Human Cardio-Pulmonary System on a Chip

描述(申请人提供)：心血管疾病和肺部疾病是美国最常见的两类疾病。环境污染物，包括纳米级的过敏原和毒素，对健康和患病的心肺系统都有有害影响。此外，心脏毒性是导致药品退出市场的最常见原因之一。临床或后期临床试验中的药物失败是导致美国医疗保健成本上升的一个因素，因为为了适应这种产品失败，药物开发的成本会增加。到目前为止，有效性和毒性测试的模型主要是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。软光刻使复制健康和疾病组织的细胞微环境的微尺度组织工程成为可能。微流控系统使长期培养和模拟器官和组织中发现的低容量间质空间的能力成为可能。通过活组织检查获取人类细胞的新技术，再加上人类胚胎干细胞(ES)和诱导多能干细胞(IPS)，所有这些都具有一定的商业可行性，这表明通常用于体外测试的动物细胞系可以被人类替代品取代。最近，我们开发了一种名为肌肉薄膜(MTF)的技术，这是一种生物杂交结构，由弹性聚合物薄膜上的2D高保真工程化组织组成，允许在工程化肌肉组织中进行广泛的测量，以查看收缩和松弛功能障碍。将所有这些技术结合到一个单一平台中表明，当前高数量、低质量数据的范例对人类患者的适用性有限，可以被最终将针对患者特定的中等数量高质量数据所取代。在这里，我们建议结合这些技术来建立人体器官的模拟，概括健康和患病的细胞和组织结构，特别是心脏、血管和呼吸道的肌肉收缩。作为单个器官的模拟，这些系统将有助于测量候选分子的有效性和作为治疗药物的药物在其他器官系统中的安全性。当这些器官模拟物被组合成一个单一芯片上的整体组织时，针对特定疾病的药物的副作用，例如哮喘，可以被评估心脏毒性。拟议的芯片上器官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中，以模拟人类疾病，并以一种比目前的工业范例更快、更便宜的方法促进药物发现和毒性筛选。 与公共卫生相关：我们将在单个和整合的芯片上建立心脏、血管系统和呼吸道中人类肌肉组织的微型复制。这些芯片既代表健康的人体组织，也代表患病的人体组织，由人体细胞组成，可以进行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.