A Translational Bioreactor for the Construction of Off-the-Shelf, Patient-Specific Heart Tissue for the Permanent Correction of Congenital Heart Defects

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PROJECT SUMMARY/ABSTRACT Congenital heart defects (CHDs) are the most common birth defect worldwide and the number one killer of live-born infants in the United States. Approximately 1% of infants are born with a CHD, and 25% of them require surgery within one year of birth. The current materials available to pediatric heart surgeons for these reconstructive surgeries are exclusively non-living and inert; they do not grow with the child or restore heart function while also increasing the risk of follow-up surgeries and arrhythmias. Furthermore, since the heart develops very early in embryogenesis, it is unlikely that CHDs will ever be fully preventable. Therefore, the most promising approach for the clinical correction of CHDs is to provide surgeons with living, engineered cardiac tissue that can fully integrate with the heart and permanently restore heart function. The overall goal of this proposal is to create suturable, autologous induced pluripotent stem cell (iPSC)-derived cardiac tissue patches (CTPs) in an automated bioreactor system that can be used for the correction of full wall-thickness CHDs. Towards this goal, my lab has identified amniotic fluid cells (AFCs) as a suitable source of patient- specific cells. AFCs belong to the baby, can be safely harvested before birth, and can be reprogrammed to iPSC, which I have successfully differentiated to several cardiac cell types. In addition, my lab has developed a suturable, fully-degradable scaffold that supports iPSC encapsulation and subsequent 3D cardiomyocyte differentiation. These preliminary results direct the project hypothesis that a hands-off bioreactor can be used to generate and maintain living and autologous CTPs, which will integrate with the heart and permanently correct full-thickness heart defects. To achieve our overall goal, we will next pursue two specific aims: 1) Construct an automated perfusion bioreactor that can drive the differentiation, growth, and maintenance of the CTPs in a hands-off manner, and 2) Assess the CTPs in vivo using our established rat model of a full-thickness right ventricular defect (a myocardial replacement model). Collectively, this technology will be promising for the permanent correction of many CHDs while also establishing a translational method for the production of engineered tissues that could be applied to the entire spectrum of tissue engineering.