Heart-on-a-Chip Model of Epicardial-Myocardial Interaction in Ischemia Reperfusion Injuryz.

Epicardial cells (EPIs) form the outer layer of the heart and play an important role in development and disease. Current heart-on-a-chip platforms still do not fully mimic the native cardiac environment due to the absence of relevant cell types, such as EPIs. Here, using the Biowire II platform, we constructed engineered cardiac tissues with a defined epicardial outer layer and inner myocardial structure, and developed an image analysis approach to track the EPI cell migration in a beating myocardial environment. Functional properties of EPI cardiac tissues improved over two weeks in culture. In conditions mimicking ischemia reperfusion injury (IRI), the EPI cardiac tissues experienced less cell death and a lower impact on functional properties. EPI cell coverage was significantly reduced and more diffuse under normoxic conditions compared to the post-IRI conditions. Upon IRI, migration of EPI cells into the cardiac tissue interior was observed, with contributions to smooth muscle positive cell population. Altogether, we designed a novel heart-on-a-chip model that incorporates EPIs through a formation process that mimics cardiac development and demonstrated that EPI cardiac tissues respond to injury differently than epicardium-free controls, highlighting the importance of including EPIs in heart-on-a-chip constructs that aim to accurately mimic cardiac environment. This article is protected by copyright. All rights reserved.