变量对正常和萎缩状态之间不同阶段材料性质变化的敏感度的预测将与SA-2中的实验观测进行比较。遵循PA-07-279的指导方针，将应用“多学科综合的系统方法”来理解复杂的肌肉结构-功能相互作用的“重要的生物、生物工程问题”。这对慢性肌肉废用、肌肉营养不良和痉挛等肌肉骨骼疾病患者的量身定制治疗具有广泛的临床潜力。 公共卫生相关性：在这项竞争性更新的母体R01中，我们调查了典型肌肉骨骼系统的结构和功能设计特征，这些设计特征可以解释当前肌肉行为描述中的明显矛盾。本提案调查了这样一种可能性，即系统结构和生理上的异质性可能是肢体强迫输出量低于传统预期的主要原因，并在萎缩后急剧减少。这种对复杂肌肉结构-功能相互作用的基本生理学理解在治疗慢性肌肉废用、肌营养不良和痉挛等肌肉骨骼疾病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. 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.