Integrated photoacoustic and fluorescence imaging system for anatomical, functional, and molecular characterization of murine models

摘要 PhotoSound Technologies，Inc.建议开发一种新的成像模式，用于表征和预成像 小鼠模型的临床研究。这项技术将能够实现三维功能和 荧光标记和报告基因的分子成像高保真地定位于强大的解剖学 组织结构，如皮肤、中央和外周血管系统以及内脏。研制成功的仪器 可用于广泛的临床前研究，包括癌症、毒理学、组织工程和 再生、心血管和发育生物学。 光学活体成像方法(荧光和生物发光)在 研究人员作为负担得起的、方便的和非常敏感的分子成像工具进行临床前研究和 动物模型的发展。然而，它们的独立应用受到空间分辨率较低的阻碍 以及图像的二维性施加的限制。一种高分辨率的活体3D成像方法， 可以很容易地与光学成像集成在一台仪器中，这将对 整个小动物研究领域。 光声断层成像是一种新兴的生物医学成像方式，它具有所有这些要求：(1) 150-500微米分辨率的3D全身图像；(2)能够使用相同的仪器激发 荧光和光声效应的产生；(3)不到1分钟的3D扫描。然而，它在体内 与常规的荧光技术相比，检测荧光团的灵敏度较低。我们的建议 是基于开创性的共同注册的荧光和光声模式在单个 紧凑型3D配置(PAFT-3D)克服了每种单独技术的缺点。 第一阶段项目以三个具体目标组织，评估可行性：(1)技术 在单个紧凑型结构中实现共同配准的3D光声层析成像和荧光 活体麻醉小鼠的成像仪器；(2)小鼠的荧光成像和解剖结构 分辨率超过已建立的荧光成像；(3)提供有价值的成像信息 临床前动物模型的发展和特征，以小鼠模型为重点的病例研究 转移性乳腺癌。 第二阶段将侧重于开发和体内验证具有灵敏度和 为动物模型开发和临床前研究的各个领域优化的成像程序。 最终的商业系统将能够实现对天然血红蛋白、荧光团、 纳米颗粒，以及用于跟踪、测绘和纵向研究的其他光敏结构。这个 Paft-3D的价值主张将不仅仅建立在Paft-3D的独特性和技术优势 不仅是通过让广大研究小组和中心买得起这一产品，而且还通过让更多的研究小组和中心买得起。

SUMMARY PhotoSound Technologies, Inc. proposes to develop a novel imaging modality for characterization and pre- clinical research of murine models. The technology will be capable of three-dimensional functional and molecular imaging of fluorescent labels and reporter genes mapped with high fidelity over robust anatomical structures, such as skin, central and peripheral vasculature, and internal organs. The developed instrument could be used in broad spectrum of pre-clinical research including cancer, toxicology, tissue engineering and regeneration, cardiovascular and developmental biology. Optical in vivo imaging methods (fluorescence and bioluminescence) found great popularity among researchers as affordable, convenient, and very sensitive molecular imaging tools for pre-clinical studies and development of animal models. However, their stand-alone application is impeded by poor spatial resolution and limitations imposed by two-dimensionality of the images. A high-resolution in vivo 3D imaging method, which could be easily integrated with optical imaging in a single instrument, would have a great impact on the entire field of small animal research. Photoacoustic tomography is an emerging biomedical imaging modality that has all those requirements: (1) 150-500 µm resolution of 3D whole body images; (2) Ability to use the same instrumentation for excitation of fluorescence and generation of photoacoustic effect; (3) 3D scans in less than 1 minute. However, its in vivo sensitivity to detection of fluorophores is inferior as compared to regular fluorescence techniques. Our proposal is based on pioneering co-registered integration of fluorescence and photoacoustic modalities in a single compact 3D configuration (PAFT-3D) defeating shortcomings of each individual technology. The Phase I project is organized in three specific aims assessing feasibility of: (1) Technological implementation for co-registered 3D photoacoustic tomography and fluorescence in a single compact instrument for imaging live anesthetized mice; (2) Imaging fluorophores and anatomical structures of mice with resolution exceeding that of established fluorescence imaging; (3) Providing imaging information valuable for development and characterization of pre-clinical animal models with case study focused on murine models of metastatic breast cancer. Phase II will be focused on development and in vivo validation of a commercial instrument with sensitivity and imaging procedures optimized for various areas of animal model development and preclinical research. Ultimate commercial system will enable in vivo visualization and analysis of native hemoglobin, fluorophores, nanoparticles, and other photosensitive constructs used for tracking, mapping, and longitudinal studies. The value proposition of the PAFT-3D will be built not only around uniqueness and technological superiority of the product, but also by making it affordable for a broad population of research groups and centers.