Human Cardio-Pulmonary System on a Chip

描述（由申请人提供）：心血管和肺部疾病是美国最常见的两类疾病。环境污染物，包括纳米级过敏原和毒素，对健康和患病的心肺系统都有有害影响。此外，心脏毒性是从市场上撤回药物的最普遍原因之一。药物在临床或后期临床试验中的失败是导致美国医疗保健成本增加的一个因素，因为药物开发成本增加以适应此类产品失败。迄今为止，疗效和毒性测试的模型主要基于体外收集的大量低质量数据的模型。最近的进展提供了另一种战略。软光刻技术使复制健康和患病组织的细胞微环境的微尺度组织工程成为可能。微流体系统能够实现长期培养和模拟器官和组织中发现的低体积间隙空间的能力。通过活组织检查收获人类细胞的新技术，加上人类胚胎干细胞（ES）和诱导多能性干细胞（iPS）细胞，所有这些都具有一定的商业可用性，表明通常用于体外测试的动物细胞系可以用人类替代品代替。最近，我们开发了一种称为肌肉薄膜（MTF）的技术，这是一种由弹性聚合物薄膜上的2D高保真工程组织组成的生物混合结构，允许在工程肌肉组织内进行广泛的测量，以观察收缩和放松功能障碍。将所有这些技术结合到一个平台中表明，当前对人类患者适用性有限的高数量、低质量数据的范式可以被最终针对患者的中等数量、高质量数据所取代。在这里，我们建议联合收割机这些技术来建立人体器官模拟，重现健康和患病的细胞和组织结构，特别是心脏，血管和气道的肌肉收缩。作为单一器官模拟物，这些系统将可用于测量候选分子的功效和在其他器官系统中作为治疗剂的药物的安全性。当这些器官模拟物在单个芯片上作为组织的集合体组合时，可以评估针对特定疾病（例如哮喘）的药物的副作用的心脏毒性。拟议的器官芯片技术的目标是作为一个独立的，或集成到一个更大的，多器官系统，以模拟人类疾病，并促进药物发现和毒性筛选比目前的工业范式更快，更便宜的方法。 公共卫生相关性：我们将在单个和合并的芯片上建立心室，血管系统和气道中人类肌肉组织的微型复制品。这些芯片将代表健康和患病的人体组织，并将由人体细胞组成，可用于药物疗效和安全性测试。

DESCRIPTION (provided by applicant): Cardiovascular and pulmonary diseases are two of the most prevalent classes of disease in the US. Environmental pollutants, to include nanoscale allergens and toxins, have deleterious effects on both the healthy and diseased cardiopulmonary system. Furthermore, cardiotoxicity is one of the most prevalent causes of withdrawal of pharmaceuticals from the marketplace. Failure of drugs in the clinic, or in late stage clinical trials, is a contributing factor to the increased cost of health care in the US, as he cost of drug development increases to accommodate such product failures. To date, the model of efficacy and toxicity testing has been largely based on a model of high quantities of low quality data gathered in vitro. Recent advances offer an alternative strategy. Soft lithography has made microscale tissue engineering possible that replicates the cellular microenvironments of healthy and diseased tissues. Microfluidic systems enable long term culture and the ability to mimic the low volume interstitial spaces found in organs and tissues. New techniques for human cell harvest thru biopsies, coupled with human embryonic stem (ES) and induced pluripotency stem (iPS) cells, all of which have some commercial availability, suggest that the animal cell lines typically used for in vitro testing can be replaced with a human surrogate. Recently, we developed a technique called muscular thin films (MTFs), a biohybrid construct composed of a 2D high fidelity, engineered tissue on an elastic polymer thin film that allows a broad spectrum of measurements within engineered muscle tissue to look at contractile and relaxed dysfunction. Combining all of these technologies into a single platform suggests that the current paradigm of high quantity, low quality data with limited applicability to the human patient can be replaced with mid-quantity, high quality data that will eventually be patient specific. Here we propose to combine these technologies to build human organ mimics that recapitulate healthy and diseased cell and tissue architectures, specifically muscular contraction of the heart, vasculature, and airway. As single organ mimics, these systems will be useful in measuring the efficacy of candidate molecules and the safety of drugs directed as therapeutics in other organ systems. When these organ mimics are combined as an ensemble of tissues on a single chip, the side effects of drugs targeted against a specific disease, for example asthma, can be assessed for cardiotoxicity. The goal of the proposed organ on chip technologies is to be used as a stand-alone, or integrated into a bigger, multi-organ system, to mimic human disease and facilitate drug discovery and toxicity screening in a faster, cheaper method than the current industrial paradigm. PUBLIC HEALTH RELEVANCE: We will build microscale replicates of the human muscular tissue in the cardiac ventricle, the vascular system, and the airway on single and consolidated chips. These chips will represent both healthy and diseased human tissues and will be comprised of human cells, amenable to testing for drug efficacy and safety.