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: 10427422
• 负责人: Zeinab Hajjarian
• 金额: $ 21万
• 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/10427422
• 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; mechanical signal; molecular subtypes; novel; particle; prevent; programs; reconstruction; spatiotemporal; therapeutic target; tissue mapping; tomography; two-dimensional; viscoelasticity; 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; mechanical signal; molecular subtypes; novel; particle; prevent; programs; reconstruction; spatiotemporal; therapeutic target; tissue mapping; 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.

项目摘要/摘要 该提案的目的是开发和验证激光斑点磁场微流行病学（Slim）技术 组织ECM的微力图，横向分辨率为10μM，轴向分辨率为60μm，A 渗透深度为5毫米，穿透深度。细胞所感知的ECM刚度正在成为突出的 微机械提示先于发病机理，并通过精心策划几乎所有方面来指导其进展 细胞行为。 ECM的过度和不规则的微型机械重塑暗示了 病理范围，包括心血管疾病，纤维性疾病和癌症，共同考虑 全球50％以上的死亡。但是，我们对基本机制的理解非常严重 限制目前尚无用于ECM的微机械映射的成像工具 与细胞相关的尺度。 Slim测量随时间变化的斑点强度波动。斑点是一种粒状强度模式，当 相干激光束从组织散射。布朗散射颗粒的位移 ECM动态调节斑点波动。这些波动又与 成像组织的粘弹性。在合规的地区，不受限制的布朗流离失所 迅速波动的斑点斑点，而在刚性区域，限制运动会引起有限的强度变化 斑点谷物。强度波动的像素优体相关性分析提供了2D深度集成图 组织内的机械性能。但是，该地图的分辨率仅限于斑点晶粒尺寸， 由光学器件的数值光圈（Na）设置。另外，由于光的多次散射，斑点波动 由整个照明体积中的散射颗粒的布朗位移调节。作为 结果，评估的地图缺乏深度信息。因此，该提议的第一个目标是解决这些问题 通过引入一个具有高分辨率，深度分辨，大型FOV的创新苗条平台，该问题 ECM的微机械映射，无需在样品上进行物理扫描和重新聚焦。我们的第二个 然后，目标是确定ECM的微机械特性与已知疾病标志之间的联系 进展，将重点放在乳腺癌作为模型上。 Slim对于微型机械的独特能力 ECM的断层扫描能够识别病原体的关键生物力学介体。它也打开了多个 基于针对细胞-ECM微电机械相互作用的途径用于疾病的治疗管理。