Multimodality X-ray transmission and diffraction scanner for molecular analysis of cancer specimens

摘要 使用生物标记物进行癌症研究需要分析大范围大小(亚毫米到厘米)的样本和大范围长度尺度上的分子组成。在许多情况下，有关标本的三维空间信息对于了解和处理疾病的进展至关重要。X射线成像已被广泛认识到在组织分析和癌症评估中发挥着关键作用。虽然透射式X射线成像(射线照相或CT)已经成功地应用于样品形态与疾病状态高度相关的一些应用中，但它缺乏分子特异性，这限制了其在样品分析中的普遍应用。许多小组已经证明了X射线衍射法在分析生物样品分子结构中的作用，然而，没有一个小组成功地在实验室环境中实现了快速而准确的三维X射线衍射测量的可行方法。与实现这种系统相关的关键挑战包括这样一个事实，即高精度的X射线衍射仪测量通常需要访问同步加速器或其他专门的源，而普通研究人员很难获得这些源。相比之下，传统的实验室衍射法速度慢，需要破坏或改变样品，并且显示出很差的或没有体积空间信息。为了克服这些挑战，我们建议开发一种新的放射成像设备，该设备可以扫描整个生物显微镜的体积，并生成共同配准的多模式X射线传输和X射线衍射图像。这种技术将使研究人员能够使用紧凑、坚固且在普通研究实验室中很容易获得的工具，以高空间分辨率和高特异性来研究组织样本的分子属性。样品将在没有造影剂的情况下进行分析，并且几乎不需要样品准备。通过以前的工作，我们已经建立、测试和演示了生物显微镜的组合透射式和衍射式成像所需的基础技术。我们现在将建立一个临床可访问的高分辨率扫描仪原型，测试和验证其性能，并展示其在骨和乳腺癌生物显微镜成像中的效用。该项目将提供第一台X射线透射式/衍射式扫描仪，用于癌症生物样本的无损分析，这将为探索X射线衍射物在组织异常中的作用的新的临床研究提供途径，最终导致更好地了解癌症的起源和进化。

ABSTRACT Cancer research using biospecimens requires the analysis of samples with a large range of sizes (sub-mm to cm) and molecular composition over a wide range of length scales. In many cases, 3-dimensional spatial information about the specimen is critical to understanding and addressing the progression of the disease. X-ray imaging has been widely recognized to play a key role in tissue analysis and cancer assessment. While transmission X-ray imaging (radiography or CT) has been used successfully in some applications wherein sample morphology is highly correlated with the disease state, it lacks molecular specificity, which limits its general utility in specimen analysis. Many groups have demonstrated the utility of X-ray diffraction (XRD) in analyzing molecular structure in biospecimens; however, none have successfully implemented a viable method of fast and accurate 3D XRD measurement in a laboratory environment. The key challenges associated with realizing such a system include the fact that high accuracy XRD measurements have typically required access to a synchrotron or another specialized source, which is difficult for the average researcher to access. In contrast, conventional laboratory diffraction methods are slow, require destruction or alteration of the specimens, and exhibit poor or no volumetric spatial information. To overcome these challenges, we propose to develop a new radiographic imaging device that can scan the entire volume of a biospecimen and generate co-registered, multi-modal X-ray transmission and XRD images. Such technology would allow researchers to study molecular properties of tissue specimens with high spatial resolution and high specificity using a tool that is compact, robust, and easily accessible in an average research laboratory. The samples would be analyzed without contrast agents and with little to no sample preparation required. Through previous work, we have built, tested, and demonstrated the underlying technology required for combined transmission and diffraction imaging of biospecimens. We will now build a clinically accessible, high-resolution prototype of the scanner, test and validate its performance, and demonstrate its utility in imaging bone and breast cancer biospecimens. This project will provide a first-of-its-kind X-ray transmission/diffraction scanner for non-destructive analysis of cancer biospecimens, which could enable pathways for new clinical studies exploring the role of XRD in tissue abnormalities, eventually leading to a better understanding of the genesis and evolution of cancer.