An integrated in vitro model of perfused tumor and cardiac tissue

描述(申请人提供)：癌症和心血管疾病仍然是美国的两大主要死亡原因。减少发病率和死亡率的治疗进展将包括新药的开发。诱导多能干细胞(IPS)技术、组织工程学和微制造技术的最新进展为开发三维微生理系统创造了独特的机会，与二维平面系统或动物模型相比，三维微生理系统可以更准确地反映体内的人类生物学。该项目的主要目标是利用iPS技术创建三维微器官系统，模拟UH2阶段的微循环、2)心肌和3)实体肿瘤，然后将这些微器官组合成三个集成的微器官系统，模拟1)灌流的心肌、2)灌流的实体肿瘤和3)UH3阶段的灌流心肌和实体肿瘤。该平台将进行初步验证，以预测抗癌效果，同时将心肌毒性降至最低。该项目的更广泛影响是创造了一种平台技术，可以准确和负担得起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。一个关键特征将是通过人体微循环(毛细血管和较大的微血管)的血液流动，这是克服现实3-D培养中营养物质和废物的扩散限制所必需的，并用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功能，我们的初步研究证明了这一能力。该项目的次要目标包括：1)设计的灵活性，以便可以轻松地插入、移除或重新排列替代器官功能(如肝脏)(即，“即插即用”)；2)制造过程和生物响应的重复性；3)手掌大小的便携式设计；4)使用iPS细胞技术创建针对患者的(或“个性化”)药物筛选；5)非侵入性和无损的光学成像方法，快速评估细胞的代谢状态。这些结果应该会产生一种有效和准确的药物和毒性筛选的新范式，最初是对心脏副作用最小的抗癌药物的筛选，以及一种最终可用于整合人体所有主要器官的平台技术。

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.