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.
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.
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|McCain, Megan L; Yuan, Hongyan; Pasqualini, Francesco S et al. (2014) Matrix elasticity regulates the optimal cardiac myocyte shape for contractility. Am J Physiol Heart Circ Physiol 306:H1525-39|
|Sheehy, Sean P; Pasqualini, Francesco; Grosberg, Anna et al. (2014) Quality metrics for stem cell-derived cardiac myocytes. Stem Cell Reports 2:282-94|
|McCain, Megan L; Sheehy, Sean P; Grosberg, Anna et al. (2013) Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc Natl Acad Sci U S A 110:9770-5|