Non invasive measurements of muscle microstructure assessed by diffusion tensor imaging

通过扩散张量成像评估肌肉微观结构的无创测量

• 批准号: 9982046
• 负责人: LAWRENCE R FRANK
• 金额: $ 45.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982046
• 关键词: 3-Dimensional; 3D Print; Address; Affect; Animal Model; Area; Atrophic; Biology; Biopsy; Carrageenan; Cell Membrane Permeability; Cells; Characteristics; Chronic; Clinical; Complex; Computer Simulation; Denervation; Dermatomyositis; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Edema; Engineering; Excision; Extracellular Matrix; Fascicle; Fatty acid glycerol esters; Fiber; Fibrosis; Geometry; Goals; Gold; Health; Health Care Costs; Histology; Hypertrophy; Image; Imaging Techniques; Impairment; Inclusion Body Myositis; Individual; Inflammation; Injections; Injury; Isometric Exercise; Knowledge; Magnetic Resonance Imaging; Measurement; Measures; Membrane; Metabolism; Methods; Microscopic; Modeling; Monitor; Morphology; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Muscular Dystrophies; Myopathy; Needles; Neuromuscular Diseases; Pain; Pathology; Patients; Performance; Permeability; Physiologic pulse; Polymyositis; Production; Property; Quality of life; Recovery; Resolution; Sampling Errors; Sarcolemma; Sarcomeres; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Specificity; Sterility; Structural Biochemistry; Structure; Structure-Activity Relationship; Techniques; Testing; Time; Tissue Model; Tissues; Water; base; cardiovascular health; clinical translation; cost; design; diagnosis standard; experimental study; extracellular; improved; in silico; in vivo; injured; innovation; muscular structure; nanofabrication; novel; phantom model; pre-clinical; simulation; tool; water diffusion

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.

骨骼肌体现了生物学中的结构与功能关系。肌节的组织如下 分层排序形成长收缩细胞，捆绑在细胞外基质中，形成更大的束和 最终完整的肌肉。结构和功能之间的紧密关系保证了肌肉的表现 （和疾病）可以从其微观结构推断出来。例如，纤维面积与等长力直接相关 肌肉的生产。随着损伤，肌纤维面积（大小）的微观结构发生变化，纤维化（纤维的积累） 观察到细胞外基质）、膜损伤（渗透性）和炎症（水肿），并损害 肌肉功能。肌肉活检，然后进行组织显微镜检查（组织学），是黄金 诊断和监测肌肉健康和疾病的标准。该工具是侵入性的，需要大孔径 在无菌条件下去除针头和组织，这使得过程痛苦且昂贵。因此，活检不 有利于肌肉健康的连续监测。它也是半定量的，并且通常很难推断 整个肌肉，限制了其科学和临床价值。由于这些原因，需要非侵入性的 肌肉微观结构的评估，这将有助于定量检查肌肉损伤 时间。磁共振成像（MRI）已被用于无创地量化体积、脂肪的变化 分布和肌肉中的水分含量。扩散张量成像 (DTI) 是 MRI 的一种版本，可测量 水的各向异性扩散，与组织微观结构有关，但往往会产生非特异性变化 无论受伤或疾病状态如何。缺乏特异性的主要原因是明确的 微观结构和扩散之间的关系尚未经过严格研究，也没有经过仔细校准。 为了解决这一知识差距，该提案的目的是比较肌肉微观结构和 MRI 新颖且严格控制的计算机模拟中肌肉的扩散特性，经过精密设计 肌肉损伤和疾病的幻影和动物模型。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，与肌肉微观结构的变化直接相关 复杂的病理学。目标#1将使用基于计算机的肌肉结构和生物化学模拟来 仔细了解扩散与多种肌肉微观结构变化的关系。目标 #2 将利用 3D 精密设计的模型可将扩散与真实 DT-MRI 实验中的肌肉结构联系起来。这些 实验将被整合到最终的体内实验组中（目标#3），旨在测试 DT-MRI 的准确性可解开肌肉萎缩时复杂的微观结构变化， 炎症、变性。这些实验将阐明之间尚未研究的关系 肌肉的微观结构和扩散。长期目标是连续量化肌肉微观结构非 侵入性地。这种方法的创新之处在于它结合了最先进的成像、模拟、纳米加工、 和形态学方法来生成有临床意义的测量工具。