An optical approach to 3-dimensional micro-mechanical imaging of the extra-cellular matrix (ECM)

细胞外基质 (ECM) 3 维微机械成像的光学方法

• 批准号: 10303697
• 负责人: Zeinab Hajjarian
• 金额: $ 25.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303697
• 关键词: 3-Dimensional; Address; Algorithms; Area; Atomic Force Microscopy; Award; Back; Biocompatible Materials; Biological; Biology; Biomechanics; Blood Vessels; Breast Carcinoma; Carcinoma; Carcinoma in Situ; Cardiovascular Diseases; Cell Proliferation; Cells; Cessation of life; Clinical; Cues; Development; Diagnostic Sensitivity; Disease; Disease Management; Disease Progression; Extracellular Matrix; Focal Adhesions; Goals; Grain; Heterogeneity; Human; Image; Imaging Device; Knowledge; Lasers; Lateral; Lead; Length; Light; Lighting; Linear Regressions; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maps; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Modality; Modeling; Mole the mammal; Molecular Conformation; Motion; Onset of illness; Optics; Pathogenesis; Pathology; Pattern; Penetration; Performance; Property; Research; Resolution; Rheology; Role; Sampling; Scanning; Sensitivity and Specificity; Side; Signal Transduction Pathway; Source; Specimen; Spottings; Technology; Testing; Therapeutic; Time; Tissue imaging; Tissues; Variant; base; breast cancer progression; cell behavior; cell motility; elastography; human disease; imaging properties; immune function; improved; indexing; innovation; innovative technologies; insight; lens; light scattering; lymph nodes; malignant breast neoplasm; mammary epithelium; mechanical properties; molecular subtypes; novel; particle; prevent; programs; reconstruction; spatiotemporal; therapeutic target; tomography; two-dimensional; viscoelasticity

Project Summary/Abstract The goal of this proposal is to develop and validate a laser SpeckLe fIeld Microrheology (SLIM) technology for micromechanical mapping of the tissue ECM, with lateral resolution of 10 μm, axial resolution of 60 μm, and a penetration depth of 5 mm penetration depth. ECM stiffness, as perceived by cells, is emerging as a prominent micro-mechanical cue that precedes pathogenesis and directs its progression by orchestrating nearly all aspects of cellular behavior. Excessive and irregular micro-mechanical remodeling of the ECM is implicated in a broad spectrum of pathologies, including cardiovascular disease, fibrotic disorders, and cancer, which together account for over 50% of death worldwide. Nevertheless, our understanding of the underlying mechanisms is severely limited as currently there are no imaging tools available for micromechanical mapping of the ECM at length scales pertinent to cells. SLIM measures the time-varying speckle intensity fluctuations. Speckle is a grainy intensity pattern, formed when a coherent laser beam is back scattered from tissue. Brownian displacements of scattering particles within the ECM dynamically modulate the speckle fluctuations. These fluctuations in turn are intimately related to the viscoelastic properties of imaged tissue. In compliant regions, unrestricted Brownian displacements provoke rapidly fluctuating speckle spots, whereas in rigid areas, restrained motions elicit limited intensity variations of speckle grains. Pixel-wise correlation analysis of intensity fluctuations provides a 2D depth-integrated map of mechanical properties within the tissue. However, the resolution of this map is limited to the speckle grain size, set by the Numerical Aperture (NA) of optics. In addition, due to multiple scattering of light, speckle fluctuations are modulated by the Brownian displacements of the scattering particles within the entire illuminated volume. As a result, the evaluated map lacks depth information. Therefore, the first goal of this proposal is to address these issues by introducing an innovative SLIM platform, capable of high resolution, depth-resolved, large FoV, micromechanical mapping of the ECM, without physical scanning and refocusing on the sample. Our second goal is then to identify the link between the micromechanical properties of ECM and known hallmarks of disease progression, by focusing on breast cancer as a model. The unique capability of SLIM for micro-mechanical tomography of ECM enables identifying the key biomechanical mediators of pathogenies. It also opens multiple avenues based on targeting the cell-ECM micromechanical interactions for therapeutic management of disease.

项目概要/摘要 该提案的目标是开发和验证激光散斑场微流变 (SLIM) 技术 组织 ECM 的微机械测绘，横向分辨率为 10 μm，轴向分辨率为 60 μm， 细胞感知到的 5 毫米的穿透深度 ECM 刚度正在成为一个突出的因素。 发病之前的微机械线索，通过协调几乎所有方面来指导其进展 ECM 的过度和不规则的微机械重塑与广泛的细胞行为有关。 一系列病理学，包括心血管疾病、纤维化疾病和癌症，它们共同解释了 然而，我们对潜在机制的了解还很深入。 有限，因为目前没有可用于 ECM 详细微机械绘图的成像工具 与细胞相关的尺度。 SLIM 测量随时间变化的散斑强度波动。散斑是一种颗粒状强度图案，形成于以下时间。 相干激光束从组织内的散射粒子的布朗位移中反向散射。 ECM 动态调制散斑波动，而这些波动又与散斑波动密切相关。 成像组织的粘弹性特性在顺应区域中引起不受限制的布朗位移。 快速波动的散斑点，而在刚性区域，受限运动引起有限的强度变化 强度波动的逐像素相关分析提供了 2D 深度积分图。 然而，该图的分辨率仅限于散斑颗粒尺寸， 由光学器件的数值孔径（NA）决定 此外，由于光的多重散射，散斑波动。 由整个照明体积内的散射粒子的布朗位移调制。 结果，评估的地图缺乏深度信息，因此，该提案的首要目标是解决这些问题。 通过引入创新的 SLIM 平台来解决问题，该平台能够实现高分辨率、深度分辨、大视场、 ECM 的微机械测绘，无需物理扫描并重新聚焦于样品 我们的第二个。 然后的目标是确定 ECM 的微机械特性与已知疾病特征之间的联系 SLIM针对微机械的独特能力 ECM 断层扫描能够识别病原体的关键生物力学介质，它还可以揭示多种病原体。 基于针对细胞-ECM微机械相互作用的疾病治疗管理途径。