Non invasive measurements of muscle microstructure assessed by diffusion tensor imaging

骨骼肌是生物学中结构与功能关系的例证。肌节的组织如下 分级排序，以形成长的收缩细胞，捆绑在细胞外基质中，以形成更大的束和 归根结底是整个肌肉。结构和功能之间的紧密关系允许肌肉表现 (和疾病)从其微观结构中推断。例如，纤维面积与等轴向力直接相关。 在肌肉方面的生产。随着损伤，肌纤维面积(大小)、纤维化(积聚)的微观结构改变 细胞外基质)，膜损伤(通透性)和炎症(水肿)，并损害 肌肉功能。肌肉活检，然后对组织进行显微镜检查(组织学)，是金 诊断和监测肌肉健康和疾病的标准。这种工具是侵入性的，需要很大的钻孔 在无菌条件下取出针头和组织，这使得它很痛苦，成本也很高。因此，活组织检查不是 有利于肌肉健康的连续监测。它也是半定量的，通常很难外推 整个肌肉，限制了它的科学和临床价值。出于这些原因，需要非侵入性的 评估肌肉微结构，这将有助于对肌肉损伤的定量检查 时间到了。磁共振成像(MRI)已经被用来非侵入性地量化体积、脂肪 以及肌肉中的水分含量。弥散张量成像(DTI)是磁共振成像的一个版本，它测量 水的各向异性扩散，这与组织微结构有关，但往往会产生非特定的变化 无论受伤或疾病状态如何。这种缺乏特异性的关键原因是，明确的 微观结构和扩散之间的关系还没有得到严格的研究，也没有经过仔细的校准。 为了解决这一认识上的差距，这项建议的目的是比较肌肉微结构和核磁共振 在新的和严格控制的计算机模拟中肌肉的扩散特性，精密工程 幻影，以及肌肉损伤和疾病的动物模型。我们的中心假设是DT-MRI可以 当使用适当的脉冲序列来解耦时，与肌肉微结构变化直接相关 复杂的病理学。目标1将使用基于计算机的肌肉结构和生化模拟来 仔细了解扩散与多种肌肉微结构变化的关系。AIM#2将使用3D 在真实的DT-MRI实验中，精确设计的模型将扩散与肌肉结构联系起来。这些 实验将被整合到最终的活体实验集(目标#3)中，这些实验旨在测试 DT-MRI了解肌肉萎缩时复杂微结构变化的准确性， 发炎和退化。这些实验将阐明未被充分研究的 肌肉中的微观结构和扩散。长期目标是连续量化肌肉的微结构，而不是 侵犯性的。这种方法是创新的，因为它结合了最先进的成像、模拟、纳米制造 和形态学方法，以生成具有临床意义的测量工具。

Skeletal muscle exemplifies structure-function relationships in biology. The organization of sarcomeres follow hierarchical ordering to form long contractile cells, bundled in extra-cellular matrix, to form larger fascicles and ultimately whole muscles. The tight relationship between structure and function allows muscle performance (and disease) to be inferred from its microstructure. For example, fiber area is directly related to isometric force production in muscle. With injury, microstructural changes in muscle fiber area (size), fibrosis (accumulation of extracellular matrix), membrane damage (permeability), and inflammation (edema) are observed, and impair muscle function. Muscle biopsy, followed by microscopic examination of the tissue (histology), is the gold standard to diagnose and monitor muscle health and disease. This tool is invasive, requiring a large bore needle and tissue removal under sterile conditions, which makes it painful and costly. Therefore, biopsy is not conducive to serial monitoring of muscle health. It is also semi-quantitative, and often difficult to extrapolate to the entire muscle, limiting its scientific and clinical value. For these reasons, there is a need for noninvasive assessment of muscle microstructure, which would facilitate the quantitative examination of muscle injury over time. Magnetic resonance imaging (MRI) has been used to noninvasively quantify changes in volume, fat distribution, and water content in muscle. Diffusion tensor imaging (DTI) is a version of MRI that measures anisotropic diffusion of water, which is related to tissue microstructure, but tends to yield non-specific changes regardless of the injury or disease state. The key reason for this lack of specificity is that the explicit relationships between microstructure and diffusion have not been rigorously studied, nor carefully calibrated. To address this gap in knowledge, the purpose of this proposal is to compare muscle microstructure and MRI diffusion properties of muscle in novel and tightly controlled computer simulations, precision engineered phantoms, and animal models of muscle injury and disease. Our central hypothesis is that DT-MRI can be directly related to muscle microstructural changes, when appropriate pulse sequences are used to uncouple complex pathology. Aim #1 will use computer-based simulations of muscle structure and biochemistry to carefully understand how diffusion is related to multiple muscle microstructural changes. Aim #2 will utilize 3D precision-engineered models to relate diffusion to muscle structure in real-world DT-MRI experiments. These experiments will be integrated into a final in vivo set of experiments (Aim #3), which are designed to test the accuracy of DT-MRI to uncouple complex microstructural changes in the presence of muscle atrophy, inflammation, and degeneration. These experiments will elucidate the understudied relationships between microstructure and diffusion in muscle. The long-term goal is to serially quantify muscle microstructure non- invasively. This approach is innovative in that it combines state-of-the art imaging, simulation, nanofabrication, and morphology methods to generate a clinically meaningful measurement tool.