A soft X-Ray Phase-Based Microscope for Biomedical Applications

摘要 生物医学图像通常利用光学光或X射线获得。光是 适用于薄组织切片，但不适用于获得厚组织的高质量3D图像 组织.厚度达毫米的组织标本提供了关于 结构，不同的细胞类型及其关系。光学的一个问题是 在厚组织中成像是光学光的散射。X射线可以穿透厚厚的 组织，但目前市售的X射线显微镜成像系统，如 由于XRadia和理学系统，不是软组织成像的最佳选择。为 Xradia Versa，最低能量X射线光谱为30 kVp，这对于软X射线来说太高了。 而Xradia Ultra的视场仅为~60 µm，3D成像需要 几个小时.在理学系统的情况下，吸收对比度太低，即使在 低能量。 我们建议提供一种基于强度调制相位的软X射线显微镜， 使用该方法对完整生物样品进行非破坏性同步加速器质量成像， 以下功能： 三维、定量和多模态（相位、衰减、散射）图像 采集时间比XRadia系统短10倍以上 分辨率可达数百nm，与可见光显微镜相同 视场从5 mm x 5 mm到1 mm x 1 mm，分辨率从2 µm到更小 小于0.5 µm 细胞组成的高对比度图像 ·成像处于其天然水合状态的组织/细胞，没有染色和其他 中断准备程序 实现两个低能量X射线源：5.4 keV和8 keV。用户可以 在两个选项之间来回切换，以及调整分辨率 动态 这将通过结合强度调制X射线相位成像（IM）来实现 XPBI）方法，具有摆线CT采集和基于实验室的 重叠关系 该显微镜将安装在纪念斯隆凯特琳癌症中心， 用现有组织样本的数据库进行验证。3D组织学结果来自 拟议的显微镜将与传统成像的组织学结果进行比较 以确定疗效的方式。还将进行癌症研究测试- 血液中的相关细胞，如循环肿瘤细胞和巨大的癌症相关细胞， Creatv MicroTech发现的巨噬细胞样细胞。可能获得高- 高分辨率高对比度的3D图像的细胞在其自然状态将提高我们的研究。 用于癌症的生物医学研究和临床应用。 这项新技术将有助于基础，临床前和临床研究相关的 许多健康状况，如癌症、骨质疏松症、关节炎、心血管疾病 并将有助于了解这些疾病的进展以及它们如何被 治疗。

Abstract Biomedical images are typically obtained utilizing optical light or X-rays. Optical light is suitable for thin tissue slices, but not suitable for obtaining quality 3D images of thick tissue. Tissue specimens up to millimeter in thickness provide information about structure, different cell types and their relationships. One of the problems with optical imaging in thick tissue is the scattering of the optical light. X-rays can penetrate thick tissue, but the currently commercially available X-ray microscope imaging systems, such as the XRadia and Rigaku systems, are not optimal for soft tissue imaging. For the Xradia Versa, the lowest energy X-ray spectrum is 30 kVp, which is too high for soft tissue, while in the Xradia Ultra the field of view is only ~60 µm, and 3D imaging requires several hours. In the case of the Rigaku system, absorption contrast is too low even at low energies. We propose to deliver an intensity-modulation phase-based soft X-ray microscope for non-destructive synchrotron-quality imaging of intact biological samples with the following features:  3D, quantitative and multimodal (phase, attenuation, scatter) images  Acquisition times more than 10 times shorter than in XRadia systems  Resolution of hundreds of nm, same as visible light microscopes  Field of view from 5 mm x 5 mm to 1 mm x 1 mm, resolution from 2 µm to less than 0.5 µm  High-contrast images of cell composition  Imaging tissue/cells in their native hydrated state, with no staining and other disrupting preparation procedures  Implementing two low energy X-ray sources: 5.4 keV and 8 keV. The user can switch back and forth between the two options, as well as adjust the resolution dynamically This will be realized by combining intensity-modulation X-ray phase-based imaging (IM XPBI) method with two innovations such as cycloidal CT acquisition and lab-based ptychography. The microscope will be installed at Memorial Sloan Kettering Cancer Center and validated with a database of existing tissue samples. The 3D histology results from the proposed microscope will be compared to histology results from conventional imaging modalities to determine efficacy. Tests will also be carried out to study cancer- associated cells in blood, such as circulating tumor cells and giant cancer-associated macrophage-like cells discovered by Creatv MicroTech. Possibility to obtain high- resolution high-contrast 3D images of cells in their native state will enhance our biomedical research and clinical utility to cancer. This novel technology will be helpful for basic, pre-clinical and clinical studies related to many health conditions, such as cancer, osteoporosis, arthritis, cardiovascular disease and will assist with understanding of how these diseases progress and how they can be treated.