An integrated in vitro model of perfused tumor and cardiac tissue

描述（由申请人提供）：癌症和心血管疾病仍然是美国的两大死亡原因。在降低发病率和死亡率的治疗方面取得的进展将包括新药的开发。诱导多能干细胞（iPS）技术，组织工程和微加工技术的最新进展创造了一个独特的机会，开发3-D微生理系统，更准确地反映在体内人体生物学相比，2-D“平面”系统或动物模型。该项目的主要目标是使用iPS技术创建3-D微器官系统，其模拟1）微循环，2）心肌，和3）UH 2阶段的实体肿瘤，然后将这些微器官联合收割机组合成三个集成的微器官系统，其模拟1）灌注心肌，2）灌注实体肿瘤，3）UH 3期灌注心肌和实体瘤。该平台将进行初步验证，以预测抗癌疗效，同时最大限度地减少心肌毒性。该项目的更广泛意义是创建一个平台技术，可以准确和经济地模拟主要人体器官系统之间的复杂相互作用，包括对新药物和现有药物的反应。一个关键的特征将是通过人体微循环（毛细血管和较大的微血管）的血流，这是克服现实3D培养中营养物质和废物扩散限制所必需的，并有助于整合多个器官系统。这是任何试图模拟集成人体器官系统的平台的必要和关键特征，我们的初步研究证明了这种能力。该项目的次要目标包括实现：1）设计的灵活性，使得替代器官功能（例如，肝脏）可以被插入、移除或重新排列（即，“plug-n-play”）; 2）制造过程和生物反应的可再现性; 3）手掌大小的便携式设计; 4）使用iPS细胞技术来创建患者特异性（或“个性化”）药物筛选，以及5）非侵入性和非破坏性光学成像方法来快速评估细胞的代谢状态。研究结果将为高效、准确的药物和毒性筛选提供一个新的范例，最初用于具有最小心脏副作用的抗癌药物，以及最终可用于整合人体所有主要器官的平台技术。 公共卫生相关性：我们的建议的中心目标是开发一个集成的三维体外高通量系统，模仿心肌和实体肿瘤的主要生理和生物学特征。该系统可用于识别新的抗癌药物，同时最大限度地减少对心肌的潜在有害毒性。

DESCRIPTION (provided by applicant): Cancer and cardiovascular disease remain the two leading causes of death in the United States. Progress in treatment to reduce morbidity and mortality will include the development of new drugs. Recent advances in induced pluripotent stem (iPS) cell technology, tissue engineering, and microfabrication techniques have created a unique opportunity to develop 3-D microphysiological systems that more accurately reflect in vivo human biology when compared to 2-D "flat" systems or animal models. The primary goal of this project is to create 3-D micro-organ systems using iPS technology that simulate 1) the microcirculation, 2) cardiac muscle, and 3) solid tumor during the UH2 phase, and then combine these micro-organs into three integrated micro- organ systems that simulate 1) perfused cardiac muscle, 2) perfused solid tumor, and 3) perfused cardiac muscle and solid tumor during the UH3 phase. The platform will be initially validated to predict anti-cancer efficacy while minimizing cardiac muscle toxicity. The broader implication of this project is the creation of a platform technology that can accurately and affordably simulate the complex interplay between the major human organ systems, including the response to new and existing drugs. A critical feature will be blood flow through a human microcirculation (capillaries and larger microvessels), which is necessary to overcome diffusion limitations of nutrients and waste products in realistic 3-D cultures, and serves to integrate multiple organ systems. This is a necessary and critical feature of any platform that seeks to simulate integrated human organ systems, and our preliminary studies demonstrate this capability. Secondary goals of the project include achieving: 1) flexibility in the design such that alternate organ functions (e.g., liver) can be eaily inserted, removed, or rearranged (i.e., "plug-n-play"); 2) reproducibility in the manufacturing process and the biological response; 3) portable design that is palm-sized; 4) the use of iPS cell technology to create patient-specific (or "personalized") drug screening, and 5) non-invasive and non-destructive optical imaging methods to rapidly assess the metabolic state of a cell. The results should produce a new paradigm for efficient and accurate drug and toxicity screening, initially for anti-cancer drugs with minimal cardiac side effects, and a platform technology that can be eventually used to integrate all of the major organs of the human body. PUBLIC HEALTH RELEVANCE: The central objective of our proposal is to develop an integrated 3-D in vitro high-throughput system that mimics the major physiologic and biologic features of cardiac muscle and solid tumor. The system can be used to identify new anti-cancer drugs while minimizing potential harmful toxicity to cardiac muscle.