Human Cardio-Pulmonary System on a Chip

人体心肺芯片系统

• 批准号: 8415197
• 负责人: KEVIN KIT PARKER
• 金额: $ 112.04万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415197
• 关键词: Adverse effects; Allergens; Anatomy; Animals; Architecture; Asthma; Atomic Force Microscopy; Biological Assay; Biological Models; Biopsy; Blood Vessels; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Clinic; Clinical Trials; Coupled; Data; Data Quality; Disease; Drug Delivery Systems; Drug Design; Drug Industry; Drug toxicity; Embryo; Engineering; Environmental Pollutants; Failure; Film; Functional disorder; Gene Expression; Genomics; Goals; Harvest; Health Care Costs; Heart; Heart Ventricle; Human; Human Engineering; Hypertrophic Cardiomyopathy; In Vitro; Lung; Lung diseases; Measurement; Measures; Mechanics; Methods; Microfluidics; Modeling; Mus; Muscle; Muscle Contraction; Myocardium; Optics; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Polymers; Property; Quality Control; Rattus; Safety; Screening procedure; Staging; Stem cells; Stress; System; Techniques; Technology; Testing; Therapeutic; Tissue Engineering; Tissues; Toxicity Tests; Toxin; Traction; United States; Vascular Diseases; Vascular System; Ventricular; Withdrawal; Work; asthmatic airway; base; body system; cardiopulmonary system; cost; design; disease phenotype; drug development; drug discovery; drug efficacy; efficacy testing; flexibility; human disease; human tissue; in vitro Assay; in vitro testing; interstitial; lithography; mathematical model; nanomaterials; nanoscale; nanotoxicity; pluripotency; protein expression; reconstitution; respiratory smooth muscle; stem

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.

描述（由申请人提供）：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，心脏毒性是药物退出市场的最普遍原因之一。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，因为药物开发成本会增加以适应此类产品失败。迄今为止，功效和毒性测试模型很大程度上基于体外收集的大量低质量数据的模型。最近的进展提供了一种替代策略。软光刻使微型组织工程成为可能，复制健康和患病组织的细胞微环境。微流体系统能够实现长期培养并能够模拟器官和组织中发现的低体积间隙空间。通过活检采集人类细胞的新技术，加上人类胚胎干（ES）和诱导多能干（iPS）细胞（所有这些细胞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细胞来替代。最近，我们开发了一种称为肌肉薄膜（MTF）的技术，这是一种生物混合结构，由弹性聚合物薄膜上的二维高保真工程组织组成，可以在工程肌肉组织内进行广泛的测量，以观察收缩和松弛功能障碍。将所有这些技术组合到一个平台中表明，当前对人类患者适用性有限的大量、低质量数据范例可以被最终针对特定患者的中等数量、高质量数据所取代。在这里，我们建议结合这些技术来构建人体器官模拟物，再现健康和患病的细胞和组织结构，特别是心脏、脉管系统和气道的肌肉收缩。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以及在其他器官系统中作为治疗药物的药物的安全性。当这些器官模拟物作为单个芯片上的组织集合组合时，可以评估针对特定疾病（例如哮喘）的药物的副作用，以评估其心脏毒性。拟议的器官芯片技术的目标是独立使用或集成到更大的多器官系统中，以比当前工业范式更快、更便宜的方法模拟人类疾病并促进药物发现和毒性筛选。 公共健康相关性：我们将在单个整合芯片上构建心室、血管系统和气道中人体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，适合测试药物功效和安全性。