High-Throughput Volumetric Photoacoustic Imaging of Living Vascularized Organoids

活体血管类器官的高通量体积光声成像

• 批准号: 9762292
• 负责人: Junjie Yao
• 金额: $ 50.95万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762292
• 关键词: 3-Dimensional; Address; Anatomy; Angiogenesis Inhibitors; Animal Model; Biochemical; Biomimetics; Bioreactors; Blood Vessels; Capital; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Detection; Development; Devices; Diabetes Mellitus; Diffusion; Dimensions; Disease; Disease model; Drug Interactions; Drug Monitoring; Drug Screening; Drug toxicity; Endothelial Cells; Equilibrium; Expenditure; Functional Imaging; Genetic Engineering; Geometry; Goals; Histologic; Human; Image; Investments; Label; Light; Location; Longitudinal Studies; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolism; Microfluidics; Microscopy; Modeling; Molecular; Monitor; Neurodegenerative Disorders; Neurology; Nutrient; Optics; Organ; Organoids; Pathologic; Pathology; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Physiology; Preclinical Drug Development; Primary carcinoma of the liver cells; Process; Property; Reaction; Resolution; Structure; System; Technology; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissue Engineering; Tissue Model; Tissues; Ultrasonics; United States Food and Drug Administration; Vascularization; anatomic imaging; angiogenesis; base; bioprinting; cancer imaging; combat; cost; density; drug candidate; drug development; drug efficacy; drug testing; experience; human disease; human tissue; imaging capabilities; imaging modality; improved; in vivo; microfluidic technology; millimeter; miniaturize; molecular imaging; novel; novel therapeutics; oncology; optical imaging; optoacoustic tomography; organ on a chip; oxygen transport; personalized medicine; photoacoustic imaging; response; screening; self assembly; success; tool; transcription factor

Abstract Over the last decade, there has been a 62% rise in the number of therapeutic compounds under development for cancers, diabetes, neurodegenerative diseases, and cardiovascular diseases, and the total expenditure has nearly doubled. Despite the significant investment, the average number of new drugs approved by the Food and Drug Administration (FDA) has declined since the 1990s, mainly due to the low success rate of human clinical trials and the insufficient efficacy and/or excessive adverse (toxic) reactions associated with the candidate drugs. Planar cell cultures and animal models used in drug testing often fail to accurately reflect human physiology and pathology. Three-dimensional (3D) human cell-based organ-on-a-chip models, combined with advanced vascularization and microfluidics technologies, have been increasingly used to improve drug testing, by recapitulating important physiological parameters of their in vivo human counterparts. However, the characterization of 3D vascularized organoid cultures is challenging with pure optical imaging methods that reach only small depths (~1 mm) and/or lacks functional imaging capability. The organoids can reach 2–3 mm in all dimensions, and the response to the drug treatment by cells at different locations may significantly vary due to non-uniform tissue properties, limited molecular diffusion, and heterogeneous vascular arborization. To address these issues, we propose to develop a novel integrated imaging-bioreactor platform that combines a miniaturized photoacoustic tomography (mini-PAT) system (Aim 1) and a human vascularized organ-on-a-chip bioreactor (Aim 2). Mini-PAT can be directly integrated onto the bioreactor and provide critical anatomical and functional information about the 3D organoid’s development, vasculature function and metabolism. As proof of concept, we will apply the integrated platform for on-chip, longitudinal, and volumetric imaging of the progression of hepatocellular carcinoma (HCC) organoids, their multiscale vascularization, and their response to anti- angiogenic drugs (Aim 3). Most importantly, both the mini-PAT and bioreactor are highly compact and low-cost (~$200 per unit), so they can be readily multiplexed for monitoring a large array of organoids in parallel. The highly heterogeneous drug-organoid interactions can thus be simultaneously studied in a statistically meaningful manner. Ultimately, this proposal will provide a platform technology for a variety of applications that require high-throughput pathological testing on human tissue models. More excitingly, it would pave the way for personalized medicine screening using an array of patient-derived disease models.

抽象的 在过去的十年中，正在开发的治疗化合物数量增加了62％ 对于癌症，糖尿病，神经退行性疾病和心血管疾病，总支出具有 几乎翻了一番。尽管投资大量投资，但食物批准的新药的平均数量和 自1990年代以来，药物管理局（FDA）已下降，这主要是由于人类临床的成功率低。 试验以及与候选药物有关的效率不足和/或过多的广告（有毒）反应。 药物测试中使用的平面细胞培养物和动物模型通常无法准确反映人类的生理学和 病理。三维（3D）人类细胞基于A-A-CHIP模型，结合了晚期 血管形成和微流体技术已越来越多地用于改善药物测试， 概括其体内人体对应物的重要物理参数。但是， 纯粹的光学成像方法挑战了3D血管化器官培养物的表征 只有较小的深度（〜1 mm）和/或缺乏功能成像能力。类器官可以达到2-3毫米 尺寸以及不同位置细胞对药物治疗的反应可能会因 非均匀的组织特性，有限的分子扩散和异质的血管木器化。解决 这些问题，我们建议开发一个新颖的集成成像 - 比率平台，该平台结合了一个小型化 光声断层扫描（Mini-PAT）系统（AIM 1）和人类血管化器官芯片生物反应器 （目标2）。迷你PAT可以直接集成到生物反应器上，并提供关键的解剖和功能性 有关3D器官的发育，脉管功能和代谢的信息。作为概念证明， 我们将将集成平台应用于芯片，纵向和体积成像的进展 肝细胞癌（HCC）类器官，它们的多尺度血管形成及其对抗抗的反应 血管生成药物（AIM 3）。最重要的是，迷你PAT和生物反应器都高度紧凑且低成本 （每单位约200美元），因此可以轻松地多路复用，以并行监测大量的类器官。这 因此，高度异质的药物 - 甲然相互作用可以简单地在统计学上有意义的 方式。最终，该建议将为需要的各种应用程序提供平台技术 对人组织模型的高通量病理测试。更令人兴奋的是，它将为 使用一系列患者来源的疾病模型进行个性化医学筛查。